Sonogashira coupling offers a new synthetic route to thieno[2,3-c]pyrazoles

Article abstract of DOI:10.1080/00397911003629382

1,3-Disubstituted-5-chloro-4-iodopyrazoles are selectively coupled with phenylacetylene under typical Sonogashira reaction conditions [PdCl ₂(PPh₃)₂, CuI, Et₃N, dimethylformamide (DMF)] to obtain the correspondi

Full text of DOI:10.1080/00397911003629382

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Sonogashira Coupling Offers a New
Synthetic Route to Thieno[2,3-
c]pyrazoles
b
b
Gernot A. Eller a , Gytė Vilkauskaitė , Eglė Arbačiauskienė ,
Algirdas Šačkus b & Wolfgang Holzer a
a Department of Drug and Natural Product Synthesis, University of
Vienna, Vienna, Austria
b Institute of Synthetic Chemistry, Kaunas University of Technology,
Kaunas, Lithuania
Version of record first published: 02 Feb 2011
To cite this article: Gernot A. Eller, Gytė Vilkauskaitė, Eglė Arbačiauskienė, Algirdas Šačkus
& Wolfgang Holzer (2011): Sonogashira Coupling Offers a New Synthetic Route to Thieno[2,3-
c]pyrazoles, Synthetic Communications: An International Journal for Rapid Communication of
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Synthetic Communications1, 41: 541–547, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911003629382
SONOGASHIRA COUPLING OFFERS A NEW
SYNTHETIC ROUTE TO THIENO[2,3-c]PYRAZOLES
1
Gernot A. Eller, Gyte Vilkauskaite, Egle Arbaciauskiene,
2
2
ˇ
˙
Algirdas Sackus, and Wolfgang Holzer
˙
˙
˙
2
1
ˇ
ˇ
1Department of Drug and Natural Product Synthesis, University of Vienna,
Vienna, Austria
2Institute of Synthetic Chemistry, Kaunas University of Technology, Kaunas,
Lithuania
Abstract 1,3-Disubstituted-5-chloro-4-iodopyrazoles are selectively coupled with phenylace-
tylene under typical Sonogashira reaction conditions [PdCl2(PPh3)2, CuI, Et3N, dimethyl-
formamide (DMF)] to obtain the corresponding 5-chloro-4-(phenylethynyl)pyrazoles in
good yield. The latter are smoothly cyclized with Na2S in DMF into the corresponding
thieno[2,3-c]pyrazoles. Detailed spectroscopic investigations (1H, 13C, and 15N NMR,
mass, and infrared) of all compounds are reported.
Keywords Fused-ring systems; NMR spectroscopy; palladium catalysis; pyrazoles
In continuation of our research on the reactivity of substituted pyrazoles toward
palladium-catalyzed cross-coupling reactions,[1,2] we investigated the suitability of
dihalopyrazole derivatives for a novel synthetic route to the thieno[2,3-c]pyrazole
nucleus using the Sonogashira coupling.[3,4] This reaction provides an effective
method for C–C bond formation and has also been applied as a key step in the
synthesis of condensed heterocyclic systems.[5]
Starting from easily accessible and commercially available 1,3-disubstituted-5-
chloro-1H-pyrazoles 1, a second halogen substituent was introduced at position 4 of
the pyrazole nucleus by a standard halogenation protocol ðI2=IOꢀ3 Þ to obtain the
corresponding 5-chloro-4-iodopyrazoles 2 (Scheme 1). The latter were selectively
linked to phenylacetylene in a Sonogashira cross-coupling reaction, yielding only
the 4-(phenylethynyl)pyrazoles 3 in good yields (87–92%). The structures of
Received September 15, 2009.
Address correspondence to Gernot A. Eller or W. Holzer, Department of Drug and Natural
Product Synthesis, University of Vienna, A-1090 Vienna, Austria. E-mail: gernot.eller@univie.ac.at or
wolfgang.holzer@univie.ac.at
541

542
G. A. ELLER ET AL.
Scheme 1. Synthetic route to thieno[2,3-c]pyrazoles 4.
compounds 3 were unambiguously confirmed by means of mass spectrometry (MS),
multinuclear NMR spectroscopy, infrared (IR), and microanalysis.
From theoretical considerations, the selectivity in this key reaction is explain-
able. Although 5-iodopyrazoles are known to be more reactive for cross-couplings
than 3- or 4-iodopyrazoles, the position of the halogen atom is by far less significant
for the reactivity than the halogen’s nature.[4,6,7] Among pyrazolyl-halides, a very clear
preference in Sonogashira reactions for the iodides over the corresponding bromides
and chlorides is evident. This effect is by far the dominating one and thus neutralizes
and reverses the positional effect that would favor the substitution in position 5.
In the final reaction step, compounds 3 were reacted with sodium sulfide in
dimethyl formamide to finally obtain the targeted fused heterocyclic ring system
of compounds 4 (Scheme 1).
All the compounds prepared were thoroughly investigated with respect to their
NMR spectra. Thus, unambiguous assignment of all proton, carbon, and nitrogen
resonances was carried out by combined application of different standard NMR meth-
ods such as fully 1H-coupled 13C NMR spectra, APT, heteronuclear multiple quantum
correlation (HMQC), gradient selected heteronuclear single quantum coherence
(gs-HSQC), gradient selected heteronuclear multiple bond coherence (gs-HMBC),
nuclear Overhauser effect spectroscopy (NOESY), and nuclear Overhauser effect
1
(NOE)–difference spectroscopy.[8] Moreover, many 13C and H coupling constants
could be unequivocally assigned using two-dimensional (2D) (d, J) insensitive nuclei
enhanced by polarization transfer (INEPT) spectra with selective excitation of
1
unambiguously assigned H resonances.[9]

NEW SYNTHETIC ROUTE TO THIENO[2,3-c]PYRAZOLES
543
The substitution pattern in compounds 3 (entry of alkyne substituent into
the 4-position after reaction of 2 with phenylacetylene) can be clearly deduced con-
sidering the 13C NMR spectrum of 3. Whereas in compounds 2 the pyrazole C-4
resonance—easily assignable in the 1H-coupled 13C NMR spectrum because of a vic-
inal coupling (3J ¼ 4.2 Hz) to the methyl protons—receives a significant high-field
shift as a result of the directly attached iodine atom (d 60.8 and 64.6 ppm, respectively,
heavy-atom effect[10]), the pyrazole C-4 signal in coupling products 3 (iodine atom
replaced by an alkyne-C atom) exhibits a much larger chemical shift [d 101.6 and
103.9 ppm, respectively; 3J(C4, Me) ¼ 3.5 Hz and 3.4 Hz, respectively]. The two
alkyne-C signals in the 13C NMR spectrum of 3 can be smoothly distinguished con-
sidering their coupling patterns: while the alkyne-C attached to pyrazole C-4 does not
show couplings to any protons, the signal of CꢁCPh is split into a triplet (J ¼ 5.3 Hz
and 5.4 Hz, respectively) because of a vicinal coupling to the phenyl protons 2 and 6.
In conclusion, we have demonstrated a hitherto unknown short synthetic route
to thieno[2,3-c]pyrazoles from the corresponding 4,5-dihalopyrazoles.
EXPERIMENTAL
Instruments
Melting points were determined on a Reichert-Kofler hot-stage microscope and
are uncorrected. Mass spectra were obtained on a Shimadzu QP 1000 instrument (EI,
70 eV, MS) and on a Finnigan MAT 8230 instrument (EI, 70 eV, HRMS). IR spectra
were recorded on a Perkin-Elmer Fourier transform (FT)–IR 1605 spectrophot-
ometer. Elemental analyses were performed at the Microanalytical Laboratory,
1
University of Vienna. The H and 13C NMR spectra were recorded on a Varian
1
UnityPlus 300 spectrometer at 28 ꢂC (299.95 MHz for H, 75.43 MHz for 13C) or on
1
a Bruker Avance 500 spectrometer at 293 K (500.13 MHz for H, 125.77 MHz for
13C). The center of the solvent signal was used as an internal standard, which was
related to tetramethylsilane (TMS) with d ¼ 7.26 ppm (1H in CDCl3) and d ¼ 77.0 ppm
(13C in CDCl3). The digital resolutions were 0.2 Hz=data point in the 1H NMR spectra
and 0.4 Hz=data point in the 13C NMR spectra (1H broadband decoupling or gated
decoupling). 15N NMR spectra were obtained on a Bruker Avance 500 instrument
with a ‘‘directly’’ detecting broadband observation probe and were referenced against
external nitromethane. Systematic names were generated with ACD=Name[11] accord-
ing to current International Union of Pure and Applied Chemistry (IUPAC) recom-
mendations and were also checked manually to ensure the correct use of nomenclature
within this publication.[12] Compound 1a is commercially available from various
suppliers (e.g., Alfa Aesar).
5-Chloro-3-methyl-1-phenyl-1H-pyrazole (1b)
This compound is commercially available from various suppliers (e.g., Alfa
Aesar) or can be prepared from 5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one
1
(bulk ware) and POCl3. H NMR spectrum (300 MHz, CDCl3), d, ppm (J, Hz):
7.35–7.57 (5H, m, Ph), 6.18 (1H, s, H-4), 2.31 (3H, s, Me). 13C NMR spectrum
(75 MHz, CDCl3), d, ppm: 149.7 (C-3), 138.2 (Ph C-1), 128.8 (Ph C-3,5), 127.8

544
G. A. ELLER ET AL.
(Ph C-4), 126.9 (C-5), 124.8 (Ph C-2,6), 106.2 (C-4), 13.9 (Me). Mass spectrum, m=z
(Irel, %): 194 [M]þ (28), 192 [M]þ (100), 157 (43), 116 (37), 77 (36), 51 (30).
5-Chloro-4-iodo-1,3-dimethyl-1H-pyrazole (2a)
The details of the synthetic preparation as well as the detailed characterization
of this compound were published by our group recently.[13]
5-Chloro-4-iodo-3-methyl-1-phenyl-1H-pyrazole (2b)
Similar to a known procedure,[14] HIO3 (0.176 g, 1 mmol) was added to a solution
of 1b (0.963g, 5 mmol) in glacial acetic acid (5 ml). After stirring for 10min, I2 (1.014 g,
4 mmol) was added, and the resulting mixture was refluxed for 4 h. Then cold aq.
Na2SO3 was added dropwise until the dark brown color disappeared, and the solution
was then extracted three times with CH2Cl2. The organic layers were combined, washed
with aqueous NaHCO3, and dried over anhydrous Na2SO4. The organic solvent was
removed under reduced pressure to afford yellow crystals, which were recrystallized
from methanol. Yield 1.004g (62%), mp 59–60ꢂC (mp 60–62ꢂC [15]). IR spectrum
(KBr), n, cmꢀ1: 1598, 1508, 1407, 1352, 1056, 754, 688. 1H NMR spectrum
(300MHz, CDCl3), d, ppm (J, Hz): 7.51 (2H, m, Ph H-2,6), 7.48 (2H, m, Ph H-3,5),
7.40 (1H, m, Ph H-4), 2.34 (3H, s, Me). 13C NMR spectrum (75MHz, CDCl3), d,
ppm (J, Hz): 152.1 (2JC-3,Me ¼ 6.9, C-3), 138.6 (Ph C-1), 131.1 (C-5), 129.0 (Ph C-3,5),
128.4 (Ph C-4), 124.7 (Ph C-2,6), 64.6 (3JC-4,Me ¼ 4.2, C-4); 14.7 (1J ¼ 128.6, Me). 15N
NMR spectrum (50 MHz, CDCl3), d, ppm: ꢀ76.0 (N-2); ꢀ 169.0 (N-1). Mass spectrum,
m=z (Irel, %): 320 [M]þ (22), 318 [M]þ (75), 150 (21), 104 (34), 77 (100), 51 (78), 50 (29).
5-Chloro-1,3-dimethyl-4-(phenylethynyl)-1H-pyrazole (3a)
Under Ar atmosphere, CuI (38 mg, 0.2 mmol) and Pd(PPh3)2Cl2 (70 mg,
0.1 mmol) were added to a solution of iodopyrazole 2a (256 mg, 1 mmol), DMF
(5 ml), Et3N (5 mmol, 0.7 ml), and phenylacetylene (1.2 mmol, 123 mg). The reaction
mixture was stirred in an oil bath at 50 ꢂC for 10 min. After completion of the reaction,
the mixture was cooled to rt, 20 ml of water were added, and the mixture was extracted
three times with ethyl acetate. The organic layers were combined, washed with brine,
dried over anhydrous. Na2SO4, filtrated, and concentrated on a rotary evaporator.
Flash chomatography (silica gel, petrolether–ethyl acetate; 1:10 to 1:4) gave pure 3a
as a brownish liquid. Yield: 200 mg (87%). IR spectrum (KBr), n, cmꢀ1: 2220
1
(CꢁC), 1545, 1492, 1360, 1295, 755, 690. H NMR spectrum (500 MHz, CDCl3), d,
ppm: 7.51 (2H, m, Ph H-2,6), 7.30–7.37 (3H, m, Ph H-3,4,5), 3.79 (3H, s, NMe),
2.33 (3H, s, CMe). 13C NMR spectrum (125 MHz, CDCl3), d, ppm (J, Hz): 150.5
(2JC-3,Me ¼ 6.9, C-3), 131.4 (Ph C-2,6), 129.7 (C-5), 128.3 (Ph C-3,5), 128.1 (Ph
C-4), 123.3 (Ph C-1), 101.6 (3JC-4,CMe ¼ 3.5, C-4), 94.1 (3J
¼ ꢃ5.3, CꢁCPh),
ꢁC,Ph-2,6
78.8 (CꢁCPh), 36.3 (1J ¼ 141.1, NMe), 13.0 (1J ¼ 128.3, CMe). 15N NMR spectrum
(50 MHz, CDCl3), d, ppm: ꢀ81.8 (N-2); ꢀ189.4 (N-1). Mass spectrum, m=z (Irel,
%): 232 [M]þ (33), 230 [M]þ (100), 189 (29), 174 (22), 148 (47), 139 (24), 113 (27),
57 (28), 43 (24). HRMS calcd. for C13H11ClN2: 230.0611. Found: 230.0610.

NEW SYNTHETIC ROUTE TO THIENO[2,3-c]PYRAZOLES
545
5-Chloro-3-methyl-1-phenyl-4-(phenylethynyl)-1H-pyrazole (3b)
Under Ar atmosphere, CuI (10 mg, 1 mol %) and PdCl2(PPh3)2 (105 mg, 3 mol%)
were added to a solution of iodopyrazole 2b (1.59 g, 5 mmol), DMF (10 ml), and Et3N
(10 ml). After stirring for 15min, phenylacetylene (7.66 g, 7.5 mmol) was added, and
the resulting reaction mixture was stirred in an oil bath at 80ꢂC for 3 h. After
completion of the reaction, the mixture was cooled to rt, filtered through Al2O3, and
concentrated on a rotary evaporator. Chromatography (silica gel, hexanes–ethyl
acetate; 20:1) gave the pure product as colorless crystals. Yield 1.35g (92%), mp
121–122 ꢂC. IR spectrum (KBr), n, cmꢀ1: 2223 (CꢁC), 1598, 1556, 1506, 1440, 1411,
1
1360, 1070, 992, 757, 693. H NMR spectrum (500 MHz, CDCl3), d, ppm: 7.58 (2H,
m, NPh H-2,6), 7.56 (2H, m, CPh H-2,6), 7.49 (2H, m, NPh H-3,5), 7.42 (1H, m,
NPh H-4), 7.32–7.39 (3H, m, CPh H-3,4,5), 2.45 (3H, s, Me). 13C NMR spectrum
(125 MHz, CDCl3), d, ppm (J, Hz): 151.8 (2JC-3,Me ¼ 6.9, C-3), 137.9 (NPh C-1),
131.4 (CPh C-2,6), 129.3 (C-5), 129.0 (NPh C-3,5), 128.30 (CPh C-3,5), 128.29 (CPh
C-4), 128.26 (NPh C-4), 124.7 (NPh C-2,6), 123.1 (CPh C-1), 103.9 (3JC-4,Me ¼ 3.4,
C-4), 95.1 (3J
¼ 5.4, CꢁCPh), 78.5 (CꢁCPh), 13.1 (1J ¼ 128.5, Me). 15N
ꢁC,Ph-2,6
NMR spectrum (50 MHz, CDCl3), d, ppm: ꢀ79.6 (N-2); ꢀ 172.5 (N-1). Mass spec-
trum, m=z (Irel, %): 294 [M]þ (32), 292 [M]þ (94), 216 (41), 189 (52), 148 (44), 139
(31), 113 (56), 77 (100), 51 (77). Found, %: C, 73.82; H, 4.65; N, 9.51. C18H13ClN2.
Calculated, %: C, 73.85; H, 4.48; N, 9.57.
1,3-Dimethyl-5-phenyl-1H-thieno[2,3-c]pyrazole (4a)
A suspension of the alkyne 3a (115 mg, 0.5 mmol), Na2S (156 mg, 2 mmol), and
DMF (5 ml) was stirred on an oil bath at 130 ꢂC overnight. Then the mixture was
diluted with cold H2O and extracted three times with ethyl acetate. The combined
organic layers were washed with brine, dried over anhydrous. Na2SO4, filtered, and
concentrated to dryness under reduced pressure. Flash chromatography (silica gel,
petrolether–ethyl acetate; 1:4 to 1:2) gave pure 4a as a pale solid. Yield: 86 mg
(75%), mp 121–124 ꢂC. IR spectrum (KBr), n, cmꢀ1: 1545, 1498, 1476, 873, 761,
1
700. H NMR spectrum (500 MHz, CDCl3), d, ppm: 7.55 (2H, m, Ph H-2,6), 7.38
(2H, m, Ph H-3,5), 7.28 (1H, m, Ph H-4), 3.91 (3H, s, NMe), 2.46 (3H, s, CMe).
13C NMR spectrum (125 MHz, CDCl3), d, ppm (J, Hz): 140.3 (2JC-3,Me ¼ 6.9, C-3),
3
140.6 (2JC-5,H-4 ¼ 5.9, C-5), 144.2 (3JC-6a,H-4 ¼ 10.2, JC-6a,NMe ¼ 2.6, C-6a), 135.2
3
(Ph C-1), 129.7 (2JC-3a,H-4 ¼ 5.1, JC-3a,CMe ¼ 3.2, C-3a), 128.9 (Ph C-3,5), 127.4
(Ph C-4), 125.5 (Ph C-2,6), 111.8 (1J ¼ 167.7, C-4), 37.9 (1J ¼ 139.8, NMe), 12.9
(1J ¼ 127.7, CMe). 15N NMR spectrum (50 MHz, CDCl3), d, ppm: ꢀ65.8
(N-2); ꢀ 208.4 (N-1). Mass spectrum, m=z (Irel, %): 228 [M]þ (100), 213 (49), 172
(34), 146 (24), 66 (26). Found, %: C, 68.13; H, 5.31; N, 12.14. C13H12N2S. Calculated,
%: C, 68.39; H, 5.30; N, 12.27.
3-Methyl-1,5-diphenyl-1H-thieno[2,3-c]pyrazole (4b)
A suspension of alkyne 3 (146 mg, 0.5 mmol), Na2S (2 mmol), and DMF (15 ml)
was stirred on an oil bath at 100 ꢂC for 4 h. Then the mixture was diluted with cold
H2O and extracted three times with ethyl acetate. The combined organic layers were

546
G. A. ELLER ET AL.
washed with brine, dried over anhydrous Na2SO4, and concentrated to dryness under
reduced pressure. The remaining solid was crystallized from methanol to afford 4b as
colorless crystals. Yield 125 mg (86%), mp 160–162 ꢂC (mp 162–166 ꢂC [16]). IR spec-
1
trum (KBr), n, cmꢀ1: 1595, 1504, 1016, 761, 753, 697, 684. 665. H NMR spectrum
(500 MHz, CDCl3), d, ppm: 7.79 (2H, m, NPh H-2,6), 7.61 (2H, m, CPh H-2,6),
7.51 (2H, m, NPh H-3,5), 7.41 (2H, m, CPh H-2,6), 7.31 (1H, m, CPh H-4), 7.25
(1H, m, NPh H-4), 7.21 (1H, s, H-4), 2.57 (3H, s, Me). 13C NMR spectrum
3
(125 MHz, CDCl3), d, ppm (J, Hz): 142.8 (2JC-3,Me ¼ 6.9, JC-3,H-4 ¼ 0.5, C-3), 141.0
(2JC-5,H-4 ¼ 6.0, C-5), 140.6 (3JC-6a,H-4 ¼ 10.5, C-6a), 139.5 (NPh C-1), 134.7 (CPh
3
C-1), 131.6 (2JC-3a,H-4 ¼ 5.0, JC-3a,Me ¼ 3.2, C-3a), 129.5 (NPh C-3,5), 129.0 (CPh
C-3,5), 127.6 (CPh C-4), 125.6 (CPh C-2,6), 125.1 (NPh C-4), 117.3 (NPh C-2,6),
111.1 (1J ¼ 168.4, C-4), 13.1 (1J ¼ 128.1, Me). 15N NMR spectrum (50 MHz, CDCl3),
d, ppm: ꢀ71.9 (N-2); ꢀ 187.5 (N-1). Mass spectrum, m=z (Irel, %): 290 [M]þ (100), 146
(28), 145 (22), 121 (20), 102 (21), 77 (83), 51 (48). Found, %: C, 74.33; H, 5.09; N, 9.43.
C18H14N2S. Calculated, %: C, 74.45; H, 4.86; N, 9.65.
ACKNOWLEDGMENTS
The authors are grateful to Dr. L. Jirovetz, University of Vienna, for recording
the mass spectra. G. V. and E. A. thank the ERASMUS student exchange program
for providing scholarships.
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