Consecutive three-component synthesis of 3-(hetero)aryl-1H-pyrazoles with propynal diethylacetal as a three-carbon building block

Article abstract of DOI:10.3390/molecules16119340

A novel consecutive three-component synthesis of 3-(hetero)aryl-1H- pyrazoles via room temperature Sonogashira arylation of propynal diethylacetal used as a propargyl aldehyde synthetic equivalent has been disclosed. The final acetal cleavage-cyclocondensation with hydrazine hydrochloride at 80 °C rapidly furnishes the title compounds in a one-pot fashion.

Full text of DOI:10.3390/molecules16119340

Molecules 2011, 16, 9340-9356; doi:10.3390/molecules16119340
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Communication
Consecutive Three-Component Synthesis of
3-(Hetero)Aryl-1H-pyrazoles with Propynal
Diethylacetal as a Three-Carbon Building Block
Lucilla Levi, Christina Boersch, Charlotte F. Gers, Eugen Merkul and Thomas J. J. Müller *
Institut für Organische Chemie und Makromolekulare Chemie, Heinrich-Heine-Universität Düsseldorf,
Universitätsstraße 1, D-40225 Düsseldorf, Germany
* Author to whom correspondence should be addressed; E-Mail: ThomasJJ.Mueller@uni-duesseldorf.de;
Tel.: +49-(0)211-8112298; Fax: +49-(0)211-8114324.
Received: 30 September 2011; in revised form: 19 October 2011 / Accepted: 21 October 2011 /
Published: 7 November 2011
Abstract: A novel consecutive three-component synthesis of 3-(hetero)aryl-1H-pyrazoles
via room temperature Sonogashira arylation of propynal diethylacetal used as a propargyl
aldehyde synthetic equivalent has been disclosed. The final acetal cleavage-cyclocondensation
with hydrazine hydrochloride at 80 °C rapidly furnishes the title compounds in a one-pot fashion.
Keywords: alkyne; cyclocondensation; multi-component reaction; pyrazole; Sonogashira
coupling
1. Introduction
Pyrazoles, i.e., diazoles with two adjacent nitrogen atoms, display a rich chemistry and are used in
numerous applications [1-3]. Their broad spectrum of biological activities, such as anti-hyperglycemic,
analgesic, anti-inflammatory, antipyretic, anti-bacterial, and sedative-hypnotic properties, has attracted
considerable interest in medicinal chemistry [4-6]. In addition, several 3,5-diaryl substituted
pyrazoles also reversibly inhibit monoamine oxidases A and B [7]. In crop protection, 1,4-dialkyl-3,5-
diphenylpyrazoles are known as potent herbicides [8]. Furthermore, pyrazoles are pluripotent as
ligands in coordination chemistry [9-12], building blocks in heterocyclic synthesis [13,14], and units in
supramolecular entities [15-17]. In addition, they have received attention as optical brighteners [18]
and UV stabilizers [19] as well as photoinduced electron transfer systems [20,21].

Molecules 2011, 16
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Since multi-component reactions (MCRs) are highly efficient and address the fundamental
principles of chemo-, regio-, and stereoselectivity, they are receiving an increasing interest in academia
and industry [22-35]. With respect to economical and ecological considerations conceptually novel
synthetic approaches [36-39] are directed towards the improvement of processes [40,41], while
simultaneously reducing the input of work and the generation of waste. Therefore, MCRs are not only
elegant, but also beneficial for the environment [39].
In the past years, we have developed and elaborated the concept of MCR syntheses of multiple
classes of heterocycles via Sonogashira coupling of alkynes and (hetero)aroyl chlorides with alkynyl
ketones, followed by Michael addition-cyclocondensation, eventually in a one-pot fashion [42-45].
Alkynyl ketones and aldehydes are ideal three-carbon building blocks as synthetic equivalents of 
-dicarbonyl compounds. However, their electrophilicity is enhanced and the inherent regioselectivity
is imposed in the Michael-type nucleophilic additions. Within this conceptual framework we have
devised regioselective three-component [46] and four-component syntheses [47] of highly luminescent
tri- and tetrasubstituted pyrazoles. Here, we communicate a straightforward consecutive three-
component synthesis of 3-(hetero)aryl-1H-pyrazoles, i.e., monosubstituted pyrazole derivatives, via the
concatenation of a Sonogashira alkynylation of (hetero)aryl iodides with the commercially available
propynal diethylacetal, an in situ acetal cleavage, and a final cyclocondensation with hydrazine
hydrochloride.
2. Results and Discussion
Monosubstituted 3-(hetero)aryl pyrazoles can be retrosynthetically traced back either to
(hetero)aroyl chlorides and TMS-acetylene via 3-trimethylsilylalk-2-yn-1-ones or to (hetero)aryl
halides and propargyl aldehyde (Scheme 1).
Scheme 1. Retrosynthetic conception of three-component pyrazole syntheses by virtue of
alkynyl carbonyl condensation.
Both disconnection approaches proceed via a retro alkynyl carbonyl condensation, thus leading to
hydrazine and either to an alkynyl ketone [46-48] or a propargyl aldehyde [49-54]. While the former
disconnection establishes the three-carbon skeleton by virtue of Sonogashira acylation [46,55,56], the
latter analysis takes advantage of the ligation of the aryl substituent to a propargyl aldehyde synthon
via Sonogashira arylation. Since the direct alkynylation of propargyl aldehyde has not been reported,
presumably due to its pronounced electrophilicity, propynal diethylacetal apparently represents a
suitable synthetic equivalent [57-59]. Although the most recent report on the coupling of aryl halides
with propynal diethylacetal taking advantage of a tetradentate phosphane ligand based upon the

Molecules 2011, 16
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cyclopentane scaffold affords high yields and requires low catalyst loadings, the requisite high reaction
temperatures are less favorable for thermally sensitive functionalities [57].
Therefore, we first set out to optimize the reaction conditions for the Sonogashira coupling step.
The transformation of p-iodoanisole (1a) and propynal diethylacetal (2) into 1-(p-anisyl)-3,3-
diethoxyprop-1-yne (3a) under standard Sonogashira conditions at room temperature was chosen as a
model reaction (Scheme 2). The amount of triethylamine, the solvent, and the reaction time were
modified (Table 1).
Scheme 2. Optimization of the Sonogashira coupling of p-iodoanisole (1a) and propynal
diethylacetal (2) to furnish 1-(p-anisyl)-3,3-diethoxyprop-1-yne (3a).
Table 1. Optimization study for the synthesis of 1-(p-anisyl)-3,3-diethoxyprop-1-yne (3a).
Entry 1
Alkyne 2
1.0 equiv.
1.0 equiv.
1.1 equivs.
1.1 equivs.
1.1 equivs.
1.1 equivs.
NEt3
Solvent
THF
Reaction time
Yield of 3a 2
64%
1
2
2.0 equivs.
2.0 equivs.
1.1 equivs.
2.0 equivs.
2.0 equivs.
2.0 equivs.
2 h
2 h
2 h
2 h
1 h
3 h
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
80%
64%
89%
87%
3
4 3
5
6
91%
1 The reactions were carried out on a 2.0 mmol scale (c(1a) = 0.4 M); 2 All yields were determined
3
after isolation and purification on silica gel; This reaction was additionally carried out on a
5.0 mmol scale [c(1a) = 0.4 M] yielding 81% of 3a.
1,4-Dioxane is apparently a better solvent for the coupling than THF (Table 1, entries 1 and 2), a
small excess of alkyne 2 furnishes a higher yield (Table 1, entry 3), and two equivalents of
triethylamine are more favorable for complete conversion (Table 1, entries 4–6), which is reached after
2 h (Table 1, entry 4). Therefore, the parameters of entry 4 were considered to be optimal for the first
step of the sequence (vide infra).
Due to the sensitivity of the deprotected 3-aryl propargyl aldehydes towards oligo- and
polymerization in the presence of nucleophiles we then addressed the sequential acetal cleavage-
cyclocondensation of 1-(p-anisyl)-3,3-diethoxyprop-1-yne (3a) in the presence of hydrazine
hydrochloride [60-62] giving rise to the formation of 3-(p-anisyl)-1H-pyrazole (4a) (Scheme 3, Table 2).
The optimal temperature of the sequential acetal cleavage-cyclocondensation is 80 °C (Table 2,
entries 1–4), as preliminary experiments showed that lower temperatures yield poorer results and
higher temperatures lead to no further improvement. Conductive heating (Table 2, entries 2–4) turns
out to be superior to dielectric heating in the microwave oven (Table 2, entry 1).

Molecules 2011, 16
Scheme 3. Optimization of the acetal cleavage-cyclocondensation of 1-(p-anisyl)-3,3-
9343
diethoxyprop-1-yne (3a) to furnish 3-(p-anisyl)-1H-pyrazole (4a).
Table 2. Optimization study for the synthesis of 3-(p-anisyl)-1H-pyrazole (4a).
Entry Deprotecting agent 1 H2N-NH2·HCl
Reaction
temperature
80 °C (MW)
80 °C 5
Reaction Yield of 4a 2
time
15 min
15 min
1 h
1 3
2 4
3 3
4 4
5 3
H2O
H2O
H2O
2.0 equivs.
2.0 equivs.
2.0 equivs.
1.0 equiv.
2.0 equivs.
53%
65%
62%
22%
55%
80 °C 5
H2O
80 °C 5
15 min
10 min
HClaq (1 N)
130 °C 5
1 2.5 mL/mmol were added; 2 All yields were determined after isolation and purification on silica gel;
3
4
The reactions were carried out on a 0.5 mmol scale [c(3a) = 0.4 M]; The reactions were carried
out on a 1.0 mmol scale [c(3a) = 0.4 M]; 5 Preheated oil bath.
While the complete conversion is already achieved within 15 min (Table 2, entries 2 and 3), the
amount of hydrazine hydrochloride is crucial for the success of the sequence (Table 2, entries 2 and 4).
Strongly Brønsted acidic conditions (Table 2, entry 5) are not required and the combination of water
and hydrazine hydrochloride is sufficient to trigger the acetal cleavage and the Michael addition
followed by cyclocondensation. Thereafter, the combination of Sonogashira coupling and sequential
acetal cleavage-cyclocondensation was performed with the established model system (Scheme 4, Table 3).
Scheme 4. Optimization of the consecutive three-component Sonogashira coupling-acetal
cleavage-cyclocondensation synthesis of 3-(p-anisyl)-1H-pyrazole (4a).
Table 3. Optimization study for the one-pot synthesis of 3-(p-anisyl)-1H-pyrazole (4a).
Entry
Deprotecting agent
Yield of 4a 1
not isolated
50%
1
2
3
4
5
1.0 equiv. of HClaq (1 N)
1.0 equiv. of CH3COOH
1.0 equiv. of PTSA·H2O
2.0 equivs. of PTSA·H2O
25%
56%
55%
1 All yields were determined after isolation and purification on silica gel.

Molecules 2011, 16
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Although the acetal cleavage-cyclocondensation conditions only require a moderate acidity (vide supra),
the excess triethylamine from the coupling step has to be buffered (Table 3, compare entry 1 with
entries 2–5), which is most efficiently achieved by addition of a stoichiometric amount of
p-toluenesulfonic acid (PTSA) (Table 3, entry 4).
With these optimized conditions for the whole sequence in hand, the stage was set for testing the
range of applicable (hetero)aryl iodides 1 in this novel consecutive three-component synthesis of
3-(hetero)aryl-1H-pyrazoles 4. After coupling of (hetero)aryl iodides 1 with propynal diethylacetal (2)
at room temperature for two hours the subsequent addition of PTSA·H2O, hydrazine hydrochloride,
and water, heating to 80 °C for 15 min gave rise to the isolation of 3-(hetero)aryl-1H-pyrazoles 4 in
moderate to good yields (Scheme 5).
Scheme 5. Consecutive three-component Sonogashira coupling-acetal cleavage-
cyclocondensation synthesis of 3-(hetero)aryl-1H-pyrazoles 4.
This first study on the methodological scope of this novel three-component pyrazole synthesis
shows that electron-rich as well as electron-poor aryl substituents can be readily introduced. Also,
chloro and fluoro substituents and even unprotected phenol derivatives, which are incompatible with
the coupling of acid chlorides, are well tolerated. Although a thienyl substituent can be carried through
the sequence, all attempts to react other heteroaryl iodides such as 3- and 4-pyridyl iodides under the
standard conditions met with failure.
3. Experimental
3.1. General
All cross coupling reactions were carried out in oven dried Schlenk or microwave tubes using septa
and syringes under a nitrogen or argon atmosphere. Dry tetrahydrofuran and 1,4-dioxane were supplied
by a MBraun system MB-SPS-800 solvent purification system. Chemicals were either commercially
obtained from ABCR GmbH & Co KG, Acros Organics, Alfa Aesar GmbH & Co KG, Fluka, Merck
KGaA, Riedel-de Haën, Sigma-Aldrich Co., and used as supplied or were already available in the
research group.

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All products were purified via column chromatography on silica gel 60 M (0.04–0.063 mm) from
Macherey-Nagel using the flash technique under a pressure of 2 bar. The crude mixtures were
absorbed on Celite® 545 (0.02–0.10 mm) from Merck KGaA, Darmstadt before chromatographic
purification. The reaction progress was observed qualitatively using TLC Silica gel 60 F254 aluminium sheets.
The spots were detected with UV light at 254 nm and with aqueous potassium permanganate solution.
1H-, 13C-, and 13C-135 DEPT NMR spectra were recorded on Bruker AVIII-300 spectrometer, using
CDCl3 or DMSO-d6 as solvents. The resonances of CDCl3 or DMSO-d6 were locked as internal
1
13
1
13
standards (CDCl3: H  7.26, C  77.0; DMSO-d6: H  2.49, C  39.7). The multiplicities of
signals were abbreviated as follows: s: singlet; d: doublet; dd: doublet of doublets; dq: doublet of
quartets; ddd: doublet of doublets of doublets; t: triplet; tdd: triplet of doublets of doublets;
13
m: multiplet and br: broad signal. The type of carbon atom was determined on the basis of C-135
DEPT NMR spectra. For the description of the 13C-NMR spectra primary carbon atoms are
abbreviated as CH3, secondary carbon atoms as CH2, tertiary carbon atoms as CH, and quaternary carbon
atoms as Cquat. EI mass spectra were measured on Finnigan MAT 200 spectrometer. IR spectra were
either obtained on Shimadzu IRAffinity or on Bruker Vector 22 FT-IR instruments. The intensity of
the signals was abbreviated as follows: s (strong), m (medium), w (weak). The melting points
(uncorrected) were measured on a Reichert Thermovar apparatus. Combustion analyses were carried
out on a Perkin Elmer Series II Analyser 2400 in the microanalytical laboratory of the Institut für
Pharmazeutische und Medizinische Chemie der Heinrich-Heine-Universität Düsseldorf.
3.2. Experimental Procedure for the Synthesis of 1-(3,3-Diethoxyprop-1-yn-1-yl)-4-methoxybenzene (3a)
In a screw-cap Schlenk tube PdCl2(PPh3)2 (28 mg, 2 mol%, 0.04 mmol) and CuI (16 mg, 4 mol%,
0.08 mmol) were tempered. Then, 1-iodo-4-methoxybenzene (1a, 278 mg, 2.00 mmol),
3,3-diethoxyprop-1-yne (2, 0.32 mL, 2.20 mmol, 1.1 equiv.), degassed dry 1,4-dioxane (5.00 mL), and
triethylamine (0.55 mL, 4.00 mmol, 2.0 equiv.) were successively added under an argon atmosphere.
The mixture was stirred for 2 h until complete conversion of 1a (TLC monitoring). The crude mixture
was absorbed onto Celite® and purified chromatographically on silica gel with hexanes/ethylacetate
(30:1, Rf = 0.26) to give the alkyne 3a (415 mg, 1.80 mmol, 89%) as a colorless oil. 1H-NMR (CDCl3,
300 MHz):  1.27 (t, J = 7.1 Hz, 6H), 3.65 (dq, J = 9.5 Hz, J = 7.1 Hz, 2H), 3.80 (s, 3H), 3.81 (dq,
13
J = 9.5 Hz, J = 7.1 Hz, 2H), 5.48 (s, 1H), 6.80–6.85 (m, 2H), 7.38–7.43 (m, 2H). C-NMR (CDCl3,
75 MHz):  15.1 (CH3), 55.2 (CH3), 60.8 (CH2), 83.0 (Cquat), 85.2 (Cquat), 91.7 (CH), 113.8 (CH),
113.9 (Cquat), 133.4 (CH), 159.9 (Cquat). EI + MS (m/z (%)): 234 (M+, 7), 205 ((M-C2H5)+, 2), 190 (16),
+
+
189 ((M-C2H5O) , 100), 175 (12), 162 (20), 161 (95), 160 (C10H8O2 , 14), 159 (22), 133 (28), 132 (18), 131
(C9H7O+, 10), 118 (12), 89 (15). IR (Oil; Shimadzu IRAffinity): 2974 (w) cm−1, 2932 (w), 2884 (w), 2839

Molecules 2011, 16
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(w), 2224 (w), 1604 (w), 1570 (w), 1508 (s), 1458 (w), 1443 (w), 1391 (w), 1356 (w), 1329 (w), 1290
(m), 1246 (s), 1172 (m), 1090 (s), 1049 (s), 1032 (s), 1005 (s), 978 (m), 895 (w), 831 (s), 806 (m), 739
(w), 665 (w), 642 (w). Anal. calcd. for: C14H18O3 (234.3): C 71.77, H 7.74; Found: C 71.75, H 7.71.
3.3. Typical Experimental Procedure (Synthesis of Pyrazole 4b)
In a screw-cap Schlenk tube PdCl2(PPh3)2 (28 mg, 0.04 mmol) and CuI (16 mg, 0.08 mmol) were
tempered. Then, 1-iodo-3,4,5-trimethoxybenzene (1b, 600 mg, 2.00 mmol), 3,3-diethoxyprop-1-yne
(2, 0.32 mL, 2.20 mmol), degassed dry 1,4-dioxane (5.00 mL), and triethylamine (0.55 mL, 4.00 mmol)
were successively added under an argon atmosphere. The mixture was stirred for 2 h at room
temperature (water bath) until complete conversion of 1b (according to TLC monitoring). Then,
hydrazine hydrochloride (280 mg, 4.00 mmol), deionized water (5.00 mL), and PTSA·H2O (388 mg,
2.00 mmol) were added. The mixture was stirred at 80 °C (preheated oil bath) until complete
conversion (according to TLC monitoring). After extraction with CH2Cl2 (10 × 10 mL) the combined
organic phases were dried with MgSO4. The solvents were removed in vacuo, the crude mixture was
purified by chromatography on silica gel (CH2Cl2/MeOH/NH3 (aq)) to give 3-(3,4,5-tri-
methoxyphenyl)-1H-pyrazole (4b, 295 mg, 63%) as an orange solid, Mp 95 °C. 1H-NMR (CDCl3, 300
MHz): δ 3.88 (s, 3H), 3.90 (s, 6H), 6.58 (d, J = 1.7 Hz, 1H), 6.99 (s, 2H), 7.61 (d, J = 1.8 Hz, 1H).
13C-NMR (CDCl3, 75 MHz): δ 56.1 (CH3), 60.9 (CH3), 102.5 (CH), 103.0 (CH), 127.9 (Cquat), 132.6
(CH), 138.0 (Cquat), 149.5 (Cquat), 153.5 (Cquat). EI+MS (m/z (%)): 235 (13), 234 (M+, 100), 219
((M−CH3)+, 68), 205 ((M−HN2)+, 2), 192 ((M−CH2N2)+, 2), 191 (30), 176 (30), 161 (20), 159 (15), 149
(13), 131 (15), 105 (22), 58 (23), 43 (67). IR (neat; Shimadzu IRAffinity): 3576 (w) cm−1, 3146 (w),
3041 (w), 2995 (w), 2963 (w), 2930 (m), 2860 (w), 2826 (w), 1730 (w), 1587 (m), 1516 (m), 1474
(m), 1449 (m), 1416 (m), 1325 (m), 1288 (w), 1261 (w), 1238 (m), 1121 (s), 1092 (m), 1057 (m), 1034
(w), 995 (s), 928 (w), 889 (w), 845 (s), 826 (m), 760 (s), 739 (m), 665 (w), 627 (m). Anal. calcd. for
C12H14N2O3 (234.3): C 61.53, H 6.03, N 11.96; Found: C 61.63, H 6.29, N 11.68.
The pyrazoles 4a, 4c–j were similarly prepared following the general procedure described above.
The corresponding reactions conditions and work-ups are summarized in Table 4.
Table 4. Synthesized 3-substituted 1H-pyrazoles 4 via alkynylation-cyclocondensation
sequence.
Entry
(Hetero)Aryl iodide 1
(2.00 mmol)
Reaction
time t
Pyrazole 4
Chromatographic
purification
(isolated yield)
2nd step
15 min
1
1a, 1-Iodo-4-methoxybenzene
195 mg
CH2Cl2/MeOH/NH3
100:2:1
Merck
(1.12 mmol, 56%)
478 mg
4a

Molecules 2011, 16
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Table 4. Cont.
Reaction
(Hetero)Aryl iodide 1
Pyrazole 4
Chromatographic
Entry
time t
2nd step
15 min
(2.00 mmol)
(isolated yield)
purification
2
1b, 1-Iodo-3,4,5-
trimethoxybenzene
Alfa Aesar
295 mg
CH2Cl2/MeOH/NH3
100:2:1
(1.26 mmol, 63%)
600 mg
4b
3
4
1c, 1-Iodo-2-hydroxybenzene
15 min
150 mg
CH2Cl2/MeOH/NH3
100:1:1
ABCR
(0.94 mmol, 47%)
449 mg
4c
1d, 1-Iodo-3-hydroxybenzene
Alfa Aesar
15 min
196 mg
CH2Cl2/MeOH/NH3
100:1:1 → 100:3:1 →
100:7:1
(1.23 mmol, 61%)
449 mg
4d
5
6
1e, 1-Iodo-4-fluorobenzene
15 min
170 mg
CH2Cl2/MeOH/NH3
ABCR
(1.05 mmol, 53%)
100:1:1 → 100:2:1
0.32 mL
4e
1f, 1-Iodo-4-chlorobenzene
30 min
121 mg
CH2Cl2/MeOH/NH3
100:2:1
ABCR
(0.68 mmol, 34%)
482 mg
4f
7
1g, 1-Iodo-4-trifluoromethyl
benzene
15 min
244 mg
CH2Cl2/MeOH/NH3
(1.15 mmol, 57%)
100:1:1 → 100:2:1
Alfa Aesar
0.30 mL
4g

Molecules 2011, 16
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Table 1. Cont.
Reaction
Entry
(Hetero)Aryl iodide 1
Pyrazole 4
Chromatographic
(2.00 mmol)
time t
2nd step
15 min
(isolated yield)
purification
8
1h, 1-Iodo-4-cyanobenzene
90 mg
CH2Cl2/NH3 100:1 →
CH2Cl2/MeOH/NH3
100:1:1
ABCR
(0.53 mmol, 27%)
467 mg
4h
9
1i, 1-Iodo-3-nitrobenzene
15 min
209 mg
CH2Cl2/MeOH/NH3
100:2:1
ABCR
(1.10 mmol, 55%)
508 mg
4i
10
1j, 2-Iodothiophene
ABCR
1 h
151 mg
CH2Cl2/MeOH/NH3
100:1:1
(1.00 mmol, 50%)
429 mg
4j
3.4. Spectroscopic Data of 1H-Pyrazoles 4
3.4.1. 3-(4-Methoxyphenyl)-1H-pyrazole (4a)
195 mg (1.12 mmol, 56%) as a pale yellow solid. Mp 128 °C. 1H-NMR (CDCl3, 300 MHz):  3.83
(s, 3H), 6.52 (d, J = 2.0 Hz, 1H), 6.89–6.94 (m, 2H), 7.59 (d, J = 2.1 Hz, 1H), 7.65–7.69 (m, 2H), 10.9
13
(br, 1H). C-NMR (CDCl3, 75 MHz):  55.3 (CH3), 102.0 (CH), 114.1 (CH), 124.7 (Cquat), 127.1
(CH), 133.6 (CH), 148.5 (Cquat), 159.5 (Cquat). EI + MS (m/z (%)): 175 (12), 174 (M+, 100), 159
((M−CH3)+, 52), 145 ((M−HN2)+, 2), 132 ((M−CH2N2)+, 5), 131 (37), 77 (11). IR (Neat; Shimadzu
IRAffinity): 3048 (w) cm−1, 2965 (w), 2914 (w), 2904 (w), 2824 (w), 2783 (w), 2725 (w), 1611 (w),
1526 (w), 1508 (m), 1454 (m), 1439 (m), 1417 (w), 1275 (m), 1248 (s), 1182 (s), 1113 (w), 1098 (m),

Molecules 2011, 16
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1055 (w), 1026 (s), 952 (m), 934 (m), 897 (m), 853 (m), 831 (s), 795 (m), 773 (s), 729 (w), 611 (m).
Anal. calcd. for C10H10N2O (174.2): C 68.95, H 5.79, N 16.08; Found: C 68.73, H 5.48, N 15.88.
3.4.2. 3-(3,4,5-Trimethoxyphenyl)-1H-pyrazole (4b)
1
295 mg (1.26 mmol, 63%) as an orange solid. Mp 60 °C. H-NMR (CDCl3, 300 MHz):  3.88 (s,
13
3H), 3.90 (s, 6H), 6.58 (d, J = 1.7 Hz, 1H), 6.99 (s, 2H), 7.61 (d, J = 1.8 Hz, 1H). C-NMR (CDCl3,
75 MHz):  56.1 (CH3), 60.9 (CH3), 102.5 (CH), 103.0 (CH), 127.9 (Cquat), 132.6 (CH), 138.0 (Cquat),
149.5 (Cquat), 153.5 (Cquat). EI + MS (m/z (%)): 235 (13), 234 (M+, 100), 219 ((M-CH3)+, 68), 205
((M-HN2)+, 2), 192 ((M-CH2N2)+, 2), 191 (30), 176 (30), 161 (20), 159 (15), 149 (13), 131 (15), 105
(22), 58 (23), 43 (67). IR (Neat; Shimadzu IRAffinity): 3576 (w) cm−1, 3146 (w), 3041 (w), 2995 (w),
2963 (w), 2930 (m), 2860 (w), 2826 (w), 1730 (w), 1587 (m), 1516 (m), 1474 (m), 1449 (m), 1416
(m), 1325 (m), 1288 (w), 1261 (w), 1238 (m), 1121 (s), 1092 (m), 1057 (m), 1034 (w), 995 (s), 928
(w), 889 (w), 845 (s), 826 (m), 760 (s), 739 (m), 665 (w), 627 (m). Anal. calcd. for C12H14N2O3
(234.3): C 61.53, H 6.03, N 11.96; Found: C 61.63, H 6.29, N 11.68.
3.4.3. 2-(1H-Pyrazol-3-yl)phenol (4c)
1
150 mg (0.94 mmol, 47%) as a yellow solid. Mp 92 °C. H-NMR (CDCl3, 300 MHz):  6.73 (d,
J = 2.6 Hz, 1H), 6.93 (ddd, J = 7.7 Hz, J = 7.3 Hz, J = 2.0 Hz, 1H), 7.05 (dd, J = 8.2 Hz, J = 1.0 Hz,
1H), 7.24 (ddd, J = 8.2 Hz, J = 7.3 Hz, J = 2.0 Hz, 1H), 7.61 (dd, J = 7.7 Hz, J = 1.6 Hz, 1H), 7.64 (d,
13
J = 2.6 Hz, 1H), 9.9–11.2 (br, 2 H). C-NMR (CDCl3, 75 MHz):  102.1 (CH), 116.5 (Cquat), 117.0
(CH), 119.3 (CH), 126.6 (CH), 129.1 (CH), 129.3 (CH), 152.0 (Cquat), 155.8 (Cquat). EI + MS
(m/z (%)): 161 (11), 160 (M+, 100), 132 (12), 131 ((M−HN2)+, 53), 104 (12). IR (KBr; Bruker Vector
22 FT-IR): 3277 (s) cm−1, 1736 (w), 1719 (w), 1686 (w), 1655 (w), 1625 (m), 1589 (s), 1560 (w), 1518
(m), 1451 (s), 1399 (m), 1286 (m), 1256 (s), 1200 (m), 1126 (m), 1110 (m), 1080 (m), 1047 (m), 952
(m), 826 (m), 779 (s), 746 (s), 600 (m), 561 (m), 517 (m). Anal. calcd. for C9H8N2O (160.2): C 67.49,
H 5.03, N 17.49; Found: C 67.41, H 4.90, N 17.26.

Molecules 2011, 16
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3.4.4. 3-(1H-Pyrazol-3-yl)phenol (4d)
1
196 mg (1.23 mmol, 61%) as a pale brown solid. Mp 154 °C. H-NMR (DMSO-d6, 300 MHz): 
6.60 (d, J = 2.0 Hz, 1H), 6.68-6.70 (m, 1H), 7.15-7.31 (m, 3H), 7.7 (br, 1H), 9.4 (br, 1H), 12.4–13.5
(2xbr, 1H).13C-NMR (DMSO-d6, 75 MHz):  102.1 (CH), 112.2 (CH), 114.7 (CH), 116.3 (CH), 129.9
(CH), 135.3 (Cquat), 150.3 (Cquat), 157.8 (Cquat). EI + MS (m/z (%)): 161 (11), 160 (M+, 100), 131
((M-HN2)+, 25), 93 (C6H5O+, 3). IR (KBr, Bruker Vector 22 FT-IR): 3245 (s) cm−1, 1610 (m), 1591 (s),
1541 (w), 1494 (m), 1478 (s), 1439 (s), 1382 (m), 1292 (m), 1258 (s), 1239 (m), 1218 (m), 1161 (w),
1117 (m), 1097 (m), 1082 (m), 1053 (m), 987 (w), 940 (m), 862 (s), 758 (s), 681 (s), 605 (w), 540 (w).
Anal. calcd. for C9H8N2O (160.2): C 67.49, H 5.03, N 17.49; Found: C 67.50, H 5.04, N 17.31.
3.4.5. 3-(4-Fluorophenyl)-1H-pyrazole (4e)
170 mg (1.05 mmol, 53%) as a pale brown solid. Mp 104 °C. 1H-NMR (CDCl3, 300 MHz):  6.56
13
(m, 1H), 7.07 (t, J = 8.7 Hz, 2H), 7.59 (m, 1H), 7.69-7.74 (m, 2H), 11.0-12.2 (br, 1H). C-NMR
(CDCl3, 75 MHz):  102.5 (CH), 115.7 (d, J = 21.7 Hz, CH), 127.5 (d, J = 8.1 Hz, CH), 128.6 (Cquat),
132.5 (CH), 148.9 (Cquat), 162.6 (d, J = 247.1 Hz, Cquat). EI + MS (m/z (%)): 163 (11), 162 (M+, 100),
161 (11), 135 (16), 133 ((M-HN2)+, 27), 108 (11), 95 (C6H4F+, 10). IR (Neat; Shimadzu IRAffinity):
3121 (w) cm−1, 3051 (w), 3034 (w), 2959 (w), 2918 (w), 2901 (w), 2882 (w), 2860 (w), 2841 (w),
2814 (w), 2776 (w), 2745 (w), 2725 (w), 2675 (w), 2627 (w), 2581 (w), 1651 (w), 1607 (w), 1524 (m),
1506 (m), 1452 (m), 1408 (w), 1352 (w), 1337 (w), 1233 (s), 1223 (s), 1204 (w), 1157 (m), 1111 (w),
1094 (m), 1082 (w), 1051 (m), 1015 (w), 953 (m), 934 (m), 885 (w), 839 (s), 812 (s), 770 (s), 752 (w),
692 (w), 673 (w), 602 (m). Anal. calcd. for C9H7FN2 (162.2): C 66.66, H 4.35, N 17.27; Found: C
66.92, H 4.41, N 17.00.
3.4.6. 3-(4-Chlorophenyl)-1H-pyrazole (4f)

Molecules 2011, 16
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1
121 mg (0.68 mmol, 34 %) as an orange-brown solid. Mp 95 °C. H-NMR (CDCl3, 300 MHz): 
6.60 (s, 1H), 7.36 (d, J = 8.4 Hz, 2H), 7.60 (s, 1H), 7.69 (d, J = 8.5 Hz, 2H), 8.5–12.1 (br, 1H).
13C-NMR (CDCl3, 75 MHz):  102.8 (CH), 127.1 (CH), 128.9 (CH), 131.0 (Cquat), 132.2 (CH), 133.8
(Cquat), 149.0 (Cquat). EI + MS (m/z (%)): 180 (M(37Cl)+, 30), 179 (14), 178 (M(35Cl)+, 100), 151
37
((M−HN2)(37Cl)+, 10), 149 ((M−HN2)(35Cl)+, 4), 116 (10), 115 (19), 113 (C6H4 Cl+, 5), 111
35
(C6H4 Cl+, 7), 89 (12). IR (Neat; Shimadzu IRAffinity): 3165 (w) cm−1, 2955 (w), 2918 (m), 2876
(w), 2847 (w), 1510 (m), 1447 (m), 1406 (w), 1115 (w), 1090 (s), 1080 (m), 1047 (m), 1013 (m), 953
(m), 924 (m), 878 (w), 833 (s), 761 (s), 723 (m), 692 (m), 613 (m). Anal. calcd. for C9H7ClN2 (178.6):
C 60.52, H 3.95, N 15.68; Found: C 60.78, H 4.15, N 15.55.
3.4.7. 3-[4-(Trifluoromethyl)phenyl]-1H-pyrazole (4g)
244 mg (1.15 mmol, 57%) as a pale brown solid. Mp 162 °C. 1H-NMR (CDCl3, 300 MHz):  6.68
(m, 1H), 7.62 (m, 1H), 7.63 (d, J = 8.1 Hz, 2H), 7.87 (d, J = 8.1 Hz, 2H), 10.9–12.7 (br, 1H). 13C-NMR
(CDCl3, 75 MHz):  103.0 (CH), 124.1 (q, J = 271.9 Hz, Cquat), 125.7 (q, J = 3.8 Hz, CH), 125.9 (CH),
129.8 (q, J = 32.5 Hz, Cquat), 132.0 (CH), 135.9 (Cquat), 149.1 (Cquat). EI + MS (m/z (%)): 213 (11), 212
(M+, 100), 211 (12), 193 ((M−F)+, 7), 185 (11), 183 ((M−HN2)+, 5), 145 (14). IR (Neat; Shimadzu
IRAffinity): 3122 (w) cm−1, 3030 (w), 3013 (w), 2959 (w), 2918 (w), 2900 (w), 2868 (w), 2779 (w),
2727 (w), 2679 (w), 1620 (m), 1468 (w), 1416 (w), 1321 (s), 1275 (w), 1182 (s), 1159 (m), 1109 (s),
1097 (s), 1064 (s), 1053 (m), 1013 (m), 957 (m), 930 (w), 881 (w), 841 (s), 783 (m), 770 (s), 741 (m),
692 (m), 673 (w), 617 (w). Anal. calcd. for C10H7F3N2 (212.2): C 56.61, H 3.33, N 13.20; Found: C
56.83, H 3.08, N 13.04.
3.4.8. 4-(1H-Pyrazol-3-yl)benzonitrile (4h)
1
90 mg (0.53 mmol, 27%) as a pale yellow solid. Mp 143 °C. H-NMR (CDCl3, 300 MHz):  6.70
(m, 1H), 7.66 (m, 1H), 7.68 (d, J = 8.5 Hz, 2H), 7.89 (d, J = 8.5 Hz, 2H), 10.4–12.5 (br, 1H).
13C-NMR (CDCl3, 75 MHz):  103.5 (CH), 111.1 (Cquat), 118.9 (Cquat), 126.1 (CH), 131.3 (CH), 132.6
(CH), 137.2 (Cquat), 149.1 (Cquat). EI + MS (m/z (%)): 170 (12), 169 (M+, 100), 142 (15), 140
((M−HN2)+, 12), 102 (C7H4N+, 7). IR (Neat; Shimadzu IRAffinity): 3248 (w) cm−1, 3237 (w), 3129
(w), 3057 (w), 2980 (m), 2972 (m), 2889 (w), 2814 (w), 2220 (w), 1929 (w), 1609 (m), 1508 (w), 1464

Molecules 2011, 16
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(w), 1449 (w), 1393 (w), 1350 (w), 1233 (w), 1221 (w), 1184 (m), 1157 (w), 1074 (w), 1051 (m), 968
(w), 951 (s), 934 (w), 841 (s), 768 (s), 731 (m), 685 (w), 608 (s). Anal. calcd. for C10H7N3 (169.2): C
70.99, H 4.17, N 24.84; Found: C 70.78, H 4.10, N 24.59.
3.4.9. 3-(3-Nitrophenyl)-1H-pyrazole (4i)
209 mg (1.10 mmol, 55%) as a pale brown solid. Mp 121 °C. 1H-NMR (CDCl3, 300 MHz):  6.74
(d, J = 2.3 Hz, 1H), 7.58 (t, J = 8.0 Hz, 1H), 7.70 (d, J = 2.4 Hz, 1H), 8.15 (tdd, J = 8.1 Hz, J = 2.2 Hz,
13
J = 1.1 Hz, 2H), 8.64 (t, J = 1.9 Hz, 1H), 9.8–12.3 (br, 1H). C-NMR (CDCl3, 75 MHz):  103.2
(CH), 120.6 (CH), 122.5 (CH), 129.7 (CH), 131.1 (CH), 131.6 (CH), 134.7 (Cquat), 148.7 (Cquat), 149.1
(Cquat). EI + MS (m/z (%)): 190 (12), 189 (M+, 100), 143 ((M−NO2)+, 33), 142 (10), 116 (39), 89 (28).
IR (Neat; Shimadzu IRAffinity): 3173 (w) cm−1, 3067 (w), 2961 (w), 2926 (w), 2851 (w), 1557 (w),
1530 (m), 1518 (m), 1504 (m), 1487 (m), 1398 (w), 1375 (m), 1344 (m), 1315 (w), 1275 (m), 1265
(w), 1221 (w), 1202 (w), 1072 (w), 993 (m), 972 (w), 897 (w), 851 (w), 829 (w), 775 (m), 735 (m),
698 (s), 683 (m), 671 (m), 615 (m). Anal. calcd. for C9H7N3O2 (189.2): C 57.14, H 3.73, N 22.21;
Found: C 57.19, H 4.02, N 22.18.
3.4.10. 3-(Thiophen-2-yl)-1H-pyrazole (4j)
1
151 mg (1.00 mmol, 50%) as an orange solid. Mp 89 °C. H-NMR (CDCl3, 300 MHz):  6.54 (d,
J = 2.1 Hz, 1H), 7.07 (dd, J = 5.1 Hz, J = 3.6 Hz, 1H), 7.27 (dd, J = 5.1 Hz, J = 1.0 Hz, 1H), 7.35 (dd,
13
J = 3.6 Hz, J = 1.1 Hz, 1H), 7.63 (d, J = 2.3 Hz, 1H), 11.55 (s, 1H). C-NMR (CDCl3, 75 MHz): 
102.7 (CH), 124.2 (CH), 124.6 (CH), 127.6 (CH), 131.5 (CH), 135.7 (Cquat), 145.6 (Cquat). EI + MS
(m/z (%)): 152 (13), 151 (26), 150 (M+, 100), 123 (20), 122 (16), 121 ((M−HN2)+, 35), 105
((M−CHS)+, 7), 96 (22), 78 (12). IR (Neat; Shimadzu IRAffinity): 3146 (w) cm−1, 3129 (w), 3117 (w),
3102 (w), 3022 (w), 2957 (w), 2913 (w), 2872 (w), 2855 (w), 2808 (w), 2361 (w), 1732 (w), 1560 (w),
1522 (w), 1464 (w), 1410 (w), 1371 (w), 1273 (w), 1179 (m), 1047 (m), 1030 (m), 910 (m), 845 (m),
824 (m), 756 (s), 723 (w), 692 (s), 644 (w), 602 (m). Anal. calcd. for C7H6N2S (150.2): C 55.97, H
4.03, N 18.65; Found: C 56.12, H 4.12, N 18.46.

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4. Conclusions
In summary, we have disclosed a novel consecutive three-component synthesis of 3-(hetero)aryl-
1H-pyrazoles 4 in moderate to good yields starting with the Sonogashira coupling of (hetero)aryl
iodides 1 and the commercially available propynal diethylacetal (2) as a propargyl aldehyde synthetic
equivalent, followed by a rapid sequential acetal cleavage-cyclocondensation with hydrazine
hydrochloride. Further studies directed to the synthesis of luminescent pyrazole derivatives as ligands
for metal organic frameworks (MOFs) are currently underway.
Acknowledgments
The work was supported by the Fonds der Chemischen Industrie and the authors gratefully thank
Merck Serono, Darmstadt, for the donation of chemicals.
References
1. Kost, A.N.; Grandberg, I.I. Progress in pyrazole chemistry. Adv. Heterocycl. Chem. 1966, 6, 347-429.
2. Elguero, J. Pyrazoles and their benzo derivatives. In Comprehensive Heterocyclic Chemistry;
Katritzky, A.R., Rees, C.W., Eds.; Pergamon: Oxford, UK, 1984; Volume 5, pp. 167-303.
3. Elguero, J. Pyrazoles. In Comprehensive Heterocyclic Chemistry II, Katritzky, A.R., Rees, C.W.,
Scriven, E.F.V., Eds.; Elsevier: Oxford, UK, 1996; Volume 3, pp. 1-75.
4. Wustrow, D.J.; Capiris, T.; Rubin, R.; Knobelsdorf, J.A.; Akunne, H.; Davis, M.D.; MacKenzie, R.;
Pugsley, T.A.; Zoski, K.T.; Heffner, T.G.; et al. Pyrazolo[1,5-a]pyrimidine CRF-1 receptor
antagonists. Bioorg. Med. Chem. Lett. 1998, 8, 2067-2070.
5. Menozzi, G.; Mosti, L.; Fossa, P.; Mattioli, F.; Ghia, M. ω-Dialkylaminoalkyl ethers of phenyl-(5-
substituted 1-phenyl-1H-pyrazol-4-yl)methanols with analgesic and anti-inflammatory activity.
J. Heterocycl. Chem. 1997, 34, 963-968.
6. Penning, T.D.; Talley, J.J.; Bertenshaw, S.R.; Carter, J.S.; Collins, P.W.; Docter, S.; Graneto, M.J.;
Lee, L.F.; Malecha, J.W.; Miyashiro, J.M.; et al. Synthesis and biological evaluation of the 1,5-
diarylpyrazole class of cyclooxygenase-2 inhibitors: Identification of 4-[5-(4-methylphenyl)-3-
(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (SC-58635, Celecoxib). J. Med. Chem.
1997, 40, 1347-1365.
7. Chimenti, F.; Fioravanti, R.; Bolasco, A.; Manna, F.; Chimenti, P.; Secci, D.; Befani, O.; Turini, P.;
Ortuso, F.; Alcaro, S. Monoamine oxidase isoform-dependent tautomeric influence in the
recognition of 3,5-diaryl pyrazole inhibitors. J. Med. Chem. 2007, 50, 425-428.
8. Walworth, B.L.; Klingsberg, E. Neue herbicide Zusammensetzungen. DE 2260485 19730628,
1973.
9. Trofimenko, S. Coordination chemistry of pyrazole-derived ligands. Chem. Rev. 1972, 72, 497-509.
10. Mukherjee, R. Coordination chemistry with pyrazole-based chelating ligands: Molecular
structural aspects. Coord. Chem. Rev. 2000, 203, 151-218.
11. Trofimenko, S. Scorpionates: Genesis, milestones, prognosis. Polyhedron 2004, 23, 197-203.

Molecules 2011, 16
9354
12. Ward, M.D.; McCleverty, J.A.; Jeffery, J.C. Coordination and supramolecular chemistry of
multinucleating ligands containing two or more pyrazolyl-pyridine ‘arms’. Coord. Chem. Rev.
2001, 222, 251-272.
13. Harb, A.-F.A.; Abbas, H.H.; Mostafa, F.H. Pyrazoles as building blocks in heterocyclic synthesis:
Synthesis of some new substituted 1-triazinylpyrazolo[3,4-d]pyrimidine and 1-triazinylpyrazolo[3,4-
b]pyridine derivatives. Chem. Pap. 2005, 59, 187-195.
14. Harb, A.-F.A.; Abbas, H.H.; Mostafa, F.H. Pyrazoles as building blocks in heterocyclic synthesis:
Synthesis of pyrazolo[3,4-d]pyrimidine, pyrazolo[3,4-e][1,4]diazepine, pyrazolo[3,4-d][1,2,3]-
triazine and pyrrolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine derivatives. J. Iranian Chem. Soc. 2005,
2, 115-123.
15. Sachse, A.; Penkova, L.; Noël, G.; Dechert, S.; Varzatskii, O.A.; Fritsky, I.O.; Meyer, F. Efficient
syntheses of some versatile 3,5-bifunctional pyrazole building blocks. Synthesis 2008, 800-806.
16. Maeda, H.; Ito, Y.; Kusunose, Y.; Nakanishi, T. Dipyrrolylpyrazoles: Anion receptors in
protonated form and efficient building blocks for organized structures. Chem. Commun. 2007,
1136-1138.
17. Gemming, S.; Schreiber, M.; Thiel, W.; Heine, T.; Seifert, G.; Avelino de Abreu, H.; Anderson
Duarte, H. Tunable discotic building blocks for liquid crystalline displays. J. Luminescence 2004,
108, 143-147.
18. Dolars, A.; Schellhammer, C.-W.; Schroeder, J. Heterocycles as structural units in new optical
brighteners. Angew. Chem. Int. Ed. Engl. 1975, 14, 665-679.
19. Catalan, J.; Fabero, F.; Claramunt, R.M.; Santa Maria, M.D.; Foces-Foces, M.C.; Hernandez Cano, F.;
Martinez-Ripoll, M.; Elguero, J.; Sastre, R. New ultraviolet stabilizers: 3- and 5-(2'-
Hydroxyphenyl)pyrazoles. J. Am. Chem. Soc. 1992, 114, 5039-5048.
20. Karatsu, T.; Shiochi, N.; Aono, T.; Miyagawa, N.; Kitamura, A. Photoinduced electron transfer
reactions of 3H-pyrazole derivatives. Formation of solvent adduct by specific sensitizer.
Bull. Chem. Soc. Jpn. 2003, 76, 1227-1231.
21. Yen, Y.-P.; Huang, T.-M.; Tseng, Y.-P.; Lin, H.-Y.; Lai, C.-C. Photoinduced electron transfer
reactions of 3,3-dialkylated 4,5-diphenyl-3H-pyrazoles: A new route to the formation of the
solvent adducts. J. Chin. Chem. Soc. 2004, 51, 393-398.
22. Zhu, J.; Bienaymé, H. Multicomponent Reactions; Wiley-VCH: Weinheim, Germany, 2005.
23. Touré, B.B.; Hall, D.G. Natural product synthesis using multicomponent reaction strategies.
Chem. Rev. 2009, 109, 4439-4486.
24 Sunderhaus, J.D.; Martin, S.F. Applications of multicomponent reactions to the synthesis of
diverse heterocyclic scaffolds. Chem. Eur. J. 2009, 15, 1300-1308.
25. Isambert, N.; Lavilla, R. Heterocycles as key substrates in multicomponent reactions: The fast
lane towards molecular complexity. Chem. Eur. J. 2008, 14, 8444-8454.
26. D’Souza, D.M.; Müller, T.J.J. Multi-component syntheses of heterocycles by transition-metal
catalysis. Chem. Soc. Rev. 2007, 36, 1095-1108.
27. Dömling, A. Recent developments in isocyanide based multicomponent reactions in applied
chemistry. Chem. Rev. 2006, 106, 17-89.
28. Orru, R.V.A.; de Greef, M. Recent advances in solution-phase multicomponent methodology for the
synthesis of heterocyclic compounds. Synthesis 2003, 1471-1499.

Molecules 2011, 16
9355
29. Bienaymé, H.; Hulme, C.; Oddon, G.; Schmitt, P. Maximizing synthetic efficiency:
Multi-component transformations lead the way. Chem. Eur. J. 2000, 6, 3321-3329.
30. Dömling, A.; Ugi, I. Multicomponent reactions with isocyanides. Angew. Chem. Int. Ed. Engl. 2000,
39, 3168-3210.
31. Ugi, I.; Dömling, A.; Werner, B. Since 1995 the new chemistry of multicomponent reactions and
their libraries, including their heterocyclic chemistry. J. Heterocycl. Chem. 2000, 37, 647-658.
32. Weber, L.; Illgen, K.; Almstetter, M. Discovery of new multi-component reactions with
combinatorial methods. Synlett 1999, 366-374.
33. Armstrong, R.W.; Combs, A.P.; Tempest, P.A.; Brown, S.D.; Keating, T.A. Multiple-component
condensation strategies for combinatorial library synthesis. Acc. Chem. Res. 1996, 29, 123-131.
34. Ugi, I.; Dömling, A.; Hörl, W. Multicomponent reactions in organic chemistry. Endeavour 1994,
18, 115-122.
35. Posner, G.H. Multicomponent one-pot annulations forming 3 to 6 bonds. Chem. Rev. 1986, 86,
831-844.
36. Tietze, L.F. Domino reactions in organic synthesis. Chem. Rev. 1996, 96, 115-136.
37. Tietze, L.F.; Beifuss, U. Sequential transformations in organic chemistry: A synthetic strategy
with a future. Angew. Chem. Int. Ed. Engl. 1993, 32, 131-163.
38. Tietze, L.F. Domino-reactions: The tandem-Knoevenagel-hetero-Diels-Alder reaction and its
application in natural product synthesis. J. Heterocycl. Chem. 1990, 27, 47-69.
39. Coquerel, Y.; Boddaert, T.; Presset, M.; Mailhol, D.; Rodriguez, J. Multiple bond-forming
transformations: The key concept toward eco-compatible synthetic organic chemistry. In Ideas in
Chemistry and Molecular Sciences: Advances in Synthetic Chemistry; Pignataro, B., Eds.;
Wiley-VCH: Weinheim, Germany, 2010; pp. 187-202.
40. Vries, J.G. The Heck reaction in the production of fine chemicals. Can. J. Chem. 2001, 79,
1086-1092.
41. Pommer, H. The Wittig reaction in industrial practice. Angew. Chem. Int. Ed. Engl. 1977, 16,
423-429.
42. Müller, T.J.J. Palladium-copper catalyzed alkyne activation as an entry to multicomponent
syntheses of heterocycles. Top. Heterocycl. Chem. 2010, 25, 25-94.
43. Willy, B.; Müller, T.J.J. Multi-component heterocycle syntheses via catalytic generation of
alkynones. Curr. Org. Chem. 2009, 13, 1777-1790.
44. Willy, B.; Müller, T.J.J. Consecutive multi-component syntheses of heterocycles via palladium-
copper catalyzed generation of alkynones. ARKIVOC 2008, 195-208.
45. Müller, T.J.J. Multi-component syntheses of heterocycles by virtue of palladium catalyzed
generation of alkynones and chalcones. Targets Heterocycl. Syst. 2006, 10, 54-65.
46. Willy, B.; Müller, T.J.J. Regioselective three-component synthesis of highly fluorescent 1,3,5-
trisubstituted pyrazoles. Eur. J. Org. Chem. 2008, 4157-4168.
47. Willy, B.; Müller, T.J.J. Rapid one-pot, four-step synthesis of highly fluorescent 1,3,4,5-
tetrasubstituted pyrazoles. Org. Lett. 2011, 13, 2082-2085.
48. Bagley, M.C.; Lubinu, M.C.; Mason, C. Regioselective microwave-assisted synthesis of
substituted pyrazoles from ethynyl ketones. Synlett 2007, 704-708.

Molecules 2011, 16
9356
49. Evans, G.B.; Furneaux, R.H.; Gainsford, G.J.; Hanson, J.C.; Kicska, G.A.; Sauve, A.A.;
Schramm, V.L.; Tyler, P.C. 8-Aza-immucillins as transition-state analogue inhibitors of purine
nucleoside phosphorylase and nucleoside hydrolases. J. Med. Chem. 2003, 46, 155-160.
50. Zhou, J.; Yang, M.; Akdag, A.; Wang, H.; Schneller, S.W. Carbocyclic 4′-epi-formycin.
Tetrahedron 2008, 64, 433-438.
51. Zhou, J.; Yang, M.; Schneller, S.W. A model study to carbocyclic formycin A and B analogues.
Tetrahedron Lett. 2004, 45, 8233-8234.
52. Buchanan, J.G.; Edgar, A.R.; Hutchison, R.J.; Stobie, A.; Wightman, R.H. C-nucleoside studies.
Part 10. A new synthesis of 3-(2,3,5-tri-O-benzyl-β-D-ribofuranosyl)pyrazole and its conversion
into 4-nitro-3(5)-β-D-ribofuranosylpyrazole. J. Chem. Soc. Perkin Trans. 1 1980, 2567-2571.
53. Buchanan, J.G.; Dunn, A.D.; Edgar, A.R.; Hutchison, R.J.; Power, M.J.; Williams, G.C.
C-nucleoside studies. Part 6. Synthesis of 3-[2,3,5-tri-O-benzyl-β-(and α)-D-ribofuranosyl]prop-2-
yn-1-ol and related compounds;
a
new synthesis of 3(5)-(2,3,5-tri-O-benzyl-β-D-
ribofuranosyl)pyrazole. J. Chem. Soc. Perkin Trans. 1 1977, 1786-1791.
54. Hüttel, R.; Büchele, F.; Jochum, P. Über Nitro-, Nitroso- und Azopyrazole. Chem. Ber. 1955, 88,
1577-1585.
55. Karpov, A.S.; Müller, T.J.J. New entry to a three-component pyrimidine synthesis by
TMS-ynones via Sonogashira coupling. Org. Lett. 2003, 5, 3451-3454.
56. Bagley, M.C.; Hughes, D.D.; Sabo, H.M.; Taylor, P.H.; Xiong, X. One-pot synthesis of pyridines or
pyrimidines by tandem oxidation-heteroannulation of propargylic alcohols. Synlett 2003, 1443-1446.
57. Lemhadri, M.; Doucet, H.; Santelli, M. Sonogashira reaction of aryl halides with propiolaldehyde
diethyl acetal catalyzed by a tetraphosphine/palladium complex. Tetrahedron 2005, 61, 9839-9847.
58. Cacchi, S.; Fabrizi, G.; Marinelli, F.; Moro, L.; Pace, P. Palladium-catalysed hydroarylation and
hydrovinylation of 3,3-dialkoxy-1-aryl-1-propynes. An approach to 3-aryl- and 3-vinylquinolines.
Tetrahedron 1996, 52, 10225-10240.
59. Sakamoto, T.; Shiga, F.; Yasuhara, A.; Uchiyama, D.; Kondo, Y.; Yamanaka, H. Preparation of
ethyl arylpropiolates from aryl iodides by palladium-catalyzed cross-coupling reaction. Synthesis
1992, 746-748.
60. Stoit, A.; Coolen, H.K.A.C.; Kruse, C.G.; Terwel, L.J.H. Heterocyclic compounds with affinity to
muscarinic receptors. PCT Int. Appl. WO 2008129054 A2, 30 October 2008.
61. Buchanan, J.G.; Quijano, M.L.; Wightman, R.H. C-nucleoside studies. Part 23. New and more
direct synthesis of 3-(β-D-xylofuranosyl)pyrazole. J. Chem. Soc. Perkin Trans. 1 1992, 1573-1576.
62. Jones, R.G.; Mann, M.J. New methods of synthesis of p-aminoethylpyrazoles. J. Am. Chem. Soc.
1953, 75, 4048-4052.
Sample Availability: Samples of the compounds 4 are available from the authors.
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