Ethyl 3- and 5-triflyloxy-1H-pyrazole-4-carboxylates in the synthesis of condensed pyrazoles by Pd-catalysed cross-coupling reactions

Article abstract of DOI:10.1002/ejoc.201001560

The easily obtainable title compounds ethyl 5- and 3-triflyloxy-1H- pyrazole-4-carboxylates (2 and 5) have been used as precursors in Sonogashira-type cross-coupling reactions with various alkynes to obtain the corresponding 5- and 3-alkynyl-4-(ethoxycarb

Full text of DOI:10.1002/ejoc.201001560

FULL PAPER
DOI: 10.1002/ejoc.201001560
Ethyl 3- and 5-Triflyloxy-1H-pyrazole-4-carboxylates in the Synthesis of
Condensed Pyrazoles by Pd-Catalysed Cross-Coupling Reactions
[a]
[a]
[a]
[b]
ˇ
ˇ
ˇ
Egle˙ Arbaciauskiene˙, Gyte˙ Vilkauskaite˙, Algirdas Sackus,* and Wolfgang Holzer*
Keywords: Heterocycles / Palladium / Cross coupling / Cyclization / NMR spectroscopy
The easily obtainable title compounds ethyl 5- and 3-triflyl-
oxy-1H-pyrazole-4-carboxylates (2 and 5) have been used as
precursors in Sonogashira-type cross-coupling reactions with
various alkynes to obtain the corresponding 5- and 3-alk-
ynyl-4-(ethoxycarbonyl)pyrazoles 3 and 6. Cyclization of the
latter ortho-difunctional synthons afforded different con-
densed pyrazoles such as pyrano[4,3-c]pyrazol-4(1H)-ones
and -4(2H)-ones 7 and 10 as well as 1,5-dihydro- and 2,5-
dihydro-4H-pyrazolo[4,3-c]pyridin-4-ones 9 and 12, respec-
tively. Suzuki coupling of triflate 2 with phenylboronic acids
gave the corresponding 5-arylpyrazoles. Heating of 5-(3-
chlorophenyl)-1-phenyl-1H-pyrazole-4-carboxylic acid (16)
with trifluoromethanesulfonic acid led to the formation of the
unexpected tetracyclic system 18. Detailed NMR spectro-
scopic investigations were undertaken on all obtained prod-
ucts.
olones (hydroxypyrazoles), which are frequently accessible
from commercial sources. In contrast, the use of O-triflated
pyrazoles in Sonogashira-type cross-coupling strategies is
largely unexplored, but it is anticipated to be a powerful
approach for the functionalization of such compounds, es-
pecially in the construction of fused systems containing
pyrazole units. In this context, we herein report the cross-
coupling (mainly Sonogashira) reactions of ethyl 3- and 5-
triflyloxypyrazole-4-carboxylates and the subsequent syn-
thesis of some annulated pyrazoles starting from the ini-
tially formed coupling products.
Introduction
Within the last three decades, transition-metal-mediated
cross-coupling reactions have emerged as tools of great im-
portance for C–X (X = C, O, N, S) bond formation.[1–4] Of
these methods, those involving Pd0 catalysis are of particu-
larly special use for the synthesis of complex molecules due
to their excellent selectivity and high functional-group com-
patibility. Thus, for instance, Sonogashira,[5,6] Suzuki,[7,8]
Stille[9,10] and Heck[11] reactions have been widely used in
the synthesis of natural products and biologically active
compounds. In recent years the above-mentioned reactions
have also been increasingly employed for the functionaliza-
tion of heteroaromatics and for the construction of corre-
sponding annulated systems.[12,13] For azoles, this has been
documented in a number of studies.[14] These heteroarenes
are found in many compounds of biological importance as
well as in natural products.[15,16] Thus, the pyrazole (1,2-
diazole) system is an important core structure in many
pharmaceuticals, agrochemicals, dyes and complexing
agents.[17–19] For the functionalization of pyrazoles by Su-
zuki,[20,21] Sonogashira[21,22] and Stille coupling reac-
tions,[21] appropriate halopyrazoles have been mainly used
as precursors. Recently, pyrazole triflates have also been
employed in Suzuki coupling reactions.[20c,23] These reactive
species are readily available from the corresponding pyraz-
Results and Discussion
Synthesis
Triflates 2 and 5 represent the key compounds in the syn-
thetic approach reported herein (Scheme 1). The general
method for the preparation of O-triflates involves the treat-
ment of hydroxylic substrates with triflic anhydride in the
presence of non-nucleophilic tertiary amines or inorganic
bases.[20c,20d,23,24] The triflate group was smoothly intro-
duced at C-5 or C-3 of the pyrazole nucleus in high yields
by the reaction of hydroxypyrazole 1 or 4 with triflic anhy-
dride in the presence of triethylamine in dichloromethane
to give 5- or 3-triflyloxy-1H-pyrazole-4-carboxylates 2 and
5 (Scheme 1). The formation of unwanted mixtures of N-
and O-triflated products was not observed. The starting
materials 1 and 4 are commercially available or easily ob-
tainable through known procedures. Thus, reaction of di-
ethyl ethoxymethylenemalonate with phenylhydrazine leads
to 1,[25] whereas treatment of diethyl ethoxymethylene-
malonate with 2-acetyl-1-phenylhydrazine in the presence
[a] Institute of Synthetic Chemistry, Kaunas University of
Technology,
Radvilenu pl. 19, 50254 Kaunas, Lithuania
Fax: +370-37-451-432
E-mail: algirdas.sackus@ktu.lt
[b] Department of Drug and Natural Product Synthesis, Faculty
of Life Sciences, University of Vienna,
Althanstrasse 14, 1090 Vienna, Austria
Fax: +43-1-4277-9556
E-mail: wolfgang.holzer@univie.ac.at
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Condensed Pyrazoles by Pd-Catalysed Cross-Coupling Reactions
of POCl3 gives 4.[25] Triflates 2 and 5 represent ortho-difunc-
Triflate 2 smoothly underwent Sonogashira-type cross-
tional synthons with the OTf moiety as an ideal leaving coupling with ethynylbenzene (80% yield of coupling prod-
group in Pd-catalysed cross-coupling reactions such as Su- uct 3a). However, the reactions of 2 with 3-ethynylthio-
zuki[7,26] and Sonogashira[6] reactions. The corresponding phene and 2-ethynylpyridine gave lower yields of the cou-
ethyl 3- or 5-iodocarboxylates can be regarded as compar- pling products 3b (40%) and 3c (32%).
able synthons for Sonogashira reactions.[6,27] However, their
The OTf group in triflate 5 turned out to be less reactive
synthesis seems less convenient and, for instance, requires than that in 2, requiring longer reaction times and a higher
the transformation of appropriate aminopyrazoles into the temperature to obtain the corresponding coupling products
iodo derivatives by diazotization[28–30] as the direct intro- 6a and 6b in comparable yields (6a: 81%; 6b: 45%;
duction of iodo substituents into the pyrazole nucleus is Scheme 1). For some unknown reason, the yield of 6c was
preferred in the electron-rich 4-position.[31] In principle, the very low (5%).
same is true for the corresponding ethyl bromopyr-
The 4,5- and 3,4-difunctionalized pyrazoles 3 and 6 are
azolecarboxylates, which are also possible starting materials potential precursors of the corresponding annulated sys-
for Suzuki coupling reactions.
tems. This was demonstrated by the treatment of com-
pounds 3 with polyphosphorus acid (PPA), which directly
resulted in the formation of 1-phenylpyrano[4,3-c]pyrazol-
4(1H)-ones 7a–c (Scheme 2) in good yields by a 6-endo-dig
ring-closing reaction.[32] The formation of a five-membered
ring system (structure X, Figure 1) by 5-exo-dig cyclization
can be ruled out on analysis of the NMR spectra of com-
pounds 7 (see NMR Spectroscopic Investigations). The syn-
thesis of related compounds has recently been reported to
occur by the reaction of 5-iodo-1-methylpyrazole-4-carbox-
ylic acid with different acetylenes under Pd/C/Cu cataly-
sis.[30] Analogously, coupling products 6 were transformed
into the corresponding 6-substituted 2-phenylpyrano[4,3-c]-
pyrazol-4(2H)-ones 10a–c in high yields. To obtain hy-
droxamic acids of type 8 and 11, the esters 3a–c and 6a,b
were treated with hydroxylamine. With 3a and 3b this
yielded the appropriate products 8a and 8b, respectively.
However, we did not isolate the expected hydroxamic acid
upon treatment of 3c with hydroxylamine, instead the cycli-
zation product 9c was obtained. The corresponding 5-hy-
droxy-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-ones 9a and
9b were achieved by reaction of 8a and 8b with triethyl-
amine in methanol. Treatment of 6a and 6b with hydroxyl-
Scheme 1. Reagents and conditions: (a) Tf2O, TEA, DCM, room
temp., 1 h; (b) R–CϵCH, [Pd(PPh3)2Cl2], TEA, CuI, DMF, 55–
80 °C, 2–24 h.
Scheme 2. Reagents and conditions: (a) PPA, 100 °C, 10 min; (b) NH2OH·HCl, NaOMe, reflux, 10 min; (c) TEA, MeOH, reflux, 2–24 h.
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E. Arbacˇiauskiene, G. Vilkauskaite, A. Sacˇkus, W. Holzer
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FULL PAPER
amine afforded the hydroxamic acids 11a and 11b, which 4-carboxylate (15a) in high yield (Scheme 4). Accordingly,
were cyclized to 12a and 12b under the reaction conditions 2 and (3-chlorophenyl)boronic acid gave 15b, which was hy-
used for the synthesis of 9a and 9b. Investigations regarding drolysed to the acid 16. To obtain tricycle 17, the latter was
the preparation of pyrazolopyridinones from vic-alkynyl/ subjected to various cyclization conditions (H2SO4, PPA,
hydrazidopyrazoles and vic-alkynylpyrazole hydroxamic ClSO3H). Whereas in most of these attempts the starting
acids have been reported by Vasilevsky and Elguero.[33]
material 16 remained unchanged, treatment of 16 with tri-
fluoromethanesulfonic acid led to the formation of an unex-
pected product. On the basis of detailed NMR spectro-
scopic investigations, this compound was finally unequivo-
cally assigned to the structure 18. A possible explanation
for the formation of 18 is given in Scheme 5: it includes
a transfer of the COOH group from the pyrazole to the
chlorophenyl system by a ring-closing/ring-opening process
followed by a condensation reaction with the N-phenyl ring.
The literature revealed only a few examples of related reac-
tions with N-phenylpyrazoles.[34,35]
Figure 1. Proof of structure 7a by diagnostic 13C,1H correlations
(expected correlations for 7a found; not found for X).
During the cyclization of 9 (and also 12), in principle,
the formation of a seven-membered ring, a 1H-pyrazolo-
[4,3-d][1,2]oxazepin-4(5H)-one system Y {or 2-phenyl-2H-
pyrazolo[4,3-d][1,2]oxazepin-4(5H)-one system Z}, is also
possible (see Figure 3). However, the NMR spectroscopic
data (see NMR Spectroscopic Investigations) allowed the
unambiguous assignment of structures 9 and 12, respec-
tively, to the cyclization products proposed above. Com-
pounds 9 and 12 are interesting as they can be further func-
tionalized at the OH group.
Compounds 3a,b were readily hydrolysed to the corre-
sponding pyrazole-4-carboxylic acids 13a,b upon reaction
with LiOH/H2O in dioxane. Moreover, treatment of alkyne
3a with hydrochloric acid led to compound 14, which re-
sults from the addition of water to the triple bond followed
by tautomerization of the thus formed enol to the corre-
sponding ketone (Scheme 3).
Scheme 4. Reagents and conditions: (a) arylboronic acid, [Pd-
(PPh3)4], K3PO4, KBr, dioxane, reflux, overnight; (b) HCl, H2O,
dioxane, reflux, 2 d; (c) TfOH, 165 °C, 4 d.
Scheme 3. Reagents and conditions: (a) LiOH, H2O, dioxane,
60 °C, overnight; (b) 4 n HCl, dioxane, reflux, 3 d.
Triflate 2 not only is an appropriate starting material for
Sonogashira reactions, but it can also be employed in Su-
zuki-type coupling reactions. This was demonstrated in
brief by the reaction of 2 with phenylboronic acid under
typical Suzuki conditions {[Pd(PPh3)4], K3PO4, KBr,
dioxane}, which produced ethyl 1,5-diphenyl-1H-pyrazole- 18.
Scheme 5. Possible mechanistic explanation for the formation of
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Condensed Pyrazoles by Pd-Catalysed Cross-Coupling Reactions
NMR Spectroscopic Investigations
In the 13C NMR spectra of compounds 7, the signals
due to C-4 are located in the range between δ = 157.4 and
The NMR spectroscopic data of all the compounds in- 157.7 ppm, typical values for carbonyl C resonances in 2H-
vestigated in this study are given in the Exp. Sect. Unequiv- pyran-2-ones.[42] Another characteristic feature is the highly
ocal assignment of the signals was carried out by the com- polarized double bond C-6=C-7 incorporated in the pyran
bined application of standard NMR spectroscopic tech- system. Whereas C-6 (attached to the ring oxygen atom)
niques such as 1H-coupled 13C NMR spectra, APT, resonates between δ = 154.9 (7c) and 158.6 ppm (7a), the
HMQC, gs-HSQC, gs-HMBC, COSY, TOCSY, NOESY 13C chemical shift of C-7 is much smaller (δ = 90.0–
and NOE difference spectroscopy.[36] Moreover, in a few 92.4 ppm), as expected. The alkene 7-H chemical shifts in
cases, experiments with selective excitation (DANTE) of 7a (δ = 7.03 ppm) and 7b (δ = 6.86 ppm) are comparable;
1
certain H resonances were performed, such as long-range however, the corresponding 7-H signal in the pyridine de-
INEPT[37] and 2D (δ,J) long-range INEPT;[38] the latter ex- rivative 7c is markedly shifted downfield (δ = 7.81 ppm). A
periments were indispensable for the unambiguous mapping possible explanation for this phenomenon can be given on
of long-range 13C,1H coupling constants. Reliable and un- the basis of the following: form A of compound 7c seems
ambiguously assigned chemical shift data such as those pre- to be the less preferred conformer as here the lone-pairs of
sented here can be considered as important and valuable the ring oxygen atom and the pyridine N atom interact as
reference material for NMR prediction programs, such as an electrostatic obstacle (Figure 2). However, in the fav-
CSEARCH[39]/NMR PREDICT[40] and ACD/C + H pre- oured form B the lone-pair of the pyridine N atom comes
dictor,[41] programs that have become very popular in the close to 7-H, which is influenced by the former (electrostatic
last few years, particularly for predicting 13C NMR chemi- field effect[43]) and thus experiences a considerable down-
cal shifts.
field shift. Similar effects can be observed, for instance, in
In the 13C NMR spectra of the starting triflates 2 and 5, 2,2Ј-bipyridine, in which 3-H (δ =8.50 ppm) has a much
the carbon atom of the trifluoromethyl group resonates as larger chemical shift than the corresponding 5-H (δ =
a quartet [1J(19F,13C) ≈ 321 Hz] at δ = 118.0 (2) and 7.12 ppm; Figure 2). Even more pronounced effects appear
118.6 ppm (5), respectively, whereas the corresponding 19F in the rigid benzo[h]quinoline, the corresponding H atom
shifts are located at δ = –73.8 (2) and –72.8 ppm (5). Cou- resonating at δ = 9.30 ppm (shifts taken from ref.[44]; Fig-
pling products 3a–c exhibit very consistent signal sets re- ure 2). In contrast, a reverse situation is present in com-
lated to the invariable part of the molecule; the same is true pound 9c. Here the pyridine N atom is involved in an intra-
for their regioisomers 6a–c. The alkyne C signals in com- molecular hydrogen bond with the OH proton, promoting
pounds of type 3, 6, 8 and 11 can be easily discriminated a conformation with 7-H and the pyridine N atom far apart
on the basis of their coupling patterns. The alkyne C atom (Figure 2). As a consequence, 7-H now shows a much
attached to the pyrazole system has no possibility of cou- smaller chemical shift (δ = 6.95 ppm) than 7-H in 7c, being
pling with adjacent protons and hence appears as a singlet now in the same range as related chemical shifts for 7a,b
1
signal in the H-coupled 13C NMR spectrum and thus also
lacks correlations in HMBC experiments. In contrast, the
alkyne C atoms appended to the phenyl (series a), 3-thienyl
(series b) or 2-pyridyl ring (series c) show couplings with
protons of the latter (hetero)aromatic systems leading to
multiplet signals in the 1H-coupled 13C NMR spectrum and
to corresponding correlations in the HMBC spectra.
Switching from triflates 2 and 5 to the corresponding
coupling products 3 and 6 results in a marked downfield
shift for both pyrazole 15N NMR resonances. Whereas
compound 2 has δ = –171.6 ppm for pyrazole N-1 and δ =
–82.3 ppm for pyrazole N-2, alkyne 3a, as an example, exhi-
bits chemical shifts of δ = –156.9 and –72.0 ppm for the
corresponding pyrazole N atoms.
The 2-pyranone substructure in compound 7a (and
thus 6-endo-dig cyclization of precursor 6a) unambiguously
follows from the appearance of the correlations
3JC-3a,7-H, 3JPhC-1,7-H and 3JC-6,Ph2,6-H in the HMBC spectra
1
(also in H-coupled 13C NMR; Figure 1). With alternative
structure X (resulting from 5-exo-dig cyclization) these cor-
relations are not possible. Instead, for X the correlations
3JPhC-2/6,alkene-H and 3JalkeneCH,Ph2,6-H are expected; however,
these were not observed (Figure 1). Analogously, structures
7b and 7c were unequivocally assigned. Proof of isomeric
structures 10a–c follows a similar approach.
1
Figure 2. Influence of lone-pair effects on the H NMR chemical
shifts of 7c, 2,2Ј-bipyridine, benzo[h]quinoline, and 9c (all in
CDCl3).
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FULL PAPER
lated values. 1H and 13C NMR spectra were recorded with a Varian
UnityPlus 300 spectrometer at 28 °C (299.95 MHz for 1H,
75.43 MHz for 13C) or Bruker Avance 500 spectrometer at 293 K
and 9a,b. The somewhat smaller 15N chemical shift of N-5
(N–OH) in 9c (δ = –178.9 ppm) relative to the correspond-
ing shifts in 9a (δ = –175.2 ppm) and 9b (δ = –175.3 ppm)
provides an additional hint for the presence of an intramo-
lecular hydrogen bond in 9c. Similar phenomena as found
in series 7 were also observed with compounds 10a–c.
As mentioned above in the Synthesis section, cyclization
of alkynes 8 and 11 in principle can also lead to the forma-
tion of seven-membered ring systems of type Y and Z,
1
(500.13 MHz for H, 125.77 MHz for 13C). The centres of the sol-
vent signals were used as internal standards and referenced to that
of TMS with δH = 7.26 (CDCl3) and 2.49 ppm ([D6]DMSO) and
δC = 77.0 (CDCl3) and 39.5 ppm ([D6]DMSO). 15N (50.68 MHz,
referenced to external nitromethane) and 19F NMR spectra
(470.56 MHz, absolute referencing by the Ξ ratio) were recorded
with a Bruker Avance 500 instrument with a “directly” detecting
respectively, by the addition of OH to the CϵC triple bond broadband observe probe (BBFO). Digital resolutions were
1
0.25 Hz/data point in the H NMR spectra and 0.4 Hz/data point
in the 13C NMR spectra. Th = thienyl. Systematic names were gen-
erated with the ACD/Name[45] program in accord with IUPAC rec-
ommendations and were checked manually.[46] For chromato-
graphic separations, Kieselgel 60 (70–230 mesh, Merck) was used.
(Figure 3). However, these structures can be ruled out as the
15N,1H HMBC spectra of the cyclization products exhibit a
clear correlation between the ring alkene H atom and the
N–O nitrogen atom (N-5), which is only possible in the six-
membered rings in structures 9 and 12 (3JN-5,H-7, Figure 3).
General Procedure for Pyrazole Triflation. Synthesis of Compounds
2 and 5: The appropriate hydroxypyrazole 1 or 4 (2.32 g, 10 mmol),
triethylamine (1.62 mL, 12 mmol) and trifluoromethanesulfonic
anhydride (1.77 mL, 10.5 mmol) were dissolved in dichloromethane
(20 mL), and the mixture was stirred at room temperature for 1 h.
The reaction mixture was poured into water (30 mL) and extracted
with ethyl acetate (3ϫ20 mL). The organic layers were combined,
washed with brine and dried with sodium sulfate. The solvent was
evaporated, and the residue was purified by column chromatog-
raphy (SiO2, eluent ethyl acetate/light petroleum, 1:7 v/v).
Figure 3. Proof of the structures 9 and 12 by 15N,1H HMBC corre-
lations.
Ethyl
1-Phenyl-5-{[(trifluoromethyl)sulfonyl]oxy}-1H-pyrazole-4-
carboxylate (2): Yield: 2.696 g, 74%; colourless solid, m.p. 84 °C.
1H NMR (300 MHz, CDCl3): δ = 1.39 (t, J = 7.1 Hz, 3 H, CH3),
4.39 (q, J = 7.1 Hz, 2 H, CH2), 7.46–7.55 (m, 5 H, Ph-H), 8.09 (s,
Careful NMR analysis permitted the elucidation of
structure 18, the formation of which had not been expected.
Whereas the precursor substance 16 still shows the typical
pattern of an N-phenyl system with joint signals of double
intensity for 2,6-H, 3,5-H, C-2,6 and C-3,5, the symmetry
1 H, 3-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.1 (1JCH3
=
127.4, 2JCH3,OCH2 = 2.7 Hz, CH3), 61.2 (1JOCH2 = 148.2, 2JOCH2,CH3
1
= 4.4 Hz, CH2), 106.3 (2JC-4,3-H = 8.7 Hz, C-4), 118.0 (q, JCF3
=
of the N-Ph system is nullified in the spectra of 18, leading 321.5 Hz, CF3), 124.2 (Ph C-2,6), 129.48 (Ph C-3,5), 129.49 (Ph C-
3
4), 136.0 (Ph C-1), 140.9 (C-5, JC-5,3-H = 5.8 Hz), 141.5 (C-3,
to the conclusion that substitution must have occurred.
Combined application of HSQC, HMBC, TOCSY, COSY
and NOESY experiments finally enabled the unambiguous
assignment of structure 18.
1JC-3,3-H = 195.5 Hz), 160.6 (C=O, JCO,OCH2 = 3.2 Hz) ppm. 15N
3
NMR (50 MHz, CDCl3): δ = –171.6 (N-1), –82.3 (N-2) ppm. 19F
NMR (470 MHz, CDCl ): δ = –73.8 (CF ) ppm. IR (KBr): ν =
˜
3
3
1708 (C=O) cm–1. MS: m/z (%) = 364 (7) [M]+, 231 (34) [M –
SO2CF3]+, 185 (27), 157 (38), 91 (24), 77 (100), 53 (21), 51 (28).
C13H11F3N2O5S (364.30): calcd. C 42.86, H 3.04, N 7.69; found C
42.99, H 2.79, N 7.59.
Conclusions
We have demonstrated that the title compounds, triflates
2 and 5, are suitable precursors for Sonogashira-type cross-
coupling reactions. The resulting ortho-functionalized alk-
ynylpyrazoles can be transformed into different condensed
systems with a pyranopyrazole or pyrazolopyridine core.
Moreover, the applicability of triflate 2 in Suzuki coupling
reactions has been shown with two examples. Further in-
vestigations in this area are in progress and will be pub-
lished elsewhere.
Ethyl
1-Phenyl-3-{[(trifluoromethyl)sulfonyl]oxy}-1H-pyrazole-4-
carboxylate (5): Yield: 2.878 g, 79%; colourless solid, m.p. 103–
105 °C. 1H NMR (500 MHz, CDCl3): δ = 1.40 (t, J = 7.2 Hz, 3 H,
CH3), 4.39 (q, J = 7.2 Hz, 2 H, CH2), 7.40 (m, 1 H, Ph 4-H), 7.50
(m, 2 H, Ph 3,5-H), 7.65 (m, 2 H, Ph 2,6-H), 8.39 (s, 1 H, 5-H) ppm.
13C NMR (125 MHz, CDCl3): δ = 14.1 (1JCH3 = 127.4, 2JCH3,OCH2
= 2.7 Hz, CH3), 61.3 (1JOCH2 = 148.2, JOCH2,CH3 = 4.4 Hz, CH2),
2
107.7 (2JC-4,5-H = 6.3 Hz, C-4), 118.6 (q, JCF3 = 321.0 Hz, CF3),
1
119.3 (Ph C-2,6), 128.4 (Ph C-4), 129.8 (Ph C-3,5), 131.9 (1JC-5,5-H
= 194.4 Hz, C-5), 138.4 (Ph C-1), 151.8 (3JC-3,5-H = 10.3 Hz, C-3),
160.3 (3JCO,OCH2 = 3.2, JCO,5-H = 0.8 Hz, C=O) ppm. 15N NMR
3
(50 MHz, CDCl3): δ = –173.4 (N-1), –94.8 (N-2) ppm. 19F NMR
Experimental Section
(470 MHz, CDCl ): δ = –72.8 (CF ) ppm. IR (KBr): ν = 1708
˜
3
3
(C=O) cm–1. MS: m/z (%) = 364 (39) [M]+, 231 (100) [M –
SO2CF3]+, 77 (95), 69 (24), 53 (21), 51 (28). C13H11F3N2O5S
(364.30): calcd. C 42.86, H 3.04, N 7.69; found C 42.97, H 2.90, N
7.62.
General: Melting points were determined with a Reichert–Kofler
hot-stage microscope. Mass spectra were obtained with Shimadzu
QP 1000 (EI, 70 eV) and Finnigan MAT 8230 (EI, 70 eV, HRMS)
instruments. IR spectra were recorded with a Perkin–Elmer
FTIR 1605 spectrophotometer. Elemental analyses (C, H, and N)
were performed at the Microanalytical Laboratory, University of
Vienna, and the data are in good agreement (Ϯ0.4%) with calcu-
General Procedure for the Sonogashira Reaction. Synthesis of Com-
pounds 3a–c and 6a–c: Triethylamine (2.08 mL, 15 mmol), the ap-
propriate arylacetylene (phenyl, 3-thienyl or 2-pyridyl; 3.6 mmol),
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Condensed Pyrazoles by Pd-Catalysed Cross-Coupling Reactions
[Pd(PPh3)2Cl2] (211 mg, 0.3 mmol) and CuI (114 mg, 0.6 mmol) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.3 (1JCH3 = 127.1,
2
were added to a solution of 2 or 5 (1.09 g, 3 mmol) in dry dimethyl-
formamide (20 mL) under argon. The reaction mixture was stirred
at 55 °C under argon for 2 h (for 5 at 80 °C for 24 h). The reaction
mixture was poured into water (30 mL) and extracted with ethyl
acetate (3ϫ20 mL). The organic layers were combined, washed
with brine and dried with sodium sulfate. The solvent was evapo-
rated, and the residue was purified by column chromatography
(SiO2; eluent ethyl acetate/light petroleum, 1:7 v/v; for 6c eluent
ethyl acetate/light petroleum, 1:5 Ǟ 1:2 v/v).
2JCH3,OCH2 = 2.7 Hz, CH3), 60.6 (1JOCH2 = 147.7, JOCH2,CH3
=
4.4 Hz, CH2), 77.2 (CCPyr), 99.4 (3JCCPyr,Pyr3-H = 3.3 Hz, CCPyr),
119.4 (2JC-4,3-H = 8.9 Hz, C-4), 123.6 (Pyr C-5), 123.9 (Ph C-2,6),
126.3 (3JC-5,3-H = 4.1 Hz, C-5), 127.7 (1JPyrC-3,Pyr3-H = 167.4,
3JPyrC-3,Pyr5-H = 6.8, 4JPyrC-3,Pyr6-H = 1.7 Hz, Pyr C-3), 128.6 (Ph C-
4), 129.1 (Ph C-3,5), 136.1 (1JPyrC-4,Pyr4-H = 164.4, JPyrC-4,Pyr6-H
=
3
6.3 Hz, Pyr C-4), 139.1 (Ph C-1), 141.9 (1JC-3,3-H = 192.6 Hz, C-3),
142.2 (Pyr C-2), 150.4 (1JPyrC-6,Pyr6-H = 188.1, JPyrC-6,Pyr5-H = 3.3,
2
3JPyrC-6,Pyr4-H = 7.1 Hz, Pyr C-6), 162.0 (3JCO,OCH2 = 3.1, JCO,3-H
3
Ͻ 1 Hz, C=O) ppm. IR (KBr): ν = 1728 (C=O) cm–1. MS: m/z (%)
˜
Ethyl 1-Phenyl-5-(phenylethynyl)-1H-pyrazole-4-carboxylate (3a):
Yield: 759 mg, 80%; colourless solid, m.p. 74 °C. 1H NMR
(300 MHz, CDCl3): δ = 1.42 (t, J = 7.1 Hz, 3 H, CH3), 4.39 (q, J
= 7.1 Hz, 2 H, CH2), 7.37 (m, 3 H, CPh 3,4,5-H), 7.44 (m, 1 H,
NPh 4-H), 7.46 (m, 2 H, CPh 2,6-H), 7.53 (m, 2 H, NPh 3,5-H),
= 317 (36) [M]+, 316 (38) [M – H]+, 288 (66) [M – CH3CH2]+, 277
(22), 272 (82) [M – OCH2CH3]+, 262 (26), 245 (30), 244 (100) [M –
COOCH2CH3]+, 218 (23), 183 (24), 108 (24), 78 (29), 77 (64), 51
(34). MS: calcd. for [C19H15N3O2 + H]+ 318.1243; found 318.1245.
7.81 (m, 2 H, NPh 2,6-H), 8.13 (s, 1 H, 3-H) ppm. 13C NMR Ethyl 1-Phenyl-3-(phenylethynyl)-1H-pyrazole-4-carboxylate (6a):
(75 MHz, CDCl3): δ = 14.4 (1JCH3 = 127.0, JCH3,OCH2 = 2.7 Hz,
Yield: 768 mg, 81%; colourless solid, m.p. 104–105 °C. 1H NMR
(300 MHz, CDCl3): δ = 1.41 (t, J = 7.2 Hz, 3 H, CH3), 4.39 (q, J
= 7.2 Hz, 2 H, CH2), 7.37 (m, 4 H, NPh 4-H, CPh 3,4,5-H), 7.49
2
2
CH3), 60.5 (1JOCH2 = 147.6, JOCH2,CH3 = 4.4 Hz, CH2), 77.5
(CCPh), 100.7 (3JCCPh,CPh2,6-H = 5.5 Hz, CCPh), 118.2 (2JC-4,3-H
=
9.0 Hz, C-4), 121.7 (CPh C-1), 124.1 (NPh C-2,6), 127.2 (3JC-5,3-H (m, 2 H, NPh 3,5-H), 7.64 (m, 2 H, CPh 2,6-H), 7.75 (m, 2 H, NPh
= 4.0 Hz, C-5), 128.45 (NPh C-4), 128.5 (CPh C-3,5), 128.9 (NPh 2,6-H), 8.44 (s, 1 H, 5-H) ppm. 13C NMR (75 MHz, CDCl3):
C-3,5), 129.5 (CPh C-4), 131.6 (CPh C-2,6), 139.2 (NPh C-1), 141.9 δ = 14.4 (1JCH3 = 127.0, JCH3,OCH2 = 2.6 Hz, CH3), 60.6 (1JOCH2
2
3
2
(1JC-3,3-H = 192.3 Hz, C-3), 162.3 (3JCO,OCH2 = 3.1, JCO,3-H
Ͻ
= 147.7, JOCH2,CH3 = 4.4 Hz, CH2), 80.6 (CCPh), 93.6
1 Hz, C=O) ppm. 15N NMR (50 MHz, CDCl3): δ = –156.9 (N-1), (3JCCPh,CPh2,6-H = 5.6 Hz, CCPh), 118.2 (2JC-4,5-H = 6.4 Hz, C-4),
–72.0 (N-2) ppm. IR (KBr): ν = 1736 (C=O) cm–1. MS: m/z (%) =
119.7 (NPh C-2,6), 122.5 (CPh C-1), 127.9 (NPh C-4), 128.3 (CPh
˜
316 (17) [M]+, 287 (25) [M – CH2CH3]+, 271 (26) [M – OCH2-
C-3,5), 128.8 (CPh C-4), 129.6 (NPh C-3,5), 130.8 (1JC-5,5-H
=
CH3]+, 97 (24), 83 (24), 77 (27), 71 (57), 69 (39), 57 (100), 56 (22), 192.5 Hz, C-5), 131.9 (CPh C-2,6), 137.0 (3JC-3,5-H = 8.1 Hz, C-3),
3
55 (50), 43 (83), 41 (55). C20H16N2O2 (316.35): calcd. C 75.93, H
5.10, N 8.86; found C 76.03, H 4.94, N 8.66.
139.0 (NPh C-1), 162.0 (3JCO,OCH2 = 3.0, JCO,5-H = 0.7 Hz, C=O)
ppm. 15N NMR (50 MHz, CDCl3): δ = –161.8 (N-1), –72.0 (N-2)
ppm. IR (KBr): ν = 1693 (C=O) cm–1. MS: m/z (%) = 317 (20) [M
˜
Ethyl 1-Phenyl-5-(3-thienylethynyl)-1H-pyrazole-4-carboxylate (3b):
Yield: 387 mg, 40%; brown liquid. 1H NMR (500 MHz, CDCl3): δ
= 1.40 (t, J = 7.1 Hz, 3 H, CH3), 4.37 (q, J = 7.1 Hz, 2 H, CH2),
+ H]+, 316 (100) [M]+, 288 (33), 287 (30) [M – CH2CH3]+, 271 (30)
[M – OCH2CH3]+, 171 (34), 77 (51), 51 (27). C20H16N2O2 (316.35):
calcd. C 75.93, H 5.10, N 8.86; found C 75.59, H 4.89, N 8.76.
3
4
7.13 (dd, JTh4-H,Th5-H = 5.0, JTh2-H,Th4-H = 1.2 Hz, 1 H, Th 4-H),
3
4
7.30 (dd, JTh4-H,Th5-H = 5.0, JTh2-H,Th5-H = 3.0 Hz, 1 H, Th 5-H),
Ethyl 1-Phenyl-3-(3-thienylethynyl)-1H-pyrazole-4-carboxylate (6b):
7.42 (m, 1 H, Ph 4-H), 7.51 (m, 2 H, Ph 3,5-H), 7.55 (dd, Yield: 435 mg, 45%; brown solid, m.p. 130–132 °C. 1H NMR
4JTh2-H,Th5-H = 3.0, JTh2-H,Th4-H = 1.2 Hz, 1 H, Th 2-H), 7.79 (m, (300 MHz, CDCl3): δ = 1.39 (t, J = 7.1 Hz, 3 H, CH3), 4.36 (q, J
4
2 H, Ph 2,6-H), 8.11 (s, 1 H, 3-H) ppm. 13C NMR (125 MHz, = 7.1 Hz, 2 H, CH2), 7.26 (dd, JTh4-H,Th5-H = 5.0, JTh2-H,Th4-H
=
=
3
4
CDCl3): δ = 14.3 (1JCH3 = 127.0, JCH3,OCH2 = 2.6 Hz, CH3), 60.4 1.2 Hz, 1 H, Th 4-H), 7.28 (dd, JTh4-H,Th5-H = 5.0, JTh2-H,Th5-H
2
3
4
(1JOCH2 = 147.5, JOCH2,CH3 = 4.4 Hz, CH2), 77.1 (CCTh), 96.1 2.9 Hz, 1 H, Th 5-H), 7.33 (m, 1 H, Ph 4-H), 7.45 (m, 2 H, Ph 3,5-
2
3
4
4
(3JCCTh,Th2-H = 3.8, JCCTh,Th4-H = 2.1 Hz, CCTh), 118.1 (2JC-4,3-H
H), 7.63 (dd, JTh2-H,Th5-H = 2.9, JTh2-H,Th4-H = 1.2 Hz, 1 H, Th
= 9.5 Hz, C-4), 120.8 (2JThC-3,Th2-H = 3.2, JThC-3,Th4-H = 4.7,
2-H), 7.72 (m, 2 H, Ph 2,6-H), 8.41 (s, 1 H, 5-H) ppm. 13C NMR
2
3JThC-3,Th5-H
=
11.1 Hz, Th C-3), 124.0 (Ph C-2,6), 125.8
(75 MHz, CDCl3): δ = 14.3 (1JCH3 = 127.0, JCH3,OCH2 = 2.6 Hz,
2
(1JThC-5,5-H = 188.1, 2JThC-5,4-H = 7.1, 3JThC-5,Th2-H = 5.6 Hz, Th C- CH3), 60.5 (1JOCH2 = 147.7, JOCH2,CH3 = 4.4 Hz, CH2), 80.2
2
5), 127.2 (3JC-5,3-H = 4.2 Hz, C-5), 128.4 (Ph C-4), 128.9 (Ph C-
(CCTh), 88.8 (3JCCTh,Th2-H = 3.8, JCCTh,Th4-H = 2.2 Hz, CCTh),
3
3,5), 129.4 (1JThC-4,Th4-H = 172.3, JThC-4,Th5-H = 4.6, JThC-4,Th2-H
117.9 (2JC-4,5-H
= 6.5 Hz, C-4), 119.5 (Ph C-2,6), 121.5
2
3
= 8.4 Hz, Th C-4), 130.5 (1JThC-2,Th2-H = 188.6, 3JThC-2,Th4-H = 8.4,
(2JThC-3,Th2-H = 3.2, JThC-3,Th4-H = 5.4, 3JThC-3,Th5-H = 10.5 Hz, Th
2
3JThC-2,Th5-H = 4.6 Hz, Th C-2), 139.2 (Ph C-1), 141.9 (1JC-3,3-H
=
C-3), 125.3 (1JThC-5,Th5-H = 187.4, JThC-5,Th4-H = 7.3, JThC-5,Th2-H
2
3
192.3 Hz, C-3), 162.3 (3JCO,OCH2 = 3.0 Hz, C=O) ppm. IR (KBr):
ν = 1706 (C=O) cm–1. MS: m/z (%) = 323 (20) [M + H]+, 322 (100)
= 5.9 Hz, Th C-5), 127.7 (Ph C-4), 129.5 (Ph C-3,5), 129.8
(1JThC-4,Th4-H = 171.7, JThC-4,Th5-H = 4.7, JThC-4,Th2-H = 8.4 Hz,
2
3
˜
[M]+, 293 (93) [M – CH2CH3]+, 277 (93) [M – OCH2CH3]+, 111 Th C-4), 129.85 (1JThC-2,Th2-H
=
188.0, JThC-2,Th4-H
=
8.3,
3
(37), 77 (65), 51 (32). MS: calcd. for [C18H14N2O2S + H]+ 323.0854; 3JThC-2,Th5-H = 5.1 Hz, Th C-2), 130.6 (1JC-5,5-H = 192.5 Hz, C-5),
found 323.0853.
136.9 (3JC-3,5-H = 8.1 Hz, C-3), 138.8 (Ph C-1), 161.9 (C=O) ppm.
15N NMR (50 MHz, CDCl3): δ = –161.3 (N-1), –80.6 (N-2) ppm.
Ethyl 1-Phenyl-5-(2-pyridylethynyl)-1H-pyrazole-4-carboxylate (3c):
Yield: 305 mg, 32%; yellow liquid. 1H NMR (300 MHz, CDCl3): δ
= 1.39 (t, J = 7.1 Hz, 3 H, CH3), 4.39 (q, J = 7.1 Hz, 2 H, CH2),
IR (KBr): ν = 1691 (C=O) cm–1. MS: m/z (%) = 323 (20)
˜
[M + H]+, 322 (100) [M]+, 294 (22), 293 (22) [M – CH2CH3]+, 277
(28) [M – OCH2CH3]+, 171 (32), 77 (42), 51 (23). C18H14N2O2S
(322.38): calcd. C 67.06, H 4.38, N 8.69; found C 67.23, H 4.37, N
8.43.
3
3
4
7.28 (ddd, JPyr4-H,Pyr5-H = 7.6, JPyr5-H,Pyr6-H = 4.9, JPyr3-H,Pyr5-H
= 1.3 Hz, 1 H, Pyr 5-H), 7.43 (m, 1 H, Ph 4-H), 7.51 (m,
4
5
3JPyr3-H,Pyr4-H = 7.8, JPyr3-H,Pyr5-H = 1.3, JPyr3-H,Pyr6-H = 1.0 Hz, 1
H, Pyr 3-H), 7.52 (m, 2 H, Ph 3,5-H), 7.68 (dt, 3JPyr3-H,Pyr4-H = 7.8,
Ethyl 1-Phenyl-3-(2-pyridylethynyl)-1H-pyrazole-3-carboxylate (6c):
3JPyr4-H,Pyr5-H = 7.6, JPyr4-H,Pyr6-H = 1.8 Hz, 1 H, Pyr 4-H), 7.83 Yield: 47 mg, 5%; brown solid, m.p. 108–110 °C. 1H NMR
4
3
(m, 2 H, Ph 2,6-H), 8.13 (s, 1 H, 3-H), 8.63 (ddd, JPyr5-H,Pyr6-H
=
(500 MHz, CDCl3): δ = 1.40 (t, J = 7.2 Hz, 3 H, CH3), 4.38 (q, J
4
5
3
4.9, JPyr4-H,Pyr6-H = 1.8, JPyr3-H,Pyr6-H = 1.0 Hz, 1 H, Pyr 6-H) = 7.2 Hz, 2 H, CH2), 7.27 (ddd, 3JPyr4-H,Pyr5-H = 7.4, JPyr5-H,Pyr6-H
Eur. J. Org. Chem. 2011, 1880–1890
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1885

ˇ
E. Arbacˇiauskiene, G. Vilkauskaite, A. Sacˇkus, W. Holzer
˙
˙
FULL PAPER
= 4.9, JPyr3-H,Pyr5-H = 1.4 Hz, 1 H, Pyr 5-H), 7.37 (m, 1 H, Ph 4-
4
1-Phenyl-6-(2-pyridyl)pyrano[4,3-c]pyrazol-4(1H)-one (7c): Yield:
H), 7.49 (m, 2 H, Ph 3,5-H), 7.62 (m, JPyr3-H,Pyr4-H = 8.0, 87 mg, 60%; colourless solid, m.p. 209–210 °C. 1H NMR
3
3
3
4JPyr3-H,Pyr5-H = 1.4 Hz, 1 H, Pyr 3-H), 7.69 (dt, JPyr3-H,Pyr4-H
=
(300 MHz, CDCl3): δ = 7.35 (ddd, JPyr4-H,Pyr5-H = 7.6,
8.0, JPyr4-H,Pyr5-H = 7.4, JPyr4-H,Pyr6-H = 1.8 Hz, 1 H, Pyr 4-H), 3JPyr5-H,Pyr6-H = 4.7, JPyr3-H,Pyr5-H = 1.2 Hz, 1 H, Pyr 5-H), 7.49
3
4
4
3
7.74 (m, 2 H, Ph 2,6-H), 8.44 (s, 1 H, 5-H), 8.67 (d, JPyr5-H,Pyr6-H (m, 1 H, Ph 4-H), 7.59 (m, 2 H, Ph 3,5-H), 7.66 (m, 2 H, Ph
4
5
= 4.9, JPyr4-H,Pyr6-H = 1.8 Hz, 1 H, Pyr 6-H) ppm. 13C NMR
2,6-H), 7.81 (d, J7-H,3-H
=
0.9 Hz, 1 H, 7-H), 7.84 (ddd,
(125 MHz, CDCl3): δ = 14.3 (1JCH3 = 127.1, JCH3,OCH2 = 2.6 Hz,
3JPyr3-H,Pyr4-H = 8.0, JPyr4-H,Pyr5-H = 7.6, JPyr4-H,Pyr6-H = 1.8 Hz, 1
2
3
4
2
3
4
CH3), 60.7 (1JOCH2 = 147.7, JOCH2,CH3 = 4.4 Hz, CH2), 80.2
H, Pyr 4-H), 8.09 (ddd, JPyr3-H,Pyr4-H = 8.0, JPyr3-H,Pyr5-H = 1.2,
5
(CCPyr), 92.4 (CCPyr), 118.7 (2JC-4,5-H = 6.6 Hz, C-4), 119.6 (Ph
C-2,6), 123.2 (Pyr C-5), 127.6 (Pyr C-3), 127.9 (Ph C-4), 129.6 (Ph
C-3,5), 130.6 (1JC-5,5-H = 192.8 Hz, C-5), 136.0 (Pyr C-4), 136.2
5JPyr3-H,Pyr6-H = 1.2 Hz, 1 H, Pyr 3-H), 8.34 (d, J7-H,3-H = 0.9 Hz,
3
4
1 H, 3-H), 8.63 (ddd, JPyr5-H,Pyr6-H = 4.7, JPyr4-H,Pyr6-H = 1.8,
5JPyr3-H,Pyr6-H = 1.2 Hz, 1 H, Pyr 6-H) ppm. 13C NMR (75 MHz,
(3JC-3,5-H = 8.1 Hz, C-3), 138.9 (Ph C-1), 142.9 (Pyr C-2), 150.1 CDCl3): δ = 92.4 (1JC-7,7-H = 177.4 Hz, C-7), 108.3 (2JC-3a,3-H = 9.7,
(Pyr C-6), 161.8 (3JCO,OCH2 = 3.2 Hz, C=O) ppm. 15N NMR 3JC-3a,7-H = 4.7 Hz, C-3a), 120.8 (Pyr C-3), 123.7 (Ph C-2,6), 124.9
(50 MHz, CDCl3): δ = –160.4 (N-1), –69.6 (N-2), –65.2 (Pyr N) (Pyr C-5), 128.7 (Ph C-4), 129.8 (Ph C-3,5), 137.2 (Pyr C-4), 138.3
ppm. IR (KBr): ν = 1696 (C=O) cm–1. MS: m/z (%) = 317 (32)
(Ph C-1), 139.5 (1JC-3,3-H = 194.4 Hz, C-3), 144.0 (3JC-7a,3-H
=
˜
[M]+, 272 (28) [M – OCH2CH3]+, 245 (56), 244 (34), 140 (23), 77
(100), 57 (45), 55 (29), 51 (49), 43 (53). MS: calcd. for [C19H15N3O2
+ H]+ 318.1243; found 318.1240.
3.2 Hz, C-7a), 149.0 (Pyr C-2), 149.6 (Pyr C-6), 156.9 (C-6), 157.4
(C-4) ppm. IR (KBr): ν = 1768 (C=O) cm–1. MS: m/z (%) = 289
˜
(100) [M]+, 261 (38) [M – CO]+, 211 (45), 183 (23), 106 (51), 78
(66), 77 (62), 51 (57). C17H11N3O2 (289.30) ·0.4H2O: calcd. C 69.07,
H 3.81, N 13.95; found C 68.87, H 4.01, N 14.17.
General Procedure for the Cyclization of 3a–c and 6a–c with PPA.
Synthesis of Compounds 7a–c and 10a–c: An appropriate carboxyl-
ate (3a–c, 6a–b; 158 mg, 0.5 mmol; for 6c 0.16 mmol of starting
2,6-Diphenylpyrano[4,3-c]pyrazol-4(2H)-one (10a): Yield: 125 mg,
material) and PPA (2 mL) were stirred at 100 °C for 10 min. Water 87%; colourless solid, m.p. 219–220 °C. 1H NMR (300 MHz,
(15 mL) was added to the reaction mixture, and the mixture was
extracted with ethyl acetate (3ϫ15 mL). The organic layers were
combined, washed with brine and dried with sodium sulfate. The
solvent was evaporated, and the residue was purified by column
chromatography (SiO2; eluent ethyl acetate/light petroleum,
1:5 v/v).
CDCl3): δ = 7.11 (s, 1 H, 7-H), 7.45 (m, 4 H, NPh 4-H, CPh 3,4,5-
H), 7.54 (m, 2 H, NPh 3,5-H), 7.78 (m, 2 H, NPh 2,6-H), 7.88 (m,
2 H, CPh 2,6-H), 8.63 (s, 1 H, 3-H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 94.9 (1JC-7,7-H = 170.4 Hz, C-7), 109.2 (2JC-3a,3-H = 6.9,
3JC-3a,7-H = 4.8 Hz, C-3a), 120.2 (NPh C-2,6), 125.5 (CPh C-2,6),
128.5 (1JC-3,3-H = 193.9 Hz, C-3), 128.5 (NPh C-4), 128.8 (CPh C-
3,5), 129.8 (NPh C-3,5), 130.0 (CPh C-4), 132.1 (CPh C-1), 139.1
(NPh C-1), 152.3 (3JC-7a,3-H = 6.9 Hz, C-7a), 156.8 (C-6), 158.6 (C-
4) ppm. 15N NMR (50 MHz, CDCl3): δ = –152.5 (N-2), –92.6 (N-
1,6-Diphenylpyrano[4,3-c]pyrazol-4(1H)-one (7a): Yield: 94 mg,
65%; colourless solid, m.p. 133–134.5 °C. 1H NMR (300 MHz,
CDCl3): δ = 7.03 (s, 1 H, 7-H), 7.45 (m, 3 H, CPh 3,4,5-H), 7.50
(m, 1 H, NPh 4-H), 7.61 (m, 2 H, NPh 2,6-H), 7.62 (m, 2 H, NPh
3,5-H), 7.86 (m, 2 H, CPh 2,6-H), 8.31 (s, 1 H, 3-H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 90.5 (1JC-7,7-H = 172.3 Hz, C-7), 107.5
1) ppm. IR (KBr): ν = 1735 (C=O) cm–1. MS: m/z (%) = 288 (100)
˜
[M]+, 260 (44) [M – CO]+, 231 (31), 77 (42), 51 (25). C18H12N2O2
(288.30) ·0.2H2O: calcd. C 74.06, H 4.28, N 9.60; found C 74.09,
H 3.92, N 9.56.
3
(2JC-3a,3-H = 9.7, JC-3a,7-H = 4.3 Hz, C-3a), 123.7 (NPh C-2,6),
125.9 (CPh C-2,6), 128.7 (NPh C-4), 128.9 (CPh C-3,5), 129.8
(NPh C-3,5), 130.8 (CPh C-4), 131.6 (CPh C-1), 138.4 (NPh C-1),
2-Phenyl-6-(3-thienyl)pyrano[4,3-c]pyrazol-4(2H)-one (10b): Yield:
116 mg, 79%; light-brown solid, m.p. 198–199 °C. 1H NMR
2
3
139.4 (1JC-3,3-H = 194.2 Hz, C-3), 144.2 (3JC-7a,3-H = 3.2, JC-7a,7-H
(500 MHz, CDCl3): δ = 6.94 (s, 1 H, 7-H), 7.39 (dd, JTh4-H,Th5-H
3
4
Ͻ 1 Hz, C-7a), 157.7 (C-4), 158.6 (2JC-6,7-H = 4.5, JC-6,CPh2,6-H
=
= 5.1, JTh2-H,Th5-H = 3.0 Hz, 1 H, Th 5-H), 7.42 (m, 1 H, Ph 4-
4.5 Hz, C-6) ppm. 15N NMR (50 MHz, CDCl3): δ = –174.0 (N-1),
H), 7.42 (dd, JTh4-H,Th5-H = 5.1, JTh2-H,Th4-H = 1.3 Hz, 1 H, Th
3
4
–66.5 (N-2) ppm. IR (KBr): ν = 1752 (C=O) cm–1. MS: m/z (%) =
4-H), 7.53 (m, 2 H, Ph 3,5-H), 7.76 (m, 2 H, Ph 2,6-H), 7.87 (dd,
˜
288 (64) [M]+, 260 (28) [M – CO]+, 105 (91), 77 (100), 57 (31), 51
(44). C18H12N2O2 (288.30): calcd. C 74.99, H 4.20, N 9.72; found
C 74.77, H 4.00, N 9.60.
4JTh2-H,Th5-H = 3.0, JTh2-H,Th4-H = 1.3 Hz, 1 H, Th 2-H), 8.61 (s, 1
4
H, 3-H) ppm. 13C NMR (125 MHz, CDCl3): δ = 94.4 (1JC-7,7-H
=
3
170.6 Hz, C-7), 109.1 (2JC-3a,3-H = 6.9, JC-3a,7-H = 4.9 Hz, C-3a),
3
120.2 (Ph C-2,6), 124.36 (1JThC-2,Th2-H = 187.4, JThC-2,Th4-H = 8.2,
1-Phenyl-6-(3-thienyl)pyrano[4,3-c]pyrazol-4(1H)-one (7b): Yield:
115 mg, 78%; colourless solid, m.p. 192–195 °C. 1H NMR
(300 MHz, CDCl3): δ = 6.86 (s, 1 H, 7-H), 7.39 (m 1 H, Th 5-H),
7.40 (m, 1 H, Th 4-H), 7.50 (m, 1 H, Ph 4-H), 7.60 (m, 4 H, Ph
3JThC-2,Th5-H = 5.0 Hz, Th C-2), 124.43 (1JThC-4,Th4-H = 168.8,
3
2JThC-4,Th5-H
=
4.7, JThC-4,Th2-H
=
8.4 Hz, Th C-4), 126.9
2
3
(1JThC-5,Th5-H = 187.1, JThC-5,Th4-H = 6.2, JThC-5,Th2-H = 6.2 Hz,
Th C-5), 128.45 (Ph C-4), 128.55 (1JC-3,3-H = 193.9 Hz, C-3), 129.8
4
4
2,3,5,6-H), 7.95 (dd, JTh2-H,Th5-H = 2.6, JTh2-H,Th4-H = 1.8 Hz, 1
H, Th 2-H), 8.29 (s, 1 H, 3-H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 90.0 (1JC-7,7-H = 172.5 Hz, C-7), 107.3 (2JC-3a,3-H = 9.8,
(Ph C-3,5), 134.3 (2JThC-3,Th2-H
=
2.7, JThC-3,Th4-H
=
4.9,
2
3JThC-3,Th5-H = 9.6, JThC-3,7-H = 2.9 Hz, Th C-3), 139.1 (Ph C-1),
3
152.2 (3JC-7a,3-H = 6.7 Hz, C-7a), 153.3 (2JC-6,7-H = 6.1, JC-6,Th2-H
3
3JC-3a,7-H = 4.5 Hz, C-3a), 123.6 (Ph C-2,6), 124.4 (1JThC-4,Th4-H
168.8, JThC-4,Th5-H = 4.6, JThC-4,Th2-H = 8.4 Hz, Th C-4), 125.9
=
= 2.9, JC-6,Th4-H = 1.1 Hz, C-6), 158.4 (C-4) ppm. 15N NMR
3
2
3
(50 MHz, CDCl3): δ = –152.8 (N-2), –93.1 (N-1) ppm. IR (KBr):
3
3
(1JThC-2,Th2-H = 187.7, JThC-2,Th4-H = 7.2, JThC-2,Th5-H = 5.8 Hz,
ν = 1741 (C=O) cm–1. MS: m/z (%) = 294 (90) [M]+, 266 (75) [M –
˜
Th C-2), 127.2 (1JThC-5,Th5-H
=
187.4, JThC-5,Th4-H
=
6.2,
2
CO]+, 237 (74), 111 (28), 77 (100), 51 (47). C16H10N2O2S (294.33):
calcd. C 65.29, H 3.42, N 9.52; found C 65.47, H 3.52, N 9.12.
3JThC-5,Th2-H = 6.2 Hz, Th C-5), 128.7 (Ph C-4), 129.8 (Ph C-3,5),
133.8 (Th C-3), 138.4 (Ph C-1), 139.5 (1JC-3,3-H = 194.2 Hz, C-3),
2
144.2 (3JC-7a,3-H = 3.2, JC-7a,7-H Ͻ 1 Hz, C-7a), 154.9 (C-6), 157.6
2-Phenyl-6-(2-pyridyl)pyrano[4,3-c]pyrazol-4(2H)-one (10c): Yield:
(C-4) ppm. IR (KBr): ν = 1748 (C=O) cm–1. MS: m/z (%) = 294
33 mg, 71%; light-brown solid, m.p. 205–206 °C. 1H NMR
˜
(100) [M]+, 266 (49) [M – CO]+, 261 (29), 237 (20), 211 (21), 111
(56), 83 (29), 77 (69), 51 (51). C16H10N2O2S (294.33) ·0.3H2O:
calcd. C 64.12, H 3.56, N 9.35; found C 64.17, H 3.26, N 9.35.
(500 MHz, CDCl3):
δ
=
7.32 (ddd, JPyr4-H,Pyr5-H
=
7.6,
3
3JPyr5-H,Pyr6-H = 4.7, JPyr3-H,Pyr5-H = 1.1 Hz, 1 H, Pyr 5-H), 7.43
4
(m, 1 H, Ph 4-H), 7.54 (m, 2 H, Ph 3,5-H), 7.80 (m, 2 H, Ph 2,6-H),
1886
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 1880–1890

Condensed Pyrazoles by Pd-Catalysed Cross-Coupling Reactions
3
3
4
7.81 (ddd, JPyr3-H,Pyr4-H = 8.0, JPyr4-H,Pyr5-H = 7.6, JPyr4-H,Pyr6-H
NMR (300 MHz, [D6]DMSO): δ = 7.40 (m, 1 H, NPh 4-H), 7.45
(m, 3 H, CPh 3,4,5-H), 7.55 (m, 2 H, NPh 3,5-H), 7.59 (m, 2 H,
CPh 2,6-H), 7.86 (m, 2 H, NPh 2,6-H), 8.89 (s, 1 H, 5-H), 10.05
5
= 1.8 Hz, 1 H, Pyr 4-H), 7.84 (d, J3-H,7-H = 0.9 Hz, 1 H, 7-H),
3
4
5
8.01 (td, JPyr3-H,Pyr4-H = 8.0, JPyr3-H,Pyr5-H = 1.1, JPyr3-H,Pyr6-H
=
0.9 Hz, 1 H, Pyr 3-H), 8.66 (d, J3-H,7-H = 0.9 Hz, 1 H, 3-H), 8.67 (br. s, 2 H, NH, OH) ppm. 13C NMR (75 MHz, [D6]DMSO): δ =
5
3
4
5
(ddd, JPyr5-H,Pyr6-H = 4.7, JPyr4-H,Pyr6-H = 1.8, JPyr3-H,Pyr6-H
=
81.5 (CCPh), 92.4 (CCPh), 119.0 (NPh C-2,6), 119.7 (C-4), 121.8
0.9 Hz, 1 H, Pyr 6-H) ppm. 13C NMR (125 MHz, CDCl3): δ = (CPh C-1), 127.5 (NPh C-4), 128.8 (CPh C-3,5), 128.8 (1JC-5,5-H
=
97.2 (1JC-7,7-H = 175.5 Hz, C-7), 109.8 (2JC-3a,3-H = 6.8, JC-3a,7-H
=
193.5 Hz, C-5), 129.2 (CPh C-4), 129.7 (NPh C-3,5), 131.4 (CPh
3
5.1 Hz, C-3a), 120.1 (Pyr C-3), 120.4 (Ph C-2,6), 124.3 (Pyr C-5), C-2,6), 134.4 (C-3), 138.7 (NPh C-1), 159.1 (C=O) ppm. 15N NMR
128.6 (Ph C-4), 128.7 (1JC-3,3-H = 194.2 Hz, C-3), 129.8 (Ph C-3,5), (50 MHz, [D6]DMSO): δ = –162.3 (N-1) ppm; N-2 signal not found
137.0 (1JPyrC-4,Pyr4-H = 164.2, JPyrC-4,Pyr6-H = 6.2 Hz, Pyr C-4), (by HMBC). IR (KBr): ν = 3388 (NH, OH), 1656 (C=O) cm–1.
3
˜
139.2 (Ph C-1), 149.68 (Pyr C-2), 149.74 (1JPyrC-6,Pyr6-H = 179.4,
MS: m/z (%) = 303 (3) [M]+, 259 (100) [M – CNHOH]+, 131 (36),
2JPyrC-6,Pyr5-H = 3.4, JPyrC-6,Pyr4-H = 7.0 Hz, Pyr C-6), 152.0 104 (69), 77 (39), 51 (26). C18H13N3O2 (303.32) ·0.2H2O: calcd. C
3
(3JC-7a,3-H = 6.7 Hz, C-7a), 155.4 (C-6), 158.4 (C-4) ppm. 15N NMR 70.44, H 4.40, N 13.69; found C 70.54, H 4.12, N 13.46.
(50 MHz, CDCl3): δ = –151.5 (N-2), –78.4 (PyrN) ppm; N-1 signal
N-Hydroxy-1-phenyl-3-(3-thienylethynyl)-1H-pyrazole-4-carboxamide
not found (by HMBC). IR (KBr): ν = 1735 (C=O) cm–1. MS: m/z
˜
(11b): Yield: 179 mg, 58%; brown solid, m.p. 168–169 °C. 1H NMR
(%) = 289 (89) [M]+, 261 (90) [M – CO]+, 211 (32), 78 (40), 77
3
(500 MHz, [D6]DMSO):
δ
=
7.28 (dd, JTh4-H,Th5-H
=
4.9,
(100), 57 (21), 51 (68). MS: calcd. for [C17H11N3O2 + H]+ 290.0930;
found 290.0933.
4JTh2-H,Th4-H = 1.0 Hz, 1 H, Th 4-H), 7.39 (m, 1 H, Ph 4-H), 7.55
3
4
(m, 2 H, Ph 3,5-H), 7.67 (dd, JTh4-H,Th5-H = 4.9, JTh2-H,Th5-H
=
General Procedure for the Synthesis of Hydroxamic Acids 8a,b and
11a,b: Hydroxylamine hydrochloride (130 mg, 2.6 mmol) was
added to a solution of Na (133 mg, 5.8 mmol) in absolute methanol
(5 mL) under argon. An appropriate carboxylate (3a,b, 6a,b;
1 mmol) was added to the prepared solution. The reaction mixture
was heated at reflux for 10 min. Methanol was distilled off under
reduced pressure, the residue was dissolved in water, and acetic acid
was added (pH = 5–6). The precipitate was filtered off and recrys-
tallized from ethanol for 8a,b and from toluene for 11a,b.
2.9 Hz, 1 H, Th 5-H), 7.84 (m, 2 H, Ph 2,6-H), 7.94 (m,
4
4JTh2-H,Th5-H = 2.9, JTh2-H,Th4-H = 1.0 Hz, 1 H, Th 2-H), 8.86 (s, 1
H, 5-H), 9.13 and 10.80 (NH, OH) ppm. 13C NMR (125 MHz,
[D6]DMSO): δ = 80.7 (CCTh), 88.0 (CCTh), 118.9 (Ph C-2,6),
119.3 (C-4), 120.6 (Th C-3), 127.1 (Th C-5), 127.5 (Ph C-4), 128.7
(C-5), 129.5 (Th C-4), 129.7 (Ph C-3,5), 130.7 (Th C-2), 134.4 (C-
3), 138.6 (Ph C-1), 159.2 (C=O) ppm. 15N NMR (50 MHz,
[D6]DMSO): δ = –161.9 (N-1) ppm; N-2 signal not found (by
HMBC). MS: m/z (%) = 309 (27) [M]+, 277 (26) [M – NHOH]+,
265 (100) [M – CNHOH]+, 131 (47), 104 (93), 77 (60), 51 (41). IR
N-Hydroxy-1-phenyl-5-(phenylethynyl)-1H-pyrazole-4-carboxamide
(8a): Yield: 255 mg, 84%; colourless solid, m.p. 158–160 °C. 1H
NMR (300 MHz, CDCl3): δ = 7.40 (m, 1 H, NPh 4-H), 7.42 (m, 2
H, CPh 3,5-H), 7.43 (m, 1 H, CPh 4-H), 7.48 (m, 2 H, CPh 2,6-
H), 7.52 (m, 2 H, NPh 3,5-H), 7.77 (m, 2 H, NPh 2,6-H), 8.20 (s,
1 H, 3-H), 8.87 (br. s, 1 H, OH), 9.36 (br. s, 1 H, NH) ppm. 13C
NMR (75 MHz, CDCl3): δ = 76.9 (CCPh), 102.5 (CCPh), 118.1
(2JC-4,3-H = 8.8 Hz, C-4), 120.3 (CPh C-1), 122.7 (3JC-5,3-H = 4.0 Hz,
C-5), 123.8 (NPh C-2,6), 128.6 (NPh C-4), 128.8 (CPh C-3,5), 129.0
(NPh C-3,5), 130.3 (CPh C-4), 131.7 (CPh C-2,6), 139.0 (NPh C-
1), 141.3 (1JC-3,3-H = 193.2 Hz, C-3), 161.1 (C=O) ppm. 15N NMR
(50 MHz, CDCl3): δ = –218.2 (NH), –157.2 (N-1), –69.9 (N-2)
(KBr): ν = 3681–3400, 3375 (NH, OH), 1676 (C=O) cm–1.
˜
C16H11N3O2S (309.35) ·0.25H2O: calcd. C 61.23, H 3.69, N 13.39;
found C 61.20, H 3.42, N 13.04.
General Procedure for the Cyclization of Hydroxamic Acids 8 and
11. Synthesis of Compounds 9a,b and 12a,b: The appropriate hy-
droxamic acid (8a,b, 11a,b; 0.25 mmol), triethylamine (0.64 mL)
and methanol (2 mL) were heated at reflux for 2 h (for 11a,b the
reaction time was 24 h). The solvent was distilled off, and the resi-
due was recrystallized from dichloromethane (9a,b) or purified by
column chromatography (SiO2; eluent dichloromethane/methanol,
100:1 v/v; 12a,b).
ppm. IR (KBr): ν = 3390–3076 (OH, NH), 1644 (C=O) cm–1. MS:
˜
m/z (%) = 303 (11) [M]+, 271 (58) [M – NHOH]+, 259 (51) [M –
CNHOH]+, 204 (40), 128 (31), 102 (21), 94 (23), 77 (100), 57 (29),
55 (30), 51 (66). C18H13N3O2 (303.32) ·0.2H2O: calcd. C 70.44, H
4.40, N 13.69; found C 70.55, H 4.37, N 13.80.
5-Hydroxy-1,6-diphenyl-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-
1
one (9a): Yield: 67 mg, 89%; colourless solid, m.p. 190–192 °C. H
NMR (300 MHz, CDCl3): δ = 6.64 (s, 1 H, 7-H), 7.30–7.77 (br. s,
1 H, OH), 7.42 (m, 1 H, NPh 4-H), 7.48 (m, 3 H, CPh 3,4,5-H),
7.53 (m, 2 H, NPh 3,5-H), 7.63 (m, 2 H, NPh 2,6-H), 7.66 (m, 2 H,
CPh 2,6-H), 8.40 (s, 1 H, 3-H) ppm. 13C NMR (75 MHz, CDCl3): δ
N-Hydroxy-1-phenyl-5-(3-thienylethynyl)-1H-pyrazole-4-carboxamide
1
(8b): Yield: 217 mg, 70%; colourless solid, m.p. 170 °C. H NMR
=
92.5 (1JC-7,7-H 173.9 Hz, C-7), 111.9 (2JC-3a,3-H
= = 9.7,
3
(500 MHz, CDCl3): δ = 7.17 (d, JTh4-H,Th5-H = 4.9 Hz, 1 H, Th 4-
3JC-3a,7-H = 5.3 Hz, C-3a), 123.3 (NPh C-2,6), 128.0 (NPh C-4),
128.3 (CPh C-3,5), 129.2 (CPh C-2,6), 129.6 (NPh C-3,5), 129.8
(CPh C-4), 132.3 (CPh C-1), 137.2 (1JC-3,3-H = 193.9 Hz, C-3),
138.9 (NPh C-1), 141.0 (3JC-7a,3-H = 3.1 Hz, C-7a), 142.3 (C-6),
154.4 (C-4) ppm. 15N NMR (50 MHz, CDCl3): δ = –179.2 (N-1),
3
4
H), 7.37 (dd, JTh4-H,Th5-H = 4.9, JTh2-H,Th5-H = 2.9 Hz, 1 H, Th
5-H), 7.44 (m, 1 H, Ph 4-H), 7.51 (m, 2 H, Ph 3,5-H), 7.64 (d,
4JTh2-H,Th5-H = 2.9 Hz, 1 H, Th 2-H), 7.76 (m, 2 H, Ph 2,6-H), 8.20
(s, 1 H, 3-H), 9.30 (br. s, 2 H, NH, OH) ppm. 13C NMR (125 MHz,
CDCl3): δ = 76.6 (CCTh), 97.9 (CCTh), 117.9 (2JC-4,3-H = 9.0 Hz,
C-4), 119.3 (Th C-3), 122.6 (C-5), 123.8 (Ph C-2,6), 126.5 (Th C-
5), 128.7 (Ph C-4), 129.1 (Ph C-3,5), 129.3 (Th C-4), 131.7 (Th C-
2), 139.0 (Ph C-1), 141.3 (1JC-3,3-H = 193.1 Hz, C-3), 161.0 (C=O)
ppm. 15N NMR (50 MHz, CDCl3): δ = –157.2 (N-1), –70.0 (N-2)
–175.2 (N-5), –66.6 (N-2) ppm. IR (KBr): ν = 3420 (NH), 1648
˜
(C=O) cm–1. MS: m/z (%) = 303 (44) [M]+, 287 (31), 111 (27), 97
(41), 95 (28), 85 (37), 83 (38), 77 (44), 69 (50), 57 (100), 51 (21).
C18H13N3O2 (303.32) ·0.6H2O: calcd. C 68.82, H 4.56, N 13.38;
found C 68.91, H 4.18, N 12.99.
ppm. IR (KBr): ν = 3380–3200 (OH, NH), 1620 (C=O) cm–1. MS:
˜
m/z (%) = 309 (23) [M]+, 278 (27) [M – NOH]+, 277 (100) [M –
NHOH]+, 265 (77) [M – CNHOH]+, 210 (30), 77 (48), 51 (29).
C16H11N3O2S (309.35) ·0.8H2O: calcd. C 59.36, H 3.92, N 12.98;
found C 59.52, H 3.61, N 12.61.
5-Hydroxy-1-phenyl-6-(3-thienyl)-1,5-dihydro-4H-pyrazolo[4,3-c]py-
ridin-4-one (9b): Yield: 72 mg, 93%; colourless solid, m.p. 167–
1
169 °C. H NMR (500 MHz, CDCl3): δ = 6.76 (s, 1 H, 7-H), 7.42
(m, 1 H, Th 5-H), 7.44 (m, 1 H, Ph 4-H), 7.49 (m, 1 H, Th 4-H),
7.55 (m, 2 H, Ph 3,5-H), 7.63 (m, 2 H, Ph 2,6-H), 7.87 (m, 1 H,
Th 2-H), 8.38 (s, 1 H, 3-H), 10.50 (br. s, 1 H, OH) ppm. 13C NMR
N-Hydroxy-1-phenyl-3-(phenylethynyl)-1H-pyrazole-4-carboxamide
(11a): Yield: 194 mg, 64%; colourless solid, m.p. 169–171 °C. 1H
Eur. J. Org. Chem. 2011, 1880–1890
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1887

ˇ
E. Arbacˇiauskiene, G. Vilkauskaite, A. Sacˇkus, W. Holzer
˙
˙
FULL PAPER
(125 MHz, CDCl3): δ = 91.4 (1JC-7,7-H = 173.4 Hz, C-7), 111.6 (C-
(br. s, 1 H, OH) ppm. 13C NMR (125 MHz, CDCl3): δ = 93.7
(1JC-7,7-H = 175.0 Hz, C-7), 113.1 (C-3a), 123.4 (Ph C-2,6), 124.3
2
3a), 123.3 (Ph C-2,6), 125.8 (1JThC-5,Th5-H = 187.2, JThC-5,Th4-H
=
3
6.2, JThC-5,Th2-H = 6.2 Hz, Th C-5), 127.4 (1JThC-2,Th2-H = 187.7, (Pyr C-5), 125.1 (Pyr C-3), 128.1 (Ph C-4), 129.7 (Ph C-3,5), 137.0
3JThC-2,Th4-H = 8.4, JThC-2,Th5-H = 4.6 Hz, Th C-2), 128.0 (Ph C-
(Pyr C-4), 137.3 (1JC-3,3-H = 193.8 Hz, C-3), 138.7 (Ph C-1), 140.6
(C-7a), 140.9 (C-6), 149.0 (Pyr C-6), 150.2 (Pyr C-2), 154.7 (C-4)
ppm. 15N NMR (50 MHz, CDCl3): δ = –178.9 (N-5), –177.8 (N-
3
4), 128.1 (1JThC-4,Th4-H = 170.8, JThC-4,Th5-H = 4.5, JThC-4,Th2-H
=
2
3
8.4 Hz, Th C-4), 129.7 (Ph C-3,5), 132.2 (Th C-3), 137.2 (1JC-3,3-H
= 193.9 Hz, C-3), 137.3 (C-6), 138.8 (Ph C-1), 141.0 (C-7a), 154.3 1), –65.5 (N-2) ppm. IR (KBr): ν = 3418 (NH), 1662 (C=O) cm–1.
˜
(C-4) ppm. 15N NMR (50 MHz, CDCl3): δ = –179.5 (N-1), –175.3
MS: m/z (%) = 304 (88) [M]+, 288 (23), 211 (28), 137 (44), 109 (25),
97 (24), 96 (52), 79 (33), 78 (72), 77 (100), 67 (69), 55 (69), 51 (92).
C17H12N4O2 (304.31) ·0.2H2O: calcd. C 66.31, H 4.06, N 18.20;
found C 66.39, H 3.87, N 17.92.
(N-5), –66.3 (N-2) ppm. IR (KBr): ν = 3424 (NH), 1652 (C=O)
˜
cm–1. MS: m/z (%) = 309 (77) [M]+, 293 (25), 289 (20), 248 (48),
111 (34), 97 (30), 96 (21), 95 (21), 78 (26), 77 (100), 69 (62), 57
(74), 51 (83). C16H11N3O2S (309.35) ·0.3H2O: calcd. C 61.06, H
3.71, N 13.35; found C 60.78, H 3.33, N 13.25.
General Procedure for Ester Hydrolysis. Synthesis of 13a,b: A solu-
tion of LiOH (17 mg, 0.7 mmol) in water (2 mL) was added to a
solution of the appropriate ester (3a,b; 0.5 mmol) in dioxane
(8 mL), and the mixture was stirred at 60 °C overnight. The reac-
tion mixture was neutralized with 2 n HCl (to pH = 7), and then
the solvent was evaporated. Water was added, and the mixture was
exhaustively extracted with ethyl acetate. The organic layers were
combined, washed with brine and dried with sodium sulfate. The
product was recrystallized from dichloromethane.
5-Hydroxy-2,6-diphenyl-2,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-
1
one (12a): Yield: 56 mg, 74%; red solid, m.p. 93–95 °C. H NMR
(300 MHz, [D6]DMSO): δ = 6.55 (s, 1 H, 7-H), 7.42 (m, 1 H, NPh
4-H), 7.45 (m, 3 H, CPh 3,4,5-H), 7.56 (m, 2 H, NPh 3,5-H), 7.58
(m, 2 H, CPh 2,6-H), 8.05 (m, 2 H, NPh 2,6-H), 9.45 (s, 1 H, 3-
H), 10.84 (s, 1 H, OH) ppm. 13C NMR (75 MHz, [D6]DMSO): δ
=
97.0 (1JC-7,7-H
=
171.8 Hz, C-7), 114.4 (2JC-3a,3-H
=
6.3,
=
3JC-3a,7-H = 6.3 Hz, C-3a), 119.8 (NPh C-2,6), 127.6 (1JC-3,3-H
1-Phenyl-5-(phenylethynyl)-1H-pyrazole-4-carboxylic Acid (13a):
Yield: 130 mg, 90%; colourless solid, m.p. 184–187 °C. 1H NMR
(300 MHz, CDCl3): δ = 7.34 (m, 2 H, CPh 3,5-H), 7.38 (m, 1 H,
CPh 4-H), 7.46 (m, 1 H, NPh 4-H), 7.48 (m, 2 H, CPh 2,6-H), 7.55
(m, 2 H, NPh 3,5-H), 7.84 (m, 2 H, NPh 2,6-H), 8.21 (s, 1 H,
3-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 77.2 (CCPh), 101.6
(3JCCPh,CPh2,6-H = 5.3 Hz, CCPh), 117.2 (2JC-4,3-H = 8.9 Hz, C-4),
121.6 (CPh C-1), 124.1 (NPh C-2,6), 128.1 (3JC-5,3-H = 4.0 Hz, C-
5), 128.5 (CPh C-3,5), 128.6 (NPh C-4), 129.0 (NPh C-3,5), 129.6
196.2 Hz, C-3), 127.8 (NPh C-4), 128.0 (CPh C-3,5), 128.7 (CPh
C-4), 129.1 (CPh C-2,6), 129.7 (NPh C-3,5), 133.9 (CPh C-1), 139.1
(NPh C-1), 145.1 (C-6), 149.2 (3JC-7a,3-H = 6.7 Hz, C-7a), 156.0 (C-
4) ppm. 15N NMR (50 MHz, [D6]DMSO): δ = –184.7 (N-5), –152.5
(N-2), –96.2 (N-1) ppm. IR (KBr): ν = 3675–3281 (OH), 1646
˜
(C=O) cm–1. MS: m/z (%) = 303 (45) [M]+, 211 (33), 105 (52), 77
(100), 51 (39). MS: calcd. for [C18H13N3O2 + H]+ 304.1086; found
304.1090.
(CPh C-4), 131.8 (CPh C-2,6), 139.1 (NPh C-1), 142.6 (1JC-3,3-H
=
5-Hydroxy-2-phenyl-6-(3-thienyl)-2,5-dihydro-4H-pyrazolo[4,3-c]pyr-
idin-4-one (12b): Yield: 53 mg, 69%; red solid, m.p. 82–84 °C. 1H
NMR (300 MHz, [D6]DMSO): δ = 6.72 (s, 1 H, 7-H), 7.42 (m, 1
H, Ph 4-H), 7.46 (m, 1 H, Th 4-H), 7.56 (m, 2 H, Ph 3,5-H), 7.62
(m, 1 H, Th 5-H), 7.93 (m, 1 H, Th 2-H), 8.05 (m, 2 H, Ph 2,6-H),
9.42 (s, 1 H, 3-H), 10.93 (s, 1 H, OH) ppm. 13C NMR (75 MHz,
[D6]DMSO): δ = 96.3 (1JC-7,7-H = 172.1 Hz, C-7), 114.2 (2JC-3a,3-H
192.8 Hz, C-3), 167.5 (C=O) ppm. IR (KBr): ν = 3430 (OH), 1678
˜
(C=O) cm–1. MS: m/z (%) = 289 (21) [M + H]+, 288 (100) [M]+,
287 (21) [M – H]+, 260 (34) [M – CO]+, 211 (24), 184 (29), 105
(93), 77 (86), 51 (34). C18H12N2O2 (288.31) ·0.3H2O: calcd. C 73.61,
H 4.32, N 9.54; found C 73.80, H 3.96, N 9.42.
1-Phenyl-5-(3-thienylethynyl)-1H-pyrazole-4-carboxylic Acid (13b):
3
Yield: 97 mg, 66%; colourless solid, m.p. 182–185 °C. 1H NMR
= 6.3, JC-3a,7-H = 6.3 Hz, C-3a), 119.7 (Ph C-2,6), 125.6 (Th C-5),
126.3 (Th C-2), 127.5 (1JC-3,3-H = 196.2 Hz, C-3), 127.8 (Ph C-4),
3
(300 MHz, CDCl3): δ = 7.10 (d, JTh4-H,Th5-H = 4.9 Hz, 1 H, Th 4-
128.7 (Th C-4), 129.6 (Ph C-3,5), 133.9 (Th C-3), 139.1 (Ph C-1),
H), 7.24 (m, 1 H, Th 5-H), 7.44 (m, 1 H, Ph 4-H), 7.49 (m, 2 H,
140.3 (C-6), 149.2 (3JC-7a,3-H = 6.7 Hz, C-7a), 156.0 (C-4) ppm. 15
N
4
Ph 3,5-H), 7.53 (d, JTh2-H,Th5-H = 2.8 Hz, 1 H, Th 2-H), 7.75 (m,
2 H, Ph 2,6-H), 8.14 (s, 1 H, 3-H), 9.62 (br. s, 1 H, OH) ppm. 13C
NMR (75 MHz, CDCl3): δ = 77.2 (CCTh), 96.9 (CCTh), 117.7 (C-
4), 120.7 (Th C-3), 124.0 (Ph C-2,6), 125.7 (Th C-5), 127.9 (C-5),
128.5 (Ph C-4), 128.8 (Ph C-3,5), 129.5 (Th C-4), 130.8 (Th C-2),
139.1 (Ph C-1), 142.6 (1JC-3,3-H = 192.5 Hz, C-3), 167.7 (C=O) ppm.
NMR (50 MHz, [D6]DMSO): δ = –184.7 (N-5), –152.5 (N-2) ppm;
N-1 signal not found (by HMBC). IR (KBr): ν = 3628–3170 (OH),
˜
1642 (C=O) cm–1. MS: m/z (%) = 309 (22) [M]+, 121 (27), 77 (100),
69 (23), 57 (46), 51 (61), 35 (32). MS: calcd. for [C16H11N3O2S +
H]+ 310.0650; found 310.0654.
IR (KBr): ν = 3430 (OH), 1686 (C=O) cm–1. MS: m/z (%) = 294
˜
5-Hydroxy-1-phenyl-6-(2-pyridyl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyr-
idin-4-one (9c): Hydroxylamine hydrochloride (65 mg, 1.3 mmol)
was added to a solution of Na (67 mg, 2.9 mmol) in dry methanol
(3 mL) under argon. Ethyl 1-phenyl-5-(2-pyridylethynyl)-1H-pyr-
azole-4-carboxylate (3c; 159 mg, 0.5 mmol) was added to the pre-
pared solution. The reaction mixture was heated at reflux for
10 min. Methanol was distilled off under reduced pressure, the resi-
due was dissolved in water (15 mL) and acetic acid was added (pH
(100) [M]+, 266 (38), 261 (23), 111 (43), 77 (34), 51 (21).
C16H10N2O2S (294.33) ·0.2H2O: calcd. C 64.50, H 3.52, N 9.40;
found C 64.27, H 3.46, N 9.28.
5-(2-Oxo-2-phenylethyl)-1-phenyl-1H-pyrazole-4-carboxylic
Acid
(14): A solution of ethyl 1-phenyl-5-(phenylethynyl)-1H-pyrazole-
4-carboxylate (3a; 151 mg, 0.5 mmol), 4 n HCl (3 mL) and dioxane
(6 mL) was heated at reflux for 3 d. The solvent was evaporated,
= 5–6). The mixture was extracted with ethyl acetate (3ϫ10 mL). water (15 mL) was added, and the mixture was extracted with ethyl
The organic layers were combined, washed with brine and dried
with sodium sulfate. The solvent was evaporated, and the product
was recrystallized from dichloromethane. Yield: 76 mg, 50%;
colourless solid, m.p. 95–97 °C. H NMR (500 MHz, CDCl3): δ =
6.96 (s, 1 H, 7-H), 7.39 (m, 1 H, Pyr 5-H), 7.41 (m, 1 H, Ph 4-H),
acetate (3ϫ10 mL). The organic layers were combined, washed
with brine and dried with sodium sulfate. The solvent was evapo-
rated, and the residue was purified by column chromatography
(SiO2; eluent dichloromethane/methanol, 100:5 v/v). Yield: 98 mg,
64%; colourless solid, m.p. 183–185 °C. 1H NMR (300 MHz,
CDCl3): δ = 4.64 (s, 2 H, CH2), 7.42 (m, 5 H, NPh-H), 7.44 (m, 2
1
7.53 (m, 2 H, Ph 3,5-H), 7.67 (m, 2 H, Ph 2,6-H), 7.84 (m, 1 H,
3
Pyr 4-H), 7.89 (d, JPyr3-H,Pyr4-H = 7.8 Hz, 1 H, Pyr 3-H), 8.30 (s, H, CPh 3,5-H), 7.58 (m, 1 H, CPh 4-H), 7.92 (m, 2 H, CPh 2,6-
3
1 H, 3-H), 8.65 (d, JPyr5-H,Pyr6-H = 4.6 Hz, 1 H, Pyr 6-H), 11.25
H), 8.15 (s, 1 H, 3-H), 7.00–11.00 (br. s, 1 H, OH) ppm. 13C NMR
1888
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 1880–1890

Condensed Pyrazoles by Pd-Catalysed Cross-Coupling Reactions
(75 MHz, CDCl3): δ = 36.1 (1JCH2 = 129.0 Hz, CH2), 113.1 (C-4),
7.25 (m, 1 H, CPh 5-H), 7.30 (m, 1 H, CPh 2-H), 7.31 (m, 3 H,
125.7 (NPh C-2,6), 128.2 (CPh C-2,6), 128.7 (CPh C-3,5), 129.2 NPh 3,4,5-H), 7.35 (m, 1 H, CPh 4-H), 8.23 (s, 1 H, 3-H), 7.00–
(NPh C-4), 129.4 (NPh C-3,5), 133.5 (CPh C-4), 136.1 (CPh C-1),
9.20 (br. s, 1 H, OH) ppm. 13C NMR (75 MHz, CDCl3): δ = 113.2
(2JC-4,3-H = 8.9 Hz, C-4), 125.4 (NPh C-2,6), 128.4 (NPh C-4),
138.4 (NPh C-1), 141.9 (C-5), 142.5 (1JC-3,3-H = 191.2 Hz, C-3),
168.4 (COOH), 194.3 (CH CO) ppm. IR (KBr): ν = 3422 (OH), 128.7 (CPh C-6), 129.0 (NPh C-3,5), 129.3 (CPh C-5), 129.5 (CPh
˜
2
1666 (C=O) cm–1. MS: m/z (%) = 306 (0.3) [M]+, 184 (67), 105
(100), 77 (59). C18H14N2O3 (306.32): calcd. C 70.58, H 4.61, N
9.15; found C 70.20, H 6.60, N 9.10.
C-4), 130.2 (CPh C-1), 130.5 (CPh C-2), 134.0 (CPh C-3), 138.7
(NPh C-1), 143.2 (1JC-3,3-H = 192.0 Hz, C-3), 144.5 (C-5), 167.6
(C=O) ppm. 15N NMR (50 MHz, CDCl3): δ = –159.2 (N-1), –74.1
(N-2) ppm. IR (KBr): ν = 3430 (OH), 1674 (C=O) cm–1. MS: m/z
˜
General Procedure for the Suzuki Reaction. Synthesis of 15a,b: An-
hydrous K3PO4 (1.27 g, 6 mmol), arylboronic acid (6 mmol),
[Pd(PPh3)4] (277 mg, 0.24 mmol) and KBr (393 mg, 3.3 mmol) were
added to a solution of ethyl 1-phenyl-5{[(trifluoromethyl)sulfonyl]-
oxy}-1H-pyrazole-4-carboxylate (2; 1.092 g, 3 mmol) in 1,4-diox-
ane (20 mL) under argon. After heating at reflux under argon over-
night, the mixture was diluted with water (20 mL) and extracted
with ethyl acetate (3ϫ20 mL). The combined organic layers were
washed with brine, dried with sodium sulfate, and the solvent was
evaporated under reduced pressure. The residue was purified by
column chromatography (SiO2; eluent ethyl acetate/light petroleum,
1:8 v/v, for 15b eluent ethyl acetate/hexane, 1:10 v/v).
(%) = 300/298 (33/100) [M]+, 299 (31), 279 (46), 281 (28), 279 (32),
253 (28), 122 (23), 77 (80), 51 (61). C16H11ClN2O2 (298.72): calcd.
C 64.33, H 3.71, N 9.38; found C 64.70, H 3.80, N 9.40.
5-Chloro-8H-dibenzo[c,f]pyrazolo[1,5-a]azepin-8-one (18): 5-(3-
Chlorophenyl)-1-phenyl-1H-pyrazole-4-carboxylic acid (16; 73 mg,
0.25 mmol) and trifluoromethanesulfonic acid (2 mL) were stirred
at 165 °C for 4 d. Water (10 mL) was added to the reaction mixture,
and the mixture was extracted with diethyl ether (2ϫ10 mL). The
organic layers were combined, washed with brine and dried with
sodium sulfate. The solvent was evaporated, and the residue was
purified by column chromatography (SiO2; eluent ethyl acetate/
light petroleum, 1:7 v/v). Yield: 60 mg, 85%; colourless solid, m.p.
Ethyl 1,5-Diphenyl-1H-pyrazole-4-carboxylate (15a): Yield: 683 mg,
1
3
198–199 °C. H NMR (500 MHz, CDCl3): δ = 6.82 (d, J2-H,3-H
=
1
78%; m.p. 120–122 °C (ref.[47] m.p. 120 °C). H NMR (300 MHz,
3
3
2.0 Hz, 1 H, 3-H), 7.44 (m, J9-H,10-H = 7.8, J10-H,11-H = 7.4 Hz, 1
CDCl3): δ = 1.22 (t, J = 7.2 Hz, 3 H, CH3), 4.21 (q, J = 7.2 Hz, 2
H, CH2), 7.20 (m, 2 H, NPh 2,6-H), 7.27 (m, 2 H, NPh 3,5-H),
7.29 (m, 3 H, CPh 2,6-H, NPh 4-H), 7.34 (m, 1 H, CPh 4-H), 7.35
(m, 2 H, CPh 3,5-H), 8.19 (s, 1 H, 3-H) ppm. 13C NMR (75 MHz,
3
4
H, 10-H), 7.47 (m, J6-H,7-H = 8.3, J4-H,6-H = 2.0 Hz, 1 H, 6-H),
7.69 (m, 3J11-H,12-H = 8.3, J10-H,11-H = 7.4 Hz, 1 H, 11-H), 7.75 (d,
3
4J4-H,6-H = 2.0 Hz, 1 H, 4-H), 7.82 (d, J2-H,3-H = 2.0 Hz, 1 H, 2-
3
3
3
H), 7.83 (m, J9-H,10-H = 7.8 Hz, 1 H, 9-H), 7.86 (d, J6-H,7-H
=
2
CDCl3): δ = 14.1 (1JCH3 = 127.0, JCH3,OCH2 = 2.6 Hz, CH3), 60.0
3
8.3 Hz, 1 H, 7-H), 8.14 (d, J11-H,12-H = 8.3 Hz, 1 H, 12-H) ppm.
13C NMR (125 MHz, CDCl3): δ = 108.8 (C-3), 123.3 (C-12), 127.3
(C-10), 127.8 (C-4), 128.4 (C-3b), 129.4 (C-6), 129.7 (C-9), 130.8
(C-7), 132.0 (C-8a), 133.7 (C-11), 136.7 (C-5), 137.5 (C-12a), 139.0
2
(1JOCH2 = 147.4, JOCH2,CH3 = 4.4 Hz, CH2), 113.9 (2JC-4,3-H
=
8.9 Hz, C-4), 125.3 (NPh C-2,6), 127.8 (NPh C-4), 128.0 (CPh C-
3,5), 128.8 (NPh C-3,5), 128.9 (CPh C-1), 129.0 (CPh C-4), 130.5
(CPh C-2,6), 139.2 (NPh C-1), 142.4 (1JC-3,3-H = 190.9 Hz, C-3),
145.4 (C-5), 162.9 (3JCO,OCH2 = 3.1 Hz, C=O) ppm. 15N NMR
(50 MHz, CDCl3): δ = –160.5 (N-1), –76.0 (N-2) ppm.
(C-7a), 140.6 (C-3a), 141.1 (C-2), 192.4 (C-8) ppm. IR (KBr): ν =
˜
1654 (C=O) cm–1. MS: m/z = 283/281 (27/82) [M]+, 257/255 (35/
100). C16H9ClN2O (280.71) ·0.15H2O: calcd. C 67.81, H 3.31, N
9.88; found C 67.81, H 3.15, N 9.83. MS: calcd. for [C16H9-
ClN2O]+ 280.0403; found 280.0409.
Ethyl 5-(3-Chlorophenyl)-1-phenyl-1H-pyrazole-4-carboxylate (15b):
Yield: 883 mg, 90%; colourless solid, m.p. 97–98 °C. 1H NMR
(500 MHz, CDCl3): δ = 1.24 (t, J = 7.1 Hz, 3 H, CH3), 4.22 (q, J
= 7.1 Hz, 2 H, CH2), 7.11 (m, 1 H, CPh 6-H), 7.20 (m, 2 H, NPh
2,6-H), 7.25 (m, 1 H, CPh 5-H), 7.31 (m, 3 H, NPh 3,4,5-H), 7.34 Acknowledgments
(m, 1 H, CPh 2-H), 7.35 (m, 1 H, CPh 4-H), 8.19 (s, 1 H, 3-H)
ppm. 13C NMR (125 MHz, CDCl3): δ = 14.1 (1JCH3 = 127.0,
We are grateful to Dr. L. Jirovetz for recording the mass spectra.
2
2JCH3,OCH2 = 2.6 Hz, CH3), 60.2 (1JOCH2 = 147.5, JOCH2,CH3
=
4.4 Hz, CH2), 114.2 (2JC-4,3-H = 8.8 Hz, C-4), 125.3 (NPh C-2,6),
128.2 (NPh C-4), 128.7 (CPh C-6), 129.0 (NPh C-3,5), 129.21 (CPh
C-5), 129.24 (CPh C-4), 130.6 (CPh C-1), 130.7 (CPh C-2), 133.8
(CPh C-3), 138.8 (NPh C-1), 142.5 (1JC-3,3-H = 191.3 Hz, C-3),
143.6 (C-5), 162.7 (3JCO,OCH2 = 3.0 Hz, C=O) ppm. 15N NMR
(50 MHz, CDCl3): δ = –160.4 (N-1), –74.8 (N-2) ppm. IR (KBr):
[1] E. Negishi in Handbook of Organopalladium Chemistry for Or-
ganic Synthesis (Ed.: A. de Meijere), Wiley, Hoboken, NJ,
2002, vols. 1 and 2.
[2] A. de Meijere in Metal-Catalyzed Cross-Coupling Reactions
(Ed.: F. Diederich), Wiley-VCH, Weinheim, 2004, vols. 1 and
2.
ν = 1716 (C=O) cm–1. MS: m/z (%) = 328/326 (2/7) [M]+, 256/254
˜
[3] S. V. Ley, A. W. Thomas, Angew. Chem. Int. Ed. 2003, 42,
(34/100) [M – COOEt + H]+, 222 (28), 218 (25), 152 (22), 109 (26),
95 (29), 77 (47), 51 (41). C18H15ClN2O2 (326.78): calcd. C 66.16,
H 4.63, N 8.57; found C 66.16, H 4.66, N 8.21.
5400–5449.
[4] D. A. Alonso, C. Nájera, Sci. Synth. 2010, 47a, 439–479.
[5] P. Wipf, T. H. Graham, J. Am. Chem. Soc. 2004, 126, 15346–
15347.
5-(3-Chlorophenyl)-1-phenyl-1H-pyrazole-4-carboxylic Acid (16): A
solution of ethyl 5-(3-chlorophenyl)-1-phenyl-1H-pyrazole-4-carb-
oxylate (15b; 978 mg, 3 mmol), 4 n HCl (15 mL) and dioxane
(30 mL) was heated at reflux for 2 d. The solvent was evaporated,
water (20 mL) was added, and the mixture was extracted with ethyl
acetate (3ϫ20 mL). The organic layers were combined, washed
with brine and dried with sodium sulfate. The solvent was evapo-
rated, and the residue was purified by column chromatography
(SiO2; eluent dichloromethane/methanol, 100:2 v/v). Yield: 831 mg,
93%; colourless solid, m.p. 174–175 °C. 1H NMR (300 MHz,
CDCl3): δ = 7.14 (m, 1 H, CPh 6-H), 7.19 (m, 2 H, NPh 2,6-H),
[6] R. Chinchilla, C. Nájera, Chem. Rev. 2007, 107, 874–922.
[7] S. Kotha, K. Lahiri, D. Kashinath, Tetrahedron 2002, 58, 9633–
9695.
[8] N. K. Garg, D. D. Capsi, B. M. Stoltz, J. Am. Chem. Soc. 2004,
126, 9552–9553.
[9] O. Krebs, R. J. K. Taylor, Org. Lett. 2005, 7, 1063–1066.
[10] J. S. Lee, Y. S. Cho, M. H. Chang, H. Y. Koh, B. Y. Chung,
A. N. Pae, Bioorg. Med. Chem. Lett. 2003, 13, 4117–4120.
[11] A. B. Dounay, L. E. Overman, Chem. Rev. 2003, 103, 2945–
2963.
[12] G. Kirsch, S. Hesse, A. Comel, Curr. Org. Synth. 2004, 1, 47–
63.
Eur. J. Org. Chem. 2011, 1880–1890
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1889

ˇ
E. Arbacˇiauskiene, G. Vilkauskaite, A. Sacˇkus, W. Holzer
˙
˙
FULL PAPER
[13]
[14]
[27] S. F. Vasilevsky, E. V. Tretyakov, J. Elguero, Adv. Heterocycl.
Chem. 2002, 82, 1–99.
M. M. Heravi, S. Sadjadi, Tetrahedron 2009, 65, 7761–7775.
M. Schnürch, R. Flasik, A. F. Khan, M. Spina, M. D. Mihovi-
lovic, P. Stanetty, Eur. J. Org. Chem. 2006, 3283–3307.
A. F. Pozharskii, A. T. Soldatenkov, A. R. Katritzky in Hetero-
cycles in Life and Society, Wiley, Chichester, New York,
Weinheim, Brisbane, Singapore, Toronto, 1997.
A. R. Katritzky, K. T. Potts, J. Elguero, J. V. Greenhill, M. R.
Grimmett in Comprehensive Heterocyclic Chemistry (Eds.:
A. R. Katritzky, C. W. Rees), Pergamon Press, Oxford, 1996,
vol. 5, pp. 1–499.
a) L. Yang, F. Okuda, K. Kobayashi, K. Nozaki, Y. Tanabe,
Y. Ishii, M. Haga, Inorg. Chem. 2008, 47, 7154–7165; b) S.-Y.
Chang, J.-L. Chen, Y. Chi, Y.-M. Cheng, G.-H. Lee, C.-M. Ji-
ang, P.-T. Chou, Inorg. Chem. 2007, 46, 11202–11212; c) E.-M.
Chang, C.-T. Lee, C.-Y. Chen, F. F. Wong, M.-Y. Yeh, Aust. J.
Chem. 2008, 61, 342–349; d) R. Mukherjee, Coord. Chem. Rev.
2000, 203, 151–218.
a) G. Theodoridis in Modern Crop Protection Compounds
(Eds.: W. Krämer, U. Schirmer), Wiley-VCH, Weinheim, 2007,
vol. 1, pp. 153–186; b) Y. Shiga, I. Okada, Y. Ikeda, E. Takiz-
awa, T. Fukuchi, J. Pestic. Sci. 2003, 28, 313–314; c) S. D. Lind-
ell, B. A. Moloney, B. D. Hewitt, C. G. Earnshaw, P. J. Dun-
field, J. E. Dancer, Bioorg. Med. Chem. Lett. 1999, 9, 1985–
1990; d) C. B. Vicentini, C. Romagnoli, E. Andreotti, D. Mares,
J. Agric. Food Chem. 2007, 55, 10331–10338; e) S. Fustero, R.
Román, J. F. Sanz-Cervera, A. Simón-Fuentes, J. Bueno, S. Vil-
lanova, J. Org. Chem. 2008, 73, 8545–8552; f) G. A. Dutra,
B. C. Hamper, D. A. Mitschke, K. Moedritzer, K. D. Rogers,
PCT Int. Appl., WO 9206962, 1992 [Chem. Abstr. 1992, 117,
69859].
[28] A. P. Truong, D. L. Aubele, G. D. Probst, M. L. Neitzel, C. M.
Semko, S. Bowers, D. Dressen, R. K. Hom, A. W. Konradi,
H. L. Sham, A. W. Garofalo, P. S. Keim, J. Wu, M. S. Dappen,
K. Wong, E. Goldbach, K. P. Quinn, J.-M. Sauer, E. F. Brig-
ham, W. Wallace, L. Nguyen, S. S. Hemphill, M. P. Bova, G.
Basi, Bioorg. Med. Chem. Lett. 2009, 19, 4920–4923.
[29] R. P. Wurz, L. H. Pettus, B. Henkle, L. Sherman, M. Plant, K.
Miner, H. J. McBride, L. M. Wong, C. J. M. Saris, M. R. Lee,
S. Chmait, C. Mohr, F. Hsieh, A. S. Tasker, Bioorg. Med. Chem.
Lett. 2010, 20, 1680–1684.
[30] D. R. Gorja, V. R. Batchu, A. Ettam, M. Pal, Beilstein J. Org.
Chem. 2009, 5, No. 64.
[31] K. Kirschke in Houben-Weyl: Methoden der Organischen
Chemie, Thieme, Stuttgart, New York, 1994, vol. E8b, pp. 399–
764.
[15]
[16]
[17]
[18]
[32] J. E. Baldwin, R. C. Thomas, L. I. Kruse, L. Silberman, J. Org.
Chem. 1977, 42, 3846–3852.
[33] a) S. F. Vasilevsky, E. V. Mshvidobadze, J. Elguero, J. Hetero-
cycl. Chem. 2002, 39, 1229–1233; b) E. V. Mshvidobadze, S. F.
Vasilevsky, J. Elguero, Tetrahedron 2004, 60, 11875–11878.
[34] S. Hernández, I. Moreno, R. SanMartin, G. Gómez, M. T.
Herrero, E. Domínguez, J. Org. Chem. 2010, 75, 434–441.
[35] S. Hernández, R. SanMartin, I. Tellitu, E. Domínguez, Org.
Lett. 2003, 5, 1095–1098.
[36] S. Braun, H.-O. Kalinowski, S. Berger in 150 and More Basic
NMR Experiments, 2nd ed., Wiley-VCH, New York, 1998.
[37] A. Bax, J. Magn. Reson. 1984, 57, 314–318.
[38] T. Jippo, O. Kamo, N. Nagayama, J. Magn. Reson. 1986, 66,
344–348.
[19]
a) A. Kleeman, J. Engel, B. Kutscher, D. Reichert in Pharma-
ceutical Substances, 3rd ed., George Thieme, Stuttgart, New
York, 1999, pp. 1190–1787; b) S. L. Dax in Antibacterial Che-
motherapeutic Agents, Blackie Academic and Professional,
London, 1997.
[39] H. Kalchhauser, W. Robien, J. Chem. Inf. Comput. Sci. 1985,
25, 103–108.
[40] NMR Predict, version 4.7, Modgraph Consultants, Ltd.,
Welwyn, UK, 2010 (www.modgraph.co.uk/product_nmr.htm,
accessed on 15 November 2010).
[20] a) J. Zhang, S. Didierlaurent, M. Fortin, D. Lefrancois, E. Uri-
dat, J. P. Vevert, Bioorg. Med. Chem. Lett. 2000, 10, 2575–2578;
b) M. G. Organ, S. Mayer, J. Comb. Chem. 2003, 5, 118–124;
c) C. A. Dvorak, D. A. Rudolph, S. Ma, N. I. Carruthers, J.
Org. Chem. 2005, 70, 4188–4190; d) P. S. Dragovich, T. M.
[41] ACD/C + H Predictors and DB, version 12.0, Advanced Chem-
istry Development, Inc., Toronto, ON, 2008 (www.acdlab-
s.com, accessed on 15 November 2010).
[42] H.-O. Kalinowski, S. Berger, S. Braun in 13C NMR Spektrosko-
pie, Thieme, Stuttgart, 1984, p. 336.
Bertolini, B. K. Ayida, L.-S. Li, D. E. Murphy, F. Ruebsam, Z. [43] T. M. Spotswood, C. I. Tanzer, Tetrahedron Lett. 1967, 10, 911–
Sun, Y. Zhou, Tetrahedron 2007, 63, 1154–1166; e) S. Guillou,
O. Nesmes, M. S. Ermolenko, Y. L. Janin, Tetrahedron 2009,
65, 3529–3535.
915.
[44] Spectral Database of Organic Compounds SDBS, National In-
stitute of Advanced Science and Technology (AIST), Japan,
[21] X.-J. Wang, J. Tan, K. Grozinger, Tetrahedron Lett. 2000, 41,
2010
(http://riodb01.ibase.aist.go.jp/sdbs/cgi-bin/cre_index.
4713–4716.
cgi?lang=eng, accessed on 15 November 2010).
[45] ACD Name, version 12.0, Advanced Chemistry Development,
Inc., Toronto, ON, 2010 (www.acdlabs.com, accessed on 15
November 2010).
[22] G. Heinisch, W. Holzer, C. Obala, Monatsh. Chem. 1988, 119,
253–262.
[23] E. Arbacˇiauskiene, G. Vilkauskaite, G. A. Eller, W. Holzer, A.
˙
˙
ˇ
Sacˇkus, Tetrahedron 2009, 65, 7817–7824.
[24] P. J. Stang, M. Hanack, L. R. Subramanian, Synthesis 1982, 2,
85–126.
[46] G. A. Eller, Molecules 2006, 11, 915–928.
[47] A. Sener, I. Tozlu, H. Genc, I. Bildirici, K. Arisoy, J. Hetero-
cycl. Chem. 2007, 44, 1077–1081.
[25] A. W. Taylor, R. T. Cook, Tetrahedron 1987, 43, 607–616.
[26] N. Miyaura, A. Suzuki, Chem. Rev. 1995, 95, 2457–2483.
Received: November 18, 2010
Published Online: February 23, 2011
1890
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Eur. J. Org. Chem. 2011, 1880–1890