The Influence of the Quinoline Moiety on Direct Pd-Catalyzed Arylation of Five-Membered Heterocycles

Article abstract of DOI:10.1002/ejoc.201800842

Herein we report a study on the reactivity of C2-quinoline-substituted furan, thiophene and pyrrole derivatives in palladium-catalyzed direct C–H arylation. The regioselectivity of the reaction was strongly influenced by site position of the attached five-membered heterocycle thus giving rise to C3- and/or C5-arylated products. Furthermore, the Hammett correlation performed on 5-substituted-8-(furan-2-yl)quinolines indicates that a marginally positive charge is building up in the rate determining transition state and thus pointing towards the electrophilic metalation-deprotonation reaction mechanism.

Full text of DOI:10.1002/ejoc.201800842

DOI: 10.1002/ejoc.201800842
Full Paper
Palladium Catalysis
The Influence of the Quinoline Moiety on Direct Pd-Catalyzed
Arylation of Five-Membered Heterocycles
Bogdan Štefane,[a] Uroš Grošelj,[a] Jurij Svete,[a] Franc Požgan,[a] Drago Kočar,[a] and
Helena Brodnik Žugelj*[a]
Dedicated to Professor Emertius Branko Stanovnik, University of Ljubljana, on the occasion of his 80th birthday.
Abstract: Herein we report a study on the reactivity of C2- and/or C5-arylated products. Furthermore, the Hammett corre-
quinoline-substituted furan, thiophene and pyrrole derivatives lation performed on 5-substituted-8-(furan-2-yl)quinolines indi-
in palladium-catalyzed direct C–H arylation. The regioselectivity cates that a marginally positive charge is building up in the
of the reaction was strongly influenced by site position of the rate determining transition state and thus pointing towards the
attached five-membered heterocycle thus giving rise to C3- electrophilic metalation-deprotonation reaction mechanism.
Introduction
Palladium-catalyzed direct arylation of five-membered hetero-
aromatics such as furan, thiophene and pyrrole generally pro-
ceeds at the C2- and/or C5-position due to their electronic ef-
fect.[1–4] However, the regioselectivity can be altered by intro-
ducing different substituents on the heterocycle, the nature of
the coupling partner, and also by type of catalyst, base, solvent
or additives used. N-containing directing groups have often
been used to mediate the regioselectivity due to the coordinat-
ing ability of the nitrogen atom. However, when using hetero-
cycles bearing such directing groups, the electronic nature of
the heteroring can often surpass the coordination assistance of
the directing group (Scheme 1).[5–7] For example, Wu and co-
workers demonstrated a low catalyst loading direct arylation of
2-(thiophen-2-yl)pyridine which resulted in C5-arylated product
excluding the pyridine ring acting as a directing group.[8] A sim-
ilar behavior was observed by Nagarajan et al. in arylation of N-
heterocycle embedded thiophenes and furans with aryl boronic
acids under Pd-catalyzed oxidative reaction conditions which
resulted in high C(5)–H arylation selectivity thus enabling an
easy access to 2,5-disubstituted thiophenes.[9]
One of the first examples of exclusive palladium-catalyzed
C3-arylation of thiophenes was reported by Miura and co-work-
ers by using a 3-carbamoyl moiety as the directing group.[10]
Furthermore, Doucet et al. observed that palladium-catalyzed
direct arylation of furans and thiophenes containing a second-
ary carbamoyl group at the C2-position proceeded regioselec-
tively either at C3- or C5-position strongly depending on the
reaction conditions used. In the presence of potassium acetate,
Scheme 1. Arylation reaction of 2-substituted five-membered heterocycles.
direct arylation proceeded at the C5-position,[11,12] whereas the
use of cesium acetate led to C3-arylated furans and thio-
phenes.[13] The same research group also showed the Pd-cata-
lyzed coupling reaction between 2-(thiophen-2-yl)pyridine and
aryl bromides to be highly non-regioselective. They assumed
that the formation of the C5-arylated product is associated with
a concerted metalation deprotonation (CMD) mechanism,[14]
whereas the formation of the C3-arylated regioisomer arose
from the coordination assisted mechanism of the pyridine nitro-
gen atom. Pd-catalyzed C–H arylation of 2-pyridyl-substituted
thiophenes in the presence of TEMPO as the external oxidant
has also been proven to undergo pyridyl-directed C–H arylation
yielding C2,C3-disubstituted products in moderate yields.[15] Re-
cently, Bach et al. demonstrated that a pyridin-2-yl group
exerted a noticeable directing influence on the Pd-catalyzed
C–H alkylation of five-membered heterocycles with alkyl-
boronic acids thus leading exclusively to C3-functionalized
products.[16]
[a] Faculty of Chemistry and Chemical Technology, University of Ljubljana,
Večna pot 113, 1000 Ljubljana, Slovenia
E-mail: Helena.brodnik@fkkt.uni-lj.si
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201800842.
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Results and Discussion
Table 1. Palladium-catalyzed direct heteroarylation of simple five-membered
heterocycles.
Recently we reported a focused set of compounds used to fur-
ther explore[17–21] the chemical space and the structure-activity
relationship of nitroxoline-based derivatives.[22] Consequently,
we have also developed a one-pot sequential Pd-catalyzed cou-
pling reaction for the direct arylation of 8-heteroarylquinolines
with aryl bromides giving rise to a variety of polyconjugated
quinoline compounds.[23] Accordingy, arylation of C2-quinolyl-
substituted pyrroles led to formation of C3-arylated products
suggesting a directing ability of the quinoline nitrogen atom in
the C–H activation reaction. To gain more insight into the reac-
tivity, regarding the directing influence of the quinoline moiety,
we prepared a series of 2-, 3-, and 8-heteroarylquinoline sub-
strates in C2-arylation of furan, thiophene and N-pyrrole with 1
by applying our previously reported protocol (Table 1).[23]
First, we examined the coupling reaction between 8-hetero-
arylquinolines 2a–c and 4-bromobenzonitrile in the presence of
a Pd(OAc)2/PPh3 catalytic system for 48 h at 120 °C in dioxane
(Table 2). According to the literature,[1–7] the direct arylation of
compounds 2a–j should proceed on the C5- and/or C3-posi-
tions of the five-membered heteroring, whereas in the case of
2k–m only C5-arylated products would be formed. To examine
the influence of the quinoline directing group on C–H arylation
of the five-membered heterocycle only a slight excess of 4-
bromobenzonitrile (1.1 equiv.) was used. However, it must be
noted that the yields of isolated products provided in Table 2
were achieved using 2 equivalents of the 4-bromobenzonitrile
as the arylating agent.
Detailed NMR analysis confirmed that arylation of 8-(furan-
2-yl)quinoline (2a) and 8-(1-methyl-1H-pyrrol-2-yl)quinoline (2c)
predominantly occurred at the C3 position to give 3a and 3c
suggesting a six-membered palladacyclic transition state due to
coordination assistance of the quinoline nitrogen atom. How-
ever, the isolation of the byproducts 5a and 5c implies that the
second arylation at the C5-position took place only after the
C3-position has been functionalized. In contrast with furan sub-
strate 2a, 8-(thiophene-2-yl)quinoline reacted with 4-bromo-
benzonitrile almost equally at the C5-position to give products
3b and 4b in a ratio of 1:1.3. The above-mentioned results sug-
gest that in less reactive furan derivative 2a[24,25] the quinoline-
directed C3-arylation surpasses the reactivity of the most nu-
cleophilic C5-site of the five-membered heteroarene, while in
thiophene substrate 2b its electronic nature equally contributes
to the mixture of C3- and C5- arylated products.
We continued our study on direct arylation of 8-heteroaryl-
quinolines 2d–g bearing different substituents on the C5-posi-
tion of the quinoline ring (Table 2, Entries 4–7). According to
our previous findings[23] we speculated that by introducing dif-
ferent electron-donating and -withdrawing substituents on the
quinoline moiety we could alter the reactivity of the furan ring
to selectively achieve the C3- or C5-functionalization. While
both quinolines bearing electron-withdrawing (2d,e) and elec-
tron-donating groups (2f,g) were preferentially arylated at the
C3-position, the reactions with the latter proceeded with signifi-
cantly higher conversion (Table 2, Entries 6 and 7).
[a] Reaction conditions: Pd(OAc)2 (5 mol-%), SPhos (10 mol-%), K3PO4
(2 equiv.), quinoline 1 (0.5 mmol), heteroarene (1.0 mL), NMP (1 mL), under
argon. [b] Isolated yields. [c] Product 2g was synthesized by reduction of 2d
with 10 % of Pd/C (10 mol-%), H2 (1 atm), methanol, 18 h. Given yield after
reduction reaction.
nitrile at slightly elevated temperature (130 °C). Surprisingly, the
C3-arylation selectivity was significantly reduced in comparison
to 8-quinolyl analogues 2a–g thus giving mixtures of 3 and 4
with predominant formation of C5-arylated products 4 (Table 2,
Entries 8–10). These results suggest that the formation of six-
membered palladacyclic intermediate resulting from 8-quinolyl
coupling partners 2a–g more efficiently promotes C3-arylation
whereas in 2-quinolyl heteroarenes 2h–j the enhanced C5-reac-
tivity of the five-membered heterocycle predominates. To con-
firm the competition between C–H arylation reactivity of the
five-membered heterocycle arising from chelation assistance of
the quinoline nitrogen atom and that being a consequence of
Next, we turned our attention to 2-heteroarylquinolines 2h– the electronic nature, compounds 2k–m bearing a 3-quinolyl
j as substrates in PdII-catalyzed arylation with 4-bromobenzo- moiety were subjected to C–H arylation reaction conditions
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Table 2. Palladium-catalyzed direct arylation of compounds 2 with 4-bromobenzonitrile.
Entry
Compound 2
Quinolyl
Y
R
Conversion [%][b]
Ratio (3/4/5)[b]
Yield (3, 4, 5) [%][c]
1
2
3
4
5
6
7
2a
2b
2c
2d
2e
2f
8-quinolyl
O
S
NMe
O
O
H
H
H
NO2
CF3
OMe
NH2
89
71
85
41
68
94
81
1.7:0:1
1:1.3:0
10:0:1
1:0:0
1.3:0:1
2.1:0:1
1:0:0
40, /, 32
22, 25, /
45, /, 35
34, /, /
44, /, 39
57, /, 28
54, /, /
O
O
2g
8
9
10
2h
2i
2j
2-quinolyl
3-quinolyl
O
S
NMe
H
H
H
65
71
62
1:7.3:0
1:2:2
1:3.3:0
7, 41, /
20, 61, 12
22, 38, /
11
12
13
2k
2l
2m
O
S
NMe
H
H
H
86
69
75
0:1:0
0:1:0
0:1:0
/, 71, /
/, 75, /
/, 67, /
[a] Reaction conditions: Compound 2 (0.50 mmol), Pd(OAc)2 (5 mol-%), PPh3 (10 mol-%), K2CO3 (2 equiv.), 4-bromobenzonitrile (1.1 equiv.), 1,4-dioxane (2 mL),
under argon. [b] Conversions and ratios were determined by 1H NMR analysis of the crude reaction mixture; reaction carried out with 1.1 equiv. of 4-
bromobenzonitrile. [c] Isolated yields using 2 equiv. of 4-bromobenzonitrile.
with 4-bromobenzonitrile. As expected, the arylation proceeded
only at the C5-position as the quinoline moiety was unable to
dictate the regioselectivity, resulting in the formation of C5-
arylated products 4 in good yields (Table 2, Entries 11–13).
To further demonstrate the directing ability of the quinoline
nitrogen atom, C2,C5-diarylated thiophene 4i was subjected
under direct C–H activation conditions given in Scheme 2 using
4-bromobenzotrifluoride as the proelectrophile. The arylation
took place at the C3 position of the thiophene ring exclusively
giving rise to a good 70 % yield of isolated product 5ia, even
though C4 arylation is not excluded. The experiment proved to
be in line with the proposed directing ability of the quinoline
nitrogen atom for the regioselective functionalization reaction
of the five-membered heterocycle. 2-(Naphthalen-1-yl)furan
(2n) and 2-(naphthalen-2-yl)furan (2o) were prepared following
the procedure given in Table 1 in order to confirm the forma-
tion of the major regioisomer where the coordination nature
of the quinoline moiety was completely excluded. The 2-furyl-
substituted compounds 2n and 2o were subjected to
palladium-catalyzed reaction giving rise to solely C5-arylated
products 4n and 4o in low to moderate yields (Scheme 3).
Other research groups reported similar yields for the prepara-
tion of such C2,C5-diarylated furans by using different synthetic
Scheme 2. Nitrogen atom-directed palladium-catalyzed arylation of C2,C5-
diarylated thiophene 4i with 4-bromobenzotrifluoride.
Scheme 3. Palladium-catalyzed direct arylation of C2-naphthyl-substituted fu-
rans 2j and 2k with 4-bromobenzonitrile.
methods.[26–28] The more sluggish reaction of C2-naphthyl difference in the chemical shift of the protons in the furan
furans 2n and 2o in comparison to 3-quinolyl analogues 2k–m ring.
additionally confirmed the influence of the quinoline directing
Furthermore, examining compound 3h (Figure 1), we noticed
that proton Hc had a strong downfield chemical shift due to
group on the regioselectivity of C–H arylation.
1
Concerning the structural determination of regioisomers, H the adjacent oxygen atom, whereas in the case of 4o and 4h,
NMR analysis of products 4o, 4h and 3h revealed a significant protons Ha and Hb were positioned in a more homogeneous
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Figure 1. Comparison of chemical shifts in 1H NMR spectra of products 4o, 4h, and 3h.
electronic environment resulting in similar chemical shifts (Fig-
ure 1). Moreover, structures of 4b, 4h and 4m were unambigu-
ously confirmed by X-ray analysis (Figure 2).
Figure 2. X-ray structures of compounds 4b, 4h, and 4m (ellipsoids are shown
in 60 % probability).
Scheme 4. Competition reaction between quinoline derivatives 2d–g and 8-
(furan-2-yl)quinoline (2a).
Finally, we carried out competition studies between electroni-
cally different 5-substituted-8-(furan-2-yl)quinolines (Scheme 4).
Equimolar amounts of 2a and substrates 2d–g were treated
with 1.1 equiv. of 4-bromobenzonitrile in the presence of the
Pd(OAc)2/PPh3 catalytic system at 120 °C for 24 h. From the
collected data we were able to construct a Hammett plot which
showed a linear (R2 = 0.93) relationship between σ and
log(kX/kH). Although, the resulting ρ value of –0.70 is relatively
small and must be interpreted with caution, the negative sign
is indicative for minor, yet mechanistically significant, adjust-
ments to the redistribution of the electron charge density dur-
ing traversal of the rate determining transition state (Fig-
ure 3).[29] The observed relatively small negative ρ value can
also be contributed to the extended conjugation of the reactive
center in the mechanistic probe, thus indicating that marginally
positive charge is building up in the rate determining transition
state and suggesting the electrophilic metalation-deprotona-
tion reaction mechanism.
Figure 3. Hammett plot for competition experiments between 2d–g and 2a.
weakly η2-heteroarene complexation) forms the corresponding
Mechanistically, it is assumed that the transformation with cyclopalladated intermediate via electrophilic metalation-
2-(heteroar-2-yl)quinolines 2h–j and 8-substituted analogues deprotonation step. Reductive elimination then gives the
2a–g follows the reaction pathway involving the coordination- C3-arylated product and regenerates the catalytic Pd0-species.
assisted direct C(3)–H arylation of the five-membered hetero- Unlike in 8-(heteroar-2-yl)quinolines 2a–g, the coordination as-
cycle as outlined in Scheme 5 for the transformation of 2 into sistance of the quinoline nitrogen atom in 2-(heteroar-2-yl)quin-
3. Oxidative addition into the aryl halide provides an arylated olines 2h–j [being in line with 2-(heteroar-2-yl)pyridine ana-
PdII species which upon coordination to the quinoline nitrogen logues][16,30] is less pronounced and intrinsic positional reactiv-
atom and the five-membered heteroarene moiety (most likely ity of C–H activation at the C5 position noticeably participates.
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clear magnetic resonance spectra were recorded either on a Bruker
Avance DPX 300 or Avance 500 MHz spectrometer in CDCl3. Chemi-
cal shifts for 1H NMR spectra are recorded in parts per million (ppm)
from tetramethylsilane as an internal standard. The multiplicities are
reported as follows: s (singlet), d (doublet), t (triplet), q (quartet),
m (multiplet), dd (doublet of doublets), ddd (doublet doublet of
doublets), and br (broad), number of equivalent nuclei (by integra-
tion), coupling constants (J) quoted in Hertz (Hz). Chemical shifts
for the 13C NMR spectra are recorded in parts per million from tetra-
methylsilane using the central peak of the solvent resonance as an
internal standard (CDCl3 triplet at δ = 77.0 ppm). All spectra were
obtained with complete proton decoupling. High-resolution mass
spectra were recorded on an Agilent 6224 Accurate Mass TOF/MS
instrument by electrospray ionization.
CCDC 1846799 (for 4b), 1846800 (for 4m), and 1846801 (for 4h)
contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre.
General Procedure for Pd-Catalyzed Direct (Hetero)arylation of
Simple Five-Membered Heterocycles with Quinolines (1a–m)
and Naphthalenes (1n–o): The corresponding quinoline (1a–m) or
naphthalene (1n–o) (0.50 mmol), Pd(OAc)2 (5.6 mg, 0.025 mmol),
SPhos (20.5 mg, 0.050 mmol) and K3PO4 (212 mg, 1.00 mmol) were
dissolved in NMP (1 mL) to which the furan, thiophene or pyrrole
(1 mL) was added. The reaction mixture was stirred in a sealed glass
tube at 150 °C for 24 h under inert atmosphere. The mixture was
cooled to room temperature (room temp.) to which water was
added (3 mL) and the product was extracted into ethyl acetate
(2 × 3 mL). The combined organic layers were dried with anhydrous
Na2SO4, filtered and the solvent was evaporated under reduced
pressure. The crude product was purified by radial chromatography
to yield pure product 2.
8-(Furan-2-yl)quinoline (2a):[23] Radial chromatography (petro-
leum ether/EtOAc, 20:1). Colorless oil (60 mg, 62 %). 1H NMR
(500 MHz, CDCl3): δ = 9.00 (dd, J = 4.0, 2.0 Hz, 1 H), 8.24 (dd, J =
7.5, 1.5 Hz, 1 H), 8.16 (dd, J = 8.5, 2.0 Hz, 1 H), 7.81 (d, J = 3.5 Hz, 1
H), 7.71 (dd, J = 8.0, 1.5 Hz, 1 H), 7.60–7.75 (m, 2 H), 7.43 (dd, J =
8.0, 4.0 Hz, 1 H), 6.61 (dd, J = 3.5, 2.0 Hz, 1 H) ppm.
Scheme 5. Mechanistic proposal for coordination-assisted Pd-catalyzed aryl-
ation of five-membered heterocycles 2a–g and 2h–j.
Conclusions
In summary, we have demonstrated that the quinolyl group
exerts a notable directing influence on the palladium-catalyzed
C–H arylation reaction of five-membered heterocycles with aryl
bromides which is more pronounced in the 8-heteroaryl series
than the 2-heteroarylquinolines. Even though direct functionali-
zation of these heteroaromatics generally proceeds at the C2-
and/or C5-position, we were able to influence the regioselecit-
vity of C–H arylation by introducing a nitrogen-directing group.
8-(Thiophen-2-yl)quinoline (2b):[23] Radial chromatography (pe-
troleum ether/EtOAc, 50:1). Colorless oil (59 mg, 56 %). 1H NMR
(500 MHz, CDCl3): δ = 9.01 (dd, J = 4.0, 2.0 Hz, 1 H), 8.16 (dd, J =
Moreover, competition studies between quinoline derivatives 8.0, 2.0 Hz, 1 H), 8.06 (dd, J = 7.5, 1.5 Hz, 1 H), 7.79 (dd, J = 3.5,
1.0 Hz, 1 H), 7.73 (dd, J = 8.0, 1.5 Hz, 1 H), 7.55 (dd, J = 8.0, 7.5 Hz,
1 H), 7.48 (dd, J = 5.0, 1.0 Hz, 1 H), 7.43 (dd, J = 8.0, 4.0 Hz, 1 H),
7.17 (dd, J = 5.0, 3.5 Hz, 1 H) ppm.
8-(1-Methyl-1H-pyrrol-2-yl)quinoline (2c):[23] Radial chromatogra-
phy (petroleum ether/EtOAc, 50:1). Colorless oil (63 mg, 61 %). 1H
NMR (500 MHz, CDCl3): δ = 8.95 (dd, J = 4.0, 2.0 Hz, 1 H), 8.18 (dd,
J = 8.0, 2.0 Hz, 1 H), 7.83 (dd, J = 8.0, 1.5 Hz, 1 H), 7.73 (dd, J = 7.0,
1.5 Hz, 1 H), 7.58–7.55 (m, 1 H), 7.39 (dd, J = 8.0, 4.0 Hz, 1 H), 6.84–
6.83 (m, 1 H), 6.32–6.29 (m, 1 H), 3.47 (s, 3 H) ppm.
8-(Furan-2-yl)-5-nitroquinoline (2d):[23] Radial chromatography
(petroleum ether/EtOAc, 20:1). Yellow solid (53 mg, 44 %); m.p. 153–
156 °C. 1H NMR (500 MHz, CDCl3): δ = 9.11 (dd, J = 9.0, 2.0 Hz, 1
H), 9.07 (dd, J = 4.0, 2.0 Hz, 1 H), 8.43 (d, J = 8.5 Hz, 1 H), 8.28 (d,
J = 8.5 Hz, 1 H), 8.08 (d, J = 3.5 Hz, 1 H), 7.67–7.65 (m, 2 H), 6.66
(dd, J = 3.5, 2.0 Hz, 1 H) ppm.
2a and 2d–g indicated that substrates with an electron-donat-
ing group at the C5-quinoline position react preferably, indicat-
ing there is a marginal localization of positive charge on the
furan ring in the rate-determining step.
Experimental Section
General Methods: The reagents and solvents were used as received
from commercial suppliers. Reactions were monitored by analytical
thin-layer chromatography (TLC) and visualization of the developed
TLC chromatogram was performed by UV absorbance. Column
chromatography was performed on 230–400 mesh silica gel with
the indicated solvent system. Merck silica gel 60 PF254 containing
gypsum was used to prepare chromatotron plates. Radial chroma-
tography was performed with a Harrison Research, model 7924 T
chromatotron. Yields refer to chromatographically and spectroscop- 8-(Furan-2-yl)-5-(trifluoromethyl)quinoline (2e): Radial chroma-
ically (1H and 13C NMR) homogeneous materials. Melting points are
tography (petroleum ether/EtOAc, 50:1). White solid (83 mg, 63 %);
uncorrected. Infra-red spectra were recorded on a FT-IR spectrome- m.p. 55–57 °C. FT- IR (ATR, neat): ν = 3076, 1580, 1507, 1489, 1317,
˜
ter and are reported in reciprocal centimetres (cm–1). Routine nu-
1183, 1094, 1078, 1018, 931, 815, 789, 734 cm–1. 1H NMR (500 MHz,
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CDCl3): δ = 9.05 (dd, J = 4.1, 1.7 Hz, 1 H), 8.52–8.49 (m, 1 H), 8.24
(d, J = 7.9 Hz, 1 H), 7.95–7.92 (m, 2 H), 7.60 (d, J = 1.6 Hz, 1 H), 7.54
(dd, J = 8.7, 4.1 Hz, 1 H), 6.63 (dd, J = 3.4, 1.8 Hz, 1 H) ppm. 13C
NMR (126 MHz, CDCl3): δ = 150.3, 150.1, 144.1, 142.9, 132.8, 132.7
(q, J = 2.4 Hz), 125.1 (q, J = 5.8 Hz), 124.8, 124.3 (q, J = 273.2 Hz),
124.2 (q, J = 30.7 Hz), 123.7, 115.5, 112.5 ppm. 19F NMR (500 MHz,
CDCl3): δ = –58.8 ppm. HRMS (ESi+): m/z calcd. for C14H9F3NO [M +
H]+ 264.0631, found 264.0630.
(126 MHz, CDCl3): δ = 153.7, 149.0, 148.1, 144.1, 136.6, 129.8, 129.4,
127.5, 127.1, 126.2, 117.4, 112.2, 110.1 ppm. HRMS (ESi+): m/z calcd.
for C13H10NO [M + H]+ 196.0757, found 196.0751.
2-(Thiophen-2-yl)quinoline (2i): Radial chromatography (petro-
leum ether/EtOAc, 50:1). White solid (66 mg, 63 %); m.p. 129–131 °C.
FT- IR (ATR, neat): ν = 3100, 3059, 1614, 1551, 1498, 1359, 1142,
˜
1056, 933, 786, 708 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 8.13 (d,
J = 8.6 Hz, 1 H), 8.08 (d, J = 8.5 Hz, 1 H), 7.80–7.76 (m, 2 H), 7.73
(dd, J = 3.7, 1.1 Hz, 1 H), 7.69 (ddd, J = 8.5, 6.9, 1.5 Hz, 1 H), 7.50–
7.46 (m, 2 H), 7.16 (dd, J = 5.1, 3.6 Hz, 1 H) ppm. 13C NMR (126 MHz,
CDCl3): δ = 152.3, 148.1, 145.4, 136.6, 129.8, 129.3, 128.5, 128.0,
127.5, 127.2, 126.1, 125.8, 117.6 ppm. HRMS (ESi+): m/z calcd. for
C13H10NS [M + H]+ 212.0528, found 212.0522.
8-(Furan-2-yl)-5-methoxyquinoline (2f): Compound 2f was pre-
pared from 1f which was synthesized from readily available
5-methoxyquinolin-8-amine according to the following procedure:
5-Methoxyquinolin-8-amine (92 mg, 0.50 mmol, 95 %) was dis-
solved in water (2 mL) and HBr (2 mL, 48 %), cooled to °C to which
NaNO2 (38 mg, 0.55 mmol) in water (1.5 mL) was added. The mix-
ture was stirred at 0 °C for 1 h after which it was slowly added to
a cooled (0 °C) suspension of CuBr (143 mg, 1.00 mmol) in HBr
(1.5 mL, 48 %). The reaction mixture was warmed to room temp.
and stirred overnight. The mixture was again cooled to 0 °C to
which aqueous ammonia was added (5 mL) and product 1f was
extracted in dichloromethane (2 × 5 mL). The combined organic
layers were dried with anhydrous Na2SO4, filtered and the solvent
was evaporated under reduced pressure. The crude product was
purified by flash chromatography (petroleum ether/EtOAc, 10:1) to
yield pure product 1f as a yellow sold (98 mg, 82 %). Compound
1f was further reacted with furan according to the given general
procedure. Radial chromatography (petroleum ether/EtOAc, 50:1).
2-(1-Methyl-1H-pyrrol-2-yl)quinoline (2j): Radial chromatography
(petroleum ether/EtOAc, 50:1). Pale yellow solid (50 mg, 48 %); m.p.
50–52 °C. FT- IR (ATR, neat): ν = 3054, 2966, 1599, 1486, 1366, 1249,
˜
1
1123, 1015, 868, 719 cm–1. H NMR (500 MHz, CDCl3): δ = 8.04 (d,
J = 8.7 Hz, 1 H), 8.01 (dd, J = 8.4, 1.0 Hz, 1 H), 7.73 (dd, J = 8.1,
1.4 Hz, 1 H), 7.69 (d, J = 8.7 Hz, 1 H), 7.65 (ddd, J = 8.5, 6.9, 1.4 Hz,
1 H), 7.44 (ddd, J = 8.1, 6.9, 1.1 Hz, 1 H), 6.80–6.79 (m, 1 H), 6.77
(dd, J = 3.8, 1.8 Hz, 1 H), 6.22 (dd, J = 3.8, 2.6 Hz, 1 H), 4.20 (s, 3 H)
ppm. 13C NMR (126 MHz, CDCl3): δ = 152.2, 147.6, 135.8, 132.2,
129.3, 129.0, 127.6, 127.4, 126.0, 125.4, 120.1, 112.3, 107.8, 37.7 ppm.
HRMS (ESi+): m/z calcd. for C14H13N2 [M + H]+ 209.1073, found
209.1072.
3-(Furan-2-yl)quinoline (2k): Radial chromatography (petroleum
ether/EtOAc, 20:1). White solid (69 mg, 71 %); m.p. 79–81 °C. FT- IR
Yellow oil (93 mg, 83 %). FT- IR (ATR, neat): ν = 2962, 2833, 1588,
˜
1467, 1298, 1277, 1226, 1089, 809, 786, 730 cm–1. 1H NMR (500 MHz,
CDCl3): δ = 9.00 (dd, J = 4.2, 1.9 Hz, 1 H), 8.61 (dd, J = 8.4 Hz, 1.9 1
H), 8.14 (d, J = 8.3 Hz, 1 H), 7.62 (dd, J = 3.3, 0.8 Hz, 1 H), 7.53 (dd,
J = 1.8, 0.8 Hz, 1 H), 7.42 (dd, J = 8.5, 4.2 Hz, 1 H), 6.93 (d, J = 8.3 Hz,
1 H), 6.58 (dd, J = 3.3, 1.8 Hz, 1 H), 4.04 (s, 3 H) ppm. 13C NMR
(126 MHz, CDCl3): δ = 154.3, 151.6, 145.0, 141.0, 130.9, 126.4, 121.9,
120.8, 111.9, 110.6, 104.2, 55.7 ppm. HRMS (ESi+): m/z calcd. for
C14H12NO2 [M + H]+ 226.0863, found 226.0862.
(ATR, neat): ν = 3850, 3109, 1492, 1336, 1292, 1048, 963, 903, 785,
˜
1
741 cm–1. H NMR (500 MHz, CDCl3): δ = 9.22 (d, J = 2.2 Hz, 1 H),
8.36 (d, J = 2.2 Hz, 1 H), 8.09 (dd, J = 8.4, 1.1 Hz, 1 H), 7.84 (dd, J =
8.1, 1.3 Hz, 1 H), 7.68 (ddd, J = 8.4, 6.8, 1.4 Hz, 1 H), 7.57 (d, J =
1.7 Hz, 1 H), 7.55 (ddd, J = 8.1, 6.9, 1.2 Hz, 1 H), 6.88 (d, J = 3.4 Hz,
1 H), 6.56 (dd, J = 3.4, 1.8 Hz, 1 H) ppm. 13C NMR (126 MHz, CDCl3):
δ = 151.4, 147.1, 147.0, 143.1, 129.3, 129.2, 129.1, 127.9, 127.8, 127.2,
124.0, 112.0, 106.7 ppm. HRMS (ESi+): m/z calcd. for C13H10NO [M
+ H]+ 196.0757, found 196.0754.
8-(Furan-2-yl)quinolin-5-amine (2g): Compound 2g was prepared
by reduction of 2d according to the following procedure: Com-
pound 2d (120 mg, 0.50 mmol) was dissolved in methanol (10 mL)
and 10 % of Pd/C (20 mg, 10 %) was added to which a flow of H2
(1 atm) was passed. The reaction mixture was shaken at room temp.
for 18 h after which it was filtered through a pad of Celite and
washed with methanol (2 × 5 mL). The solvent was evaporated un-
der reduced pressure. The crude product was purified by radial
chromatography to yield pure product 2g. Radial chromatography
(petroleum ether/EtOAc, 5:1). Yellow solid (76 mg, 72 %); m.p. 88–
3-(Thiophen-2-yl)quinoline (2l): Radial chromatography (petro-
leum ether/EtOAc, 20:1). Pale yellow solid (54 mg, 51 %); m.p. 62–
66 °C. FT- IR (ATR, neat): ν = 3065, 3034, 1568, 1490, 1429, 1346,
˜
1122, 1023, 859, 781, 746, 688 cm–1. 1H NMR (500 MHz, CDCl3): δ =
9.21 (d, J = 2.3 Hz, 1 H), 8.29 (dd, J = 2.4, 0.8 Hz, 1 H), 8.10 (dd, J =
8.4, 1.0 Hz, 1 H), 7.86–7.84 (m, 1 H), 7.70 (ddd, J = 8.4, 6.9, 1.5 Hz,
1 H), 7.57 (ddd, J = 8.2, 6.9, 1.2 Hz, 1 H), 7.51 (dd, J = 3.6, 1.1 Hz, 1
H), 7.41 (dd, J = 5.1, 1.1 Hz, 1 H), 7.18 (dd, J = 5.1, 3.6 Hz, 1 H) ppm.
13C NMR (126 MHz, CDCl3): δ = 148.6, 147.3, 140.8, 131.4, 129.3,
128.4, 127.9, 127.8, 127.6, 1217.2, 126.1, 124.4 ppm. HRMS (ESi+):
m/z calcd. for C13H10NS [M + H]+ 212.0528, found 212.0539.
90 °C. FT- IR (ATR, neat): ν = 3427, 3317, 1626, 1582, 1467, 1356,
˜
1
1022, 952, 809, 785, 729 cm–1. H NMR (500 MHz, CDCl3): δ = 8.99
(dd, J = 4.1, 1.8 Hz, 1 H), 8.18 (dd, J = 8.5, 1.8 Hz, 1 H), 8.04 (d, J =
8.0 Hz, 1 H), 7.53 (dd, J = 3.3, 0.8 Hz, 1 H), 7.54–7.50 (m, 1 H), 7.39
(dd, J = 8.5, 4.1 Hz, 1 H), 6.87 (d, J = 8.0 Hz, 1 H), 6.57 (dd, J = 3.3,
1.8 Hz, 1 H), 4.24 (s, 2 H) ppm. 13C NMR (126 MHz, CDCl3): δ = 152.0,
149.8, 145.1, 141.6, 140.7, 129.5, 127.2, 120.6, 119.5, 118.6, 111.8,
110.0, 109.9 ppm. HRMS (ESi+): m/z calcd. for C13H11N2O [M + H]+
211.0866, found 211.0875.
3-(1-Methyl-1H-pyrrol-2-yl)quinoline (2m): Radial chromatogra-
phy (petroleum ether/EtOAc, 10:1). Pale yellow oil (56 mg, 54 %).
FT- IR (ATR, neat): ν = 3053, 1493, 1188, 1124, 1057, 1001, 908, 786,
˜
1
780, 711 cm–1. H NMR (500 MHz, CDCl3): δ = 9.02 (d, J = 2.3 Hz, 1
H), 8.11 (dd, J = 8.4, 1.0 Hz, 1 H), 8.09 (dd, J = 2.3, 0.8 Hz, 1 H), 7.81
(dd, J = 8.1, 1.4 Hz, 1 H), 7.69 (ddd, J = 8.4, 6.9, 1.4 Hz, 1 H), 7.55
(ddd, J = 8.1, 6.9, 1.2 Hz, 1 H), 6.81 (dd, J = 2.7, 1.8 Hz, 1 H), 6.41
(dd, J = 3.7, 1.8 Hz, 1 H), 6.28 (dd, J = 3.6, 2.7 Hz, 1 H), 3.73 (s, 3 H)
ppm. 13C NMR (126 MHz, CDCl3): δ = 150.9, 146.6, 133.6, 130.9,
129.2, 129.1, 127.7, 127.6, 127.0, 126.4, 124.9, 124.9, 110.2, 108.3,
35.2 ppm. HRMS (ESi+): m/z calcd. for C14H13N2 [M + H]+ 209.1073,
found 209.1076.
2-(Furan-2-yl)quinoline (2h): Radial chromatography (petroleum
ether/EtOAc, 50:1). White solid (66 mg, 68 %); m.p. 87–89 °C. FT- IR
(ATR, neat): ν = 3106, 3061, 1385, 1306, 1286, 1126, 1008, 912, 787,
˜
741 cm–1. 1H NMR (500 MHz, CDCl3): δ = 8.17 (dd, J = 8.6, 0.8 Hz, 1
H), 8.13 (dd, J = 8.5, 1.0 Hz, 1 H), 7.83 (d, J = 8.6 Hz, 1 H), 7.79 (dd,
J = 8.0, 1.4 Hz, 1 H), 7.71 (ddd, J = 8.4, 6.9, 1.5 Hz, 1 H), 7.63 (dd,
J = 1.8, 0.8 Hz, 1 H), 7.50 (ddd, J = 8.0, 6.8, 1.1 Hz, 1 H), 7.22 (dd,
J = 3.4, 0.8 Hz, 1 H), 6.60 (dd, J = 3.4, 1.8 Hz, 1 H) ppm. 13C NMR
2-(Naphthalen-1-yl)furan (2n): Radial chromatography (petroleum
ether). Colorless oil (82 mg, 85 %). FT- IR (ATR, neat): ν = 3049, 1509,
˜
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1391, 1014, 970, 796, 771, 731, 655 cm–1. 1H NMR (500 MHz, CDCl3): CDCl3): δ = 9.01 (dd, J = 8.8, 1.7 Hz, 1 H), 8.69 (dd, J = 4.1, 1.7 Hz,
δ = 8.40 (dd, J = 8.8, 1.1 Hz, 1 H), 7.90–7.88 (m, 1 H), 7.84 (d, J =
8.3 Hz, 1 H), 7.73 (dd, J = 7.2, 1.3 Hz, 1 H), 7.62 (dd, J = 1.8, 0.8 Hz,
1 H), 7.55–7.79 (m, 3 H), 6.72 (dd, J = 3.3, 0.8 Hz, 1 H), 6.59 (dd, J =
3.3, 1.8 Hz, 1 H) ppm. 13C NMR (126 MHz, CDCl3): δ = 153.5, 142.4,
1 H), 8.40 (d, J = 8.1 Hz, 1 H), 7.95 (d, J = 8.1 Hz, 1 H), 7.77 (d, J =
1.9 Hz, 1 H), 7.59 (dd, J = 8.9, 4.1 Hz, 1 H), 7.45 (AA′BB′, J = 8.5 Hz,
2 H), 7.23 (AA′BB′, J = 8.5 Hz, 2 H), 6.84 (d, J = 1.9 Hz, 1 H) ppm.
13C NMR (126 MHz, CDCl3): δ = 151.0, 146.5, 145.4, 145.0, 144.4,
133.9, 130.4, 128.6, 128.5, 128.4, 126.5, 126.1, 125.9, 125.5, 125.3, 139.1, 136.5, 132.1, 132.0, 129.1, 128.3, 125.8, 124.2, 124.1, 121.7,
111.4, 109.2 ppm.
118.8, 112.6, 110.2 ppm. HRMS (ESi+): m/z calcd. for C20H12N3O3 [M
+ H]+ 342.0873, found 342.0870.
2-(Naphthalen-2-yl)furan (2o): Radial chromatography (petroleum
ether). White solid (89 mg, 92 %); m.p. 63–64 °C. FT- IR (ATR, neat):
4-{2-[5-(Trifluoromethyl)quinolin-8-yl]-furan-3-yl}benzonitrile
(3e): Radial chromatography (petroleum ether/EtOAc, 5:1). Yellow
ν = 3050, 1155, 1009, 862, 801, 749 cm–1. 1H NMR (500 MHz, CDCl3):
˜
δ = 8.14 (d, J = 1.6 Hz, 1 H), 7.86–7.75 (m, 4 H), 7.51 (d, J = 2.1 Hz,
1 H), 7.48–7.42 (m, 2 H), 6.76 (dd, J = 3.4, 0.7 Hz, 1 H), 6.51 (dd, J =
3.3, 1.8 Hz, 1 H) ppm. 13C NMR (126 MHz, CDCl3): δ = 154.0, 142.3,
133.5, 132.6, 128.3, 128.2, 128.1, 127.7, 126.4, 125.9, 122.3, 122.1,
111.8, 105.6 ppm.
oil (80 mg, 44 %). FT- IR (ATR, neat): ν = 2926, 2226, 1607, 1507,
˜
1318, 1117, 957, 839, 729 cm–1. 1H NMR (500 MHz, CDCl3): δ = 8.75
(dd, J = 4.1, 1.7 Hz, 1 H), 8.55–8.52 (m, 1 H), 7.96 (d, J = 7.7 Hz, 1
H), 7.86 (d, J = 7.7 Hz, 1 H), 7.73 (d, J = 1.9 Hz, 1 H), 7.51 (dd, J =
8.7, 4.1 Hz, 1 H), 7.44 (AA′BB′, J = 8.5 Hz, 2 H), 7.25 (AA′BB′, J =
8.5 Hz, 2 H), 6.83 (d, J = 1.9 Hz, 1 H) ppm. 13C NMR (126 MHz,
CDCl3): δ = 150.8, 147.4, 145.6, 143.9, 139.0, 134.5, 132.6 (q, J =
2.6 Hz), 132.0, 129.7, 128.1, 127.1 (q, J = 31.1 Hz), 124.9, 124.7 (q,
J = 5.7 Hz), 124.5, 123.8 (q, J = 274.1 Hz), 122.6, 118.9, 112.1,
109.9 ppm. 19F NMR (377 MHz, CDCl3): δ = –59.1 ppm. HRMS (ESi+):
m/z calcd. for C21H12F3N2O [M + H]+ 365.0896, found 365.0894.
General Procedure for Pd-Catalyzed Direct Arylation of Com-
pounds 2 with 4-Bromobenzonitrile: Corresponding compound 2
(0.50 mmol), 4-bromobenzonitrile (183 mg, 1.00 mmol), Pd(OAc)2
(5.6 mg, 0.025 mmol), PPh3 (13.1 mg, 0.050 mmol) and K2CO3
(207 mg, 1.50 mmol) were dissolved in 1,4-dioxane (2 mL). The reac-
tion mixture was stirred in a sealed glass tube at 120 or 130 °C
for 48 h under inert atmosphere. The mixture was cooled to room
temperature (room temp.) to which water was added (3 mL) and the
product was extracted into ethyl acetate (2 × 3 mL). The combined
organic layers were dried with anhydrous Na2SO4, filtered and the
solvent was evaporated under reduced pressure. The crude prod-
ucts were purified by radial chromatography to yield pure products
3–5.
4-[2-(5-Methoxyquinolin-8-yl)-furan-3-yl]benzonitrile (3f): Ra-
dial chromatography (petroleum ether/EtOAc, 5:1). Yellow solid
(93 mg, 57 %); m.p. 175–177 °C. FT- IR (ATR, neat): ν = 2965, 2926,
˜
2840, 2223, 1621, 1605, 1225, 1085, 839, 783, 748, 727, 631 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 8.79 (dd, J = 4.2, 1.8 Hz, 1 H), 8.63
(dd, J = 8.4, 1.8 Hz, 1 H), 7.67 (d, J = 1.9 Hz, 1 H), 7.65 (d, J = 8.0 Hz,
1 H), 7.42–7.37 (m, 3 H), 7.28 (AA′BB′, J = 8.5 Hz, 2 H), 6.88 (d, J =
8.1 Hz, 1 H), 6.81 (d, J = 1.9 Hz, 1 H), 4.06 (s, 3 H), ppm. 13C NMR
(126 MHz, CDCl3): δ = 156.4, 151.0, 149.6, 147.0, 142.9, 139.2, 132.3,
131.9, 130.9, 127.8, 122.2, 122.1, 121.1, 120.6, 119.2, 111.2, 109.3,
104.0, 55.9 ppm. HRMS (ESi+): m/z calcd. for C21H15N2O2 [M + H]+
327.1128, found 327.1127.
4-[2-(Quinolin-8-yl)furan-3-yl]benzonitrile (3a): Radial chroma-
tography (petroleum ether/EtOAc, 5:1). Yellow solid (59 mg, 40 %);
m.p. 82–84 °C. FT- IR (ATR, neat): ν = 2923, 2223, 1700, 1685, 1605,
˜
1570, 1491, 830, 793, 726 cm–1. 1H NMR (500 MHz, CDCl3): δ = 8.77
(dd, J = 4.2, 1.8 Hz, 1 H), 8.21 (dd, J = 8.3, 1.8 Hz, 1 H), 7.92 (dd, J =
8.2, 1.5 Hz, 1 H), 7.78 (dd, J = 7.2, 1.5 Hz, 1 H), 7.71 (d, J = 1.9 Hz, 1
H), 7.58 (dd, J = 8.2, 7.1 Hz, 1 H), 7.42–7.40 (m, 3 H), 7.28–7.26 (m,
2 H), 6.83 (d, J = 2.0 Hz, 1 H) ppm. 13C NMR (126 MHz, CDCl3): δ =
150.7, 149.0, 146.1, 143.3, 139.1, 136.3, 132.0, 131.8, 130.0, 129.6,
128.8, 128.0, 126.2, 123.1, 121.5, 119.1, 111.5, 109.6 ppm. HRMS
(ESi+): m/z calcd. for C20H13N2O [M + H]+ 297.1022, found 297.1020.
4-[2-(5-Aminoquinolin-8-yl)-furan-3-yl]benzonitrile (3g): Radial
chromatography (petroleum ether/EtOAc, 5:1). Yellow solid (84 mg,
54 %); m.p. 92–95 °C. FT- IR (ATR, neat): ν = 3460, 3372, 3212, 2222,
˜
1605, 1582, 1509, 1467, 1324, 908, 833, 724 cm–1. 1H NMR (500 MHz,
CDCl3): δ = 8.77 (dd, J = 4.2, 1.6 Hz, 1 H), 8.19 (dd, J = 8.5,
1.7 Hz, 1 H), 7.64 (d, J = 2.0 Hz, 1 H), 7.53 (d, J = 7.8 Hz, 1 H), 7.40
(AA′BB′, J = 8.5 Hz, 2 H), 7.35 (dd, J = 8.5, 4.2 Hz, 1 H), 7.29
(AA′BB′, J = 8.5 Hz, 2 H), 6.81 (d, J = 7.9 Hz, 1 H), 6.79 (d, J = 2.0 Hz,
1 H), 4.45 (s, 2 H), ppm. 13C NMR (126 MHz, CDCl3): δ = 150.6, 147.1,
144.0, 142.7, 139.4, 133.9, 132.9, 132.0, 131.9, 129.5, 128.0, 127.7,
121.7, 120.0, 115.8, 111.1, 109.3, 109.1 ppm. HRMS (ESi+): m/z calcd.
for C20H14N3O [M + H]+ 312.1131, found 312.1131.
4-[2-(Quinolin-8-yl)thiophen-3-yl]benzonitrile (3b): Radial chro-
matography (petroleum ether/EtOAc, 7:1). Yellow solid (34 mg,
22 %); m.p. 120–123. FT- IR (ATR, neat): ν = 2922, 2852, 2223, 1599,
˜
1493, 1310, 1176, 835, 806, 787, 749 cm–1
.
1H NMR (500 MHz,
CDCl3): δ = 9.05 (dd, J = 4.1, 1.8 Hz, 1 H), 8.22 (dd, J = 8.3, 1.8 Hz,
1 H), 8.14 (dd, J = 7.4, 1.4 Hz, 1 H), 7.82–7.79 (m, 4 H), 7.68–7.66 (m,
2 H), 7.62–7.59 (m, 1 H), 7.51–7.48 (m, 2 H) ppm. 13C NMR (126 MHz,
CDCl3): δ = 149.5, 144.4, 144.1, 141.4, 139.2, 136.5, 132.9, 132.7,
128.8, 127.9, 127.7, 127.5 (2 C), 126.5, 125.8, 124.7, 121.4, 110.1 ppm.
HRMS (ESi+): m/z calcd. for C20H13N2S [M + H]+ 313.0794, found
313.0803.
4-[2-(Quinolin-2-yl)furan-3-yl]benzonitrile (3h): Radial chroma-
tography (petroleum ether/diethyl ether, 5:1). Pale yellow solid
(10 mg, 7 %); m.p. 83–86 °C. FT- IR (ATR, neat): ν = 3057, 2923, 2221,
˜
1598, 1508, 1445, 905, 825, 740 cm–1
.
1H NMR (500 MHz, CDCl3):
δ = 8.14 (d, J = 8.6 Hz, 1 H), 7.90 (dd, J = 8.6, 1.1 Hz, 1 H), 7.81–7.78
(m, 3 H), 7.72–7.67 (m, 5 H), 7.52 (ddd, J = 8.1, 6.8, 1.2 Hz, 1 H), 6.70
(d, J = 1.8 Hz, 1 H), ppm. 13C NMR (126 MHz, CDCl3): δ = 149.2,
148.6, 147.7, 143.4, 138.7, 136.5, 131.8, 130.1, 129.9, 129.4, 127.5,
127.2, 126.8, 124.9, 119.1, 119.0, 114.1, 110.9 ppm. HRMS (ESi+): m/z
calcd. for C20H13N2O [M + H]+ 297.1022, found 297.1025.
4-[1-Methyl-2-(quinolin-8-yl)-1H-pyrrol-3-yl]benzonitrile (3c):[23]
Radial chromatography (petroleum ether/diethyl ether, 2:1). Pale
1
yellow solid (70 mg, 45 %). H NMR (500 MHz, CDCl3): δ = 8.96 (dd,
J = 4.2, 1.8 Hz, 1 H), 8.26 (dd, J = 8.3, 1.8 Hz, 1 H), 7.93 (dd, J = 7.5,
2.2 Hz, 1 H), 7.56–7.51 (m, 2 H), 7.46 (dd, J = 8.3, 4.2 Hz, 1 H), 7.29
(AA′BB′, J = 8.5 Hz, 2 H), 7.09 (AA′BB′, J = 8.5 Hz, 2 H), 6.88 (d, J =
2.9 Hz, 1 H), 6.55 (d, J = 2.9 Hz, 1 H), 3.35 (s, 3 H) ppm.
4-[2-(Quinolin-2-yl)thiophen-3-yl]benzonitrile (3i): Radial chro-
matography (petroleum ether/diethyl ether, 5:1). Pale yellow solid
4-[2-(5-Nitroquinolin-8-yl)-furan-3-yl]benzonitrile (3d): Radial
(31 mg, 20 %); m.p. 136–138 °C. FT- IR (ATR, neat): ν = 3054, 2217,
˜
1
chromatography (petroleum ether/EtOAc, 5:1). Red solid (58 mg, 1595, 1499, 1316, 861, 829, 817, 796, 741 cm–1. H NMR (500 MHz,
34 %); m.p. 127–130 °C. FT- IR (ATR, neat): ν = 2925, 2224, 1606, CDCl3): δ = 8.16 (d, J = 8.5 Hz, 1 H), 8.09 (dd, J = 8.4, 1.0 Hz, 1 H),
˜
1
1502, 1331, 1179, 844, 815, 804, 792, 753 cm–1. H NMR (500 MHz, 7.81–7.76 (m, 5 H), 7.70 (d, J = 3.9 Hz, 1 H), 7.68 (AA′BB′, J = 8.5 Hz,
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2 H), 7.51 (ddd, J = 8.1, 6.8, 1.2 Hz, 1 H), 7.46 (d, J = 3.9 Hz, 1 H)
ppm. 13C NMR (126 MHz, CDCl3): δ = 151.6, 148.1, 146.8, 144.3,
13C NMR (126 MHz, CDCl3): δ = 151.7, 147.7, 137.7, 137.5, 136.3,
136.2, 132.3, 129.6, 129.1, 129.0, 127.5, 126.3, 126.0, 120.7, 119.0,
143.5, 138.4, 136.7, 132.8, 132.7, 130.0, 129.2, 127.9, 127.5, 127.3, 112.8, 110.9, 110.3, 36.0 ppm. HRMS (ESi+): m/z calcd. for C21H16N3
126.7, 126.4, 126.0, 117.2 ppm. HRMS (ESi+): m/z calcd. for [M + H]+ 310.1339, found 310.1338.
C20H13N2S [M + H]+ 313.0794, found 313.0789.
4-[5-(Quinolin-3-yl)furan-2-yl]benzonitrile (4k): Radial chroma-
tography (petroleum ether/diethyl ether, 1:1). Yellow solid (105 mg,
4-[1-Methyl-2-(quinolin-2-yl)-1H-pyrrol-3-yl]benzonitrile (3j):
Radial chromatography (petroleum ether/diethyl ether, 5:1). Yellow
71 %); m.p. 132–135 °C. FT- IR (ATR, neat): ν = 2923, 2224, 1605,
˜
1
1489, 977, 953, 900, 840, 787, 746 cm–1. H NMR (500 MHz, CDCl3):
solid (34 mg, 22 %); m.p. 82–86 °C. FT- IR (ATR, neat): ν = 2923, 2222,
˜
1596, 1509, 1498, 1427, 830, 742, 729, 717 cm–1. 1H NMR (500 MHz,
CDCl3): δ = 8.14 (dd, J = 8.4, 1.0 Hz, 1 H), 7.99 (dd, J = 8.6, 0.9 Hz,
1 H), 7.81 (dd, J = 8.1, 1.4 Hz, 1 H), 7.76 (ddd, J = 8.4, 6.9, 1.5 Hz, 1
H), 7.57 (ddd, J = 8.1, 6.8, 1.2 Hz, 1 H), 7.47 (AA′BB′, J = 8.5 Hz, 2 H),
7.30 (AA′BB′, J = 8.5 Hz, 2 H), 7.16 (d, J = 8.5 Hz, 1 H), 6.84 (d, J =
2.8 Hz, 1 H), 6.39 (d, J = 2.8 Hz, 1 H), 3.85 (s, 3 H) ppm. 13C NMR
(126 MHz, CDCl3): δ = 151.8, 148.2, 141.6, 135.9, 132.1, 130.1, 129.8,
129.3, 128.8, 127.6, 126.7, 126.6, 125.4, 124.1, 124.0, 119.3, 108.9,
108.6, 35.9 ppm. HRMS (ESi+): m/z calcd. for C21H16N3 [M + H]+
310.1339, found 310.1342.
δ = 9.26 (d, J = 2.2 Hz, 1 H), 8.45 (d, J = 2.1 Hz, 1 H), 8.11 (d, J =
8.5 Hz, 1 H), 7.89 (dd, J = 8.3, 1.4 Hz, 1 H), 7.86 (AA′BB′, J = 8.5, Hz,
2 H), 7.74–7.71 (m, 3 H), 7.61–7.58 (m, 1 H), 7.01 (d, J = 3.6 Hz, 1 H),
6.97 (d, J = 3.6 Hz, 1 H) ppm. 13C NMR (126 MHz, CDCl3): δ = 152.4,
152.3, 147.4, 146.9, 134.0, 132.7, 129.7, 129.5, 129.4, 128.0, 127.7,
127.5, 124.0, 123.3, 118.9, 110.6, 110.5, 109.3 ppm. HRMS (ESi+): m/z
calcd. for C20H13N2O [M + H]+ 297.1022, found 297.1023.
4-[5-(Quinolin-3-yl)thiophen-2-yl]benzonitrile (4l): Radial chro-
matography (petroleum ether/diethyl ether, 1:1). Orange solid
(117 mg, 75 %); m.p. 204–205 °C. FT- IR (ATR, neat): ν = 3053, 2225,
˜
1
1600, 1537, 1496, 928, 903, 801, 784, 745 cm–1. H NMR (500 MHz,
4-[5-(Quinolin-8-yl)thiophen-2-yl]benzonitrile (4b): Radial chro-
CDCl3): δ = 9.21 (d, J = 2.3 Hz, 1 H), 8.30 (d, J = 2.1 Hz, 1 H), 8.11
(dd, J = 8.4, 1.0 Hz, 1 H), 7.86 (dd, J = 8.1, 1.4 Hz, 1 H), 7.75–7.67
(m, 5 H), 7.59 (ddd, J = 8.2, 6.9, 1.2 Hz, 1 H), 7.52 (d, J = 3.9 Hz, 1
H), 7.47 (d, J = 3.9 Hz, 1 H) ppm. 13C NMR (126 MHz, CDCl3): δ =
148.1, 147.5, 142.3, 142.2, 138.1, 132.8, 131.4, 129.7, 129.4, 127.9,
127.8, 127.5, 126.9, 126.3, 125.9, 125.7, 118.7, 110.9 ppm. HRMS
(ESi+): m/z calcd. for C20H13N2S [M + H]+ 313.0794, found 313.0792.
matography (petroleum ether/EtOAc, 7:1). Yellow solid (34 mg,
22 %); m.p. 161–162 °C. FT- IR (ATR, neat): ν = 3054, 2922, 2223,
˜
1603, 1493, 834, 824, 797, 749 cm–1. 1H NMR (500 MHz, CDCl3): δ =
8.83 (dd, J = 4.1, 1.8 Hz, 1 H), 8.18 (dd, J = 8.3, 1.8 Hz, 1 H), 7.83
(dd, J = 8.2, 1.5 Hz, 1 H), 7.58–7.55 (m, 2 H), 7.46 (dd, J = 8.2, 7.2 Hz,
1 H), 7.41–7.38 (m, 3 H), 7.30 (d, J = 5.3 Hz, 1 H), 7.26 (AA′BB′, J =
8.5 Hz, 2 H) ppm. 13C NMR (126 MHz, CDCl3): δ = 150.4, 146.3, 141.9,
138.5, 137.2, 136.2, 132.8, 132.5, 131.9, 129.1, 128.7, 128.6, 128.5,
126.7, 126.1, 121.4, 119.0, 109.8 ppm. HRMS (ESi+): m/z calcd. for
C20H13N2S [M + H]+ 313.0794, found 313.0800.
4-[1-Methyl-5-(quinolin-3-yl)-1H-pyrrol-2-yl]benzonitrile (4m):
Radial chromatography (petroleum ether/diethyl ether, 1:1). Pale
yellow solid (104 mg, 67 %); m.p. 164–167 °C. FT- IR (ATR, neat): ν =
˜
2917, 2220, 1603, 1514, 1458, 863, 833, 787, 765, 753 cm–1. 1H NMR
(500 MHz, CDCl3): δ = 9.08 (d, J = 2.3 Hz, 1 H), 8.19 (d, J = 1.8 Hz,
1 H), 8.14 (dd, J = 8.4, 1.0 Hz, 1 H), 7.87 (dd, J = 8.1, 1.3 Hz, 1 H),
7.76–7.71 (m, 3 H), 7.62–7.59 (m, 3 H), 6.53 (d, J = 3.8 Hz, 1 H), 6.51
(d, J = 3.8 Hz, 1 H), 3.71 (s, 3 H) ppm. 13C NMR (126 MHz, CDCl3):
δ = 150.7, 146.9, 137.3, 136.1, 135.3, 134.3, 132.4, 129.6, 129.3, 128.5,
127.8, 127.7, 127.2, 126.0, 118.9, 111.2, 110.1, 34.7 ppm. HRMS
(ESi+): m/z calcd. for C20H13N2S [M + H]+ 313.0794, found 313.0792.
4-[5-(Quinolin-2-yl)furan-2-yl]benzonitrile (4h): Radial chroma-
tography (petroleum ether/diethyl ether, 5:1). Yellow solid (61 mg,
41 %); m.p. 154–158 °C. FT- IR (ATR, neat): ν = 3060, 2226, 1605,
˜
1594, 1496, 1018, 927, 808, 788, 755 cm–1
.
1H NMR (500 MHz,
CDCl3): δ = 8.22 (d, J = 8.5 Hz, 1 H), 8.11 (dd, J = 8.5, 1.0 Hz, 1 H),
7.94 (d, J = 8.6 Hz, 1 H), 7.89 (AA′BB′, J = 8.5 Hz, 2 H), 7.81 (dd, J =
8.1, 1.3 Hz, 1 H), 7.75–7.70 (m, 3 H), 7.53 (ddd, J = 8.1, 6.8, 1.2 Hz,
1 H), 7.39 (d, J = 3.6 Hz, 1 H), 7.01 (d, J = 3.6 Hz, 1 H) ppm. 13C NMR
(126 MHz, CDCl3): δ = 154.7, 152.9, 148.4, 148.2, 136.8, 134.1, 132.6,
130.0, 129.3, 127.6, 127.3, 126.5, 124.2, 118.9, 117.3, 112.3, 110.9,
110.7 ppm. HRMS (ESi+): m/z calcd. for C20H13N2O [M + H]+
297.1022, found 297.1019.
4-[5-(Naphthalen-1-yl)furan-2-yl]benzonitrile (4n): Radial chro-
matography (petroleum ether/EtOAc, 50:1). Yellow solid (63 mg,
43 %); m.p. 106–109 °C. FT- IR (ATR, neat): ν = 2954, 2220, 1606,
˜
1527, 1412, 992, 840, 831, 789, 774 cm–1. 1H NMR (500 MHz, CDCl3):
δ = 8.45 (dd, J = 8.5, 1.2 Hz, 1 H), 7.93–7.87 (m, 2 H), 7.84–7.80 (m,
3 H), 7.68 (AA′BB′, J = 8.5 Hz, 2 H), 7.59–7.53 (m, 3 H), 7.00 (d, J =
3.5 Hz, 1 H), 6.86 (d, J = 3.5 Hz, 1 H) ppm. 13C NMR (126 MHz,
CDCl3): δ = 154.7, 151.6, 134.5, 134.0, 132.6, 130.2, 129.2, 128.7,
127.8, 126.9, 126.4, 126.1, 125.3, 125.2, 123.8, 119.0, 111.8, 110.1
(2 C) ppm. HRMS (ESi+): m/z calcd. for C21H14NO [M + H]+ 296.1070,
found 296.1071.
4-[5-(Quinolin-2-yl)thiophen-2-yl]benzonitrile (4i): Radial chro-
matography (petroleum ether/diethyl ether, 5:1). Pale yellow solid
(96 mg, 61 %); m.p. 139–143 °C. FT- IR (ATR, neat): ν = 3058, 2224,
˜
1591, 1501, 1456, 1427, 841, 823, 742, 727 cm–1. 1H NMR (500 MHz,
CDCl3): δ = 8.07 (dd, J = 8.4, 1.0 Hz, 1 H), 7.93 (dd, J = 8.6, 0.8 Hz,
1 H), 7.75 (dd, J = 8.1, 1.4 Hz, 1 H), 7.72 (ddd, J = 8.5, 6.9, 1.5 Hz, 1
H), 7.63 (AA′BB′, J = 8.5, Hz, 2 H), 7.54–7.48 (m, 4 H), 7.16 (d, J =
5.2 Hz, 1 H), 7.08 (d, J = 8.6 Hz, 1 H) ppm. 13C NMR (126 MHz,
CDCl3): δ = 152.4, 148.2, 141.4, 141.0, 138.3, 136.1, 132.3, 130.3,
130.0 (2 C), 129.3, 127.8, 127.5, 126.9, 126.7, 120.8, 118.8, 111.1 ppm.
HRMS (ESi+): m/z calcd. for C20H13N2S [M + H]+ 313.0794, found
313.0794.
4-[5-(Naphthalen-2-yl)furan-2-yl]benzonitrile (4o): Radial chro-
matography (petroleum ether/EtOAc, 50:1). Yellow solid (71 mg,
48 %); m.p. 158–162 °C. FT- IR (ATR, neat): ν = 2855, 2218, 1602,
˜
1177, 1025, 866, 827, 786, 753 cm–1. 1H NMR (500 MHz, CDCl3): δ =
8.18 (s, 1 H), 7.89–7.77 (m, 6 H), 7.66 (AA′BB′, J = 8.5 Hz, 2 H), 7.52–
7.46 (m, 2 H), 6.90 (d, J = 3.6 Hz, 1 H), 6.86 (d, J = 3.6 Hz, 1 H) ppm.
13C NMR (126 MHz, CDCl3): δ = 155.1, 151.4, 134.4, 133.4, 132.9,
132.6, 128.6, 128.2, 127.8, 127.3, 126.7, 126.3, 123.7, 122.6, 122.1,
119.0, 110.6, 110.0, 108.2 ppm. HRMS (ESi+): m/z calcd. for C21H14NO
[M + H]+ 296.1070, found 296.1073.
4-[1-Methyl-5-(quinolin-2-yl)-1H-pyrrol-2-yl]benzonitrile (4j):
Radial chromatography (petroleum ether/diethyl ether, 5:1). Yellow
solid (59 mg, 38 %); m.p. 140–145 °C. FT- IR (ATR, neat): ν = 2946,
˜
2224, 1597, 1498, 1346, 1218, 1069, 841, 823, 762 cm–1
.
1H NMR
(500 MHz, CDCl3): δ = 8.13 (dd, J = 8.7, 0.8 Hz, 1 H), 8.06 (dd, J =
8.4, 0.9 Hz, 1 H), 7.79 (dd, J = 8.0, 1.4 Hz, 1 H), 7.74–7.69 (m, 4 H),
7.62 (AA′BB′, J = 8.5, Hz, 2 H), 7.50 (ddd, J = 8.1, 6.9, 1.2 Hz, 1 H),
6.83 (d, J = 3.9 Hz, 1 H), 6.44 (d, J = 3.9 Hz, 1 H), 4.09 (s, 3 H) ppm.
4,4′-[5-(Quinolin-8-yl)furan-2,4-diyl]dibenzonitrile (5a): Radial
chromatography (petroleum ether/EtOAc, 5:1). Yellow solid (64 mg,
32 %); m.p. 247–250 °C. FT- IR (ATR, neat): ν = 2922, 2220, 1602,
˜
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1493, 1176, 851, 798, 789, 762 cm–1. 1H NMR (500 MHz, CDCl3): δ = ture was stirred in a sealed glass tube at 130 °C for 48 h under inert
8.69 (dd, J = 4.1, 1.8 Hz, 1 H), 8.22 (dd, J = 8.3, 1.8 Hz, 1 H), 7.97
(dd, J = 8.2, 1.5 Hz, 1 H), 7.92 (dd, J = 7.2, 1.5 Hz, 1 H), 7.85 (AA′BB′
, J = 8.5 Hz, 2 H), 7.70 (AA′BB′, J = 8.5 Hz, 2 H), 7.65 (dd, J = 8.2,
7.2 Hz, 1 H), 7.44 (AA′BB′, J = 8.5 Hz, 2 H), 7.41 (dd, J = 8.3, 4.1 Hz,
1 H), 7.30 (AA′BB′, J = 8.5 Hz, 2 H), 7.23 (s, 1 H) ppm. 13C NMR
(126 MHz, CDCl3): δ = 152.2, 150.7, 149.9, 145.7, 138.6, 136.3, 134.2,
atmosphere. The mixture was cooled to room temperature (room
temp.) to which water was added (3 mL) and the product was ex-
tracted into ethyl acetate (2 × 3 mL). The combined organic layers
were dried with anhydrous Na2SO4, filtered and the solvent was
evaporated under reduced pressure. The crude product was purified
by radial chromatography to yield pure product 5ia. Radial chroma-
132.7, 132.0, 131.7, 130.0, 129.5, 128.8, 127.9, 126.2, 125.7, 124.1, tography (petroleum ether/ethyl acetate, 10:1). Yellow solid (80 mg,
121.7, 118.9, 118.8, 110.7, 110.1, 109.7 ppm. HRMS (ESi+): m/z calcd. 70 %); m.p. 199–202 °C. FT- IR (ATR, neat): ν = 3066, 2226, 1609,
˜
for C27H16N3O [M + H]+ 398.1288, found 398.1284.
1591, 1501, 1321, 1163, 1109, 1067, 1013, 825, 816, 748 cm–1
.
1H
NMR (500 MHz, CDCl3): δ = 8.10 (d, J = 8.4 Hz, 1 H), 7.94 (d, J =
8.6 Hz, 1 H), 7.82–7.80 (m, 2 H), 7.78–7.73 (m, 2 H), 7.69–7.68 (m, 4
H), 7.56–7.53 (m, 3 H), 7.42 (s, 1 H), 7.09 (d, J = 8.6 Hz, 1 H) ppm.
13C NMR (126 MHz, CDCl3): δ = 152.0, 148.4, 144.3, 141.6, 141.3,
139.4, 137.1, 136.4, 132.7, 130.5, 130.3, 130.1, 129.5, 127.7, 127.6,
127.2, 127.1, 126.2 (q, J = 3.7 Hz), 126.1, 124.3 (q, J = 271.9 Hz),
120.5, 118.8, 111.8 ppm. 19F NMR (377 MHz, CDCl3): δ = –62.6 ppm.
HRMS (ESi+): m/z calcd. for C27H16F3N2S [M + H]+ 457.0981, found
457.0976.
4,4′-[1-Methyl-5-(quinolin-8-yl)-1H-pyrrol-2,4-diyl]dibenzo-
nitrile (5c):[23] Radial chromatography (petroleum ether/diethyl
ether, 2:1). Pale yellow solid (72 mg, 35 %). 1H NMR (500 MHz,
CDCl3): δ = 9.01 (dd, J = 4.0, 2.0 Hz, 1 H), 8.30 (dd, J = 8.5, 2.0 Hz,
1 H), 7.97 (dd, J = 8.0, 2.0 Hz, 1 H), 7.74 (AA′BB′, J = 8.5 Hz, 2 H),
7.68 (AA′BB′, J = 8.5 Hz, 2 H), 7.61–7.54 (m, 2 H), 7.51 (dd, J = 8.5,
4.0 Hz, 1 H), 7.34 (AA′BB′, J = 8.5 Hz, 2 H), 7.13 (AA′BB′, J = 8.5 Hz,
2 H), 6.74 (s, 1 H), 3.37 (s, 3 H) ppm.
4,4′-{5-[5-(Trifluoromethyl)quinolin-8-yl]furan-2,4-diyl}dibenzo-
nitrile (5e): Radial chromatography (petroleum ether/EtOAc, 5:1).
Acknowledgments
We thank the Slovenian Research Agency for financial support
through grant P1-0179. We also acknowledge the Centre of Ex-
cellence EN-FIST.
Yellow solid (91 mg, 39 %); m.p. 228–232 °C. FT- IR (ATR, neat): ν =
˜
3059, 2223, 1604, 1507, 1316, 1097, 964, 848, 798, 786, 732 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 8.70 (dd, J = 4.1, 1.7 Hz, 1 H), 8.56–
8.54 (m, 1 H), 8.03–7.98 (m, 2 H), 7.86 (AA′BB′, J = 8.5 Hz, 2 H), 7.71
(AA′BB′, J = 8.5 Hz, 2 H), 7.52 (dd, J = 8.7, 4.1 Hz, 1 H), 7.48 (AA′BB′,
J = 8.5 Hz, 2 H), 7.29 (AA′BB′, J = 8.5 Hz, 2 H), 7.24 (d, J = 1.9 Hz, 1
H) ppm. 13C NMR (126 MHz, CDCl3): δ = 152.8, 150.8, 148.2, 145.4,
138.4, 133.9, 133.8, 132.8, 132.6 (q, J = 2.4 Hz), 132.1, 129.7, 128.1,
127.5 (q, J = 31.0 Hz), 127.1, 125.0, 124.7 (q, J = 5.7 Hz), 124.2, 123.8
(q, J = 274.6 Hz), 122.7, 118.7 (2 C), 111.0, 110.4, 110.1 ppm. 19F
NMR (377 MHz, CDCl3): δ = –59.2 ppm. HRMS (ESi+): m/z calcd. for
C28H15F3N3O [M + H]+ 466.1162, found 466.1166.
Keywords: Quinoline · C–H arylation · Nitrogen directed
reaction · Palladium catalysis · Heterocycles
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2223, 1603, 1588, 1465, 1405, 1266, 1222, 1086, 840, 812, 786 cm–1
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1H NMR (500 MHz, CDCl3): δ = 8.71 (dd, J = 4.1, 1.8 Hz, 1 H), 8.64
(dd, J = 8.5, 1.8 Hz, 1 H), 7.83 (AA′BB′, J = 8.5 Hz, 2 H), 7.80 (d, J =
8.1 Hz, 1 H), 7.68 (AA′BB′, J = 8.5 Hz, 2 H), 7.43 (AA′BB′, J = 8.5 Hz,
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7.22 (s, 1 H), 6.95 (d, J = 8.1 Hz, 1 H), 4.09 (s, 3 H) ppm. 13C NMR
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132.6, 132.2, 132.0, 131.0, 127.8, 124.8, 124.0, 121.6, 121.1, 120.7,
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4,4′-[5-(Quinolin-2-yl)thiophene-2,4-diyl]dibenzonitrile (5i): Ra-
dial chromatography (petroleum ether/diethyl ether, 5:1). Yellow
solid (25 mg, 12 %); m.p. 196–199 °C. FT- IR (ATR, neat): ν = 3044,
˜
2222, 1592, 1556, 1495, 1425, 826, 786, 751 cm–1. 1H NMR (500 MHz,
CDCl3): δ = 8.09 (dd, J = 8.6, 1.1 Hz, 1 H), 7.95 (d, J = 8.6 Hz, 1 H),
7.81–7.68 (m, 8 H), 7.57–7.54 (m, 3 H), 7.45 (s, 1 H), 7.08 (d, J =
8.6 Hz, 1 H) ppm. 13C NMR (126 MHz, CDCl3): δ = 151.6, 148.2, 143.4,
142.3, 140.9, 139.4, 137.8, 136.3, 132.9, 132.6, 130.2, 129.9, 129.3,
128.0, 127.6, 127.1, 126.0, 120.2, 118.6, 118.5, 111.7, 111.4 ppm.
HRMS (ESi+): m/z calcd. for C27H16N3S [M + H]+ 414.1059, found
414.1056.
Nitrogen Atom-directed Pd-Catalyzed Arylation of Compound
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0.50 mmol) were dissolved in 1,4-dioxane (1 mL). The reaction mix-
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Received: June 1, 2018
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Full Paper
Palladium Catalysis
B. Štefane, U. Grošelj, J. Svete,
F. Požgan, D. Kočar,
H. Brodnik Žugelj* .......................... 1–11
The Influence of the Quinoline Moi-
ety on Direct Pd-Catalyzed Arylation
of Five-Membered Heterocycles
The regioselectivity of the arylation re- strongly influenced by site position of
action of five-membered heterocycles the attached five-membered hetero-
bearing a quinoline directing group cycle thus giving rise to C3- and/or C5-
was studied. The transformation was arylated products.
DOI: 10.1002/ejoc.201800842
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim