New 4-pyridyl nonaflates as precursors for push-pull solvatochromic dyes

Article abstract of DOI:10.1055/s-0033-1340839

2,6-Disubstituted 4-pyridyl nonaflates including methyl, phenyl, 2-thienyl and 2-furyl groups were prepared by cyclocondensation reactions of the appropriate β-ketoenamides. Palladium-catalyzed cross-couplings (Suzuki-Miyaura, Mizoroki-Heck and Sonogashira reactions) led to buildings blocks that are direct precursors for the envisioned synthesis of push-pull solvatochromic dyes. Georg Thieme Verlag Stuttgart? New York.

Full text of DOI:10.1055/s-0033-1340839

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PAPER
paper
New 4-Pyridyl Nonaflates as Precursors for Push–Pull Solvatochromic Dyes
New 4-Pyridyl Nonaflates as Precursors for Solvatochromic Dyes
Moisés Domínguez, Hans-Ulrich Reissig*
Institut für Chemie und Biochemie, Freie Universität Berlin, Takustr. 3, 14195 Berlin, Germany
Fax +49(30)83855367; E-mail: hans.reissig@chemie.fu-berlin.de
Received: 19.12.2013; Accepted after revision: 28.01.2014
Abstract: 2,6-Disubstituted 4-pyridyl nonaflates including methyl,
phenyl, 2-thienyl and 2-furyl groups were prepared by cyclocon-
O
O
densation reactions of the appropriate β-ketoenamides. Palladium-
catalyzed cross-couplings (Suzuki–Miyaura, Mizoroki–Heck and
Sonogashira reactions) led to buildings blocks that are direct precur-
sors for the envisioned synthesis of push–pull solvatochromic dyes.
N
Key words: enamides, pyridines, cyclocondensations, nonaflates,
cross-couplings
N
N
O
Me
Me
Pyridinium phenolates are the most prominent members
in the class of solvatochromic push–pull dyes, a group of
molecules that exhibits outstanding changes in their spec-
troscopic properties when the polarity of the surrounding
medium is modified.1 In particular, their extreme sensitiv-
ity in the UV/Vis–IR region, made them convenient
probes to explore very different chemical environments,
such as pure solvents and solvent mixtures,2 micellar,2b,3
dendrimer4 and electrolyte solutions.5
1
2
3
Figure 1 Prominent members of the family of solvatochromic pyri-
dinium phenolate dyes
methanesulfonate/base-promoted intramolecular conden-
sation of β-ketoenamides.12 Smooth O-nonaflation of the
resulting 4-hydroxypyridines and subsequent functional-
izations by palladium-catalyzed cross-coupling reactions
led to a broad range of specifically substituted pyridine
derivatives.13 In the present report, we focus on the prep-
aration of 2,6-disubstituted 4-pyridyl nonaflates and their
palladium-catalyzed couplings for the flexible preparation
of a series of precursors for pyridine-based solvatochro-
mic push–pull dyes.
Figure 1 shows three important examples of solvatochro-
mic pyridinium phenolates, ET(30) or Reichardt’s betaine
1,6 Brooker’s merocynine (2)7 and POMP (3) [4-(N-meth-
yl-4-pyridinio)phenolate].8 Besides their spectroscopic
properties that have been subject of experimental and theo-
retical investigations,9 they represent adequate examples
of how this class of compounds is generally prepared in
literature. In all cases, the precursors of the donor (pheno-
late) and the acceptor (pyridinium) moieties are prepared
separately and subsequently linked. ANROC reactions
(Addition of the Nucleophile, Ring Opening, and Ring
Closure) of pyrylium salts using suitable aminophenols as
nucleophiles have been used to prepare several com-
pounds similar to 1.10 Alternatively compounds like 2 can
be accessed by condensation reactions between N-alkylat-
ed pyridinium salts and hydroxybenzaldehydes.11 Finally,
Suzuki–Miyaura cross-coupling reactions between 4-pyr-
idineboronic esters and bromophenols allowed the access
to a library of compounds like 3.8 This last approach has
been less explored and represents a rapid and versatile
path to new and highly functionalized solvatochromic
dyes if suitable pyridine derivatives for palladium-cata-
lyzed reactions can be easily prepared.
The synthetic sequence starts with the preparation of β-ke-
toenamines 6 employing three different methods (Scheme
1). The condensation reaction of 1,3-diketones with aque-
ous ammonia in the presence of catalytic amounts of
SiO214 represents a simple and economical procedure for
the amination of symmetrical compounds such as 4 giving
intermediate 6a (R1 = Me), but it cannot be applied for the
regioselective preparation of compounds 6b–d (R1 ≠ Me).
For that reason enamines 6b–d were prepared by alterna-
tive methods. The hydrogenolysis of 5-methyl-3-phenyl-
isoxazole (5) in the presence of Raney-Nickel at room
temperature provided β-ketoenamines 6b (R1 = Ph) in
good yield.15 β-Ketoenamines 6c,d (R1 = 2-thienyl or 2-
furyl) were prepared by treatment of acetone with sodium
hydride in presence of 2-furancarbonitrile or 2-thiophene-
carbonitrile under reflux conditions (see Supporting In-
formation for details). Surprisingly, this simple reaction
did not provide the desired products when nitriles such as
benzonitrile or 2-chloro- or 4-chloropyridyl carbonitrile
derivatives were employed, giving only traces of hydro-
lyzed nitriles as products even after prolonged reaction
times. By N-acylation of β-ketoenamines 6a–d with dif-
ferent carboxylic acid chlorides in presence of Et3N, the
In recent years, our group has developed a new and flexi-
ble procedure for the preparation of highly functionalized
4-hydroxypyridines by means of a trimethylsilyl trifluoro-
SYNTHESIS 2014, 46, 1100–1106
Advanced online publication: 21.02.2014
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8
1
1
4
3
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1
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DOI: 10.1055/s-0033-1340839; Art ID: SS-2013-T0823-OP
© Georg Thieme Verlag Stuttgart · New York

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New 4-Pyridyl Nonaflates as Precursors for Solvatochromic Dyes
1101
required β-ketoenamides 8a–j were obtained in good
yields (Scheme 1).
Table 1 TMSOTf/Base-Promoted Cyclocondensations of β-Keto-
enamides 8a–j and Subsequent O-Nonaflation Reactionsa
ONf
O
1) TMSOTf, i-Pr2NEt
DCE, 85 °C, 3 d
O
O
O
HN
R2
2) NaH, NfF
THF, overnight
R1
N
R2
R1
4
9a–j
8a–j
NH3 (25% aq)
SiO2, r.t., 16 h
96%
Entry
8
R1
R2
9
Yield (%)b
1
2
8a
8b
8c
8d
8e
8f
Me
Me
Ph
9a
9b
9c
9d
9e
9f
32
83
62
69
78
74
73
75
75
71
N
H2, Raney-Ni
O
O
NH2
R1
Me
Ph
EtOH, r.t., 18 h
81%
3
Me
2-thienyl
5
6a–d
4
Me
2-furyl
Ph
R2COCl, Et3N
CH2Cl2, r.t., 16 h
71–99%
5
Ph
X
NC
6
2-thienyl
2-thienyl
2-furyl
2-furyl
2-furyl
2-thienyl
Ph
7
8g
8h
8i
9g
9h
9i
X = O, S
NaH
THF, reflux
2 h
O
8
Ph
O
HN
R2
O
74–85%
9
2-thienyl
2-furyl
R1
10
8j
9j
8a–j
R1, R2 = Me, Ph, 2-furyl, 2-thienyl
7
a Reaction conditions: TMSOTf (5.0 equiv), i-Pr2NEt (4.0 equiv),
1,2-dichloroethane (DCE) (c = 0.04 M), NaH (7.0 equiv),
NfF (2.5 equiv); Nf = SO2C4F9.
Scheme 1 Preparation of β-ketoenamines 6a (R1 = Me), 6b
(R1 = Ph), 6c (R1 = 2-thienyl), and 6d (R1 = 2-furyl) and β-ketoen-
amides 8a–j (for substituents R1 and R2 of compounds 8, see Table 1)
b Yields over two steps.
The CH-acidic methyl ketone moiety in compounds of
type 8 is susceptible to undergo an intramolecular aldol-
type condensation reaction with the amide carbonyl moi-
ety upon treatment with trimethylsilyl trifluoromethane-
sulfonate (TMSOTf) in the presence of i-Pr2NEt. The
cyclized primary 4-pyridinols were not isolated and puri-
fied but directly subjected to O-nonaflation employing
nonafluorobutanesulfonyl fluoride (NfF) to provide the
desired 4-pyridyl nonaflates 9 in moderate to good overall
yields (Table 1).
OMe
4-MeOC6H4B(OH)2
Pd(OAc)2
Ph3P, K2CO3
ONf
N
DMF, 80 °C, 16 h
75–92%
R1
R2
R1
N
R2
9a–e
10a–e
Scheme 2 Suzuki–Miyaura couplings of 4-pyridyl nonaflates 9a–e
leading to 4-(4-methoxyphenyl)pyridines 10a (R1 = Me, R2 = Me),
10b (R1 = Me, R2 = Ph), 10c (R1 = Me, R2 = 2-thienyl), 10d
(R1 = Me, R2 = 2-furyl), and 10e (R1 = Ph, R2 = Ph)
Since our strategy for the preparation of pyridinium phe-
nolate solvatochromic dyes proposes 4-pyridyl nonaflates
as key intermediates, different palladium-catalyzed cross-
coupling reactions were carried out with anisole deriva-
tives that serve as a latent phenolate donor. It was expect-
ed that the anisole moiety can easily be demethylated in
the resulting pyridine derivatives.16 Suzuki–Miyaura
(Scheme 2), Heck–Mizoroki (Scheme 3) and Sonogashira
(Scheme 4) coupling reactions of 4-pyridyl nonaflates
9a–d with 4-methoxyphenylboronic acid, 4-methoxysty-
rene and 4-ethynylanisole, respectively, provided the
expected 4-(4-methoxyphenyl)pyridines 10, 4-(4-meth-
oxystyryl)pyridines 11 and 4-[(4-methoxyphenyl)eth-
ynyl]pyridines 12 in good yields.
OMe
ONf
4-MeOC6H4CH=CH2
Pd(OAc)2, LiCl
Et3N, DMF, 80 °C, 16 h
N
R
87–90%
9a–d
N
R
11a–d
Scheme 3 Heck–Mizoroki couplings of 4-pyridyl nonaflates 9a–d
leading to (E)-4-(4-methoxystyryl)pyridines 11a (R = Me), 11b
(R = Ph), 11c (R = 2-thienyl), and 11d (R = 2-furyl)
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 1100–1106

1102
M. Domínguez, H.-U. Reissig
PAPER
blocks are ready for further functionalizations leading to
new pyridine derivatives (Scheme 5).
OMe
TIPS
4-MeOC6H4C CH
Pd(OAc)2
Ph3P, CuI, i-Pr2NH
ONf
TIPS
[PdCl2(PPh3)2]
CuI
ONf
N
TBAF
DMF, 80 °C, 16 h
79–96%
N
R
THF
30 min
R2
94–98%
Et3N, 90 °C, 4 h
R2
95–98%
R1
R1
N
R2
R1
N
N
R
9a–d
12a–d
9a–j
14a–j
13a–j
R1, R2 = Me, Ph, 2-thienyl, 2-furyl
Scheme 4 Sonogashira reactions of 4-pyridyl nonaflates 9a–d lead-
ing to 4-[(4-methoxyphenyl)ethynyl]pyridines 12a (R = Me), 12b
(Ph), 12c (2-thienyl), and 12d (2-furyl)
Scheme 5 Sonogashira couplings of 4-pyridyl nonaflates 9a–f lead-
ing to 4-ethynylpyridines 14a–j
The above described coupling reactions clearly reveal the
potential of this type of 4-pyridyl nonaflates for palladi-
um-catalyzed processes. In addition, compounds 9a–j
were subjected to Sonogashira couplings with TIPS-acet-
ylene. Subsequent treatment of the resulting products
13a–j with tetra-n-butylammonium fluoride (TBAF) fur-
nished the 2,6-disubstituted 4-ethynylpyridines 14a–j in
excellent overall yields (89–96%). These new building
As an example of possible subsequent reactions, ethynyl-
pyridine 14a was subjected to Sonogashira reactions un-
der standard conditions employing 1,4-diiodobenzene and
1,3,6,8-tetrabromopyrene (17) that led to new rigid chro-
mophores 15 and 18 in high yields (Scheme 6). Com-
pound 15 was smoothly N-methylated by methyl triflate
to furnish bis(pyridinium) salt 16.
Me
TfO
N
N
Me
OTf
16
MeOTf
toluene
0 °C to r.t., 2 h
98%
I
I
Pd(PPh3)4
CuI
N
N
Et3N
16 h, 80 °C
90%
N
15
14a
Br
Br
Br
Br
N
N
17
[PdCl2(PPh3)2], CuI
i-Pr2NH, 18 h, 90 °C
89%
N
N
18
Scheme 6 Sonogashira couplings of 4-ethynyl-2,6-dimethylpyridine (14a) leading to rigid chromophores 15, 16 and 18
Synthesis 2014, 46, 1100–1106
© Georg Thieme Verlag Stuttgart · New York

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New 4-Pyridyl Nonaflates as Precursors for Solvatochromic Dyes
1103
mmol) in 1,2-dichloroethane (30 mL). The obtained crude 4-hy-
droxypyridine was treated with NaH (333 mg, 8.33 mmol) and NfF
(0.53 mL, 2.98 mmol) in THF (15 mL). After workup, the obtained
crude product was purified by column chromatography on silica gel
(hexanes–EtOAc = 40:1) to provide compound 9c (352 mg, 62%)
as a light yellow oil.
In conclusion, nine new 2,6-disubstituted 4-pyridyl nona-
flates were prepared and subsequently subjected to palla-
dium-catalyzed cross-couplings (Suzuki–Miyaura, Heck–
Mizoroki and Sonogashira reactions) leading to a series of
4-(4-methoxyphenyl)pyridine, 4-(4-methoxystyryl)pyri-
dine and 4-[(4-methoxyphenyl)ethynyl]pyridine deriva-
tives in good overall yields. These compounds are direct
precursors for solvatochromic pyridinium-phenolate
dyes. In addition, the prepared nonaflates were converted
to 2,6-disubstituted 4-ethynylpyridine derivatives in ex-
cellent yields, providing new building blocks for further
coupling reactions. The preparation of push–pull solvato-
IR (ATR): 3130–2920 (=C–H), 2855 (C–H), 1605 (C=C), 1575
cm–1 (C=N).
1H NMR (CDCl3, 400 MHz): δ = 2.62 (s, 3 H, CH3), 6.92 (d, J = 2.1
Hz, 1 H, 3-H), 7.12 (dd, J = 5.1, 3.8 Hz, 1 H, Thio-4-H), 7.33 (d,
J = 2.1 Hz, 1 H, 5-H), 7.44 (dd, J = 5.1, 1.1 Hz, 1 H, Thio-5-H),
7.60 (dd, J = 3.8, 1.1 Hz, 1 H, Thio-3-H).
13C NMR (CDCl3, 101 MHz): δ = 24.8 (q, CH3), 108.0 (d, C-5),
chromic dyes from compounds 10, 11 and 12 (by N-meth- 113.2 (d, C-3), 125.9, 128.3, 129.0 (3 d, Thio-C-3, -C-4, -C-5),
143.3 (s, Thio-C-2), 154.9, 157.4, 162.0 (3 s, C-2, C-4, C-6).
ylation, O-demethylation and deprotonation) and their
photophysical properties, including their solvatochromic
behavior will be published in a future report.
19F NMR (CDCl3, 376 MHz): δ = –125.7, –120.8 (2 mc, 2 F each,
CF2), –108.5 (t, J = 14.0 Hz, 2 F, CF2), –80.6 (t, J = 9.4 Hz, 3 F,
CF3).
HRMS (ESI-TOF): m/z calcd for C14H9F9NO3S2 [M + H]+:
473.9875; found: 473.9863.
Reactions were generally performed under argon in flame-dried
flasks and liquid components were added by syringe. Column chro-
matography was performed with silica gel (230–400 mesh,
Macherey & Nagel). All yields refer to analytically pure samples.
1H NMR [CHCl3 (δ = 7.26), TMS (δ = 0.00) as internal standard],
13C NMR spectra [CDCl3 (δ = 77.0) as internal standard] and 19F
NMR spectra were recorded with Bruker (AC 500, VIII 700), Jeol
ECX 400, or Jeol Eclipse 500 instruments in CDCl3 solutions. Inte-
grals are in accordance with assignments; coupling constants are
given in Hz. All 13C NMR spectra are proton-decoupled. 13C NMR
signals of Nf groups [CF3(CF2)3] are not given since unambiguous
assignment was not possible due to strong splitting by coupling with
the 19F nuclei. IR spectra were measured with a Jasco FT/IR-4100
spectrometer. HRMS analyses were performed with Varian Ionspec
QFT-7 (ESI-FT ICRMS) and Agilent 6210 ESI-TOF instruments.
The elemental analyses were recorded with Perkin-Elmer CHN-An-
alyzer 2400, Vario EL or Vario EL III instruments. Melting points
were measured with a Reichert apparatus and are uncorrected.
CH2Cl2 was purified with a MB SPS-800 dry solvent system and
dry DMF was acquired from Across Organics. Unless stated other-
wise all other solvents and reagents were purchased from commer-
cial suppliers and were used without further purification. The
preparation of compound 9a12k and 9b12f has been previously report-
ed. Synthesis of the precursor β-ketoenamines 6c,d and ketoen-
amides 8a–j is described in detail in the Supporting Information.
Pd-Catalyzed Coupling of Pyridyl Nonaflates with 4-Methoxy-
phenylboronic Acid; General Procedure 2
Dry DMF (~7 mL/mmol) was transferred to a Schlenk flask charged
with the 4-pyridyl nonaflate (1.0 equiv), Pd(OAc)2 (6 mol%), Ph3P
(20 mol%), K2CO3 (1.0 equiv) and 4-methoxyphenylboronic acid
(1.2 equiv) under argon atmosphere. The mixture was stirred at
80 °C for 16 h. After cooling to r.t., the mixture was diluted with
water (~35 mL/mmol) and extracted with EtOAc (3 × ~50
mL/mmol). The combined organic layers were dried with Na2SO4,
filtered and evaporated under reduced pressure. The obtained crude
product was purified by column chromatography.
4-(4-Methoxyphenyl)-2-methyl-6-(thiophen-2-yl)pyridine (10c)
According to general procedure 2, 2-methyl-6-(thiophen-2-yl)pyri-
din-4-yl nonaflate (9c; 400 mg, 0.85 mmol) was treated with
Pd(OAc)2 (12 mg, 0.05 mmol), Ph3P (45 mg, 0.17 mmol), K2CO3
(118 mg, 0.85) and 4-methoxyphenylboronic acid (155 mg, 1.02
mmol) in DMF (6.0 mL). The obtained crude product was purified
by column chromatography on silica gel (hexanes–EtOAc = 20:1)
to provide compound 10c (180 mg, 75%) as a yellow oil.
IR (ATR): 3030–2800 (=C–H, C–H), 1600 (C=C), 1515 (C=N),
1255 cm–1 (C–O–CH3).
1H NMR (CDCl3, 400 MHz): δ = 2.62 (s, 3 H, CH3), 3.87 (s, 3 H,
OCH3), 6.99–7.03 (m, 2 H, Ar), 7.09–7.13 (m, 1 H, Thio-4-H), 7.19
(d, J = 1.5 Hz, 1 H, 3-H), 7.35–7.39 (m, 1 H, Thio-5-H), 7.59–7.65
(m, 4 H, Thio-3-H, Ar, 5-H).
13C NMR (CDCl3, 101 MHz): δ = 24.7 (q, CH3), 55.5 (q, OCH3),
113.8, 114.5 (2 d, C-3, Ar), 119.3, 121.3 (2 d, C-5, Ar), 127.3,
128.0, 128.3 (3 d, Thio-C-3, -C-4, -C-5), 130.9 (s, Thio-C-1), 137.6,
143.1 (2 s, C-4, Ar-C-4), 154.8, 158.9, 160.5 (3 s, C-2, C-6, Ar-
C-1).
TMSOTf-Promoted Cyclization of β-Ketoenamides and Subse-
quent Nonaflation; General Procedure 1
TMSOTf (5.0 equiv) was added dropwise to a stirred solution of the
β-ketoenamide (1.0 equiv) and i-Pr2NEt (4.0 equiv) in 1,2-dichloro-
ethane (0.04 mol/L) under argon atmosphere. The resulting reaction
mixture was stirred at 90 °C in a Schlenk flask equipped with a re-
flux condenser for 3 d. After cooling the reaction mixture to r.t., the
solvent was carefully evaporated under reduced pressure. The re-
sulting brown crude solid was dissolved in THF (~12 mL per mmol
of β-ketoenamide) and transferred to a suspension of NaH (7.0
equiv, 60% in mineral oil) in a small amount of THF. After 30 min,
NfF (2.5 equiv) was added and the mixture was stirred at r.t. over-
night. Sat. aq NH4Cl solution was slowly added and the layers were
separated. The aqueous layer was extracted with CH2Cl2 (3 × ~50
mL per mmol of β-ketoenamide) and the combined organic layers
were dried with Na2SO4, filtered and evaporated under reduced
pressure. The obtained crude product was purified by column chro-
matography on silica gel.
HRMS (ESI-TOF): m/z calcd for C17H16NOS [M + H]+: 282.0947;
found: 282.0980.
Pd-Catalyzed Coupling of Pyridyl Nonaflates with 1-Methoxy-
4-vinylbenzene; General Procedure 3
Dry DMF (~4.2 mL/mmol) was transferred to a Schlenk flask
charged with the 4-pyridyl nonaflate (1.0 equiv), Pd(OAc)2 (7
mol%), LiCl (5.0 equiv), Et3N (2.1 mL/mmol) and 1-methoxy-4-vi-
nylbenzene (6.0 equiv) under argon atmosphere. The mixture was
stirred at 80 °C for 16 h. After cooling to r.t. the mixture was diluted
with water (~21 mL/mmol) and extracted with EtOAc (~50
mL/mmol). The combined organic layers were dried with Na2SO4,
filtered and evaporated under reduced pressure. The obtained crude
product was purified by column chromatography.
2-Methyl-6-(thiophen-2-yl)pyridin-4-yl Nonaflate (9c)
According to general procedure 1, (Z)-N-(4-oxopent-2-en-2-
yl)thiophene-2-carboxamide (8c; 248 mg, 1.19 mmol) was treated
with i-Pr2NEt (0.83 mL, 4.76 mmol) and TMSOTf (1.08 mL, 5.95
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 1100–1106

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M. Domínguez, H.-U. Reissig
PAPER
(E)-4-(4-Methoxystyryl)-2-methyl-6-(thiophen-2-yl)pyridine
(11c)
CuI (~2.5 mol%), and triisopropylsilylacetylene (1.2 equiv) under
argon atmosphere. The mixture was stirred at 80 °C for 4 h. After
cooling to r.t., the mixture was diluted with water (~15 mL/mmol)
and extracted with EtOAc (3 × ~30 mL/mmol). The combined or-
ganic layers were dried with Na2SO4, filtered and evaporated under
reduced pressure. The obtained crude product was purified by col-
umn chromatography.
According to general procedure 3, 2-methyl-6-(thiophen-2-yl)pyri-
din-4-yl nonaflate (9c; 400 mg, 0.85 mmol) was treated with
Pd(OAc)2 (12 mg, 0.05 mmol), LiCl (180 mg, 4.25 mmol), Et3N
(1.8 mL) and 1-methoxy-4-vinylbenzene (0.70 mL, 5.22 mmol) in
DMF (3.6 mL). The obtained crude product was purified by column
chromatography on silica gel (hexanes–EtOAc = 20:1) to provide
compound 11c (221 mg, 85%) as a yellow oil.
2-Methyl-6-(thiophen-2-yl)-4-[(triisopropylsilyl)ethynyl]pyri-
dine (13c)
IR (ATR): 3010–2840 (=C–H, C–H), 1600 (C=C), 1510 (C=N),
1250 cm–1 (C–O–CH3).
According to general procedure 5, 2-methyl-6-(thiophen-2-yl)pyri-
din-4-yl nonaflate (9c; 70 mg, 0.15 mmol) was treated with
[PdCl2(PPh3)2] (6 mg, 8 μmol), CuI (1 mg, 5 μmol), and triisopro-
pylsilylacetylene (33 mg, 0.18 mmol) in Et3N (0.5 mL). The ob-
tained crude product was purified by column chromatography on
silica gel (hexanes–EtOAc = 20:1) to provide compound 13c (51
mg, 96%) as a yellow oil.
1H NMR (CDCl3, 400 MHz): δ = 2.04 (s, 3 H, CH3), 3.84 (s, 3 H,
OCH3), 6.88 (d, J = 16.3 Hz, 1 H, PyCH=), 6.92 (d, J = 8.8 Hz, 2 H,
Ar), 7.08–7.09 (m, 1 H, 3-H), 7.11 (dd, J = 5.1, 3.7 Hz, 1 H, Thio-
3-H), 7.27 (d, J = 16.3 Hz, 1 H, PyCH=CH), 7.35–7.39 (m, 1 H,
Thio-5-H), 7.47–7.52 (m, 3 H, Ar, Thio-3-H) 7.60–7.64 (m, 1 H,
5-H).
13C NMR (CDCl3, 101 MHz): δ = 24.6 (q, CH3), 55.3 (q, OCH3),
100.0, 108.6 (2 d, Thio-C-3, -C-4), 112.0, 113.2, 114.8, 118.8 (4 d,
C-3, C-5, Ar, PyCH=), 124.7, 128.3, 129.0, 132.5 (s, 3 d, Ar,
PyCH=C, Thio-C-5), 143.2, 146.0, 149.3 (3 s, C-2, C-4, C-6),
158.8, 160.0 (2 s, Thio-C-1, Ar-C-1).
IR (ATR): 3200–2850 (=C–H, C–H), 2100 (C≡C), 1595 (C=C),
1535 (C=N), 1440, 1220 cm–1.
1H NMR (CDCl3, 400 MHz): δ = 1.13–1.17 (m, 21 H, TIPS), 2.55
(s, 3 H), 7.04–7.06 (m, 1 H, 5-H), 7.09 (dd, J = 5.0, 3.7 Hz, 1 H,
Thio-4-H), 7.37 (dd, J = 5.0, 1.2 Hz, 1 H, Thio-5-H), 7.45–7.48 (m,
1 H, 3-H), 7.59 (dd, J = 3.7, 1.2 Hz, 1 H, Thio-3-H).
13C NMR (CDCl3, 101 MHz): δ = 11.3, 18.7 (q, d, TIPS), 24.4 (q,
CH3), 95.8, 104.6 (2 s, TIPS-C≡C), 118.2, 123.7, 124.9, 127.7,
128.1 (5 d, C-3, C-5, Thio-C-3, -C-4, -C-5), 132.2 (s, C-4), 144.6 (s,
Thio-C-2), 152.2, 158.6 (2 s, C-2, C-6).
HRMS (ESI-TOF): m/z calcd for C19H18NOS [M + H]+: 308.1104;
found: 308.1113.
Pd-Catalyzed Coupling of Pyridyl Nonaflates with 1-Ethynyl-4-
methoxybenzene; General Procedure 4
HRMS (ESI-TOF): m/z calcd for C21H30NSSi [M + H]+: 356.1863;
found: 356.1863.
Dry DMF (~4.6 mL/mmol) was transferred to a Schlenk flask
charged with the 4-pyridyl nonaflate (1.0 equiv), Pd(OAc)2 (7
mol%), CuI (5 mol%), Ph3P (25 mol%), i-Pr2NH (2.3 mL/mmol)
and 1-ethynyl-4-methoxybenzene (1.2 equiv) under argon atmo-
sphere. The mixture was stirred at 80 °C for 16 h. After cooling to
r.t., the mixture was diluted with water (~23 mL/mmol) and extract-
ed with EtOAc (3 × ~50 mL/mmol). The combined organic layers
were dried with Na2SO4, filtered and evaporated under reduced
pressure. The obtained crude product was purified by column chro-
matography.
TIPS-Deprotection of [(TIPS)ethynyl]pyridines; General Pro-
cedure 6
TBAF (~2.0 equiv) was transferred to a Schlenk flask charged with
the [(triisopropylsilyl)ethynyl]pyridine (1.0 equiv) in dry THF
(~2.0 mL/mmol) at r.t. under argon atmosphere. After 30 min, the
reaction mixture was diluted with water (~10 mL/mmol) and ex-
tracted with CH2Cl2 (3 × 30 mL/mmol). The combined organic lay-
ers were dried with Na2SO4, filtered and evaporated under reduced
pressure. The obtained crude product was purified by flash chroma-
tography.
4-[(4-Methoxyphenyl)ethynyl]-2-methyl-6-(thiophen-2-yl)pyri-
dine (12c)
According to general procedure 4, 2-methyl-6-(thiophen-2-yl)pyri-
din-4-yl nonaflate (9c; 400 mg, 0.85 mmol) was treated with
Pd(OAc)2 (14 mg, 0.06 mmol), CuI (9 mg, 0.05 mmol), Ph3P (56
mg, 0.214 mmol), i-Pr2NH (2.0 mL) and 1-ethynyl-4-methoxyben-
zene (135 mg, 1.02 mmol) in DMF (4.0 mL). The obtained crude
product was purified by column chromatography on silica gel (hex-
anes–EtOAc = 40:1) to provide compound 12c (205 mg, 79%) as a
yellow oil.
4-Ethynyl-2-methyl-6-(thiophen-2-yl)pyridine (14c)
According to general procedure 6, 2-methyl-6-(thiophen-2-yl)-4-
[(triisopropylsilyl)ethynyl]pyridine (13c; 50 mg, 0.14 mmol) was
treated with TBAF (0.3 mL, 1 M in THF) in dry THF (0.3 mL). The
obtained crude product was purified by flash chromatography on
silica gel (hexanes–EtOAc = 20:1) to provide compound 14c (27
mg, 97%) as a yellow oil.
IR (ATR): 3300–2860 (=C–H, C–H), 2095 (C≡C), 1595 (C=C),
IR (ATR): 3030–2840 (=C–H, C–H), 2105 (C≡C), 1600 (C=C),
1540 (C=N), 1460, 1220 cm–1.
1500 (C=N), 1280 cm–1 (C–O–CH3).
1H NMR (CDCl3, 400 MHz): δ = 2.52 (s, 3 H, CH3), 3.24 (s, 1 H,
CH), 7.02–7.04 (m, 1 H, 5-H), 7.04–7.09 (m, 1 H, Thio-4-H), 7.33–
7.38 (m, 1 H, Thio-5-H), 7.48 (s, 1 H, 3-H), 7.52–7.56 (m, 1 H,
Thio-3-H).
13C NMR (CDCl3, 101 MHz): δ = 24.4 (q, CH3), 68.0 (s, C≡CH),
81.3 (d, C≡CH), 118.4, 123.7, 124.9, 127.8, 128.1 (5 d, C-3, C-5,
Thio-C-3, -C-4, -C-5), 131.0 (s, C-4), 144.4 (s, Thio-C-2), 152.3,
158.7 (2 s, C-2, C-6).
1H NMR (CDCl3, 400 MHz): δ = 2.57 (s, 3 H, CH3), 3.84 (s, 3 H,
OCH3), 6.88−6.92 (m, 2 H, Ar), 7.09 (d, J = 1.2 Hz, 1 H, 3-H),
7.10−7.12 (m, 1 H, Thio-3-H), 7.38 (d, J = 5.1, 1.1 Hz, 1 H, Thio-
4-H), 7.48−7.51 (m, 2 H, Ar), 7.54 (d, J = 1.2 Hz, 1 H, 5-H),
7.57−7.61 (m, 1 H, Thio-5-H).
13C NMR (CDCl3, 101 MHz): δ = 24.7 (q, CH3), 55.4 (q, OCH3),
86.1 (s, PyC≡), 113.9, 114.4 (s, d, Ar, PyC≡C), 100.3, 108.9 (2 d,
Thio-C-3, -C-4), 113.0, 118.9, 119.5 (s, 2 d, Ar, C-3, C-5), 132.0,
132.9, 133.5 (s, 2 d, C-4, Thio-C-5, Ar), 157.0, 158.0, 159.3, 160.2
(4 s, C-2, C-6, Thio-C-1, Ar-C-1).
HRMS (ESI-TOF): m/z calcd for C12H10NS [M + H]+: 200.0528;
found: 200.0533.
HRMS (ESI-TOF): m/z calcd for C19H16NOS [M + H]+: 306.0947;
found: 306.0956.
1,4-Bis[(2,6-dimethylpyridin-4-yl)ethynyl]benzene (15)
Dry Et3N (4.0 mL) was transferred to a Schlenk flask charged with
the 4-ethynyl-2,6-dimethylpyridine (14a; 100 mg, 0.76 mmol),
Pd(PPh3)4 (88 mg, 0.08 mmol), CuI (8 mg, 0.04 mmol), 1,4-diiodo-
benzene (302 mg, 0.92 mmol) under an argon atmosphere. The mix-
ture was stirred at 80 °C for 16 h. After cooling to r.t., the mixture
Pd-Catalyzed Coupling of Pyridyl Nonaflates with TIPS-acetyl-
ene; General Procedure 5
Dry Et3N (~3 mL/mmol) was transferred to a Schlenk flask charged
with the 4-pyridyl nonaflate (1.0 equiv), [PdCl2(PPh3)2] (~5 mol%),
Synthesis 2014, 46, 1100–1106
© Georg Thieme Verlag Stuttgart · New York

PAPER
New 4-Pyridyl Nonaflates as Precursors for Solvatochromic Dyes
1105
was diluted with water (20 mL) and extracted with CH2Cl2 (3 × 50
mL). The combined organic layers were dried with Na2SO4, filtered
and evaporated under reduced pressure. The obtained crude product
was purified by column chromatography on silica gel (hexanes–
EtOAc = 10:1 → 10:1) to provide compound 15 (231 mg, 90%) as
a light yellow solid; mp 171–173 °C.
Acknowledgment
Support from BECAS CHILE, the Dierks-von-Zweck-Stiftung
(Essen) (fellowships to M.D.), the Deutsche Forschungsgemein-
schaft and Bayer HealthCare is gratefully acknowledged. We also
thank Dr. Paul Hommes and Dr. Reinhold Zimmer for their help du-
ring preparation of the manuscript.
IR (ATR): 3100–2920 (=C–H, C–H), 2120 (C≡C), 1600 (C=C),
1540 (C=N), 1440, 1400, 1215 cm–1.
1H NMR (CDCl3, 400 MHz): δ = 2.51 (s, 12 H, CH3), 7.05–7.07 (m,
4 H, 3-H, 5-H), 7.48–7.52 (s, 4 H, C6H4).
13C NMR (CDCl3, 101 MHz): δ = 24.5 (q, CH3), 89.4 (s, Py-C≡C),
92.2 (s, Py-C≡C), 122.1, 123.0, 131.4, 131.9 (2 s, 2 d, C-4, C-3, C-
5, C6H4), 158.0 (s, C-2, C-6).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis. Included
are experimental procedures for the synthesis of compounds 6a,b,d,
8a,b,d–j, 9d–j, 10a,b,d,e, 11a,b,d, 12a,b,d, 13a,b,d–j, 14b,d–j as
well as copies of NMR spectra for all new compounds.SnuIpfooimpntgrirSatonIuigfop
r
t
iornat
HRMS (ESI-TOF): m/z calcd for C24H21N2 [M + H]+: 337.1699;
found: 337.1709.
References
4,4′-[1,4-Phenylenebis(ethyne-2,1-diyl)]bis(1,2,6-trimethylpyri-
din-1-ium) Triflate (16)
(1) (a) Reichardt, C. Chem. Rev. 1994, 94, 2319. (b) Rezende,
M. C. Encyclopedia of Supramolecular Chemistry; Taylor &
Francis: Boca Ratón, 2007, 1330.
(2) (a) El Seoud, O. A. Pure Appl. Chem. 2009, 81, 697.
(b) Martins, C. T.; Lima, M. S.; El Seoud, O. A. J. Org.
Chem. 2006, 71, 9068. (c) Millán, D.; Domínguez, M.;
Rezende, M. C. Dyes Pigments 2008, 77, 441. (d) Rezende,
M. C.; Oñate, R.; Núñez, G.; Domínguez, M.; Mascayano,
C. Dyes Pigments 2009, 83, 391.
(3) (a) Quintana, S. S.; Falcone, R. D.; Silber, J. J.; Correa, N.
M. ChemPhysChem 2012, 13, 115. (b) Durantini, A. M.;
Falcone, R. D.; Silber, J. J.; Correa, N. M. J. Phys. Chem. B
2011, 115, 5894. (c) Aliaga, C.; Briones, L.; Rezende, M. C.;
Tirapegui, C. J. Colloid Interface Sci. 2010, 349, 565.
(4) Morgan, M. T.; Carnaban, M. A.; Immoos, C. E.; Ribeiro, A.
A.; Finkelstein, S.; Lee, S. J.; Ginstaff, M. W. J. Am. Chem.
Soc. 2003, 125, 15485.
Methyl triflate (0.1 mL, 0.9 mmol) was slowly added to a Schlenk
flask charged with 1,4-bis[(2,6-dimethylpyridin-4-yl)ethynyl]ben-
zene (15; 100 mg, 0.30 mmol) in dry toluene (3.4 mL) at 0 °C under
argon atmosphere. The reaction mixture was allowed to warm up to
r.t. in 2 h, after filtration the crude product was washed with n-hex-
anes (2.0 mL) and EtOAc (2.0 mL). Compound 16 (195 mg, 98%)
was obtained as a light yellow solid; mp <300 °C.
IR (ATR): 3080 (=C–H, C–H), 2125 (C≡C), 1630, 1460, 1260 cm–1.
1H NMR (DMSO-d6, 500 MHz): δ = 2.80 (s, 12 H, CH3), 4.03 (s, 6
H, NCH3), 7.82, 8.09 (2 s, 3-H, 5-H, C6H4).
13C NMR (DMSO-d6, 126 MHz): δ = 21.7 (q, CH3), 40.9 (q, NCH3),
88.1 (s, Py-C≡C), 99.4 (s, Py-C≡C), 122.7, 128.7, 133.4 (s, 2 d,
C6H4, C-3, C-5), 137.1 (s, C-4), 156.8 (s, C-2, C-6).
19F NMR (DMSO-d6, 471 MHz): δ = –77.6 (s, CF3).
(5) (a) Zanotto, S. P.; Scremin, M.; Machado, C.; Rezende, M.
C. J. Phys. Org. Chem. 1993, 6, 637. (b) Rezende, M. C.;
Oñate, R.; Domínguez, M.; Millán, D. Spectrosc. Lett. 2009,
42, 81.
(6) Dimroth, K.; Reichardt, C.; Siepmann, T.; Bohlmann, F.
Liebigs Ann. Chem. 1963, 661, 1.
HRMS (ESI-TOF): m/z calcd for C28H26F6N2NaO6S2 [M + Na]+:
687.1029; found: 687.1002.
Anal. Calcd for C28H26F6N2O6S2 (664.6): C, 50.60; H, 3.94; N, 4.21;
S, 9.65. Found: C, 50.60; H, 3.96; N, 4.21; S, 9.67.
1,3,6,8-Tetrakis[(2,6-dimethylpyridin-4-yl)ethynyl]pyrene (18)
Dry DMF (2.0 mL) was transferred to a Schlenk flask charged with
4-ethynyl-2,6-dimethylpyridine (14a; 75 mg, 0.57 mmol),
[PdCl2(PPh3)2] (28 mg, 39 μmol), CuI (8 mg, 0.04 mmol), i-Pr2NH
(0.9 mL) and 1,3,6,8-tetrabromopyrene (17;17 49 mg, 0.095 mmol)
under argon atmosphere. The mixture was stirred at 90 °C for 18 h.
After cooling to r.t., the mixture was diluted with water (10 mL) and
the resulting suspension extracted with EtOAc (1 × 10 mL, discarded).
The remaining water phase was extracted with CH2Cl2 (ca. 40 × 30
mL) until no green extract was observed. The combined CH2Cl2
phases were dried with Na2SO4, filtered and evaporated under re-
duced pressure. The obtained crude product was washed succes-
sively with benzene, hexanes and EtOAc (3.0 mL each). As residue,
compound 18 (61 mg, 89%) was obtained as an orange solid; mp
<300 °C.
(7) Brooker, L. G. S.; Keyes, H.; Heseltine, D. W. J. Am. Chem.
Soc. 1951, 73, 5350.
(8) Diemer, V.; Chaumeil, H.; Defoin, A.; Jacques, P.; Carré, C.
Tetrahedron Lett. 2005, 46, 4737.
(9) For a general view about this phenomenon, see:
(a) Reichardt, C.; Welton, T. Solvents and Solvent Effects in
Organic Chemistry, 4th ed.; Wiley-VCH: Weinheim, 2011,
359. For reviews on the behavior of compounds such as 1
see: (b) Reichardt, C. Pure Appl. Chem. 2004, 76, 1903.
(c) Reichardt, C. Pure Appl. Chem. 2008, 80, 1415.
(d) Kharlanov, V.; Rettig, W. J. Phys. Chem. A 2009, 113,
10693. For further details about the behavior of compounds
like 3, see: (e) Jacques, P.; Graff, B.; Diemer, V.; Ay, E.;
Chaumeil, H.; Carré, C.; Malval, J.-P. Chem. Phys. Lett.
2012, 531, 242.
(10) (a) Katritzky, A. R.; Zakaria, Z.; Lunt, E. J. Chem. Soc.,
Perkin Trans. 1 1980, 1879. (b) Kjaer, A. M.; Ulstrup, J.
J. Am. Chem. Soc. 1988, 110, 3874. (c) Reichardt, C.;
Eschner, M.; Schäfer, G. J. Phys. Org. Chem. 2001, 14, 737.
(d) Reichardt, C.; Che, D.; Hackenkemper, G.; Schäfer, G.
Eur. J. Org. Chem. 2001, 2343. (e) Tsubaki, K.; Morimoto,
T.; Otsubo, T.; Fuji, K. Org. Lett. 2002, 4, 2301.
(f) Reichardt, C.; Röchling, A.; Schäfer, G. J. Phys. Org.
Chem. 2003, 16, 682. (g) Shekhovtsov, S. V.; Omelchenko,
I. V.; Dyakomenko, V. V.; Shishkin, R. A.; Libor, T.;
IR (ATR): 3000–2920 (=C–H, C–H), 2110 (C≡C), 1600 (C=C),
1540 (C=N), 1440 cm–1.
1H NMR (CDCl3, 700 MHz): δ = 2.64 (s, 24 H, CH3), 7.27 (s, 8 H,
3-H, 5-H), 8.43 (s, 2 H, 2-H′, 7-H′), 8.70 (s, 4 H, 4-H′, 5-H′, 9-H′,
10-H′).
Due to the very poor solubility, the recording of a 13C NMR spec-
trum was not possible.
HRMS (ESI-TOF): m/z calcd for C52H39N4 [M + H]+: 719.3169;
found: 719.3190.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 1100–1106

1106
M. Domínguez, H.-U. Reissig
PAPER
Reichardt, C.; Mchedlov-Petrossyan, N. Dyes Pigments
2012, 92, 1394. (h) Gieling, R. G.; Babur, M.; Mamnani, L.;
Burrows, N.; Telfer, B. A.; Carta, F.; Winum, J.-Y.;
Scozzafava, A.; Supuran, C. T.; Williams, K. J. J. Med.
Chem. 2012, 55, 5591.
D.; Reissig, H.-U. J. Org. Chem. 2010, 75, 726. (g) Lechel,
T.; Dash, J.; Eidamshaus, C.; Brüdgam, I.; Lentz, D.;
Reissig, H.-U. Org. Biomol. Chem. 2010, 8, 3007. (h) Bera,
M. K.; Reissig, H.-U. Synthesis 2010, 2129. (i) Eidamshaus,
C.; Kumar, R.; Bera, M. K.; Reissig, H.-U. Beilstein J. Org.
Chem. 2011, 7, 962. (j) Hommes, P.; Jungk, P.; Reissig, H.-
U. Synlett 2011, 2311. (k) Hommes, P.; Berlin, S.; Reissig,
H.-U. Synthesis 2013, 45, 3288. (l) Bera, M. K.; Domínguez,
M.; Hommes, P.; Reissig, H.-U. Beilstein J. Org. Chem.
2014, 10, 394.
(11) (a) Arai, S.; Ymazaki, M.; Nagakura, K.; Ishikawa, M.;
Hida, M. J. Chem. Soc., Chem. Commun. 1983, 1037.
(b) van Gent, J.; Sudhölter, E. J. R.; Lambeck, P. V.; Popma,
T. J. A.; Gerritsma, G.; Reinhoudt, D. N. J. Chem. Soc.,
Chem. Commun. 1988, 893. (c) Wang, L.-Y.; Zhang, X.-G.;
Shi, Y.-P.; Zhang, Z.-X. Dyes Pigments 2004, 62, 21.
(d) García-Acosta, B.; Martínez-Máez, R.; Ros-Lis, J. V.;
Sancenón, F.; Soto, J. Tetrahedron Lett. 2008, 49, 1997.
(e) Kolev, T.; Koleva, B. B.; Stoyanov, S.; Spiteller, M.;
Petkov, I. Spectrochim. Acta A: Mol. Biomol. Spectrosc.
2008, 70, 1087. (f) Zimmermann-Dimer, L. M.; Reis, D. C.;
Machado, C.; Machado, V. G. Tetrahedron 2009, 65, 4239.
(g) Posada, P.; Braña, M. F.; Villarino, A. L.; Domínguez,
V.; Ortuño, I.; Martínez, C. J. Heterocycl. Chem. 2011, 48,
549. (h) Karton-Lifshin, N.; Albertazzi, L.; Bendikov, M.;
Baran, P. S.; Shabat, D. J. Am. Chem. Soc. 2012, 134, 20412.
(i) Iliopulos, G. K.; Todorova, M.; Bakalska, R.; Penchev,
P.; Sotirov, S.; Kolev, T.; Serbezov, V.; Arbaoui, A.;
Bakasse, M.; Sahraoui, B. J. Phys. Chem. C 2012, 116, 7144.
(12) (a) Flögel, O.; Dash, J.; Brüdgam, I.; Hartl, H.; Reissig, H.-
U. Chem. Eur. J. 2004, 10, 4283. (b) Dash, J.; Lechel, T.;
Reissig, H.-U. Org. Lett. 2007, 9, 5541. (c) Lechel, T.; Dash,
J.; Brüdgam, I.; Reissig, H.-U. Eur. J. Org. Chem. 2008,
3647. (d) Eidamshaus, C.; Reissig, H.-U. Adv. Synth. Catal.
2009, 351, 1162. (e) Dash, J.; Reissig, H.-U. Chem. Eur. J.
2009, 15, 6811. (f) Lechel, T.; Dash, J.; Hommes, P.; Lentz,
(13) For a review about the advantages of alkenyl and aryl
nonaflates in transition-metal-catalyzed reactions, see:
(a) Högermeier, J.; Reissig, H.-U. Adv. Synth. Catal. 2009,
351, 2747. For recent examples utilizing pyrid-4-yl
nonaflates, see: (b) Bera, M. K.; Hommes, P.; Reissig, H.-U.
Chem. Eur. J. 2011, 17, 11838. (c) Eidamshaus, C.;
Hommes, P.; Reissig, H.-U. Synlett 2012, 23, 1670.
(d) Gholap, S. L.; Hommes, P.; Neuthe, K.; Reissig, H.-U.
Org. Lett. 2013, 15, 318. (e) Bera, M. K.; Gholap, S. L.;
Hommes, P.; Neuthe, K.; Trawny, D.; Rabe, J. P.; Lentz, D.;
Zimmer, R.; Reissig, H.-U. Adv. Synth. Catal. 2013, 355,
3463.
(14) Gao, Y.; Zhang, Q.; Xu, J. Synth. Commun. 2004, 34, 909.
(15) Akiba, K.; Kashiwagi, K.; Ohyama, Y.; Yamamoto, Y.;
Ohkata, K. J. Am. Chem. Soc. 1985, 107, 2721.
(16) (a) Zeng, F.; Zimmerman, S. C.; Kolotuchin, S.; Reichert, D.
E. C.; Ma, Y. Tetrahedron 2002, 58, 825. (b) Prühs, C.;
Kunick, C. Bioorg. Med. Chem. Lett. 2007, 17, 1850.
(17) Bernhardt, S.; Kastler, M.; Enkelmann, V.; Baumgarten, M.;
Müllen, K. Chem. Eur. J. 2006, 12, 6117.
Synthesis 2014, 46, 1100–1106
© Georg Thieme Verlag Stuttgart · New York