One-Pot Coupling-Coupling-Cyclocondensation Synthesis of Fluorescent Pyrazoles

Article abstract of DOI:10.1021/acs.joc.6b01326

Consecutive four-component coupling-coupling-cyclocondensation syntheses of pyrazoles and pyrimidines were developed by taking advantage of the provisional, sequentially Pd-catalyzed one-pot generation of alkynones from aryl iodides, ethynylmagnesium bromide, and acid chlorides. This one-pot methodology allows the concise, diversity-oriented generation of a set of donor-, acceptor-, and donor-acceptor-substituted pyrazoles, which are interesting fluorophores. Most distinctly, donor-acceptor pyrazoles display remarkably red-shifted emission maxima and pronounced positive solvochromicity, spanning an overall range from 363 nm (cyclohexane) to 595 nm (acetonitrile). DFT and TD-DFT calculations elucidate the electronic structure and the photophysical behavior. Upon photonic excitation, considerable charge-transfer character becomes apparent, which rationalizes the origin of huge Stokes shifts and solvochromic behavior.

Full text of DOI:10.1021/acs.joc.6b01326

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Article
One-Pot Coupling-Coupling-Cyclocondensation
Synthesis of Fluorescent Pyrazoles
Alissa C. Götzinger, Florian A. Theßeling, Corinna Hoppe, and Thomas J. J. Mueller
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01326 • Publication Date (Web): 12 Jul 2016
Downloaded from http://pubs.acs.org on July 12, 2016
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OneꢀPot CouplingꢀCouplingꢀCyclocondensation Synthesis of Fluorescent Pyrazoles
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Alissa C. Götzinger, Florian A. Theßeling, Corinna Hoppe, and Thomas J. J. Müller ∆ *
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Institut für Organische Chemie und Makromolekulare Chemie, HeinrichꢀHeineꢀUniversität
Düsseldorf, Universitätsstraße 1, Dꢀ40225 Düsseldorf, Germany.
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ABSTRACT
Consecutive fourꢀcomponent couplingꢀcouplingꢀcyclocondensation syntheses of pyrazoles and
pyrimidines were developed by taking advantage of the provisional, sequentially Pdꢀcatalyzed oneꢀpot
generation of alkynones from aryl iodides, ethynyl magnesium bromide, and acid chlorides. This oneꢀ
pot methodology allows the concise, diversityꢀoriented generation of a set of donor, acceptor, and
donorꢀacceptor substituted pyrazoles, which are interesting fluorophores. Most distinctly, donorꢀ
acceptor pyrazoles display remarkably redꢀshifted emission maxima and pronounced positive
solvochromicity, spanning an overall range from 363 nm (cyclohexane) to 595 nm (acetonitrile). DFT
and TDꢀDFT calculations elucidate the electronic structure and the photophysical behavior. Upon
photonic excitation, a considerable chargeꢀtransfer character becomes apparent, which rationalizes the
origin of huge Stokes shifts and solvochromic behavior.
Introduction
Pyrazoles possess interesting photophysical properties as UV absorbers1 and have received
considerable attention in technological applications, e.g. as optical brighteners in detergents,2 UVꢀ
stabilizers for polystyrene,3 and highly selective fluorescence sensors.4 Furthermore, pyrazoles often
display blue emission and large Stokes shifts, which makes them particularly interesting for OLED
technologies.5 In addition, applications of pyrazoles in dyeꢀsensitized solar cells6 and in nonlinear
optics1a, 1b have been considered. Therefore, novel syntheses of pyrazoles remain highly attractive
evergreens in heterocyclic chemistry.
Challenged by the photophysical profile of pyrazoles as fluorophores and the ongoing mission to
access tailorꢀmade πꢀsystems by diversityꢀoriented syntheses (DOS)7 such as multicomponent
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reactions (MCR),8 we have developed regioselective consecutive threeꢀ and fourꢀcomponent
Sonogashira couplingꢀcyclocondensation(ꢀcoupling) syntheses of fluorescent 1,3,5ꢀtrisubstitued and
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1,3,4,5ꢀtetrasubstitued pyrazoles in a oneꢀpot fashion. In this context we could probe and efficiently
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illustrate the concept of sequentially Pdꢀcatalyzed processes10 for oneꢀpot syntheses of pyrazoles9a by
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concatenating Sonogashira and Suzuki coupling in
cyclocondensation.
a
oneꢀpot fashion intercepted by
Alkynones are particularly useful electrophilic threeꢀcarbon building blocks in the synthesis of
heterocyclic compounds.11 We have very recently reported a sequentially palladiumꢀcatalyzed
synthesis of alkynones 4 from aryl iodides 1 by in situ generation of terminal alkynes via a Kumadaꢀ
type coupling with ethynyl magnesium bromide (2)12 followed by a sequentially Pdꢀcatalyzed
Sonogashira coupling with aroyl chlorides 3 (Scheme 1).13
The modular, diversityꢀoriented, and catalystꢀeconomical nature of this sequence allows for quick and
convenient synthesis of diversely substituted examples, combining short reaction times, easy work up
and readily available starting materials.
Scheme 1. Sequentially Pdꢀcatalyzed threeꢀcomponent KumadaꢀSonogashira synthesis of
alkynones 4 (ac0(1a) = 0.42
M
).13
Here we report the concatenation of this sequentially Pdꢀcatalyzed alkynone formation with
cyclocondensation, giving direct access to functional heterocycles in the sense of a consecutive fourꢀ
component couplingꢀcouplingꢀcyclocondensation process. In addition, photophysical properties and
studies on the electronic structure of selected novel 1,3,5ꢀtrisubstituted pyrazoles are reported and
discussed.
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Results and Discussion
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Synthesis. We first set out to investigate the consecutive fourꢀcomponent synthesis of pyrazoles 6. As
shown in previous couplingꢀcyclocondensation studies, the cyclocondensation step can be
considerably accelerated using microwave irradiation in the presence of acetic acid and methanol as a
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polar cosolvent.9, Extensive optimization studies, particularly on the conditions of the terminal
cyclocondensation, were conducted employing 4ꢀiodoanisole (1a), ethynyl magnesium bromide (2),
benzoyl chloride (3a), and methyl hydrazine (5a) to give 5ꢀ(4ꢀmethoxyphenyl)ꢀ1ꢀmethylꢀ3ꢀphenylꢀ1Hꢀ
pyrazole (6a) as a model reaction (
Scheme 2). Most importantly, the presence of magnesium ions considerably hampered the
cyclocondensation with methyl hydrazine (3a), presumably due to competing coordination. This
problem was solved by employing a slight excess of hydrazine 3a and by addition of phenanthroline as
a coordinating ligand for Mg2+. Consequently, model pyrazole 6a could be isolated in 77% yield.
Scheme 2. Optimized conditions for the fourꢀcomponent synthesis of pyrazole 6a (ac0(1a) = 0.42
M
. bV(MeOH) = V(AcOH) = 0.4 mL/mmol).
With these modified conditions in hand, the consecutive fourꢀcomponent couplingꢀcouplingꢀ
cyclocondensation synthesis of 3,5ꢀdiarylpyrazoles 6 was illustrated in 17 preparative examples,
furnishing the title compounds in moderate to very good yields (Table 1).
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Table 1. Consecutive fourꢀcomponent couplingꢀcouplingꢀcyclocondensation synthesis of
pyrazoles 6 from aryl iodides 1, ethynyl magnesium bromide (2), aroyl chlorides 3, and
6
7
hydrazines 5 (ac0(1a) = 0.42
M
. bV(MeOH) = V(AcOH) = 0.4 mL/mmol).
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Entry
1
aryl1
aryl2
R1
Pyrazole 6 [yield][a]
6a (77%)[b]
6b (68%)
6c (68%)
4ꢀMeOC6H4
4ꢀMeOC6H4
4ꢀClC6H4
4ꢀClC6H4
4ꢀClC6H4
Ph
Ph
Me
H
2
Ph
3
Ph
Me
Me
H
4
4ꢀTol
Ph
6d (59%)
6e (64%)
5
6
4ꢀTol
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
6f (79%)
7
2ꢀnaphthyl
OCF3
6g (70%)[b]
6h (58%)
6i (72%)
8
Ph
9
Ph
Ph
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Ph
4ꢀF3CC6H4
4ꢀNCC6H4
4ꢀF3CC6H4
4ꢀNCC6H4
Ph
6j (44%)
Ph
6k (35%)
6l (58%)
4ꢀMeOC6H4
4ꢀMeOC6H4
Me2NC6H4
Me2NC6H4
Me2NC6H4
4ꢀMeOC6H4
6m (43%)
6n (60%)
6o (58%)
6p (60%)
6q (47%)[c]
4ꢀF3CC6H4
4ꢀNCC6H4
Ph
[a]Isolated yield (after chromatography on silica gel). [b]Regioisomeric ratio of 10:1 (determined by
1H NMR). [c]Regioisomeric ratio of 1:2 (determined by 1H NMR).
In most cases the synthesis is completely regioselective, only for a few derivatives the corresponding
regioisomer placing aryl1 in position 3 is obtained as a side product (Table 1, entries 1 and 7). The
modular nature of the reaction allows introducing a variety of aryl substituents bearing electronꢀ
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donating as well as electronꢀwithdrawing substituents. Employing phenyl hydrazine, a 1:2 mixture of
regioisomers is obtained. As previously shown for aryl hydrazines, the Michael attack of the terminal
hydrazine nitrogen atom becomes prevalent due to the reduced electron density at the internal nitrogen
atom, in contrary to the behavior of aliphatic hydrazines.9b
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When 1,4ꢀdiiodobenzene (1b) is employed as an aryl iodide, 1,4ꢀbis(1ꢀmethylꢀ3ꢀphenylꢀ1Hꢀpyrazolꢀ5ꢀ
yl)benzene (6r) can be obtained in 57% yield (Scheme 3). Taking into account that eight bonds are
formed in a pseudoꢀseven component fashion the average yield per bond forming step accounts to
93%.
2.40 equiv ethynylꢀMgBr (2)
10.0 mol% PdCl2(PPh3)2
THFa, 45 °C, 30 min
then: 0.600 equiv NEt3—HCl
2.60 equiv PhCOCl (3a)
2.10 equiv NEt3
Ph
Ph
10.0 mol% CuI, 45 °C, 1 h
I
I
N
N
then: 3.00 equiv MeNHNH2 (5a)
4.00 equiv phen
N
N
Me
Me
AcOH/MeOHb
1b
6r (57%)
MW, 150 °C, 15 min
Scheme 3. Pseudoꢀseven component couplingꢀcouplingꢀcyclocondensation synthesis of 1,4ꢀbis(1ꢀ
methylꢀ3ꢀphenylꢀ1Hꢀpyrazolꢀ5ꢀyl)benzene (6r) from 1,4ꢀdiiodobenzene (1a), ethynyl magnesium
b
bromide (2), benzoyl chloride (3a), and methyl hydrazine (5a) (ac0(1a) = 0.21
= V(AcOH) = 0.8 mL/mmol). phen: phenanthroline (ligand).
M
. V(MeOH)
We could also establish a consecutive fourꢀcomponent couplingꢀcouplingꢀcyclocondensation synthesis
of 2,4,6ꢀtriarylꢀsubstituted pyrimidine derivatives by employing benzamidinium chloride (7) as a
precursor of the bifunctional nucleophile (Table 2).15
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Table 2. Consecutive fourꢀcomponent couplingꢀcouplingꢀcyclocondensation synthesis of
pyrimidines 8 from aryl iodides 1, ethynyl magnesium bromide (2), aroyl chlorides 3, and
6
7
benzamidine hydrochloride (7) (ac0(1a) = 0.42
M
. bV(H3C(CH2)2OH) = 2.0 mL/mmol).
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1.20 equiv ethynylꢀMgBr (2)
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5.00 mol% PdCl2(PPh3)2, THFa, 45 °C, 30 min
then: 0.300 equiv NEt3—HCl
aryl1
aryl2
1.30 equiv aryl2COCl 3, 1.05 equiv NEt3
5.00 mol% CuI, 45 °C, 1 h
N
N
aryl1
I
then: 2.00 equiv benzamidine—HCl (7)
Ph
2.50 equiv K2CO3, H3CO(CH2)2OHb, 90 °C, 16 h
1
8
Product
aryl1
aryl2
Ph
Yield (%)[a]
4ꢀMeOC6H4
4ꢀTol
51
43
46
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49
8a
8b
8c
8d
8e
8f
Ph
2ꢀnaphthyl
4ꢀF3CC6H4
4ꢀClC6H4
4ꢀBrC6H4
4ꢀTol
Ph
Ph
3ꢀClC6H4
[a]After chromatography on silica gel and recrystallization, if necessary.
The use of microwave irradiation did not prove to be beneficial; neither did the addition of
phenanthroline as a ligand for Mg2+. Conventional heating for 16 h at 90 °C (oil bath) with two
equivalents of benzamidine hydrochloride (7) in the presence of potassium carbonate and 2ꢀ
methoxyethanol as a polar cosolvent turned out to be most favorable. Under these conditions, six
pyrimidine derivatives 8 were obtained in moderate yields.
Photophysical properties of pushꢀpull substituted pyrazoles. Previous studies on 3,5ꢀdiaryl
pyrazoles have shown interesting photophysical properties,9a especially for donorꢀacceptor substituted
diaryl methylpyrazoles, which display bathochromically shifted emission maxima and large Stokes
shifts.9b Due to the polar auxochrome and antiꢀauxochrome substituents, solvochromic emission
properties can also be expected.
For a more systematic treatment of this phenomenon, various combinations of donor and acceptor
substituents were considered. While 4ꢀmethoxyꢀ and 4ꢀdimethylaminophenyl as donors at position 5
were introduced by aryl iodide 1, 4ꢀcyanobenzoyl chloride and 4ꢀ(trifluoromethyl)benzoyl chloride
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enabled access to the corresponding 3ꢀacceptorꢀsubstituted pyrazoles. In each case, the synthesized
corresponding donor (6a, 6n), acceptor (6j, 6k), and donorꢀacceptor substituted (6l, 6m, 6o, 6p)
pyrazole derivatives were characterized by absorption and emission spectroscopy (Table 3).
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Table 3. Selected UV/Vis absorption and emission data of pyrazoles 6a, 6i–6p.
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Structure
λmax,Abs [nm] (ε [Mꢀ1cmꢀ1])[a]
257 (37640)
λmax,Em [nm] (ΦF)[b,c]
333 (0.21)
ꢀν̃
[cmꢀ1]
8900
6a
6i
254 (33534)
338 (0.42)
9800
260 (20709)
341 (0.52)
9100
6j
282 (27398)
348 (0.70)
6700
6k
6l
262 (34792)
367 (0.20)
10900
10300
8300
281 (35307)
394 (0.30)
6m
6n
6o
6p
280 (29184)
365 (0.06)
283 (31218)
448 (0.11)
13000
292 (40062)
499 (0.21)
14100
[a]Recorded in dichloromethane, T = 293 K, c(6) = 10ꢀ5 M.[b]Recorded in dichloromethane, T = 293 K,
c(6) = 10ꢀ7 M. [c]Fluorescence quantum yields were determined relative to diphenyloxazole (ΦF =
0.84)16 as a standard in cyclohexane.
The absorption maximum of the parent compound, diphenyl derivative 6i, lies at 254 nm. Generally,
separate donor as well as separate acceptor substitution leads to a modest bathochromic shift of the
longest wavelength absorption band. The absorption maxima of methoxy and trifluoromethyl
substituted derivatives 6a and 6j can be found at 257 and 260 nm, respectively, while 6k and 6n,
carrying a cyano and a dimethylamino group, exhibit absorption maxima at 282 nm and 280 nm.
However, the absorption maximum of pushꢀpull substituted derivative 6p bearing both a
dimethylamino and a cyano moiety is most bathochromically shifted. Figure 1 shows the absorption
and emission spectra of donorꢀacceptor substituted pyrazoles 6l, 6m, 6o, and 6p.
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Figure 1. UV/Vis absorption (solid lines) and emission (dashed lines) spectra of donorꢀacceptor
substituted pyrazoles 6l, 6m, 6o, and 6p. Recorded in dichloromethane, T = 293 K.
The emission maximum of parent diphenyl derivative 6i lies at 338 nm with a Stokes shift of
9800 cmꢀ1. Introduction of the weaker methoxy donor (6a) or trifluoromethyl acceptor (6j) only
moderately affects the emission energy, while introduction of the strong dimethylamino donor (6n)
leads to a substantial bathochromic shift to 365 nm. Acceptor substituted pyrazole 6k bearing the
stronger cyano moiety also shows a redꢀshifted maximum at 348 nm. In these cases, smaller Stokes
shifts can be found since the shift in absorption is more pronounced than that in emission. Methoxy
substituted derivatives 6l and 6m with a trifluoromethyl or cyano acceptor functionality exhibit a
stronger bathochromic shift to 367 and 394 nm, respectively, while pushꢀpull systems 6o and 6p
carrying a dimethylamino donor functionality create the strongest red shifts with emission maxima at
448 and 499 nm. In these cases, extraordinarily large Stokes shifts of 13000 cmꢀ1 and 14100 cmꢀ1 can
be determined. The decadic molar extinction coefficients of the absorption bands lie between 20000
and 40000 Mꢀ1cmꢀ1, with the strongest absorption for pushꢀpull derivative 6p. Dimethylamino
substituted compound 6n is the only one to exhibit a second, longer wavelength emission maximum at
489 nm, which probably stems from a twisted intramolecular charge transfer.17 Relative fluorescence
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quantum yields18 were measured with diphenyloxazole as a standard in cyclohexane (ΦF = 0.84)16 and
a variation with donor and acceptor strength is observed. Introduction of donor substituents appears to
have a detrimental effect on quantum yield, with only 6% for dimethylamino substituted derivative 6n.
Acceptor substitution, however, appears to increase fluorescence efficiency, so that the highest relative
quantum yield of 70% can be found for cyano substituted derivative 6k.
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Intrigued by the strongly redꢀshifted emission, we undertook solvochromicity studies with
dimethylaminoꢀcyano substituted pyrazole 6p to scrutinize the effect of the solvent environment on its
absorption and emission properties. It is evident upon eyesight that compound 6p exhibits a positive
emission solvatochromism, i. e. the emission is shifted bathochromically with increasing solvent
polarity (Figure 2).
Figure 2. Fluorescence of 6p with variable solvent polarity (left to right: cyclohexane, toluene, ethyl
acetate, dichloromethane, N,Nꢀdimethyl formamide, acetonitrile; λexc = 365 nm, handꢀheld UV lamp).
This effect was further investigated by recording absorption and emission spectra in solvents with
different solvent polarity (Figure 3). Interestingly, the absorption maximum exhibits no
solvatochromicity, with the maximum remaining almost unchanged at between 298 and 295 nm. On
the other hand, the influence of the solvent polarity on the emission maximum is very pronounced,
with maxima ranging from 362 nm in cyclohexane to 595 nm in acetonitrile (Table 4). This positive
solvatochromism correlates with a considerable increase of the dipole moment upon photonic
excitation.19
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Figure 3. UV/Vis absorption in dichloromethane (solid line) and emission (dashed lines) spectra in
seven solvents of different polarity (recorded at T = 293 K).
Table 4. UV/vis absorption and emission data for 6p in seven solvents of different polarity.
Solvent
λmax,Abs [nm]
288
λmax,Em [nm]
363
ꢀν̃
[cmꢀ1]
cyclohexane
toluene
7200
292
410
9900
diethyl ether
ethyl acetate
dichloromethane
N,Nꢀdimethyl formamide
acetonitrile
289
429
11300
13700
13900
16900
17400
290
481
294
498
295
590
292
595
Plotting the Stokes shifts Δν̃ against the orientation polarizabilities ꢀf of the respective solvent
(Lippert plot) furnished a good linear correlation with a fit of r2 = 0.92 (Figure 4). Orientation
polarizabilities ꢀf (Equation 1) were calculated according to
ꢋ
ꢃ ꢅꢆ
ꢊ ꢅꢆ
ꢄ
ꢀꢁ ꢂ ꢇꢃ ꢈꢆ ꢉ ꢇꢊ ꢈꢆ
(1)
ꢋ
r
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from the relative permittivity εr and the optical refractive index n of the respective solvent.
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Figure 4. Lippert plot for compound 6p (n = 7, r2 = 0.92).
The change in dipole moment from the ground to the excited state can be calculated using SI units in
the LippertꢀMataga equation (Equation 2)20
ꢇꢐꢏ
ꢖ
ꢚꢇ
ꢗꢘ ꢉ ꢗꢙ ꢛ ꢜꢝꢞꢟꢠ
ꢌꢍꢎ ꢉ ꢌꢍꢏ ꢂ
(2)
ꢕ
ꢑꢒꢃ0ꢓꢔꢎ
where ꢁνã and ꢁνf̃
represent the absorption and emission maxima (in mꢀ1), µE and µG are the dipole
moments in the excited and ground state (in Cm), ε0 (8.8542ꢂ10ꢀ12 AsVꢀ1mꢀ1) is the vacuum permittivity
constant, h (6.6256ꢂ10ꢀ34 Js) is Planck’s constant, c (2.9979ꢂ108 msꢀ1) is the speed of light and a is the
radius of the solvent cavity occupied by the molecule (in m).
The Onsager radius a, which is used to approximate the molecular volume of the molecule in solution,
was estimated from the optimized ground state structure obtained by DFT calculations. Using a value
of 8.7 Å (8.7 · 10ꢀ10 m), the change in dipole moment was calculated to ꢁ
ꢀ
= 46 D (1.54 · 10ꢀ28 Cm).
This remarkably large value corresponds to a pronounced charge separation.
Calculated Electronic Structure. The geometries of the electronic ground state structures were
optimized using Gaussian09 with the B3LYP functional21 and the Pople 6ꢀ311G* basis set.22 Since
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absorption and emission properties were measured in dichloromethane solutions, the Polarizable
Continuum Model (PCM) with dichloromethane as a solvent was employed.23 All minimum structures
were unambiguously assigned by analytical frequency analysis.
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Table 6 summarizes the calculated torsional angels for pyrazoles 6a, 6i–p.
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8
Table 5. TDꢀDFT calculations (CAMꢀB3LYP 6ꢀ311G(d,p)) of the absorption maxima for
pyrazoles 6a, 6i–6p.
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Structure Experimental λmax,abs Calculated
λmax,abs Most dominant contributions
[nm][a]
[nm]
257
250
HOMO → LUMO
(44%),
(46%),
6a
6i
HOMOꢀ1 → LUMO (41%)
HOMO → LUMO
254
248
235
HOMO → LUMO+1 (37%)
HOMOꢀ1 → LUMO
(46%),
(19%),
HOMO → LUMO
HOMOꢀ1 → LUMO+2 (10%)
HOMO → LUMO
260
282
262
281
280
257
274
257
275
266
(77%),
(82%),
(63%),
(61%),
6j
HOMOꢀ1 → LUMO (17%)
HOMO → LUMO
6k
6l
HOMOꢀ1 → LUMO (13%)
HOMOꢀ1 → LUMO
HOMO → LUMO (30%)
HOMOꢀ1 → LUMO
6m
6n
HOMO → LUMO (34%)
HOMOꢀ1 → LUMO
(65%),
(14%),
HOMO → LUMO
HOMO → LUMO+3 (12%)
HOMO → LUMO+1
HOMO → LUMO+3 (32%)
HOMO → LUMO
283
292
267
(44%),
(46%),
6o
6p
281
271
HOMOꢀ1 → LUMO (46%)
HOMO → LUMO
(27%),
(18%),
(18%),
HOMO → LUMO+1
HOMOꢀ1 → LUMO
HOMO → LUMO+3 (17%)
[a]Recorded in dichloromethane, T = 293 K, c(6) = 10ꢀ7 M.
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Figure 5. Optimized ground (bottom) and excited state (top) geometry at the B3LYP 6ꢀ311G level of
DFT theory for 6p.
In accordance with previous results,9a the calculated equilibrium ground state structures show that the
3ꢀaryl substituent (aryl1) adopts an almost coplanar orientation showing angles between 5 and 8°,
while the substituent at position 5 (aryl2) is distinctly twisted out of plane with torsional angels
between 45 and 47°. However, upon excitation the substituent aryl2 adopts a diminished torsional
angle in the excited state (Figure 5). These geometrical changes upon excitation from ground to
excited state already rationalize that in the excited state the overlap will be increased, eventually
favoring delocalization and ultimately associated with a pronounced charge transfer character.
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Table 6 summarizes the calculated equilibrium ground state and excited state structures for pyrazoles
6a, 6i–6p.
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Table 6. Calculated equilibrium ground state and excited state torsional angles for aryl
substituent at position 5 (aryl2) of pyrazoles 6a, 6i–6p.
6
7
8
Structure
ground state Θcalc (aryl2)
excited state (aryl2)
47°
46°
46°
46°
47°
47°
45°
46°
46°
0°
9
6a
6i
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20°
24°
26°
20°
19°
22°
26°
26°
6j
6k
6l
6m
6n
6o
6p
In addition, TDꢀDFT calculations were employed for determining and rationalizing the absorption
characteristics, again applying PCM with dichloromethane as a solvent. For calculation of the
absorption characteristics, the hybrid exchange correlation functional CAMꢀB3LYP was
implemented.24 The computed results are in good agreement with measured absorption maxima. In
cases where more than one excited state significantly contributes to absorption, both wavelengths are
stated (
Table 5).
In most cases, the computed KohnꢀSham frontier molecular orbitals show a distribution of coefficient
density over the whole system in the HOMO and a shift to the acceptorꢀsubstituted aryl moiety in the
LUMO. However, in the case of dimethylaminoꢀcyano substituted pyrazole 6p, transitions from
HOMO to LUMO and HOMOꢀ1 to LUMO contribute equally to the S1 state. Both, HOMO and
HOMOꢀ1 indicate a pronounced charge transfer character, though, in the HOMO the coefficient
density is predominantly localized on the pꢁdimethylamino phenyl donor, whereas the HOMOꢀ1
displays equal contributions on the pyrazole and the acceptor moiety (Figure 6). The LUMO possesses
dominant coefficient density on the pꢀcyano phenyl acceptor. Therefore, the central pyrazole core,
which bears substantial coefficient density in all involved frontier molecular orbitals, ensures overlap
for the overall chargeꢀtransfer transition. This interpretation is in agreement with the strong
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solvochromicity associated with the experimentally observed large change in dipole moment. Hence,
this considerable change in dipole moment rationalizes the observed enormous Stokes shift of
compound 6p.
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TDꢀDFT calculations were also employed for the optimization of the excited state geometry to
calculate the emission characteristics. All minimum structures were unambiguously assigned by
analytical frequency analysis. However, in this case, using the CAMꢀB3LYP functional calculated
values did not reproduce the experimental values well. Upon changing the functional to B3LYP, again
using PCM with dichloromethane as a solvent, a good correlation with the experimental data in
dichloromethane was obtained. According to Kasha’s rule, where fluorescence only occurs from the
excited singlet state of lowest energy, only the calculated energies for S1 states were considered for
computing the emission maxima (
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Table 57).
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Figure 6. Selected DFTꢀcomputed (B3LYP 6ꢀ311G(d,p)) KohnꢀSham frontier molecular orbitals for
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5
6p.
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Table 7. TDꢀDFT calculations (B3LYP 6ꢀ311G(d,p)) of the emission maxima for pyrazoles 6a, i–
p.
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Structure
Experimental λmax,Em [nm]
Computed λmax,Em [nm]
333
338
341
348
367
394
365
489
448
499
343
337
341
362
377
402
384
6a
6i
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6n
439
470
6o
6p
Conclusion
In conclusion, we present a novel, efficient consecutive fourꢀcomponent couplingꢀcouplingꢀ
cyclocondensation synthesis of pyrazoles, taking advantage of the sequentially Pdꢀcatalyzed oneꢀpot
generation of alkynones from aryl iodides, ethynyl magnesium bromide, and acid chlorides. The ease
of the fourꢀcomponent process was additionally illustrated for the oneꢀpot synthesis of pyrimidines.
The pyrazole synthesis was employed to tackle the photophysical properties of donorꢀacceptor
substituted pyrazoles. These pushꢀpull substituted derivatives exhibit strongly redꢀshifted emission
maxima with large Stokes shifts. Moreover, electronic absorption and emission spectroscopy reveals
that the emission is highly solvochromic, whereas the absorption is not affected at all. The positive
solvochromicity allows altering the emission color for the dimethylaminoꢀcyano derivative in a range
from 363 nm (cyclohexane) to 595 nm (acetonitrile). This feature is particularly favorable for
photophysical probing of polarity environments in biological samples. In addition, the photophysical
measurements were corroborated and rationalized by accompanying stateꢀofꢀtheꢀart DFT and TDꢀDFT
calculations. This combined methodological, physical organic study nicely illustrates that a set of
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structurally related luminophores can be accessed rapidly and efficiently, opening new ways to
tackling biophysical and materials scientific questions by offering a practical synthetic tool. Further
studies directed towards the expansion of the sequentially Pdꢀcatalyzed entry to reactive intermediates
and their implementation in physical organic studies on functional chromophores are currently
underway.
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Experimental Section
General Considerations. All reactions were performed in flameꢀdried Schlenk tubes or microwave
vials under a nitrogen atmosphere. Microwave reactions were controlled and monitored with an
external surface sensor. Reaction progress was monitored qualitatively by thin layer chromatography
using silica gel layered aluminum foil (F254). For detection, UV light of wavelengths 254 and 366 was
employed. Commercially available chemicals were used as received without any further purification.
1H and 13C NMR spectra were measured on a 300 MHz, 500 MHz, or 600 MHz spectrometer.
Chemical shifts are given in ppm (δ) and were referenced to the internal solvent signal: CDCl3 (1H δ
7.26, 13C δ 77.2) or acetoneꢀd6 (1H δ 2.05, 13C δ 29.8). Multiplicities are stated as: s (singlet), d
(doublet), t (triplet), q (quartet), m (multiplet), brs (broad singlet). Coupling constants (J) are given in
Hz. The assignment of primary (CH3), secondary (CH2), tertiary (CH) and quaternary carbon nuclei
(Cquat) was made using DEPTꢀ135 spectra. Mass spectroscopic measurements were conducted on a
quadrupole (EI) or TOF (HRMS) analyzer. IR spectra were measured using ATR technique. The
intensities of the IR bands are abbreviated as w (weak), m (medium), s (strong). Melting points are
uncorrected.
General Procedure (GP1) for the FourꢀComponent Synthesis of Pyrazoles 5.
Bis(triphenylphosphane)ꢀpalladium(II)dichloride (35.1 mg, 50.0 µmol, 5.00 mol%) and aryl iodide
(1.00 mmol, 1.00 equiv, if solid) were placed in a flameꢀdried 10 mL microwave vial under a nitrogen
atmosphere and the vial was evacuated and flushed with nitrogen two more times. A solution of
ethynyl magnesium bromide in THF (2.40 mL, 0.500 m, 1.20 mmol) was added, as was aryl iodide, if
liquid. The resulting yellow solution was stirred at 45 °C to complete conversion (ca. 30 min, TLC
control). Towards the end of the reaction, the mixture turned turbid. It was cooled to rt, triethylamine
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hydrochloride (41.3 mg, 0.300 mmol, 0.300 equiv) was added and stirred for several minutes before
the addition of triethylamine (106 mg, 1.05 mmol, 1.05 equiv), aroyl chloride (1.40 mmol, 1.40 equiv)
and copper(I) iodide (9.50 mg, 50.0 µmol, 5.00 mol%), upon which the reaction mixture darkened to
brown. The reaction mixture was stirred for 1 to 2 h at 45 °C (TLC control). After cooling to rt, MeOH
(0.400 mL), AcOH (0.400), phenanthroline (360 mg, 2.00 mmol, 2.00 equiv), and the respective
hydrazine (1.50 mmol, 1.50 equiv) were added to the mixture and it was heated to 150 °C for 15 min
under microwave irradiation. The reaction mixture was quenched with sat. aq. NaHCO3 and extracted
with EtOAc (5 × 20 mL). The combined organic phases were washed with brine, dried (MgSO4) and
the crude product was adsorbed on Celite®. Purification was performed using a flash purification
system with eluents consisting of nꢀhexane and EtOAc or acetone.
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5ꢁ(4ꢁMethoxyphenyl)ꢁ1ꢁmethylꢁ3ꢁphenylꢁ1Hꢁpyrazole (6a). According to GP1 using 4ꢀiodoanisole,
benzoyl chloride, and methyl hydrazine, 209 mg (0.775 mmol, 77%) of 6a were obtained as a yellow
solid with a regioisomeric ratio of 10:1 (1H NMR). Purification was performed with a gradient of nꢀ
1
hexane/EtOAc 19:1 → 2:1. Mp 108–110 °C (109–110 °C25). H NMR (CDCl3, 300 MHz): δ 3.87 (s,
3 H), 3.91 (s, 3 H), 6.56 (s, 1 H), 6.98–7.03 (m, 2 H), 7.27–733 (m, 1 H), 7.37–7.44 (m, 4 H), 7.81–
7.85 (m, 2 H). 13C NMR (CDCl3, 75 MHz): δ 37.6 (CH3), 55.5 (CH3), 103.0 (CH), 114.3 (CH), 123.2
(Cquat), 125.6 (CH), 127.7 (CH), 128.7 (CH), 130.2 (CH), 133.7 (Cquat), 145.0 (Cquat), 150.5 (Cquat),
159.9 (Cquat). EI + MS (m/z (%)): 264 (100) [M+], 249 (38) [C16H13N2O+ꢂ], 176 (11), 158 (11)
+ꢂ
[C10H8NO+ꢂ], 105 (17) [C7H5O+ꢂ], 77 (10) [C6H5 ]. FTꢀIR: ν
̃
[cmꢀ1] = 606 (m), 667 (m), 677 (m), 692
(s), 745 (m), 764 (s), 799 (m), 835 (s), 957 (m), 997 (m), 1016 (m), 1028 (m), 1036 (m), 1177 (m),
1248 (s), 1290 (m), 1443 (m), 1460 (m), 1491 (s), 1612 (m), 2835 (w), 2911 (w), 2938 (w), 3001 (w),
3057 (w). Anal. calcd. for C17H16N2O (264.1): C 77.25, H 6.10, N 10.60; found: C 77.03, H 6.38, N
10.41.
5ꢁ(4ꢁMethoxyphenyl)ꢁ3ꢁphenylꢁ1Hꢁpyrazole (6b). According to GP1 using 4ꢀiodoanisole, benzoyl
chloride, and hydrazine hydrate, 169 mg (0.675 mmol, 68%) of 6b were obtained as a yellow solid.
Purification was performed with a gradient of nꢀhexane/acetone 9:1 → 1:1. Mp 157–159 °C (160–
1
161 °C26). H NMR (CDCl3, 300 MHz): δ 3.74 (s, 3 H), 6.63 (s, 1 H), 6.76–6.78 (m, 2 H), 7.21–7.27
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(m, 3 H), 7.53–7.55 (m, 2 H), 7.61–7.63 (m, 2 H), 11.39 (brs, 1 H). 13C NMR (CDCl3, 75 MHz): δ
55.4 (CH3), 99.4 (CH), 114.3 (CH), 12.40 (Cquat), 125.7 (CH), 127.0 (CH), 128.1 (CH), 128.8 (CH),
131.7 (Cquat), 148.2 (Cquat), 149.2 (Cquat), 159.6 (Cquat). EI + MS (m/z (%)): 250 (100) [M+], 235 (40)
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9
+ꢂ
+ꢂ
[C15H11N2O+ꢂ], 207 (17) [C14H11N2 ], 178 (13), 123 (18), 105 (31) [C7H5O+ꢂ], 77 (15) [C6H5 ]. FTꢀIR:
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ν
̃
[cmꢀ1] = 611 (m), 689 (s), 760 (s), 797 (m), 831 (s), 968 (m), 1028 (m), 1175 (m), 1252 (s), 1273
(m), 1300 (m), 1439 (m), 1456 (m), 1508 (m), 1614 (m), 2833 (m), 2860 (w), 2899 (w), 2934 (w),
3003 (w), 3042 (w), 3061 (w), 3111 (w). Anal. calcd. for C16H14N2O (250.3): C 76.78, H 5.64, N
11.19; found: C 76.57, H 5.72, N 10.90.
5ꢁ(4ꢁChlorophenyl)ꢁ1ꢁmethylꢁ3ꢁphenylꢁ1Hꢁpyrazole (6c). According to GP1 using 1ꢀchloroꢀ4ꢀ
iodobenzene, benzoyl chloride, and methyl hydrazine, 183 mg (0.680 mmol, 68%) of 6c were obtained
as a light brown resin. Purification was performed with a gradient of nꢀhexane/EtOAc 19:1 → 2:1.
1H NMR (CDCl3, 300 MHz): δ 3.92 (s, 3 H), 6.60 (s, 1 H), 7.29–7.35 (m, 1 H), 7.38–7.48 (m, 6 H),
7.80–7.84 (m, 2 H). 13C NMR (CDCl3, 75 MHz): δ 37.6 (CH3), 103.6 (CH), 125.7 (CH), 127.9 (CH),
128.8 (CH), 129.1 (CH), 130.1 (CH), 133.3 (Cquat), 134.9 (Cquat), 144.0 (Cquat), 150.7 (Cquat), one Cquat
not detectable due to signal overlap. EI + MS (m/z (%)): 270 (8) [M+, 37Cl] 268 (25) [M+, 35Cl], 122
(96), 105 (100) [C6H5N2 ], 77 (57) [C6H5 ], 51 (18). FTꢀIR: ν̃
[cmꢀ1] = 667 (m), 692 (s), 712 (m), 764
+ꢂ
+ꢂ
(s), 799 (m), 833 (s), 957 (m), 1005 (m), 1090 (m), 1460 (m), 1481 (s), 2930 (w), 2945 (w), 2984 (w),
3057 (w), 3119 (w). HRMS (ESI) calcd. for [C16H1435ClN2 ]: 269.0840; found: 269.0841.
+
5ꢁ(4ꢁChlorophenyl)ꢁ1ꢁmethylꢁ3ꢁ(pꢁtolyl)ꢁ1Hꢁpyrazole (6d). According to GP1 using 1ꢀchloroꢀ4ꢀ
iodobenzene, pꢀtoluoyl chloride, and methyl hydrazine, 167 mg (0.590 mmol, 59%) of 6d were
obtained as a yellow solid. Purification was performed with a gradient of nꢀhexane/EtOAc 19:1 → 2:1.
1
Mp 100–102 °C. H NMR (CDCl3, 300 MHz): δ 2.38 (s, 3 H), 3.91 (s, 3 H), 6.57 (s, 1 H), 7.20–7.23
(m, 2 H), 7.37–7.48 (m, 4 H), 7.69–7.73 (m, 2 H). 13C NMR (CDCl3, 75 MHz): δ 21.4 (CH3), 37.7
(CH3), 103.3 (CH), 125.6 (CH), 129.1 (CH), 129.2 (Cquat), 129.5 (CH), 130.1 (CH), 130.5 (Cquat),
134.8 (Cquat), 137.6 (Cquat), 143.9 (Cquat), 150.8 (Cquat). EI + MS (m/z (%)): 284 (100) [M+, 37Cl], 282
(100) [M+, 35Cl], 269 (5) [C16H1237ClN2 ], 267 (15) [C16H1235ClN2 ], 119 (18). FTꢀIR: ν [cmꢀ1] = 793
̃
+ꢂ
+ꢂ
(s), 822 (m), 835 (m), 1001 (m), 1016 (m), 1088 (m), 1483 (m), 2731 (w), 2855 (w), 2913 (w), 2943
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(w), 2963 (w), 3017 (w), 3051 (w). HRMS (ESI) calcd. for [C17H1635ClN2 ]: 283.0997; found:
4
5
283.0995.
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5ꢁ(4ꢁChlorophenyl)ꢁ3ꢁphenylꢁ1Hꢁpyrazole (6e). According to GP1 using 1ꢀchloroꢀ4ꢀiodobenzene,
benzoyl chloride, and hydrazine hydrate, 163 mg (0.640 mmol, 64%) of 6e were obtained as a
colorless solid. Purification was performed with a gradient of nꢀhexane/EtOAc 19:1 → 2:1. Mp 214–
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215 °C (216–217 °C27). H NMR (acetoneꢀd6, 600 MHz): δ 7.15 (s, 1 H), 7.35–7.38 (m, 1 H), 7.45–
7.48 (m, 4 H), 7.86–7.88 (m, 2 H), 7.90–7.92 (m, 2 H). NH not visible due to quick exchange.
13C NMR (acetoneꢀd6, 150 MHz): δ 100.6 (CH), 126.2 (CH), 127.8 (CH), 128.9 (CH), 129.65 (CH),
129.73 (CH), 133.7 (Cquat). Other Cquat not detectable due to aggregation effects. EI + MS (m/z (%)):
254 (100) [M+], 225 (11) [C15H1035Cl+ꢂ], 189 (15), 94 (15). FTꢀIR: ν [cmꢀ1] = 662 (m), 677 (s), 739 (m),
̃
756 (s), 793 (m), 824 (s), 974 (m), 1011 (m), 1061 (m), 1086 (m), 1096 (m), 1456 (m), 1477 (m), 2729
(w), 2762 (w), 2797 (w), 2841 (w), 2857 (w), 2868 (w), 2920 (w), 2980 (w); 3005 (w), 3065 (w), 3100
(w), 3144 (w), 3194 (w); 3746 (w). Anal. calcd. for C15H11ClN2 (254.7): 70.73, H 4.35, N 11.00;
found: C 71.02, H 4.37, N 10.73.
1ꢁMethylꢁ5ꢁphenylꢁ3ꢁ(pꢁtolyl)ꢁ1Hꢁpyrazole (6f). According to GP1 using iodobenzene, pꢀtoluoyl
chloride, and methyl hydrazine, 196 mg (0.789 mmol, 79%) of 6f were obtained as a yellow solid.
Purification was performed with a gradient of nꢀhexane/EtOAc 19:1 → 2:1. Mp 125–126 °C (129–
131 °C25). 1H NMR (CDCl3, 300 MHz): δ 2.38 (s, 3 H), 3.93 (s, 3 H), 6.59 (s, 1 H), 7.21–7.24 (s, 2 H),
7.37–7.49 (m, 5 H), 7.71–7.75 (m, 2 H). 13C NMR (CDCl3, 75 MHz): δ 21.4 (CH3), 37.7 (CH3), 103.2
(CH), 125.6 (CH), 128.6 (CH), 128.8 (CH), 128.9 (CH), 129.5 (CH), 130.8 (Cquat), 130.9 (Cquat), 137.5
+ꢂ
(Cquat), 145.1 (Cquat), 150.7 (Cquat). EI + MS (m/z (%)): 248 (100) [M+], 233 (12) [C16H13N2 ]. FTꢀIR: ν
̃
[cmꢀ1] = 669 (m), 696 (s), 768 (s), 799 (s), 829 (s), 1485 (m), 2735 (w), 2832 (w); 2857 (w), 2918 (w),
2945 (w), 2994 (w), 3021 (w), 3119 (w). Anal. calcd. for C17H16N2 (248.3): C 82.22, H 6.49, N 11.28;
found: C 81.97, H 6.48, N 11.15.
1ꢁMethylꢁ5ꢁ(naphthalenꢁ2ꢁyl)ꢁ3ꢁphenylꢁ1Hꢁpyrazole (6g). Deviating from GP1, the reaction was
performed on a 0.880 mmol scale. Using 2ꢀiodonaphthalene, benzoyl chloride, and methyl hydrazine,
176 mg (0.619 mmol, 70%) of 6g were obtained as a yellow resin. Purification was performed with a
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gradient of nꢀhexane/EtOAc 19:1 → 2:1. H NMR (CDCl3, 300 MHz): δ 4.01 (s, 3 H), 6.72 (s, 1 H),
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7
8
9
7.30–7.36 (m, 2 H), 7.40–7.46 (m, 3 H), 7.85 – 7.97 (m, 6 H). 13C NMR (CDCl3, 75 MHz): δ 37.9
(CH3), 103.7 (CH), 125.7 (CH), 126.4 (CH), 126.9 (CH), 127.8 (CH), 127.9 (CH), 128.1 (CH), 128.1
(Cquat), 128.3 (CH), 128.6 (CH), 128.8 (CH), 133.1 (Cquat), 133.2 (Cquat), 133.6 (Cquat), 145.2 (Cquat),
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150.8 (Cquat). EI + MS (m/z (%)): 284 (100) [M+], 153 (11) [C11H7N+ꢂ]. FTꢀIR: ν [cmꢀ1] = 669 (m), 692
̃
(s), 737 (m), 750 (s), 762 (s), 797 (m), 820 (m), 860 (m959 (m), 1458 (m), 2803 (w), 2945 (w), 2984
+
(w), 3022 (w), 3053 (w). HRMS (ESI) calcd. for [C20H17N2 ]: 285.1386; found: 285.1389.
1ꢁMethylꢁ3ꢁphenylꢁ5ꢁ(4ꢁ(trifluoromethoxy)phenyl)ꢁ1Hꢁpyrazole (6h). According to GP1 using 1ꢀiodoꢀ
4ꢀtrifluoromethoxyiodobenzene, benzoyl chloride, and methyl hydrazine, 186 mg (0.584 mmol, 58%)
of 6h were obtained as a beige solid. Purification was performed with a gradient of nꢀhexane/EtOAc
1
19:1 → 2:1. Mp. 135–137 °C. H NMR (CDCl3, 300 MHz): δ 3.93 (s, 3 H), 6.61 (s, 1 H), 7.31–7.34
(m, 3 H), 7.40–7.43 (m, 2 H), 7.49–7.51 (m, 2 H), 7.82–7.84 (m, 2 H). 13C NMR (CDCl3, 75 MHz): δ
1
37.7 (CH3), 103.7 (CH), 120.6 (q, Cquat, JH = 259 Hz), 121.3 (CH), 125.7 (CH), 127.9 (CH), 128.8
(CH), 129.5 (Cquat), 130.4 (CH), 133.3 (Cquat), 143.8 (Cquat), 149.5 (Cquat), 150.8 (Cquat). EI + MS (m/z
(%)): 318 (100) [M+], 202 (5) [C9H7F3NO+ꢂ]. FTꢀIR: ν [cmꢀ1] = 658 (m), 692 (s), 764 (s), 799 (m), 854
̃
(m), 1005 (m), 1107 (m), 1161 (s), 1204 (s), 1252 (s), 1491 (m), 2853 (w), 2884 (w), 2924 (w), 2957
(w), 3061 (w). Anal. calcd. for C17H13F3N2O (318.3): C 64.15, H 4.12, N 8.80; found: C 63.94, H 4.27,
N 8.50.
1ꢁMethylꢁ3,5ꢁdiphenylꢁ1Hꢁpyrazole (6i). According to GP1 using iodobenzene, benzoyl chloride, and
methyl hydrazine, 168 mg (0.717 mmol, 72%) of 6i were obtained as a yellow resin which crystallized
over several weeks. Purification was performed with a gradient of nꢀhexane/EtOAc 19:1 → 4:1.
1H NMR (CDCl3, 300 MHz): δ 3.94 (s, 3 H), 6.62 (s, 1 H), 7.28–7.34 (m, 1 H), 7.39–7.50 (m, 7 H),
7.82–7.86 (m, 2 H). 13C NMR (CDCl3, 75 MHz): δ 37.7 (CH3), 103.4 (CH), 125.7 (CH), 127.7 (CH),
128.7 (CH), 128.8 (CH), 128.8 (CH), 128.9 (CH), 130.8 (Cquat), 133.6 (Cquat), 145.2 (Cquat), 150.6
+ꢂ
(Cquat). EI + MS (m/z (%)): 234 (100) [M+], 77 (10) [C6H5 ]. FTꢀIR: ν
̃
[cmꢀ1] = 671 (m), 691 (s), 746
(s), 762 (s), 1485 (m), 2943 (w), 2986 (w), 3044 (w), 3059 (w), 3119 (w). Anal. calcd. for C16H14N2
(234.3): C 82.02, H 6.02, N 11.96; found: C 82.10, H 5.91, N 11.72.
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1ꢁMethylꢁ3ꢁphenylꢁ5ꢁ(4ꢁ(trifluoromethyl)phenyl)ꢁ1Hꢁpyrazole
(6j). According to GP1 using
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iodobenzene and 4ꢀtrifluoromethyl benzoyl chloride, 133 mg (0.440 mmol, 44%) of 6k were obtained
as a light yellow solid. Purification was performed twice with gradients of nꢀhexane/EtOAc 5: → 2:1
and 19:1 → 9:1, respectively, followed by manual flash chromatography (nꢀhexane/EtOAc 40:1). Mp
76–77 C. 1H NMR (CDCl3, 300 MHz): δ 3.95 (s, 3 H), 6.66 (s, 1 H), 7.44–7.50 (m, 5 H), 7.64–7.67
(m, 2 H), 7.92–7.96 (m, 2 H). 13C NMR (CDCl3, 75 MHz): δ 37.9 (CH3), 103.8 (CH), 124.4 (q, Cquat,
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1JF = 273 Hz), 125.7 (CH), 125.7 (q, CH, JF = 4 Hz), 128.9 (CH), 128.9 (CH), 128.9 (CH), 129.5 (q,
2
5
Cquat, JF = 32 Hz), 130.5 (Cquat), 137.0 (q, Cquat, JF = 1 Hz), 145.6 (Cquat), 149.1 (Cquat). EI + MS (m/z
+ꢂ
+ꢂ
(%)): 302 (28) [M+], 173 (100) [C8H6F3N2 ], 145 (31) [C7H4F3 ], 114 (12) [C8H4N+ꢂ], 71 (17), 54 (46)
[C3H4N+ꢂ], 43 (47) [CH3N2 ]. FTꢀIR: ν
̃
[cmꢀ1] = 671 (m), 692 (m), 768 (s), 800 (m), 839 (m), 853 (m),
+ꢂ
959 (m), 1007 (m), 1043 (m), 1063 (s), 1107 (s), 1159 (m), 1182 (m), 1238 (m), 1275 (m), 1323 (s),
+
2859 (w), 2938 (w), 2955 (w), 2988 (w), 3082 (w). HRMS (ESI) calcd. for [C17H14F3N2 ]: 303.1104;
found: 303.1109.
4ꢁ(1ꢁMethylꢁ5ꢁphenylꢁ1Hꢁpyrazolꢁ3ꢁyl)benzonitrile (6k). According to GP1 using iodobenzene and 4ꢀ
cyanobenzoyl chloride, 91 mg (0.350 mmol, 35%) of 6k were obtained as a colorless solid.
Purification was performed with a gradient of nꢀhexane/EtOAc 19:1 → 2:1, an analytical sample for
1
photophysical characterization was recrystallized from nꢀhexane. Mp 141–143 °C. H NMR (CDCl3,
300 MHz): δ 3.94 (s, 3 H), 6.66 (s, 1 H), 7.42–7.53 (m, 5 H), 7.66–7.70 (m, 2 H), 7.91–7.95 (m, 2 H).
13C NMR (CDCl3, 75 MHz): δ 38.0 (CH3), 104.0 (CH), 110.9 (Cquat), 119.3 (Cquat), 125.9 (CH), 128.9
(CH), 128.97 (CH), 129.02 (CH), 130.3 (CH), 132.7 (CH), 138.0 (Cquat), 145.7 (Cquat), 148.6 (Cquat).
One Cquat not detectable due to signal overlap. EI + MS (m/z (%)): 259 (32) [M+], 130 (100) [C10H10+ꢂ],
+ꢂ
114 (11) [C8H4N+ꢂ], 102 (29) [C7H4N+ꢂ], 71 (23), 54 (60) [C3H4N+ꢂ], 43 (65) [CH3N2 ]. FTꢀIR: ν
̃
[cmꢀ1]
= 691 (m), 702 (m), 766 (s), 770 (m), 847 (m), 957 (m), 1007 (m), 1022 (m), 1059 (m), 1109 (m),
1128 (m), 1179 (m), 1248 (m), 1260 (m), 1283 (m), 2882 (w), 2909 (w), 2949 (w). HRMS (ESI)
+
calcd. for [C17H14N3 ]: 260.1182; found: 260.1181.
5ꢁ(4ꢁMethoxyphenyl)ꢁ1ꢁmethylꢁ3ꢁ(4ꢁtrifluoromethyl)phenyl)ꢁ1Hꢁpyrazole (6l). According to GP1 using
4ꢀiodoanisole and 4ꢀ(trifluoromethyl)benzoyl chloride, 192 mg (0.577 mmol, 58%) of 6l were
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obtained as a light yellow solid. Purification was performed with a gradient of nꢁhexane/EtOAc 19:1
→ 2:1, an analytical sample for photophysical characterization was recrystallized from nꢀhexane. Mp
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7
1
110–112 °C. H NMR (CDCl3, 300 MHz): δ 3.87 (s, 3 H), 3.92 (s, 3 H), 6.60 (s, 1 H), 6.99–7.03 (m,
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2 H), 7.37–7.40 (m, 2 H), 7.63–7.67 (m, 2 H), 7.91–7.95 (m, 2 H). 13C NMR (CDCl3, 75 MHz): δ 37.8
(CH3), 55.5 (CH3), 103.5 (Cquat), 114.4 (CH), 124.5 (q, Cquat, 1JF = 272 Hz), 122.8 (CH), 125.67 (CH),
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125.70 (q, CH, JF = 4 Hz), 130.2 (CH), 137.1 (q, Cquat, JF = 1 Hz), 145.4 (Cquat), 149.1 (Cquat), 160.1
(Cquat). EI + MS (m/z (%)): 332 (100) [M+], 317 (32) [C17H12F3N2O+ꢂ]. FTꢀIR: ν [cmꢀ1] = 608 (m), 633
̃
(m), 675 (m), 770 (m), 791 (s), 833 (s), 849 (s), 959 (m), 999 (m), 1015 (m), 1038 (m), 1065 (s), 1090
(m), 1111 (s), 1161 (s), 1177 (m), 1252 (s), 1292 (m), 1321 (s), 1425 (m), 1447 (m), 1462 (m), 1495
(m), 1614 (m), 2841 (w), 2886 (w), 2909 (w), 2936 (w), 2967 (w), 3076 (w). Anal. calcd. for
C18H15F3N2O (332.3): C 65.06, H 4.55, N 8.43; found: C 65.33, H 4.72, N 8.19.
4ꢁ(5ꢁ(4ꢁMethoxyphenyl)ꢁ1ꢁmethylꢁ1Hꢁpyrazolꢁ3ꢁyl)benzonitrile (6m). According to GP1 using 4ꢀ
iodoanisole and 4ꢀcyanobenzoyl chloride, 125 mg (0.432 mmol, 43%) of 6m were obtained as a
colorless solid. Purification was performed with a gradient of nꢀhexane/EtOAc 19:1 → 2:1. An
analytical sample for photophysical characterization was recrystallized from nꢀhexane. Mp 161–
1
162 °C. H NMR (CDCl3, 300 MHz): δ 3.87 (s, 3 H), 3.91 (s, 3 H), 6.60 (s, 1 H), 7.01 (m, 2 H), 7.37
(m, 2 H), 7.67 (m, 2 H), 7.91 (m, 2 H). 13C NMR (CDCl3, 75 MHz): δ 37.8 (CH3), 55.5 (CH3), 103.6
(CH), 110.7 (Cquat), 114.4 (CH), 119.3 (Cquat), 122.6 (Cquat), 125.9 (CH), 130.2 (CH), 132.6 (CH),
138.1 (Cquat), 145.5 (Cquat), 148.5 (Cquat), 160.2 (Cquat). EI + MS (m/z (%)): 289 (100) [M+], 274 (29)
[C17H12N3O+ꢂ]. FTꢀIR: ν [cmꢀ1] = 613 (m), 677 (m), 712 (m), 768 (s), 812 (m), 827 (s), 841 (m), 1001
̃
(m), 1013 (m), 1030 (m), 1111 (m), 1177 (s), 1254 (s), 1296 (m), 1423 (m), 1445 (m), 1468 (m), 1491
(s), 1611 (m), 2226 (m), 2847 (w), 2911 (w), 2953 (w), 2982 (w), 3044 (w). HRMS (ESI) calcd. for
[C18H16N3O +]: 290.1288; found: 290.1290.
N,NꢁDimethylꢁ4ꢁ(1ꢁmethylꢁ3ꢁphenylꢁ1Hꢁpyrazolꢁ5ꢁyl)aniline (6n). According to GP1 using 4ꢀiodoꢀ
N,Nꢀdimethylaniline, benzoyl chloride, and methyl hydrazine, 180 mg (0.595 mmol, 60%) of 6n were
obtained as a light brown resin. Purification was performed with a gradient of nꢀhexane/EtOAc 4:1 →
1
1:1. H NMR (CDCl3, 300 MHz): δ 3.02 (s, 6 H), 3.93 (s, 3 H), 6.54 (s, 1 H), 6.77–6.82 (m, 2 H),
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7.27–7.44 (m, 5 H), 7.82–7.85 (m, 2 H). 13C NMR (CDCl3, 75 MHz): δ 37.6 (CH3), 40.5 (CH3), 102.6
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(CH), 112.2 (CH), 118.3 (CH), 125.6 (CH), 127.5 (Cquat), 128.7 (CH), 129.7 (CH), 133.8 (Cquat), 145.7
6
7
+ꢂ
(Cquat), 150.4 (Cquat), 150.5 (Cquat). EI + MS (m/z (%)): 277 (23) [M+], 158 (100) [C10H10N2 ], 130 (19),
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+ꢂ
+ꢂ
205 (30), 103 (10), 77 (22) [C6H5 ], 43 (22) [CH3N2 ]. FTꢀIR: ν̃
[cmꢀ1] = 667 (m), 675 (m), 692 (s),
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762 (s), 797 (m), 820 (m), 945 (m), 957 (m), 1167 (m), 1188 (m), 1227 (m), 1360 (s), 1445 (m), 1460
(m), 1495 (s), 1522 (m), 1612 (m), 2725 (w), 2805 (w), 2855 (w), 2887 (w), 2980 (w), 3034 (w), 3055
+
(w). HRMS (ESI) calcd. for [C18H20N3 ] 278.1652; found: 278.1652.
N,NꢁDimethylꢁ4ꢁ(1ꢁmethylꢁ3ꢁ(4ꢁ(trifluoromethyl)phenyl)ꢁ1Hꢁpyrazolꢁ5ꢁyl)aniline (6o). According to
GP1 using 4ꢀiodoꢀN,Nꢀdimethylaniline and 4ꢀ(trifluoromethyl)benzoyl chloride, 180 mg (0.576 mmol,
58%) of 6o were obtained as a light yellow solid. Purification was performed with a gradient of
nꢀhexane/acetone 19:1 → 2:1, an analytical sample for photophysical characterization was
1
recrystallized from nꢀhexane. Mp 150–152 °C. H NMR (CDCl3, 300 MHz): δ 3.03 (s, 6 H), 3.93 (s,
3 H), 6.57 (s, 1 H), 6.77–6.82 (m, 2 H), 7.31–7.36 (m, 2 H), 7.63–7.66 (m, 2 H), 7.92–7.95 (m, 2 H).
13C NMR (CDCl3, 75 MHz): δ 37.8 (CH3), 40.5 (CH3), 102.2 (CH), 112.2 (CH), 117.9 (Cquat), 124.5
(q, Cquat, 1JF = 272 Hz), 125.66 (CH), 125.69 (q, CH, 3JF = 4 Hz), 129.3 (q, Cquat, 32.2 Hz), 129.7 (CH),
137.3 (Cquat), 146.1 (Cquat), 149.0 (Cquat), 150.6 (Cquat). EI + MS (m/z (%)): 345 (100) [M+], 172 (25)
[C8H5F3N+ꢂ]. FTꢀIR: ν [cmꢀ1] = 779 (m), 841 (m), 851 (m), 945 (m), 959 (m), 1013 (m), 1063 (m),
̃
1092 (m), 1109 (s), 1155 (m), 1292 (m), 1323 (m), 1497 (m), 1609 (m), 2714 (w), 2810 (w), 2862 (w),
2901 (w), 2928 (w), 2999 (w), 3030 (w). Anal. calcd. for C19H18F3N3 (345.4): C 66.08, H 5.25, N
12.17; found: C 66.18, H 4.99, N 12.08.
4ꢁ(5ꢁ(4ꢁ(Dimethylamino)phenyl)ꢁ1ꢁmethylꢁ1Hꢁpyrazolꢁ3ꢁyl)benzonitrile (6p). According to GP1 using
4ꢀiodoꢀN,Nꢀdimethylaniline and 4ꢀcyanobenzoyl chloride, 180 mg (0.595 mmol, 60%) of 6p were
obtained as a colorless solid. Purification was performed with a gradient of nꢀhexane/EtOAc 19:1 →
9:1, an analytical sample for photophysical characterization was recrystallized from nꢀhexane. Mp
1
187–188 °C. H NMR (CDCl3, 300 MHz): δ 3.30 (s, 6 H), 3.93 (s, 3 H), 6.57 (s, 1 H), 6.78–6.81 (m,
2 H), 7.29–7.34 (m, 2 H), 7.65–7.69 (m, 2 H), 7.90–7.94 (m, 2 H). 13C NMR (CDCl3, 75 MHz): δ 37.9
(CH3), 40.5 (CH3), 103.2 (CH), 110.7 (Cquat), 112.2 (CH), 117.6 (Cquat), 119.4 (Cquat), 125.9 (CH),
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129.7 (CH), 132.6 (CH), 138.3 (Cquat), 146.3 (Cquat), 148.4 (Cquat), 150.7 (Cquat). EI + MS (m/z (%)):
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302 (100) [M+], 151 (20). FTꢀIR: ν [cmꢀ1] = 673 (m), 716 (m), 729 (m), 764 (m), 777 (s), 822 (s), 845
̃
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(s), 947 (m), 1016 (m), 1038 (m), 1072 (m), 1090 (m), 1117 (m), 1125 (m), 1175 (m), 1233 (m), 1277
(m), 1300 (m), 1325 (m), 1358 (m), 1422 (m), 1445 (m), 1470 (m), 1470 (m), 1526 (m), 1607 (m),
2220 (m), 2812 (w), 2866 (w), 2899 (w), 2992 (w), 3030 (w), 3048 (w), 3073 (w), 3215 (w). Anal.
calcd. for C19H18N4 (302.5): C 75.47, H 6.00, N 18.53; found: C 75.28, H 5.98, N 18.23.
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3ꢁ(4ꢁMethoxyphenyl)ꢁ1,5ꢁdiphenylꢁ1Hꢁpyrazole (6q). Deviating from GP1, the reaction time for the
cyclization was prolonged to 45 min. After purification with a gradient of nꢁhexane/EtOAc 19:1 →
2:1, 153 mg (0.469 mmol, 47%) of 6q were obtained as a yellow resin with a regioisomeric ratio of
1:2. An analytical sample was precipitated by immersion of an nꢀhexane solution in an ultrasonic bath,
1
which gave 6q as a single regioisomer. H NMR (CDCl3, 500 MHz): δ 3.86 (s, 3 H), 6.76 (s, 1 H),
6.96–6.99 (m, 2 H), 7.28–7.38 (m, 10 H), 7.85–7.87 (m, 2 H). 13C NMR (CDCl3, 125 MHz): δ 55.5
(CH3), 105.0 (CH), 114.3 (CH), 125.5 (CH), 126.1 (Cquat), 127.3 (CH), 127.4 (CH), 128.4 (CH), 128.6
(CH), 128.9 (CH), 129.0 (CH), 131.0 (Cquat), 140.4 (Cquat), 144.5 (Cquat), 152.0 (Cquat), 159.8 (Cquat).
EI + MS (m/z (%)): 326 (100) [M+], 311 (20) [C21H15N2O+ꢂ]. FTꢀIR: ν [cmꢀ1] = 677 (m), 692 (s), 760
̃
(s), 804 (m), 840 (m), 955 (m), 972 (m), 1028 (m), 1065 (m), 1252 (m), 1431 (m), 1452 (m), 1487
(m), 1501 (m), 2841 (w), 2974 (w), 3007 (w), 3057 (w). HRMS (ESI) calcd. for [C22H19N2O+]:
327.1492; found: 327.1498.
1,4ꢁBis(1ꢁmethylꢁ3ꢁphenylꢁ1Hꢁpyrazolꢁ5ꢁyl)benzene (6r). Deviating from GP1, 1.00 equiv of 1,4ꢀ
diiodobenzene were used and the amounts of all other reactants and catalysts were doubled. 223 mg
(0.571 mmol, 57%) of 6q were obtained as a yellow solid. Purification was performed with a gradient
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of nꢀhexane/EtOAc 19:1 → 2:1. Mp 227–229 °C. H NMR (CDCl3, 300 MHz): δ 4.00 (s, 6 H), 6.68
(s, 2 H), 7.30–7.36 (m, 4 H), 7.41–7.46 (m, 4 H), 7.59 (s, 4 H), 7.84–7.87 (m, 4 H). 13C NMR (CDCl3,
75 MHz): δ 37.9 (CH3), 103.7 (CH), 125.7 (CH), 127.9 (CH), 128.8 (CH), 129.1 (CH), 130.9 (Cquat),
133.4 (Cquat), 144.4 (Cquat), 150.8 (Cquat). EI + MS (m/z (%)): 390 (100) [M+], 195 (16). FTꢀIR: ν [cmꢀ1]
̃
= 667 (m), 692 (s), 766 (s), 804 (m), 851 (m), 1005 (m), 1460 (m), 2803 (w), 2926 (w), 2951 (w),
+
3032 (w), 3063 (w), 3130 (w). HRMS (ESI) calcd. for [C26H23N4 ]: 391.1917; found: 391.1920.
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General Procedure (GP2) for the FourꢀComponent Synthesis of Pyrimidines 8.
Bis(triphenylphosphane)ꢀpalladium(II)dichloride (35.1 mg, 50.0 µmol, 5.00 mol%) and aryl iodide
(1.00 mmol, 1.00 equiv, if solid) were placed in a flameꢀdried 20 mL Schlenk tube under a nitrogen
atmosphere and the vial was evacuated and flushed with nitrogen two more times. A solution of
ethynyl magnesium bromide in THF (2.40 mL, 0.500 m, 1.20 mmol, 1.20 equiv) was added, as was
aryl iodide, if liquid. The resulting yellow solution was stirred at 45 °C until complete conversion (ca.
30 min, TLC control). Towards the end of the reaction the mixture turned turbid. It was cooled to rt,
triethylamine hydrochloride (41.3 mg, 0.300 mmol, 0.300 equiv) was added and stirred for several
minutes before the addition of triethylamine (106 mg, 1.05 mmol, 1.05 equiv), aroyl chloride
(1.40 mmol, 1.40 equiv) and copper(I) iodide (9.50 mg, 50.0 µmol, 5.00 mol%), upon which the
reaction mixture darkened to brown. The reaction mixture was stirred for 1 to 2 h at 45 °C (TLC
control). After cooling to rt, THF (2.60 mL), 2ꢀmethoxyethanol (2.00 mL) and a solution of
benzamidineꢂHCl (392 mg, 2.50 mmol, 2.50 equiv) and K2CO3 (346 mg, 2.50 mmol, 2.50 equiv) in
H2O (1.50 mL) were added to the mixture and it was heated to 90 °C for 16 h in a preꢀheated oil bath.
The reaction mixture was quenched with sat. aq. NH4Cl and extracted with EtOAc (3 × 20 mL). The
combined organic phases were washed with brine, dried (MgSO4) and the crude product was adsorbed
on Celite®. Purification was performed using a flash purification system (nꢀhexane/acetone 19:1),
followed by recrystallization from nꢁhexane, if necessary.
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4ꢁ(4ꢁMethoxyphenyl)ꢁ2,6ꢁdiphenylpyrimidine (8a). According to GP2 using 4ꢀiodoanisole and benzoyl
chloride, 171 mg (0.505 mmol, 51%) of 8a were obtained as a colorless solid. Purification was
performed using the flash purification system. Mp 140–142 °C (138–140 °C28). 1H NMR (CDCl3, 600
MHz): δ 3.90 (s, 3 H), 7.06–7.08 (m, 2 H), 7.51–7.58 (m, 6 H), 7.94 (s, 1 H), 8.27–8.39 (m, 4 H),
8.73–8.74 (m, 2 H). 13C NMR (CDCl3, 75 MHz): δ 55.6 (CH3), 109.5 (CH), 114.4 (CH), 127.4 (CH),
128.5 (CH), 128.6 (CH), 128.9 (CH), 129.0 (CH), 130.1 (Cquat), 130.7 (CH), 130.8 (CH), 137.8 (Cquat),
138.4 (Cquat), 162.0 (Cquat), 164.3 (Cquat), 164.5 (Cquat), 164.6 (Cquat). EI + MS (m/z (%)): 338 (100)
[M+], 235 (21) [C16H13NO+ꢂ], 220 (32) [C18H12NO+ꢂ], 132 (11), 102 (10) [C7H5N2 ]. FTꢀIR: ν
̃
[cmꢀ1] =
+ꢂ
689 (s), 731 (m), 752 (s), 773 (m), 829 (s), 1026 (m), 1171 (s), 1236 (m), 1256 (m), 1366 (s), 1495
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(m), 1512 (s), 1526 (s), 1566 (s), 1587 (m), 1609 (m), 2841 (w), 2951 (w), 3005 (w), 3034 (w). Anal.
calcd. for C23H18N2O (338.4): C 81.63, H 5.36, N 8.28; found: C 81.60, H 5.60, N 8.02.
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2,4ꢁDiphenylꢁ6ꢁ(pꢁtolyl)pyrimidine (8b). According to GP2 using 4ꢀiodotoluene and benzoyl chloride,
138 mg (0.428 mmol, 43%) of 8b were obtained as colorless crystals. Purification was performed
using the flash purification system, followed by recrystallization of the impure fractions from nꢀ
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hexane (5 mL). Mp 149–150 °C (148–150 °C29). H NMR (CDCl3, 600 MHz): δ 2.47 (s, 3 H), 7.35–
7.39 (m, 2 H), 7.50–7.61 (m, 6 H), 7.99 (s, 1 H), 8.19–8.23 (m, 2 H), 8.27–8.32 (m, 2 H), 8.72–8.77
(m, 2 H). 13C NMR (CDCl3, 75 MHz): δ 21.6 (CH3), 110.1 (CH), 127.3 (CH), 127.4 (CH), 128.55
(CH), 128.60 (CH), 129.0 (CH), 129.8 (CH), 130.7 (CH), 130.8 (CH), 134.9 (Cquat), 137.8 (Cquat),
138.4 (Cquat), 141.3 (Cquat), 164.6 (Cquat), 164.7 (Cquat), 164.8 (Cquat). EI + MS (m/z (%)): 322 (100)
+ꢂ
[M+], 219 (79) [C15H11N2 ], 204 (48) [C16H12+ꢂ], 115 (32) [C8H5N+ꢂ], 102 (31) [C7H4N+ꢂ]. FTꢀIR: ν
̃
[cmꢀ
1] = 631 (s), 642 (m), 664 (s), 685 (s), 718 (m), 746 (s), 773 (m), 824 (m), 1016 (m), 1070 (m), 1171
(m), 1236 (m), 1360 (s), 1497 (m), 1510 (s), 1522 (s), 1566 (s), 1589 (m), 2918 (w), 2990 (w), 3030
(w), 3057 (w). Anal. Calcd. for C23H18N2 (322.41): C 85.68, H 5.63, N 8.69; found: C 85.83, H 5.33,
N 8.49.
4ꢁ(Naphthalenꢁ2ꢁyl)ꢁ2ꢁphenylꢁ6ꢁ(pꢁtolyl)pyrimidine (8c). According to GP2 using 2ꢀiodonaphthalene
and pꢀtoluoyl chloride, 170 mg (0.456 mmol, 46%) of 8c were obtained as light yellow crystals.
Purification was performed using the flash purification system, followed by recrystallization from nꢀ
1
hexane (15 mL). Mp 153–155 °C. H NMR (CDCl3, 600 MHz): δ 2.48 (s, 3 H), 7.37–7.40 (m, 2 H),
7.50–7.61 (m, 5 H), 7.90–7.95 (m, 1 H), 8.00–8.06 (m, 2 H), 8.12–8.13 (m, 1 H), 8.23–8.26 (m, 2 H),
8.38–8.42 (m, 1 H), 8.76–8.80 (m, 3 H). 13C NMR (CDCl3, 75 MHz): δ 21.7 (CH3), 110.3 (CH), 124.4
(CH), 126.7 (CH), 127.36 (CH), 127.39 (CH), 127.5 (CH), 127.9 (CH), 128.6 (CH), 128.7 (CH), 128.8
(CH), 129.2 (CH), 129.8 (CH), 130.7 (CH), 133.5 (Cquat), 134.7 (Cquat), 134.9 (Cquat), 135.1 (Cquat),
138.4 (Cquat), 141.3 (Cquat), 164.6 (Cquat), 164.8 (Cquat). One Cquat not detectable due to signal overlap.
EI + MS (m/z (%)): 372 (100) [M+], 269 (45) [C20H15N+ꢂ], 254 (34) [C20H14+ꢂ], 167 (11) [C12H9N+ꢂ],
152 (27), 149 (42), 115 (19), 97 (11), 85 (11), 83 (11), 71 (21), 57 (37). FTꢀIR: ν̃
[cmꢀ1] = 613 (m), 660
(m), 692 (s), 746 (s), 756 (s), 816 (s), 853 (m), 885 (m), 1016 (m), 1115 (m), 1339 (m), 1371 (m),
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