Sonogashira-type reactions with 5-chloro-1-phenyl-1H-pyrazole-4- carbaldehydes: A straightforward approach to pyrazolo[4,3-c]pyridines

Article abstract of DOI:10.1002/ejoc.201100626

The easily obtainable 5-chloro-1-phenyl-1H-pyrazole-4-carbaldehydes 2 were used as precursors in Sonogashira-type cross-coupling reactions with various alkynes to provide the corresponding 5-alkynyl-1H-pyrazole-4-carbaldehydes 3. Treatment of these with t

Full text of DOI:10.1002/ejoc.201100626

FULL PAPER
DOI: 10.1002/ejoc.201100626
Sonogashira-Type Reactions with 5-Chloro-1-phenyl-1H-pyrazole-4-
carbaldehydes: A Straightforward Approach to Pyrazolo[4,3-c]pyridines
[b]
[a]
Gyte˙ Vilkauskaite˙,[a,b] Algirdas Sackus,* and Wolfgang Holzer*
ˇ
ˇ
Keywords: Nitrogen heterocycles / C–C coupling / Palladium / Cyclization
The easily obtainable 5-chloro-1-phenyl-1H-pyrazole-4-
carbaldehydes 2 were used as precursors in Sonogashira-
type cross-coupling reactions with various alkynes to provide
the corresponding 5-alkynyl-1H-pyrazole-4-carbaldehydes
3. Treatment of these with tert-butylamine with microwave
assistance afforded the corresponding 1-phenylpyrazolo[4,3-
c]pyridines 4. The oximes 5 – derived from the aldehydes 3 –
were transformed into the corresponding 1-phenylpyrazolo-
[4,3-c]pyridine 5-oxides 6 through silver-triflate-catalysed re-
gioselective cyclisation. Ring closure of the oximes 5 in the
presence of iodine in ethanol gave the 7-iodo-1-phenylpyr-
azolo[4,3-c]pyridine 5-oxides 7. Detailed NMR spectroscopic
investigations were undertaken with all obtained products.
Introduction
Condensed pyrazole units are important substructures of
several biologically active molecules, some well-known drug
molecules among them. Examples include sildenafil
(Figure 1, a pyrazolo[4,3-d]pyrimidine),[1,2] allopurinol[1,3]
(a pyrazolo[3,4-d]pyrimidin-4-one), riociguat[4] (a pyrazolo-
[3,4-b]pyridine) and zaleplon[5] (a pyrazolo[1,5-a]pyrimid-
ine).
Whereas pyrazolo[3,4-b]pyridines are routinely available
and a number of synthetic pathways for their construction–
mostly starting from easily available 5-aminopyrazoles – are
known, comparably little is known with regard to the iso-
meric pyrazolo[4,3-c]pyridines. Conventional synthetic
routes to the pyrazolo[4,3-c]pyridine core involve either
pyridine ring closure of an appropriately functionalised pyr-
azole derivative or, inversely, pyrazole ring formation start-
ing from a suitably functionalised pyridine.[6] Some known
synthetic approaches for compounds of this type are shown
in Scheme 1.
Molina et al. reported an aza-Wittig-type reaction for the
synthesis of the pyrazolo[4,3-c]pyridine core, starting from
1-phenylpyrazole-5-carbaldehyde. This was converted into
an iminophosphorane derivative and subsequently treated
with isocyanates, ketenes and aliphatic and aromatic alde-
hydes to afford pyrazolo[4,3-c]pyridines (Scheme 1,
Figure 1. Drug molecules containing a condensed pyrazole unit.
route a).[7] The desired heterocyclic system was also pre-
pared by starting from a pyrazole-5-carboxylate, which was
transformed into an acrylic acid derivative and then into
the corresponding acrylic azide. Closure of the pyridine ring
afforded a pyrazolo[4,3-c]pyridin-4-one, which was con-
verted into the 4-chloro derivative by treatment with phos-
phorus oxychloride (Scheme 1, route b).[8] Commeiras et al.
presented a pyrazolo[4,3-c]pyridine synthesis based on
cyclisation of bisacetylenic N-acylated hydrazones with
aqueous ammonia (Scheme 1, route c).[9] An approach
starting from functionalised pyridines was published by
Tyvorskii and co-workers: diazotisation of 5-alkylated 4-
aminopyridines, followed by sodium acetate treatment of
the obtained diazonium salts, gave trifluoromethylated pyr-
azolo[4,3-c]pyridines (Scheme 1, route d).[10] Fucini et al.
reported a four-step synthesis of 5-chloro-3-methylpyr-
[a] 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
[b] Institute of Synthetic Chemistry, Kaunas University of
Technology,
Radvilenu pl. 19, 50254 Kaunas, Lithuania
Fax: +370-37-451432
E-mail: algirdas.sackus@ktu.lt
Eur. J. Org. Chem. 2011, 5123–5133
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G. Vilkauskaite, A. Sacˇkus, W. Holzer
˙
FULL PAPER
Scheme 1. Some known syntheses of pyrazolo[4,3-c]pyridines.
azolo[4,3-c]pyridine starting from methyl 2,4-dichloronicot-
inate (Scheme 1, route e).[11] Various 4-chloro-3-aroylpyrid-
ines underwent condensation with hydrazine hydrate to af-
ford correspondingly substituted pyrazolo[4,3-c]pyridines
(Scheme 1, route f).[12–14] Another synthesis of substituted
Results and Discussion
Synthesis
The starting compounds for the synthetic pathway dis-
pyrazolopyridinones was based on treatment of 4-meth- played in Scheme 2 are the 5-chloropyrazole-4-carbal-
ylthio-3-cyano-2-pyridones with hydrazine and subsequent dehydes 2a and 2b. These compounds are easily accessible
pyrazole ring closure of the intermediate substitution prod- through Vilsmeier reactions[24] of the commercially avail-
ucts, followed by conversion of the pyridinone into a chlo- able pyrazolones 1a and 1b, with simultaneous introduction
ropyridine substructure with the aid of POCl3 (Scheme 1, of the chloro function by replacement of the hydroxy func-
route g).[15]
tion (or its tautomeric equivalent) by treatment with POCl3
Recently, Pd-assisted cross-coupling reactions have be- in excess.[25] Initial investigations with 2a and 2b revealed
come increasingly commonly employed for the functionalis- high reactivities of these compounds under the Sonogashira
ation of heteroaromatic compounds[16,17] and subsequently reaction conditions. Although iodo(hetero)arenes are usu-
for the construction of the corresponding annulated hetero- ally preferred as starting materials in such reactions (in view
cyclic systems.[18,19] In the case of condensed pyrazoles, for of the general reactivity trend I Ͼ Br/OTf ϾϾ Cl[26]), in the
instance, pyrazolo[4,3-c]pyridinones,[20,21] pyrano[4,3-c]- cases of 2a and 2b the chloro atoms are obviously highly
pyrazolones[20,22] and thieno[2,3-c]pyrazoles[23] have been activated, thus permitting smooth conversions into the cor-
synthesised by such approaches.
responding coupling products. The alkynes 3a–f were hence
In view of these facts and in continuation of our efforts obtained in 66–76% yields on treatment of 2a and 2b with
relating to the synthesis of condensed pyrazoles, we wish appropriate terminal alkynes (ethynylbenzene, 3-ethynyl-
to report here on the synthesis of pyrazolo[4,3-c]pyridines thiophene and hex-1-yne) as outlined in Scheme 2.
through Sonogashira reactions between 5-chloropyrazole-4-
carbaldehydes and various alkynes and subsequent pyridine closure reactions in that it carries an alkyne function and
ring formation in the obtained coupling products. a nucleophilic substituent in an ortho relationship on the
A compound of type 3 is an interesting precursor for ring
Scheme 2. Reagents and conditions: a) POCl3, DMF, reflux, 2 h; b) R–CϵCH, Pd(PPh3)2Cl2, TEA, CuI, DMF, 80 °C, 2 h; c) tert-
butylamine, DMF, MW, 1 h.
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Pyrazolo[4,3-c]pyridines Through Sonogashira-Type Reactions
Scheme 3. Reagents and conditions: a) NH2OH·HCl, NaOAc, EtOH, room temp., 1 h; b) AgOTf, DCM, room temp., 0.5–2 h; c) I2,
EtOH, room temp., 2 h.
pyrazole nucleus. In order to construct a pyridine ring from do not play a role in the outcomes of the cyclisation reac-
this particular starting arrangement of functionalities we tions.
made use of the approach of Larock and co-workers: con-
Further functionalised pyrazolo[4,3-c]pyridine N-oxides
version of the aldehyde moiety into a N-tert-butylimino were obtained by iodine-mediated cyclisation[30] of the pre-
function and subsequent pyridine ring closure of this inter- cursors 5b and 5e, as demonstrated with the representatives
mediate.[27] Such a strategy has been used for syntheses of, 7b and 7e. The resulting iodo derivatives 7b and 7e would
for instance, pyrido[4,3-d]pyrimidines.[28]
be expected to be suitable for further decoration through
By this approach and with microwave assistance we suc- Pd-assisted cross-coupling reactions at C-7 or, for instance,
cessfully converted the coupling products 3a–f into the cor- by α-cyanation at C-4.
responding pyrazolo[4,3-c]pyridines (Scheme 2) in accept-
able to good yields (50–86%).
NMR Spectroscopic Investigations
The N-oxides of the bicycles 4 (i.e., compounds 6,
Scheme 3) also seemed to be of considerable interest. Such
The NMR spectroscopic data for all compounds investi-
structures can be regarded as pyrazole analogues of iso- gated in this study are given in the Experimental Section.
quinoline N-oxides, which are important in materials Unequivocal assignment of signals was carried out by com-
science because of their optochemical/physical proper- bined application of standard NMR spectroscopic tech-
1
ties.[29] Moreover, such N-oxides can be used as starting niques such as H-coupled 13C NMR spectroscopy, APT,
compounds for further functionalisation, such as α-cyan- HMQC, gs-HSQC, gs-HMBC, COSY, TOCSY, NOESY
ation and α-chlorination.[30,31] Direct oxidation of the pyr- and NOE-difference spectroscopy.[34] In numerous cases ex-
1
azolopyridines 4 to the N-oxides 6 would bear a risk of periments with selective excitation (DANTE) of certain H
competing N-oxidation at the pyrazole N-2,[32] so to access resonances, such as long-range INEPT[35] and 2D(δ,J) long-
the N-oxides 6 we envisaged a synthesis by ring closure of range INEPT,[36] were performed; these experiments were
suitable precursors with preformed N–O moieties.
indispensable for the unambiguous mapping of long-range
Such precursors are oximes of type 5 (Scheme 3), which 13C,1H coupling constants.
were easily obtained from the primary coupling products 3
The coupling products 3a–f show very consistent signal
under standard conditions. Whereas treatment of 3a–c with sets with regard to the invariable part of the molecule. The
hydroxylamine hydrochloride/NaOAc in ethanol afforded alkyne C signals in compounds of type 3 (and also 5) can
mixtures of the stereoisomers (Z)-5a–c and (E)-5a–c, from easily be distinguished by consideration of their coupling
3d–f only the corresponding (E)-oximes (5d–f) were isolated patterns. An alkyne C attached to the pyrazole system
(see also NMR spectroscopic investigations). This behav- (smaller chemical shift) appears as a singlet signal in the
iour can readily be explained in steric terms (methyl group 1H-coupled 13C NMR spectrum for it has no opportunity
at C-3). The conversions of compounds 5 into 6 involve for couplings with adjacent protons and so also lacks corre-
regioselective (6-endo-dig) electrophilic cyclisation[33] with lations in HMBC experiments. On the other hand, an al-
the oxime N lone pairs attacking the CϵC triple bonds. kyne C appended to a phenyl (series a, d), 3-thienyl (series
This process can be catalysed by electrophilic metals; in our b, e) or n-butyl moiety (series c, f) shows couplings with
case, and consistently with investigations by Shin and co- protons of these systems, accordingly resulting in multiplet
authors,[29] the use of silver triflate gave the best results. signals in the H-coupled 13C NMR spectra or giving rise
1
Obviously, the initial configurations of the starting oximes to correlations signals in the HMBC spectra.
Eur. J. Org. Chem. 2011, 5123–5133
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G. Vilkauskaite, A. Sacˇkus, W. Holzer
˙
FULL PAPER
The existence of pyrazolo[4,3-c]pyridine cores in com- cause in A there would be an explicit steric hindrance of
pounds 4, 6 and 7 (and thus 6-endo-dig cyclisation) un- C=N–OH and the substituent attached to pyrazole C-5
ambiguously follows from numerous correlations in the (Figure 2). The preference for conformer A in (Z)-5a is ad-
3
3
HMBC spectra, such as J(C3a,H7), J(Ph C-1,H7) (series ditionally reflected by the magnitude of 3J(C3,NCH). In
3
3
a and d), J(Th C-3,H7) (series b and e) and J(N5,CH2) (E)-5a, in which both conformers A and B have to be taken
(series c and f). With the alternative 5-exo-dig cyclisation into account, this coupling is smaller (3J = 4.8 Hz, mean
products (with 6-ylidene-1,6-dihydropyrrolo[3,4-c]pyrazole value of “cis” and “trans” coupling) than that in (Z)-5a (3J
structures) these correlations are not possible.
= 6.7 Hz), in which a “trans” situation of the coupled nuclei
Some oximes of type 5 were found to exist as mixtures is favoured (Figure 2).
of E and Z isomers. For 5a, for instance, a 1:1 ratio of E
Interestingly, in CDCl3 solution the isomeric ratios were
and Z forms was detected in [D6]DMSO solution. Discrimi- found to change with time. In the case of 5c, for instance,
nation of E and Z diastereomers in the case of the oximes an E/Z ratio of 3:2 was observed initially, whereas after 4 d
5 was accomplished by considering the magnitude of the same sample now showed a 1:2 ratio. Furthermore, it
1J(N=C–H). It is well known, that – due to lone-pair ef- should be mentioned that specific lines (particularly those
fects – this coupling is considerably larger when the nitro- of the C–CH=NOH moiety in the Z forms) were broad to
gen’s lone pair and the coupled proton are in a cis relation- be very broad in this solvent, indicating dynamic behaviour.
1
ship about the C=N double bond (Z isomer) than in a trans
Figure 3 shows a comparison of H, 13C and 15N NMR
one (E isomer).[37] The 1J(N=C–H) value in (Z)-5a was thus chemical shifts of the related congeners 4e, 6e and 7e. From
found to be 176.3 Hz, whereas in (E)-5a the corresponding these data, the influence of N-oxidation at N-5 (4eǞ6e)
coupling constant (in [D6]DMSO) was only 165.1 Hz (Fig- and of iodination at C-7 (6eǞ7e) can be studied. As would
ure 2). These assignments were confirmed by NOE differ- be expected, upon switching from 4e to the corresponding
ence (or NOESY) experiments: in the E forms the OH pro- N-oxide 6e
a marked upfield shift of δ(N-5) (4e:
ton and the iminyl proton N=CH are spatially close and so –94.6 ppmǞ6e: –108.2 ppm) is apparent, although smaller
marked NOEs between the concerning nuclei were detected, than that in the transition from pyridine to pyridine N-ox-
whereas such through-space connections were absent (or ide (ca. 23 ppm upfield shift).[39] In the 13C NMR spectra
very small) for the corresponding Z isomers[38] (Figure 2).
of 6e, the expected upfield shifts for the carbons in ortho-
and para-positions to N-5 (C-4: –12.1 ppm, C-6: –6.5 ppm,
C7a: –7.8 ppm) can be observed (relative to the correspond-
ing shifts in the parent compound 4e). Furthermore, an in-
1
1
crease in the coupling constants J(C4,H4), J(C7,H7) and
a distinct decrease in 2J(C3a,H4) (9.4 HzǞ4.6 Hz) and
3J(C6,H4) (12.0 HzǞ4.9 Hz) is noticeable, running com-
pletely parallel to the pyridineǞpyridine N-oxide transi-
tion.[40] An interesting phenomenon emerges when the 13C
NMR chemicals shifts of the iodo derivative 7e are com-
pared with those of 6e. Apart from the marked upfield shift
of C-7 (6e: 106.2 ppm; 7e: 76.8 ppm) induced by the heavy
atom effect of the iodine substituent there is a noteworthy
Figure 2. Configurational assignment in oxime 5a by means of
NOEs (arrows) and 13C,1H coupling constants; important 1H
NMR (in italics) and 13C NMR chemical shifts.
In the course of these NOE experiments, distinct NOEs
between pyrazole H-3 and N=CH were also observed for
the E isomers, whereas in the corresponding Z isomers no
such interactions were found (or were found to be very
small). An explanation based on steric factors can be of-
fered for this phenomenon. Whereas for the E isomers both
the s-cis and s-trans forms about the C4–CN bond are pos-
sible (and thus also a form A, with spatial proximity of H3
and N=CH, Figure 2), for the Z isomers only form B with
OH group and pyrazole H-3 being spatially close (and thus
1
Figure 3. H NMR (in italics), 13C NMR and 15N NMR (in bold)
giving no NOE between H3 and N=CH) is probable, be- chemical shifts of 4e, 6e and 7e (CDCl3 solution).
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Pyrazolo[4,3-c]pyridines Through Sonogashira-Type Reactions
1-Phenyl-5-(phenylethynyl)-1H-pyrazole-4-carbaldehyde (3a): Yield
2.080 g, 76%; light brown solid, m.p. 72–73 °C. 1H NMR
(500 MHz, CDCl3): δ = 7.38 (m, 2 H, CPh 3,5-H), 7.41 (m, 1 H,
CPh 4-H), 7.45 (m, 1 H, NPh 4-H), 7.49 (m, 2 H, CPh 2,6-H), 7.53
(m, 2 H, NPh 3,5-H), 7.84 (m, 2 H, NPh 2,6-H), 8.15 (s, 1 H, 3-
H), 10.11 (s, 1 H, CHO) ppm. 13C NMR (125 MHz, CDCl3): δ =
75.7 (CCPh), 101.4 (3JCCPh,CPh2,6-H = 5.4 Hz, CCPh), 120.6 (CPh
C-1), 123.6 (NPh C-2,6), 126.2 (2JC-4,CHO = 25.1, 2JC-4,3-H = 9.6 Hz,
C-4), 128.58 (CPh C-3,5), 128.60 (NPh C-4), 129.0 (NPh C-3,5),
downfield shift for carbons 2 and 6 of the N-phenyl ring
(6e: 122.1 ppmǞ7e: 129.3 ppm). This can be explained by
steric effects: because of the presence of the bulky iodo
atom at C-7 the angle between the benzene and the pyrazole
ring is twisted, leading to a decrease in the electronic effects
due to the azole system. It is known from the literature that
the ortho (and the para) carbons of the N-phenyl rings in
1-phenyl-1H-pyrazoles are very sensitive to such steric ef-
fects. The δ(Ph C-2,6) value in 1-phenyl-1H-pyrazole (δ
129.2 (C-5), 130.0 (CPh C-4), 131.7 (CPh C-2,6), 138.7 (NPh C-1),
3
=118.8 ppm), for instance, rises to 129.0 ppm in the 139.8 (1JC-3,3-H = 191.9, JC-3,CHO = 4.2 Hz, C-3), 183.8 (1JCHO
=
176.6, JCHO,3-H = 1.2 Hz, CHO) ppm. 15N NMR (50 MHz,
3
crowded 3,5-di-tert-butyl-1-phenyl-1H-pyrazole.[41,42]
CDCl ): δ = –156.9 (N-1), –69.7 (N-2) ppm. IR (KBr): ν = 2212
˜
3
(CϵC), 1674 (C=O) cm–1. MS: m/z (%) = 272 (30) [M]+, 271 (90)
[M – H]+, 77 (100), 71 (22), 69 (94), 67 (24), 65 (20), 63 (33), 57
(55), 55 (65), 51 (84), 50 (20), 43 (59), 41 (50). C18H12N2O (272.30):
calcd. C 79.39, H 4.44, N 10.29; found C 79.06, H 4.43, N 10.18.
Conclusions
In conclusion, we present a simple and straightforward
approach to various pyrazolo[4,3-c]pyridines starting from
easily available 5-chloro-1H-pyrazole-4-carbaldehydes. Fur-
ther studies to exploit the synthetic potential of the latter
compounds are in progress in our laboratory.
1-Phenyl-5-(3-thienylethynyl)-1H-pyrazole-4-carbaldehyde
(3b):
Yield 1.920 g, 69%; light brown solid, m.p. 99–101 °C. 1H NMR
3
4
(500 MHz, CDCl3): δ = 7.16 (dd, JTh4-H,Th5-H = 5.0, JTh2-H,Th4-H
3
=
1.1 Hz,
1 H, Th 4-H), 7.34 (dd, JTh4-H,Th5-H = 5.0,
4JTh2-H,Th5-H = 3.0 Hz, 1 H, Th 5-H), 7.45 (m, 1 H, Ph 4-H), 7.53
4
4
(m, 2 H, Ph 3,5-H), 7.61 (dd, JTh2-H,Th5-H = 3.0, JTh2-H,Th4-H
=
1.1 Hz, 1 H, Th 2-H), 7.82 (m, 2 H, Ph 2,6-H), 8.14 (s, 1 H, 3-H),
10.08 (s, 1 H, CHO) ppm. 13C NMR (125 MHz, CDCl3): δ = 75.5
Experimental Section
3
(CCTh), 96.8 (3JCCTh,Th2-H = 3.8, JCCTh,Th4-H = 2.0 Hz, CCTh),
General Comments: Melting points were determined with a Reich-
ert–Kofler hot-stage microscope and are uncorrected. Mass spectra
were obtained with a Shimadzu QP 1000 instrument (EI, 70 eV)
and a Finnigan MAT 8230 instrument (EI, 70 eV, HRMS). Infra-
red spectra were recorded with a Perkin–Elmer Spectrum One spec-
trometer and potassium bromide pellets. Elemental analyses (C, H,
N) were performed with an Exeter Analytical CE-440 Elemental
Analyser at the Microanalytical Laboratory, Kaunas University of
Technology, and were in good agreement (Ϯ0.4%) with the calcu-
lated values. 1H and 13C NMR spectra were recorded with a Varian
UnityPlus 300 spectrometer at 28 °C (299.95 MHz for 1H NMR,
75.43 MHz for 13C NMR) or a Bruker Avance 500 spectrometer at
293 K (500.13 MHz for 1H, 125.77 MHz for 13C). The centre of the
solvent signal was used as an internal standard and correlated to
TMS with δ = 7.26 ppm (1H in CDCl3), δ = 2.49 ppm (1H in [D6]-
DMSO), δ = 77.0 ppm (13C in CDCl3) and δ = 39.5 ppm (13C in
[D6]DMSO). 15N NMR spectra (50.68 MHz, referenced against ex-
ternal nitromethane) were obtained with a Bruker Avance 500 in-
strument with a “directly” detecting broadband observe probe
2
3
120.0 (2JThC-3,Th2-H = 3.2, JThC-3,Th4-H = 4.9, JThC-3,Th5-H
=
11.0 Hz, Th C-3), 123.6 (Ph C-2,6), 126.2 (1JThC-5,Th5-H = 188.6,
3
2JThC-5,Th4-H
=
7.1, JThC-5,Th2-H
=
5.5 Hz, Th C-5), 126.3
(2JC-4,CHO = 25.0, JC-4,3-H = 9.6 Hz, C-4), 128.6 (Ph C-4), 129.1
2
(Ph C-3,5), 129.2 (3JC-5,3-H = 4.3 Hz, C-5), 129.4 (1JThC-4,Th4-H
=
2
3
172.5, JThC-4,Th5-H = 4.6, JThC-4,Th2-H = 8.4 Hz, Th C-4), 131.2
(1JThC-2,Th2-H = 188.8, JThC-2,Th4-H = 8.4, JThC-2,Th5-H = 4.5 Hz,
3
3
Th C-2), 138.8 (Ph C-1), 139.8 (1JC-3,3-H = 192.0, JC-3,CHO
=
3
4.3 Hz, C-3), 183.8 (1JCHO = 176.6 Hz, CHO) ppm. 15N NMR
(50 MHz, CDCl3): δ = –157.0 (N-1), –69.8 (N-2) ppm. IR (KBr):
ν = 2211 (CϵC), 1679 (C=O) cm–1. MS: m/z (%) = 278 (10) [M]+,
˜
277 (39) [M – H]+, 205 (23), 77 (78), 69 (39), 63 (28), 57 (43), 55
(36), 51 (100), 50 (29), 45 (21), 43 (47), 41 (26). C16H10N2OS
(278.33): calcd. C 69.04, H 3.62, N 10.06; found C 69.40, H 3.58,
N 9.93.
5-Hex-1-ynyl-1-phenyl-1H-pyrazole-4-carbaldehyde (3c): Yield
1.903 g, 76%; brown liquid. 1H NMR (500 MHz, CDCl3): δ = 0.91
(t, J = 7.4 Hz, 3 H, CH3CH2), 1.41 (m, 2 H, CH3CH2), 1.57 (m, 2
H, CH3CH2CH2), 2.48 (t, J = 7.1 Hz, 2 H, CCCH2), 7.42 (m, 1 H,
Ph 4-H), 7.49 (m, 2 H, Ph 3,5-H), 7.75 (m, 2 H, Ph 2,6-H), 8.07 (s,
1 H, 3-H), 9.98 (s, 1 H, CHO) ppm. 13C NMR (125 MHz, CDCl3):
δ = 13.4 (1JCH3 = 125.1 Hz, CH3CH2), 19.4 (CCCH2), 21.9
(CH2CH3), 29.8 (CH2CH2CH3), 67.5 (3JCCCH2,CH2 = 4.4 Hz,
1
(BBFO). Digital resolutions were 0.25 Hz per data point in the H
spectra and 0.4 Hz per data point in the 13C NMR spectra. System-
atic names were generated with ACD/Name according to the IU-
PAC recommendations. For chromatographic separations, Kiesel-
gel 60 (70–230 mesh, Merck) was used.
3
CCCH2), 104.2 (2JCCCH2,CH2 = 10.5, JCCCH2,CCH2CH2 = 6.0 Hz,
General Procedure for the Sonogashira Reactions (3a–h): Triethyl-
amine (6.95 mL, 50 mmol), the appropriate arylacetylene (phenyl-,
3-thienyl-) or hex-1-yne (15 mmol), Pd(PPh3)2Cl2 (701 mg, 1 mmol)
and CuI (380 mg, 2 mmol) were added under argon to a solution
of 2a or 2b (10 mmol) in dry dimethylformamide (20 mL) and the
reaction mixture was stirred at 80 °C for 2 h. Dimethylformamide
was evaporated under reduced pressure. The residue was dissolved
in dichloromethane (20 mL), water (40 mL) was added, and the
mixture was extracted with dichloromethane (3ϫ 40 mL). The or-
ganic layers were combined, washed with brine and dried with so-
dium sulfate. The solvent was evaporated and the residue was puri-
fied by column chromatography (SiO2, eluent ethyl acetate/light pe-
troleum 1:7, v/v).
2
CCCH2), 123.6 (Ph C-2,6), 126.2 (2JC-4,CHO = 34.3, JC-4,3-H = 9.5,
5JC-4,CH2 = 0.9 Hz, C-4), 128.4 (Ph C-4), 128.9 (Ph C-3,5), 130.1
3
(C-5), 138.8 (Ph C-1), 139.5 (1JC-3,3-H = 191.6, JC-3,CHO = 4.3 Hz,
C-3), 184.2 (1JCHO = 176.3 Hz, CHO) ppm. 15N NMR (50 MHz,
CDCl ): δ = –157.0 (N-1), –71.4 (N-2) ppm. IR (KBr): ν = 2236
˜
3
(CϵC), 1683 (C=O) cm–1. MS: m/z (%) = 252 (4) [M]+, 210 (87),
209 (24), 181 (26), 154 (29), 77 (100), 63 (34), 51 (79), 50 (24), 43
(30), 41 (51). MS: calcd. for [C16H16N2O – H]+ 251.1184; found
251.1185.
3-Methyl-1-phenyl-5-(phenylethynyl)-1H-pyrazole-4-carbaldehyde
(3d): Yield 2.044 g, 71%; light brown solid, m.p. 70–72 °C. 1H
NMR (500 MHz, CDCl3): δ = 2.59 (s, 3 H, CH3), 7.37 (m, 2 H,
Eur. J. Org. Chem. 2011, 5123–5133
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5127

ˇ
G. Vilkauskaite, A. Sacˇkus, W. Holzer
˙
FULL PAPER
CPh 3,5-H), 7.40 (m, 1 H, CPh 4-H), 7.43 (m, 1 H, NPh 4-H), 7.48
= 7.42 (m, 1 H, CPh 4-H), 7.43 (m, 1 H, NPh 4-H), 7.49 (m, 2 H,
(m, 2 H, CPh 2,6-H), 7.52 (m, 2 H, NPh 3,5-H), 7.82 (m, 2 H, CPh 3,5-H), 7.59 (m, 2 H, NPh 3,5-H), 7.74 (m, 2 H, NPh 2,6-H),
NPh 2,6-H), 10.17 (s, 1 H, CHO) ppm. 13C NMR (125 MHz, 7.95 (s, 1 H, 7-H), 8.03 (m, 2 H, CPh 2,6-H), 8.33 (s, 1 H, 3-H),
CDCl3): δ = 13.5 (1J3-Me = 129.2 Hz, CH3), 75.8 (CCPh), 101.1 9.23 (d, J = 1.0 Hz, 1 H, 4-H) ppm. 13C NMR (125 MHz, CDCl3):
4
(3JCCPh,CPh2,6-H = 5.4 Hz, CCPh), 120.9 (CPh C-1), 123.4 (2JC-4,CHO δ = 101.3 (1JC-7,7-H = 165.3, JC-7,4-H = 1.7 Hz, C-7), 121.5
3
2
3
= 24.2, JC-4,3-Me = 2.5 Hz, C-4), 123.5 (NPh C-2,6), 128.3 (NPh
(2JC-3a,3-H = 11.2, JC-3a,4-H = 9.7, JC-3a,7-H = 4.0 Hz, C-3a), 122.8
C-4), 128.6 (CPh C-3,5), 129.0 (NPh C-3,5), 129.9 (CPh C-4), 130.6
(NPh C-2,6), 127.4 (NPh C-4), 127.3 (CPh C-2,6), 128.7 (CPh C-
(C-5), 131.7 (CPh C-2,6), 138.8 (NPh C-1), 151.7 (2JC-3,3-Me = 7.0, 3,5), 128.8 (CCh C-4), 129.6 (NPh C-3,5), 135.3 (1JC-3,3-H = 191.9,
3JC-3,CHO = 5.1 Hz, C-3), 184.9 (1JCHO = 174.9 Hz, CHO) ppm.
15N NMR (50 MHz, CDCl3): δ = –163.1 (N-1), –74.2 (N-2) ppm.
3JC-3,4-H = 1.3 Hz, C-3), 139.2 (NPh C-1), 139.6 (3JCPhC-1,7-H
=
3
2.6 Hz, CPh C-1), 142.8 (2JC-7a,7-H = 1.1, JC-7a,3-H = 3.5,
IR (KBr): ν = 2214 (CϵC), 1675 (C=O) cm–1. MS: m/z (%) = 286
3JC-7a,4-H = 6.2 Hz, C-7a), 145.1 (1JC-4,4-H = 181.3, JC-4,7-H
=
5
˜
(0.6) [M]+, 77 (95), 51 (100). C19H14N2O (286.33)·0.36H2O: calcd. 0.7 Hz, C-4), 153.9 (3JC-6,4-H = 12.0 Hz, C-6) ppm. 15N NMR
C 77.94, H 5.07, N 9.57; found C 77.93, H 4.93, N 9.96.
(50 MHz, CDCl3): δ = –185.2 (N-1), –90.7 (N-5), –59.9 (N-2) ppm.
MS: m/z (%) = 271 (15) [M]+, 77 (22), 71 (43), 69 (51), 57 (100),
56 (30), 55 (75), 51 (20), 43 (76), 41 (44). C18H13N3 (271.32)·
0.29H2O: calcd. C 78.18, H 4.95, N 15.19; found C 78.20, H 5.22,
N 14.81.
3-Methyl-1-phenyl-5-(3-thienylethynyl)-1H-pyrazole-4-carbaldehyde
(3e): Yield 1.826 g, 66 %; light brown solid, m.p. 95–96 °C. 1H
NMR (500 MHz, CDCl3): δ = 2.58 (s, 3 H, CH3), 7.15 (dd,
3JTh4-H,Th5-H = 5.0, 4JTh2-H,Th4-H = 1.1 Hz, 1 H, Th 4-H), 7.34 (dd,
4
3JTh4-H,Th5-H = 5.0, JTh2-H,Th5-H = 3.0 Hz, 1 H, Th 5-H), 7.43 (m,
1-Phenyl-6-(3-thienyl)-1H-pyrazolo[4,3-c]pyridine (4b): Yield
4
1 H, Ph 4-H), 7.51 (m, 2 H, Ph 3,5-H), 7.59 (dd, JTh2-H,Th5-H
=
104 mg, 75 %; yellowish solid, m.p. 124–125 °C. 1H NMR
3.0, 4JTh2-H,Th4-H = 1.1 Hz, 1 H, Th 2-H), 7.80 (m, 2 H, Ph 2,6-H),
10.14 (s, 1 H, CHO) ppm. 13C NMR (125 MHz, CDCl3): δ = 13.5
(1J3-Me = 129.2 Hz, CH3), 75.5 (CCTh), 96.4 (3JCCTh,Th2–H = 3.8,
3JCCTh,Th4–H = 2.2 Hz, CCTh), 120.0 (2JThC-3,Th 2–H = 3.2,
3
4
(500 MHz, CDCl3): δ = 7.40 (dd, JTh4-H,Th5-H = 5.1, JTh2-H,Th5-H
= 3.1 Hz, 1 H, Th 5-H), 7.43 (m, 1 H, Ph 4-H), 7.58 (m, 2 H, Ph
3
4
3,5-H), 7.67 (dd, JTh4-H,Th5-H = 5.1, JTh2-H,Th4-H = 1.2 Hz, 1 H,
Th 4-H), 7.73 (m, 2 H, Ph 2,6-H), 7.84 (s, 1 H, 7-H), 7.98 (dd,
3
2JThC-3,Th 4–H = 4.9, JThC-3,Th 5–H = 11.1 Hz, Th C-3), 123.4
4
4JTh2-H,Th5-H = 3.1, JTh2-H,Th4-H = 1.2 Hz, 1 H, Th 2-H), 8.30 (d,
(2JC-4,CHO = 24.2, 3JC-4,3–Me = 2.5 Hz, C-4), 123.5 (Ph C-2,6), 126.2
J = 1.0 Hz, 1 H, 3-H), 9.15 (s, 1 H, 4-H) ppm. 13C NMR
1
2
(Th C-5, JTh C-5,Th 5–H = 188.3 Hz, JTh C-5,Th 4–H = 7.0 Hz,
(125 MHz, CDCl3): δ = 100.6 (1JC-7,7-H = 165.4 Hz, C-7), 121.3 (C-
3JThC-5,Th2–H = 5.5 Hz), 128.3 (Ph C-4), 129.0 (Ph C-3,5), 129.4
3
3a), 122.8 (Ph C-2,6), 123.9 (1JThC-2,Th2-H = 185.5, JThC-2,Th4-H
=
1
2
(Th C-4, JTh C-4,Th 4–H = 171.5 Hz, JTh C-4,Th 5–H = 5.4 Hz,
8.6, JThC-2,Th5-H = 4.6 Hz, Th C-2), 126.2 (1JThC-4,Th4-H = 167.3,
3
3JThC-4,Th2–H = 8.4 Hz), 130.6 (C-5), 131.1 (Th C-2, JThC-2,Th2–H
1
2JThC-4,Th 5-H = 4.8, JThC-4,Th 2-H = 8.6 Hz, Th C-4), 126.4
3
3
3
= 188.5 Hz, JThC-2,Th4–H = 8.4 Hz, JThC-2,Th5–H = 4.8 Hz), 138.8
(1JThC-5,Th5-H = 186.0, JThC-5,Th4-H = 7.1, JThC-5,Th2-H = 5.9 Hz,
Th C-5), 127.4 (Ph C-4), 129.7 (Ph C-3,5), 135.4 (1JC-3,3-H = 191.9,
3JC-3,4-H = 1.2 Hz, C-3), 139.2 (Ph C-1), 142.1 (Th C-3), 142.7
2
3
(Ph C-1), 150.8 (C-3, 2JC-3,3–Me = 7.0 Hz, 3JC-3,CHO = 5.0 Hz), 184.9
(CHO, JCHO = 174.9 Hz) ppm. 15N NMR (50 MHz, CDCl3): δ =
1
–163.2 (N-1), –74.4 (N-2) ppm. IR (KBr): ν = 2217 (CϵC), 1675
˜
(2JC-7a,7-H = 1.1, JC-7a,3-H = 3.4, JC-7a,4-H = 6.2 Hz, C-7a), 145.2
(1JC-4,4-H = 181.4 Hz, C-4), 149.8 (C-6) ppm. 15N NMR (50 MHz,
CDCl3): δ = –185.4 (N-1), –91.9 (N-5), –60.3 (N-2) ppm. MS: m/z
(%) = 277 (30) [M]+, 149 (20), 77 (24), 71 (31), 69 (49), 57 (100),
56 (23), 55 (65), 51 (27), 43 (64), 41 (45). C16H11N3S (277.34): calcd.
C 69.28, H 4.00, N 15.15; found C 60.00, H 4.24, N 15.18.
3
3
(C=O) cm–1. MS: m/z (%) = 292 (17) [M]+, 291 (65) [M – H]+, 77
(66), 69 (100), 57 (70), 51 (65), 45 (23), 43 (65), 42 (23), 41 (59).
C17H12N2OS (292.35): calcd. C 69.84, H 4.14, N 9.58; found C
70.11, H 4.42, N 9.58.
5-Hex-1-ynyl-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde
(3f):[43] Yield 1.748 g, 66 %; brown liquid. 1H NMR (300 MHz,
CDCl3): δ = 0.91 (t, J = 7.3 Hz, 3 H, CH3CH2), 1.40 (m, 2 H,
CH3CH2), 1.57 (m, 2 H, CH3CH2CH2), 2.47 (t, J = 7.0 Hz, 2 H,
CCCH2), 2.53 (s, 3 H, CH3C), 7.39 (m, 1 H, Ph 4-H), 7.47 (m, 2
H, Ph 3,5-H), 7.73 (m, 2 H, Ph 2,6-H), 10.03 (s, 1 H, CHO) ppm.
13C NMR (75 MHz, CDCl3): δ = 13.4 (1J3-Me = 129.2 Hz, CH3C),
13.4 (1JCH3 = 125.0 Hz, CH3CH2), 19.3 (CCCH2), 21.9 (CH2CH3),
29.9 (CH2CH2CH3), 67.7 (3JCCCH2,CH2 = 4.3 Hz, CCCH2), 103.8
6-Butyl-1-phenyl-1H-pyrazolo[4,3-c]pyridine (4c): Yield 72 mg,
1
57%; yellowish liquid. H NMR (300 MHz, CDCl3): δ = 0.94 (t, J
= 7.3 Hz, 3 H, CH3CH2), 1.40 (m, 2 H, CH3CH2), 1.76 (m, 2 H,
CH3CH2CH2), 2.91 (m, 2 H, CCH2), 7.39 (m, 1 H, Ph 4-H), 7.42
(d, J = 1.0 Hz, 1 H, 7-H), 7.56 (m, 2 H, Ph 3,5-H), 7.69 (m, 2 H,
Ph 2,6-H), 8.26 (d, J = 1.0 Hz, 1 H, 3-H), 9.08 (s, 1 H, 4-H) ppm.
13C NMR (75 MHz, CDCl3): δ = 13.9 (CH3CH2), 22.5 (CH2CH3),
32.4 (CH2CH2CH3), 38.5 (CCH2), 102.8 (1JC-7,7-H = 165.3 Hz, C-
7), 121.0 (C-3a), 122.6 (Ph C-2,6), 127.1 (Ph C-4), 129.6 (Ph C-
3
(2JCCCH2,CH2 = 10.5, JCCCH2,CCH2CH2 = 6.0 Hz, CCCH2), 123.3
(C-4), 123.5 (Ph C-2,6), 128.1 (Ph C-4), 128.9 (Ph C-3,5), 131.5 (C-
3
3,5), 135.2 (1JC-3,3-H = 191.5, JC-3,4-H = 1.3 Hz, C-3), 139.4 (Ph C-
3
5), 138.8 (Ph C-1), 150.5 (2JC-3,3-Me = 7.1, JC-3,CHO = 5.2 Hz, C-
3
1), 142.6 (3JC-7a,3-H = 3.5, JC-7a,4-H = 6.4 Hz, C-7a), 144.8
3), 185.2 (1JCHO = 174.2 Hz, CHO) ppm. 15N NMR (50 MHz,
CDCl3): δ = –163.2 (N-1), –76.6 (N-2) ppm.
(1JC-4,4-H = 180.4 Hz, C-4), 158.6 (C-6) ppm. 15N NMR (50 MHz,
CDCl3): δ = –186.6 (N-1), –87.8 (N-5), –62.4 (N-2) ppm. MS: m/z
(%) = 251 (2) [M]+, 209 (100), 77 (28) 57 (35), 55 (30), 43 (31), 41
(35). MS: calcd. for [C16H17N3 + H]+ 252.1501; found 252.1505.
General Procedure for the Preparation of Pyrazolo[4,3-c]pyridines
(4a–f): The appropriate pyrazole aldehyde (3a–f, 0.5 mmol) was dis-
solved in dimethylformamide (12 mL) and tert-butylamine
(365 mg, 5 mmol) was added. The reaction was performed under
microwave irradiation conditions with an Anton Paar Synthos 3000
reactor and P-Program (800 W, p-Rate 2.0 bars–1, IR: 150 °C, p:
80 bar for 1 h). The dimethylformamide was then removed under
reduced pressure and the residue was purified by column
chromatography (SiO2, eluent ethyl acetate/light petroleum
1:7Ǟ1:5Ǟ1:3, v/v).
3-Methyl-1,6-diphenyl-1H-pyrazolo[4,3-c]pyridine (4d): Yield
100 mg, 70 %; colourless solid, m.p. 115–117 °C. 1H NMR
(500 MHz, CDCl3): δ = 2.73 (s, 3 H, CH3), 7.39 (m, 1 H, NPh 4-
H), 7.41 (m, 1 H, CPh 4-H), 7.48 (m, 2 H, CPh 3,5-H), 7.56 (m, 2
H, NPh 3,5-H), 7.71 (m, 2 H, NPh 2,6-H), 7.90 (s, 1 H, 7-H), 8.03
(m, 2 H, CPh 2,6-H), 9.12 (s, 1 H, 4-H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 12.0 (1J3-Me = 128.6 Hz, CH3), 101.2 (1JC-7,7-H = 165.0,
1,6-Diphenyl-1H-pyrazolo[4,3-c]pyridine (4a): Yield 117 mg, 86%; 4JC-7,4-H = 1.7 Hz, C-7), 121.1 (2JC-3a,4-H = 9.4, JC-3a,7-H = 4.1,
3
1
colourless solid, m.p. 103–105 °C. H NMR (500 MHz, CDCl3): δ
3JC-3a,3-Me = 2.9 Hz, C-3a), 122.4 (NPh C-2,6), 126.9 (NPh C-4),
5128
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 5123–5133

Pyrazolo[4,3-c]pyridines Through Sonogashira-Type Reactions
127.3 (CPh C-2,6), 128.69 (CPh C-3,5), 128.73 (CPh C-4), 129.6 rated and the residue was purified by column chromatography
(NPh C-3,5), 139.3 (NPh C-1), 139.8 (CPh C-1), 143.6 (2JC-7a,7-H (SiO2, eluent ethyl acetate/light petroleum 1:7Ǟ1:5, v/v).
= 1.0, JC-7a,4-H = 6.3 Hz, C-7a), 144.5 (1JC-4,4-H = 179.6 Hz, C-4),
3
1-Phenyl-5-(phenylethynyl)-1H-pyrazole-4-carbaldehyde Oxime
(E/Z) Mixture (5a): Yield 663 mg, 77%; colourless solid, m.p. 132–
162 °C.
3
144.6 (2JC-3,3-Me = 7.0, JC-3,4-H = 1.1 Hz, C-3), 154.0 (3JC-6,4-H
=
11.7 Hz, C-6) ppm. 15N NMR (50 MHz, CDCl3): δ = –190.9 (N-
1), –93.1 (N-5), –66.1 (N-2) ppm. MS: m/z (%) = 285 (30) [M]+, 77
(48), 71 (28), 69 (100), 57 (82), 56 (22), 55 (56), 51 (42), 43 (54), 41
(60). C19H15N3 (285.34): calcd. C 79.98, H 5.30, N 14.73; found C
80.18, H 5.45, N 14.79.
E Isomer: 1H NMR (300 MHz, CDCl3): δ = 7.38 (m, 3 H, CPh
3,4,5-H), 7.42 (m, 1 H, NPh 4-H), 7.48 (m, 2 H, CPh 2,6-H), 7.51
(m, 2 H, NPh 3,5-H), 7.85 (m, 2 H, NPh 2,6-H), 8.06 (s, 1 H, 3-
H), 8.31 (s, 1 H, NCH), 9.22 (s, 1 H, OH) ppm. 13C NMR
(75 MHz, CDCl3): δ = 76.64 (CCPh), 100.65 (CCPh), 119.82
(2JC-4,3–H = 9.6, 2JC-4,NCH = 6.4 Hz, C-4), 121.51 (CPh C-1), 123.30
3-Methyl-1-phenyl-6-(3-thienyl)-1H-pyrazolo[4,3-c]pyridine (4e):
Yield 80 mg, 55%; light brown solid, m.p. 136–138 °C. 1H NMR
(500 MHz, CDCl3): δ = 2.71 (s, 3 H, CH3), 7.39 (m, 1 H, Ph 4-H),
7.40 (dd, 3JTh4-H,Th5-H = 5.1, 4JTh2-H,Th5-H = 3.1 Hz, 1 H, Th 5-H),
3
(NPh C-2,6), 124.59 (3JC-5,3–H = 4.5, JC-5,NCH = 2.9 Hz, C-5),
127.93 (NPh C-4), 128.50 (CPh C-3,5), 128.92 (NPh C-3,5), 129.45
3
7.56 (m, 2 H, Ph 3,5-H), 7.66 (dd, JT h 4 - H , T h 5 - H = 5.1,
1
(CPh C-4), 131.51 (CPh C-2,6), 137.91 (C-3, JC-3,3–H = 191.1 Hz,
4JTh2-H,Th4-H = 1.2 Hz, 1 H, Th 4-H), 7.70 (m, 2 H, Ph 2,6-H), 7.78
1
3JC-3,NCH = 4.9 Hz), 139.36 (NPh C-1), 142.16 (NCH, JNCH
=
4
4
(s, 1 H, 7-H), 7.97 (dd, JTh2-H,Th5-H = 3.1, JTh2-H,Th4-H = 1.2 Hz,
1 H, Th 2-H), 9.04 (s, 1 H, 4-H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 12.0 (1J3-Me = 128.6 Hz, CH3), 100.5 (1JC-7,7-H = 165.0,
166.0 Hz) ppm. 15N NMR (50 MHz, CDCl3): δ = –160.5 (N-1),
–71.2 (N-2), –24.7 (NOH) ppm.
Z Isomer: 1H NMR (300 MHz, CDCl3): δ = 7.38 (m, 3 H, CPh
3,4,5-H), 7.42 (m, 1 H, NPh 4-H), 7.48 (m, 2 H, CPh 2,6-H), 7.51
(m, 2 H, NPh 3,5-H), 7.70 (s, 1 H, NCH), 7.87 (m, 2 H, NPh 2,6-
H), 8.56 (s, 1 H, 3-H), 9.71 (s, 1 H, OH) ppm. 13C NMR (75 MHz,
CDCl3): δ = 76.41 (CCPh), 100.91 (CCPh), 117.71 (2JC-4,3-H = 9.6,
2JC-4,NCH = 5.8 Hz, C-4), 121.35 (CPh C-1), 123.43 (NPh C-2,6),
3
4JC-7,4-H = 1.7 Hz, C-7), 120.9 (2JC-3a,4-H = 9.4, JC-3a,7-H = 4.1,
3JC-3a,3-Me = 2.9 Hz, C-3a), 122.4 (Ph C-2,6), 123.8 (1JThC-2,Th2-H
185.6, JThC-2,Th4-H = 8.6, JThC-2,Th5-H = 4.6 Hz, Th C-2), 126.2
=
3
3
2
3
(1JThC-4,Th4-H = 167.3, JThC-4,Th5-H = 4.8, JThC-4,Th2-H = 8.6 Hz,
Th C-4), 126.3 (1JThC-5,Th 5-H = 186.0, JThC-5,Th 4-H = 7.1,
2
3JThC-5,Th2-H = 5.9 Hz, Th C-5), 126.9 (Ph C-4), 129.6 (Ph C-3,5),
3
125.59 (3JC-5,3-H = 4.6, JC-5,NCH = 2.5 Hz, C-5), 128.07 (NPh C-
139.3 (Ph C-1), 142.2 (2JThC-3,Th 2-H = 2.9, JThC-3,Th 4-H = 4.5,
2
3JThC-3,Th5-H = 9.5, JThC-3,7-H = 2.9 Hz, Th C-3), 143.4 (2JC-7a,7-H
3
4), 128.57 (CPh C-3,5), 128.96 (NPh C-3,5), 129.58 (CPh C-4),
131.53 (CPh C-2,6), 138.51 (1JNCH = 175.7 Hz, NCH), 139.31
(NPh C-1), 142.95 (1JC-3,3-H = 196.9, 3JC-3,NCH = 6.7 Hz, C-3) ppm.
15N NMR (50 MHz, CDCl3): δ = –161.9 (N-1), –72.5 (N-2) ppm;
= 0.8, JC-7a,4-H = 6.2 Hz, C-7a), 144.6 (1JC-4,4-H = 179.4 Hz, C-4),
3
3
144.7 (2JC-3,3-Me = 7.0, JC-3,4-H = 1.1 Hz, C-3), 149.8 (3JC-6,4-H
=
12.0 Hz, C-6) ppm. 15N NMR (50 MHz, CDCl3): δ = –191.2 (N-
1), –94.6 (N-5), –66.4 (N-2) ppm. MS: m/z (%) = 292 (20)
[M + H]+, 291 (94) [M]+, 230 (30), 201 (21), 81 (27), 77 (30), 71
(27), 69 (100), 57 (58), 55 (40), 51 (20), 43 (20). C17H13N3S (291.37)·
0.1H2O: calcd. C 69.65, H 4.54, N 14.33; found C 69.60, H 4.63,
N 13.99.
NOH not found (HMBC). IR (KBr): ν = 3215 (OH), 2216
˜
(CϵC) cm–1. MS: m/z (%) = 287 (21) [M]+, 286 (27) [M – H]+, 270
(100) [M – OH]+, 268 (21), 243 (21), 77 (100), 63 (23), 51 (82).
C18H13N3O (287.32): calcd. C 75.25, H 4.56, N 14.63; found C
75.00, H 4.49, N 14.48.
1-Phenyl-5-(3-thienylethynyl)-1H-pyrazole-4-carbaldehyde Oxime
(E/Z) Mixture (5b): Yield 712 mg, 81 %; brown solid, m.p. 88–
138 °C.
6-Butyl-3-methyl-1-phenyl-1H-pyrazolo[4,3-c]pyridine (4f): Yield
79 mg, 60%; light brown liquid. H NMR (500 MHz, CDCl3): δ =
1
0.93 (t, J = 7.3 Hz, 3 H, CH3CH2), 1.39 (m, 2 H, CH3CH2), 1.74
(m, 2 H, CH3CH2CH2), 2.66 (s, 3 H, CH3C), 2.88 (m, 2 H, CCH2),
7.33 (m, 1 H, Ph 4-H), 7.35 (br. s, 1 H, 7-H), 7.51 (m, 2 H, Ph 3,5-
H), 7.66 (m, 2 H, Ph 2,6-H), 8.97 (br. s, 1 H, 4-H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 12.0 (1J3-Me = 128.5 Hz, CH3C), 13.9
(CH3CH2), 22.5 (CH2CH3), 32.4 (CH2CH2CH3), 38.4 (CCH2),
102.7 (C-7), 120.5 (C-3a), 122.2 (Ph C-2,6), 126.6 (Ph C-4), 129.5
E I s o mer: 1 H NMR (500 MHz, CDCl3 ): δ = 7. 15 (dd,
3JTh4-H,Th5-H = 5.0, 4JTh2-H,Th4-H = 1.1 Hz, 1 H, Th 4-H), 7.31 (dd,
4
3JTh4-H,Th5-H = 5.0, JTh2-H,Th5-H = 3.0 Hz, 1 H, Th 5-H), 7.40 (m,
4
1 H, Ph 4-H), 7.50 (m, 2 H, Ph 3,5-H), 7.56 (dd, JTh2-H,Th5-H
=
3.0, 4JTh2-H,Th4-H = 1.1 Hz, 1 H, Th 2-H), 7.83 (m, 2 H, Ph 2,6-H),
8.03 (s, 1 H, C-3), 8.28 (s, 1 H, NCH), 8.4–10.2 (br. s, 1 H,
OH) ppm. 13C NMR (125 MHz, CDCl3): δ = 76.3 (CCTh), 95.9
(CCTh), 119.7 (C-4), 120.6 (Th C-3), 123.3 (Ph C-2,6), 124.5 (C-
5), 125.9 (Th C-5), 127.9 (Ph C-4), 128.9 (Ph C-3,5), 129.4 (Th C-
(Ph C-3,5), 139.4 (Ph C-1), 143.3 (3JC-7a,4-H = 6.3 Hz, C-7a), 144.1
3
(1JC-4,4-H = 178.5 Hz, C-4), 144.5 (2JC-3,3-Me = 7.0, JC-3,4-H
=
0.9 Hz, C-3), 158.6 (C-6) ppm. 15N NMR (50 MHz, CDCl3): δ =
–192.6 (N-1), –68.6 (N-2) ppm; N-5 not found (HMBC). MS: m/z
(%) = 265 (4) [M]+, 223 (100), 77 (43), 71 (27), 69 (33), 57 (71), 56
(25), 55 (66), 51 (27), 43 (71), 42 (21), 41 (68). C17H19N3 (265.35)
·0.3H2O: calcd. C 75.41, H 7.30, N 15.52; found C 75.47, H 7.38,
N 15.13.
3
4), 130.3 (Th C-2), 138.0 (1JC-3,3-H = 190.8, JC-3,NCH = 4.9 Hz, C-
3), 139.4 (Ph C-1), 142.1 (1JNCH = 166.2 Hz, NCH) ppm. 15N
NMR (50 MHz, CDCl3): δ = –160.6 (N-1), –71.7 (N-2), –26.0
(NOH) ppm.
Z Isomer: 1 H NMR (500 MHz, CDCl3 ): δ = 7. 16 (dd,
General Procedure for the Preparation of Pyrazole Carbaldehyde 3JTh4-H,Th5-H = 5.0, 4JTh2-H,Th4-H = 1.0 Hz, 1 H, Th 4-H), 7.33 (dd,
4
Oximes (5a–f): Hydroxylamine hydrochloride (209 mg, 3 mmol)
and sodium acetate (408 mg, 3 mmol) were added to the appropri-
ate pyrazole aldehyde (3a–f, 3 mmol) in ethanol. The reaction mix-
3JTh4-H,Th5-H = 5.0, JTh2-H,Th5-H = 3.0 Hz, 1 H, Th 5-H), 7.41 (m,
4
1 H, Ph 4-H), 7.51 (m, 2 H, Ph 3,5-H), 7.58 (dd, JTh2-H,Th5-H
=
3.0, 4JTh2-H,Th4-H = 1.0 Hz, 1 H, Th 2-H), 7.67 (s, 1 H, NCH), 7.84
ture was stirred at room temperature for 1 h. After cooling, it was (m, 2 H, Ph 2,6-H), 8.56 (s, 1 H, C-3), 8.4–10.2 (br. s, 1 H,
poured into ice-cold water. The solid product was filtered off and
purified by column chromatography (SiO2, eluent ethyl acetate/
light petroleum 1:5, v/v). Workup procedure for the synthesis of
5a–c: the reaction mixture was diluted with water and extracted
with DCM (3ϫ 20 mL). The organic layers were combined, washed
with brine and dried with sodium sulfate. The solvent was evapo-
OH) ppm. 13C NMR (125 MHz, CDCl3): δ = 76.0 (CCTh), 96.2
(CCTh), 117.6 (C-4), 120.4 (Th C-3), 123.4 (Ph C-2,6), 125.7 (C-
5), 126.0 (Th C-5), 128.1 (Ph C-4), 129.0 (Ph C-3,5), 129.4 (Th C-
4), 130.5 (Th C-2), 138.4 (NCH), 139.3 (Ph C-1), 142.9 (1JC-3,3-H
=
196.3 Hz, C-3) ppm. 15N NMR (50 MHz, CDCl3): δ = –162.1 (N-
1), –73.0 (N-2) ppm; NOH not found (HMBC).
Eur. J. Org. Chem. 2011, 5123–5133
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5129

ˇ
G. Vilkauskaite, A. Sacˇkus, W. Holzer
˙
FULL PAPER
E Isomer: 1H NMR (300 MHz, [D6]DMSO): δ = 7.45 (m, 3 H, CPh
3,4,5-H), 7.47 (m, 1 H, NPh 4-H), 7.58 (m, 4 H, CPh 2,6-H, NPh
3,5-H), 7.82 (m, 2 H, NPh 2,6-H), 8.07 (s, 1 H, 3-H), 8.16 (s, 1 H,
3
5.8, JC-4,3-Me = 2.9 Hz, C-4), 121.6 (CPh C-1), 123.2 (NPh C-2,6),
125.5 (C-5), 127.7 (NPh C-4), 128.5 (CPh C-3,5), 128.9 (NPh C-
3,5), 129.4 (CPh C-4), 131.5 (CPh C-2,6), 139.3 (NPh C-1), 143.3
NCH), 11.39 (s, 1 H, OH) ppm. 13C NMR (75 MHz, [D6]DMSO): (NCH, JNCH = 164.4 Hz), 148.2 (2JC-3,3-Me = 6.9, JC-3,NCH
=
1
3
δ = 76.7 (CCPh), 100.4 (CCPh), 120.8 (C-4, CPh C-1), 122.7 (C-
5.3 Hz, C-3) ppm. 15N NMR (50 MHz, CDCl3): δ = –166.5 (N-1),
5), 123.1 (NPh C-2,6), 128.2 (NPh C-4), 128.91 (CPh C-3,5), 129.26 –76.5 (N-2), –24.8 (NOH) ppm. IR (KBr): ν = 3259 (OH), 2211
˜
(NPh C-3,5), 129.9 (CPh C-4), 131.4 (CPh C-2,6), 137.9 (1JC-3,3-H (CϵC) cm–1. MS: m/z (%) = 301 (10) [M]+, 284 (44) [M – OH]+, 77
3
= 191.3, JC-3,NCH = 4.8 Hz, C-3), 138.86 (NPh C-1), 139.6 (1JNCH
(100), 63 (28), 51 (83), 50 (20). C19H15N3O (301.34): calcd. C 75.73,
H 5.02, N 13.94; found C 75.46, H 5.34, N 13.70.
3
= 165.1, JNCH,3-H = 9.6 Hz, NCH) ppm. 15N NMR (50 MHz,
[D6]DMSO): δ = –160.6 (N-1), –67.2 (N-2), –10.4 (NOH) ppm.
(E)-3-Methyl-1-phenyl-5-(3-thienylethynyl)-1H-pyrazole-4-carb-
aldehyde Oxime (5e): Yield 783 mg, 85%; brownish solid, m.p. 139–
Z Isomer: 1H NMR (300 MHz, [D6]DMSO): δ = 7.45 (m, 2 H, CPh
3,5-H), 7.47 (m, 1 H, NPh 4-H), 7.48 (m, 1 H, NPh 4-H), 7.54 (m,
2 H, CPh 2,6-H), 7.58 (s, 1 H, NCH), 7.60 (m, 2 H, NPh 3,5-H),
7.84 (m, 2 H, NPh 2,6-H), 8.48 (s, 1 H, 3-H), 11.78 (s, 1 H,
OH) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 76.3 (CCPh), 99.9
(CCPh), 118.1 (2JC-4,3-H = 9.8, 2JC-4,NCH = 6.6 Hz, C-4), 120.6 (CPh
C-1), 123.3 (NPh C-2,6), 123.9 (C-5), 128.3 (NPh C-4), 128.91
(CPh C-3,5), 129.31 (NPh C-3,5), 130.0 (CPh C-4), 131.5 (CPh C-
2,6), 136.2 (1JNCH = 176.3, 3JNCH,3-H = 7.8 Hz, NCH), 138.77 (NPh
1
141 °C. H NMR (500 MHz, CDCl3): δ = 2.51 (s, 3 H, CH3), 7.14
4
(dd, 3JTh4-H,Th5-H = 5.0, JTh2-H,Th4-H = 1.0 Hz, 1 H, Th 4-H), 7.31
4
(dd, 3JTh4-H,Th5-H = 5.0, JTh2-H,Th5-H = 3.0 Hz, 1 H, Th 5-H), 7.37
4
(m, 1 H, Ph 4-H), 7.48 (m, 2 H, Ph 3,5-H), 7.56 (dd, JTh2-H,Th5-H
4
= 3.0, JTh2-H,Th4-H = 1.0 Hz, 1 H, Th 2-H), 7.80 (m, 2 H, Ph 2,6-
H), 8.32 (s, 1 H, NCH), 8.98 (br. s, 1 H, OH) ppm. 13C NMR
(125 MHz, CDCl3): δ = 14.1 (1J3-Me = 128.6 Hz, CH3), 76.5
3
(CCTh), 95.7 (3JCCTh,Th2-H = 3.9, JCCTh,Th4-H = 2.3 Hz, CCTh),
3
C-1), 142.2 (1JC-3,3-H = 196.5, JC-3,NCH = 6.7 Hz, C-3) ppm. 15N
3
117.4 (2JC-4,NCH
=
5.8, JC-4,3-Me
=
2.9 Hz, C-4), 120.6
(2JThC-3,Th2-H = 3.2, 2JThC-3,Th4-H = 4.9, 3JThC-3,Th5-H = 11.1 Hz, Th
C-3), 123.1 (Ph C-2,6), 125.4 (3JC-5,NCH = 3.1 Hz, C-5), 125.8
NMR (50 MHz, [D6]DMSO): δ = –161.9 (N-1), –68.7 (N-2), –14.0
(NOH) ppm. IR (KBr): ν = 3215 (OH), 2217 (CϵC) cm–1. MS: m/z
˜
(%) = 293 (9) [M]+, 276 (51) [M – OH]+, 77 (92), 69 (58), 63 (28),
57 (24), 55 (20), 51 (100), 45 (39). C16H11N3OS (293.34): calcd. C
65.51, H 3.78, N 14.32; found C 65.62, H 3.92, N 14.13.
(1JThC-5, Th5-H = 188.3, JThC-5,Th4-H = 6.6, JThC-5,Th2-H = 5.8 Hz,
2
3
Th C-5), 127.7 (Ph C-4), 128.9 (Ph C-3,5), 129.5 (1JThC-4,Th4-H
=
2
3
172.2, JThC-4,Th5-H = 4.6, JThC-4,Th2-H = 8.4 Hz, Th C-4), 130.2
(1JThC-2,Th2-H = 188.5, JThC-2,Th4-H = 8.5, JThC-2,Th5-H = 4.8 Hz,
3
3
5-(Hex-1-ynyl)-1-phenyl-1H-pyrazole-4-carbaldehyde Oxime (E/Z)
Mixture (5c): Yield 569 mg, 71%; yellowish solid, m.p. 55–75 °C.
Th C-2), 139.3 (Ph C-1), 143.3 (1JNCH = 164.6 Hz, NCH), 148.3
(2JC-3,3-Me
=
6.9, JC-3,NCH = 5.3 Hz, C-3) ppm. 15N NMR
3
1
E Isomer: H NMR (300 MHz, CDCl3): δ = 0.91 (t, J = 7.3 Hz, 3
(50 MHz, CDCl3):
δ = –166.5 (N-1), –76.2 (N-2), –24.8
˜
H, CH3CH2), 1.42 (m, 2 H, CH3CH2), 1.57 (m, 2 H, CH3CH2CH2),
2.46 (t, J = 7.0 Hz, 2 H, CCCH2), 7.37 (m, 1 H, Ph 4-H), 7.46 (m,
2 H, Ph 3,5-H), 7.77 (m, 2 H, Ph 2,6-H), 7.97 (s, 1 H, 3-H), 8.19
(s, 1 H, NCH), 9.30 (br. s, 1 H, OH) ppm. 13C NMR (75 MHz,
CDCl3): δ = 13.45 (CH3CH2), 19.36 (CCCH2), 21.90 (CH2CH3),
30.03 (CH2CH2CH3), 68.32 (CCCH2), 102.95 (CCCH2), 119.30
(2JC-4,3-H = 9.6, 3JC-4,NCH = 6.4 Hz, C-4), 123.30 (Ph C-2,6), 125.27
(C-5), 127.70 (Ph C-4), 128.77 (Ph C-3,5), 137.69 (1JC-3,3-H = 190.2,
(NOH) ppm. IR (KBr): ν = 3199 (OH), 2217 (CϵC) cm–1. MS: m/z
(%) = 307 (8) [M]+, 290 (53) [M – OH]+, 222 (40), 77 (100), 69 (41),
64 (21), 63 (28), 51 (97), 45 (29), 41 (24). C17H13N3OS (307.37):
calcd. C 66.43, H 4.26, N 13.67; found C 66.81, H 4.29, N 13.70.
(E)-5-Hex-1-ynyl-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde
Oxime (5f): Yield 632 mg, 75%; yellowish solid, m.p. 109–111 °C.
1H NMR (300 MHz, CDCl3): δ = 0.91 (t, J = 7.2 Hz, 3 H,
CH3CH2), 1.40 (m, 2 H, CH3CH2), 1.56 (m, 2 H, CH3CH2CH2),
2.46 (t, J = 6.9 Hz, 2 H, CCCH2), 2.47 (s, 3 H, CH3C), 7.34 (m, 1
H, Ph 4-H), 7.45 (m, 2 H, Ph 3,5-H), 7.75 (m, 2 H, Ph 2,6-H), 8.23
(s, 1 H, NCH), 9.07 (br. s, 1 H, OH) ppm. 13C NMR (75 MHz,
CDCl3): δ = 13.5 (CH3CH2), 14.0 (1J3-Me = 128.6 Hz, CH3C), 19.4
(CCCH2), 21.9 (CH2CH3), 30.1 (CH2CH2CH3), 68.6 (3JCCCH2,CH2
= 4.4 Hz, CCCH2), 102.7 (CCCH2), 117.1 (2JC-4,NCH = 5.8,
3JC-4,3-Me = 2.9 Hz, C-4), 123.2 (Ph C-2,6), 126.2 (C-5), 127.4 (Ph
3JC-3,NCH = 4.9 Hz, C-3), 139.39 (Ph C-1), 142.31 (1JNCH
=
165.9 Hz, NCH) ppm. 15N NMR (50 MHz, CDCl3): δ = –160.6
(N-1), –74.1 (N-2), –27.8 (NOH) ppm.
1
Z Isomer: H NMR (300 MHz, CDCl3): δ = 0.93 (t, J = 7.3 Hz, 3
H, CH3CH2), 1.42 (m, 2 H, CH3CH2), 1.57 (m, 2 H, CH3CH2CH2),
2.48 (t, J = 7.0 Hz, 2 H, CCCH2), 7.38 (m, 1 H, Ph 4-H), 7.47 (m,
2 H, Ph 3,5-H), 7.57 (br. s, 1 H, NCH), 7.79 (m, 2 H, Ph 2,6-H),
8.52 (s, 1 H, 3-H), 9.30 (br. s, 1 H, OH) ppm. 13C NMR (75 MHz,
CDCl3): δ = 13.45 (CH3CH2), 19.34 (CCCH2), 21.90 (CH2CH3),
30.05 (CH2CH2CH3), 68.18 (CCCH2), 103.20 (CCCH2), 117.4 (C-
4), 123.43 (Ph C-2,6), 126.36 (C-5), 127.84 (Ph C-4), 128.81 (Ph C-
3,5), 138.6 (NCH), 139.34 (Ph C-1), 142.70 (1JC-3,3-H = 196.3,
3JC-3,NCH = 6.4 Hz, C-3) ppm. 15N NMR (50 MHz, CDCl3): δ =
–162.1 (N-1), –75.5 (N-2) ppm; NOH not found (HMBC). IR
C-4), 128.7 (Ph C-3,5), 139.4 (Ph C-1), 143.5 (NCH), 148.0
3
(2JC-3,3-Me
=
6.9, JC-3,NCH = 5.2 Hz, C-3) ppm. 15N NMR
(50 MHz, CDCl3):
δ = –166.4 (N-1), –78.9 (N-2), –27.2
˜
(NOH) ppm. IR (KBr): ν = 3244 (OH), 2230 (CϵC) cm–1. MS: m/z
(%) = 281 (9) [M]+, 239 (22), 223 (20), 222 (100), 77 (55), 51 (37), 41
(22). C17H19N3O (281.35): calcd. C 72.57, H 6.81, N 14.94; found C
72.39, H 6.81, N 14.81.
(KBr): ν = 3227 (OH), 2237 (CϵC) cm–1. MS: m/z (%) = 267 (9)
˜
[M]+, 225 (24), 208 (100), 77 (78), 69 (28), 57 (32), 55 (38), 51 (57),
43 (48), 41 (46). C16H17N3O (267.33)·0.35H2O: calcd. C 70.23, H
6.52, N 15.36; found C 70.59, H 6.37, N 14.96.
General Procedure for the Preparation of the Pyrazolo[4,3-c]pyridine
5-Oxides (6a–f): AgOTf (13 mg, 0.05 mmol) was added to a solu-
tion of appropriate oxime 5a–f (1 mmol) in DCM (4 mL) and the
reaction mixture was stirred at room temp. for 30 min to 2 h. The
mixture was directly loaded onto a silica gel column and eluted
with ethyl acetateǞDCM/MeOH 9:1, v/v.
(E)-3-Methyl-1-phenyl-5-(phenylethynyl)-1H-pyrazole-4-carb-
aldehyde Oxime (5d): Yield 731 mg, 81%; yellowish solid, m.p. 152–
1
154 °C. H NMR (500 MHz, CDCl3): δ = 2.53 (s, 3 H, CH3), 7.36
(m, 2 H, CPh 3,5-H), 7.37 (m, 1 H, CPh 4-H), 7.38 (m, 1 H, NPh
1,6-Diphenyl-1H-pyrazolo[4,3-c]pyridine 5-Oxide (6a): Yield
4-H), 7.47 (m, 2 H, CPh 2,6-H), 7.48 (m, 2 H, NPh 3,5-H), 7.83 212 mg, 74%; yellowish solid, m.p. 74–76 °C. 1H NMR (300 MHz,
(m, 2 H, NPh 2,6-H), 8.44 (s, 1 H, NCH), 9.02 (br. s, 1 H, CDCl3): δ = 7.42 (m, 1 H, NPh 4-H), 7.46 (m, 3 H, CPh 3,4,5-H),
OH) ppm. 13C NMR (125 MHz, CDCl3): δ = 14.2 (1J3-Me
128.7 Hz, CH3), 76.9 (CCPh), 100.4 (CCPh), 117.6 (2JC-4,NCH
=
=
7.55 (m, 2 H, NPh 3,5-H), 7.67 (m, 2 H, NPh 2,6-H), 7.68 (s, 1 H,
7-H), 7.76 (m, 2 H, CPh 2,6-H), 8.21 (d, J = 1.0 Hz, 1 H, 3-H),
5130
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 5123–5133

Pyrazolo[4,3-c]pyridines Through Sonogashira-Type Reactions
8.90 (s, 1 H, 4-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 108.2 C-3,5), 132.2 (1JC-4,4-H = 186.9 Hz, C-4), 133.3 (CPh C-1), 135.5
(1JC-7,7-H = 169.8, 4JC-7,4-H = 1.0 Hz, C-7), 122.0 (C-3a), 122.5 (NPh (C-7a), 138.7 (NPh C-1), 142.9 (2JC-3,3-Me = 7.1, 3JC-3,4-H = 1.9 Hz,
C-2,6), 127.9 (NPh C-4), 128.2 (CPh C-3,5), 129.5 (CPh C-4), 129.7 C-3), 148.2 (C-6) ppm. 15N NMR (50 MHz, CDCl3): δ = –189.1
(CPh C-2,6), 129.8 (NPh C-3,5), 132.5 (1JC-4,4-H = 188.2 Hz, C-4),
(N-1), –107.3 (N-5), –60.1 (N-2) ppm. MS: m/z (%) = 301 (26)
3
133.2 (CPh C-1), 133.5 (1JC-3,3-H = 195.1, JC-3,4-H = 2.0 Hz, C-3), [M]+, 300 (25) [M – H]+, 77 (100), 71 (25), 69 (39), 63 (24), 57 (57),
134.8 (C-7a), 138.6 (NPh C-1), 148.4 (C-6) ppm. 15N NMR 55 (52), 51 (74), 43 (41), 41 (23). C19H15N3O (301.34): calcd. C
(50 MHz, CDCl3): δ = –183.4 (N-1), –105.7 (N-5), –53.9 (N-
2) ppm. MS: m/z (%) = 287 (30) [M]+, 286 (41) [M – H]+, 77 (100),
69 (35), 63 (26), 57 (32), 55 (26), 51 (74), 43 (24). C18H13N3O
(287.32)·0.5H2O: calcd. C 73.18, H 4.74, N 14.22; found C 73.20,
H 5.07, N 13.90.
75.73, H 5.02, N 13.94; found C 75.97, H 5.41, N 13.79.
3-Methyl-1-phenyl-6-(3-thienyl)-1H-pyrazolo[4,3-c]pyridine 5-Oxide
(6e): Yield 257 mg, 84%; yellowish solid, m.p. 214–216 °C. 1H
NMR (500 MHz, CDCl3): δ = 2.62 (s, 3 H, CH3), 7.38 (dd,
4
3JTh4-H,Th5-H = 5.1, JTh2-H,Th5-H = 3.1 Hz, 1 H, Th 5-H), 7.39 (m,
3
1 H, Ph 4-H), 7.54 (m, 2 H, Ph 3,5-H), 7.63 (dd, JTh4-H,Th5-H
=
1-Phenyl-6-(3-thienyl)-1H-pyrazolo[4,3-c]pyridine 5-Oxide (6b):
5.1, 4JTh2-H,Th4-H = 1.3 Hz, 1 H, Th 4-H), 7.64 (m, 2 H, Ph 2,6-H),
1
Yield 180 mg, 61%; light brown solid, m.p. 162–164 °C. H NMR
4
3
4
7.79 (d, J = 0.5 Hz, 1 H, 7-H), 8.46 (dd, JTh2-H,Th5-H = 3.1,
(500 MHz, CDCl3): δ = 7.38 (dd, JTh4-H,Th5-H = 5.1, JTh2-H,Th5-H
4JTh2-H,Th4-H = 1.3 Hz, 1 H, Th 2-H), 8.80 (d, J = 0.5 Hz, 1 H, 4-
= 3.1 Hz, 1 H, Th 5-H), 7.43 (m, 1 H, Ph 4-H), 7.57 (m, 2 H, Ph
H) ppm. 13C NMR (125 MHz, CDCl3): δ = 11.9 (1J3-Me
=
3
4
3,5-H), 7.63 (dd, JTh4-H,Th5-H = 5.1, JTh2-H,Th4-H = 1.3 Hz, 1 H,
Th 4-H), 7.67 (m, 2 H, Ph 2,6-H), 7.84 (s, 1 H, 7-H), 8.18 (d, J =
4
129.0 Hz, CH3), 106.2 (1JC-7,7-H = 168.5, JC-7,4-H = 1.2 Hz, C-7),
3
3
121.1 (2JC-3a,4-H = 4.6, JC-3a,7-H = 6.2, JC-3a,3-Me = 3.1 Hz, C-3a),
4
4
1.0 Hz, 1 H, 3-H), 8.44 (dd, JTh2-H,Th5-H = 3.1, JTh2-H,Th4-H
=
122.1 (Ph C-2,6), 125.1 (1JThC-5,Th5-H = 186.9, JThC-5,Th4-H = 7.1,
2
1.3 Hz, 1 H, Th 2-H), 8.88 (s, 1 H, 4-H) ppm. 13C NMR (125 MHz,
3JThC-5,Th2-H
= 6.0 Hz, Th C-5), 127.4 (Ph C-4), 127.9
CDCl3): δ = 106.3 (1JC-7,7-H = 168.8, 4JC-7,4-H = 1.2 Hz, C-7), 121.3
2
3
(1JThC-4,Th4-H = 169.6, JThC-4,Th5-H = 5.1, JThC-4,Th2-H = 8.6 Hz,
2
3
(2JC-3a,3-H = 11.0, JC-3a,4-H = 4.7, JC-3a,7-H = 6.2 Hz, C-3a), 122.5
Th C-4), 128.8 (1JThC-2,Th2-H
=
190.1, JThC-2,Th4-H
=
8.5,
3
(Ph C-2,6), 125.2 (1JThC-5,Th5-H = 187.0, JThC-5,Th4-H = 7.0,
2
3JThC-2,Th5-H = 4.5 Hz, Th C-2), 129.8 (Ph C-3,5), 132.5 (1JC-4,4-H
3JThC-5,Th2-H
= 6.0 Hz, Th C-5), 127.88 (Ph C-4), 127.92
= 186.7, JC-4,7-H = 1.2 Hz, C-4), 132.7 (2JThC-3,Th2-H = 2.7,
4
(1JThC-4,Th4-H = 169.6, JThC-4,Th5-H = 5.1, JThC-4,Th2-H = 8.6 Hz,
2
3
3
3
2JThC-3,Th4-H
=
4.5, JThC-3,Th5-H
=
10.5, JThC-3,7-H
=
3.5,
=
=
Th C-4), 128.9 (1JThC-2,Th2-H
=
190.1, JThC-2,Th4-H
=
8.5,
3
4JThC-3,Th4-H = 0.8 Hz, Th C-3), 135.5 (2JC-7a,7-H = 2.0, JC-7a,4-H
3
3JThC-2,Th5-H
= 4.5 Hz, Th C-2), 129.8 (Ph C-3,5), 132.6
7.2 Hz, C-7a), 138.8 (Ph C-1), 142.9 (2JC-3,3-Me = 7.1, JC-3,4-H
3
(2JThC-3,Th2-H = 2.7, JThC-3,Th4-H = 4.5, JThC-3,Th5-H = 10.3,
2
3
1.9 Hz, C-3), 143.3 (2JC-6,7-H = 1.6, 3JC-6,4-H = 4.9, 3JC-6,Th2-H = 2.3,
3JC-6,Th4-H = 0.9 Hz, C-6) ppm. 15N NMR (50 MHz, CDCl3): δ =
–189.9 (N-1), –108.2 (N-5), –59.5 (N-2) ppm. MS: m/z (%) = 307
(57) [M]+, 278 (50), 234 (76), 77 (97), 69 (22), 63 (34), 51 (100), 50
(20), 45 (49). C17H13N3OS (307.37)·0.25H2O: calcd. C 65.47, H
4.36, N 13.47; found C 65.49, H 4.51, N 13.47.
3JThC-3,7-H = 3.4 Hz, Th C-3), 132.8 (1JC-4,4-H = 188.4, JC-4,7-H
=
4
1.3 Hz, C-4), 133.4 (1JC-3,3-H = 195.2, 3JC-3,4-H = 2.1 Hz, C-3), 134.8
3
3
(2JC-7a,7-H = 1.9, JC-7a,4-H = 7.1, JC-7a,3-H = 3.3 Hz, C-7a), 138.6
(Ph C-1), 143.4 (C-6) ppm. 15N NMR (50 MHz, CDCl3): δ =
–184.0 (N-1), –106.4 (N-5), –53.3 (N-2) ppm. MS: m/z (%) = 293
(14) [M]+, 220 (22), 77 (63), 69 (38), 61 (20), 57 (30), 55 (25), 51
(52), 45 (34), 43 (100). C16H11N3OS (293.34): calcd. C 65.51, H
3.78, N 14.32; found C 65.26, H 3.93, N 13.95.
6-Butyl-3-methyl-1-phenyl-1H-pyrazolo[4,3-c]pyridine 5-Oxide (6f):
Yield 261 mg, 92%; brownish solid, m.p. 61–63 °C. 1H NMR
(500 MHz, CDCl3): δ = 0.95 (m, 3 H, CH3CH2), 1.45 (m, 2 H,
CH3CH2), 1.72 (m, 2 H, CH3CH2CH2), 2.57 (s, 3 H, CH3C), 3.01
(m, 2 H, CCH2), 7.37 (m, 1 H, Ph 4-H), 7.44 (s, 1 H, 7-H), 7.53
(m, 2 H, Ph 3,5-H), 7.61 (m, 2 H, Ph 2,6-H), 8.73 (s, 1 H, 4-H) ppm.
13C NMR (125 MHz, CDCl3): δ = 11.9 (CH3C), 13.8 (CH3CH2),
22.5 (CH2CH3), 28.9 (CH2CH2CH3), 31.1 (CCH2), 105.5 (C-7),
120.9 (C-3a), 122.1 (Ph C-2,6), 127.2 (Ph C-4), 129.7 (Ph C-3,5),
131.6 (C-4), 135.5 (C-7a), 138.8 (Ph C-1), 142.8 (C-3), 151.3 (C-
6) ppm. 15N NMR (50 MHz, CDCl3): δ = –190.5 (N-1), –106.2 (N-
5), –62.1 (N-2) ppm. MS: m/z (%) = 281 (12) [M]+, 264 (25), 239
(61), 223 (34), 222 (100), 77 (73), 63 (21), 51 (51), 41 (29).
C17H19N3O (281.35): calcd. C 72.57, H 6.81, N 14.93; found C
72.28, H 7.03, N 14.81.
6-Butyl-1-phenyl-1H-pyrazolo[4,3-c]pyridine 5-Oxide (6c): Yield
162 mg, 61%; brownish solid, m.p. 76–78 °C. 1H NMR (500 MHz,
CDCl3): δ = 0.95 (t, J = 7.4 Hz, 3 H, CH3CH2), 1.46 (m, 2 H,
CH3CH2), 1.73 (m, 2 H, CH3CH2CH2), 3.02 (m, 2 H, CCH2), 7.42
(m, 1 H, Ph 4-H), 7.49 (s, 1 H, 7-H), 7.56 (m, 2 H, Ph 3,5-H), 7.64
(m, 2 H, Ph 2,6-H), 8.15 (s, 1 H, 3-H), 8.81 (s, 1 H, 4-H) ppm. 13C
NMR (125 MHz, CDCl3): δ = 13.8 (1JCH3 = 124.9 Hz, CH3CH2),
22.5 (CH2CH3), 28.9 (CH2CH2CH3), 31.2 (CCH2), 105.6 (1JC-7,7-H
3
4
= 168.1, JC-7,CH2 = 4.6, JC-7,4-H = 1.2 Hz, C-7), 121.1 (2JC-3a,3-H
= 11.0, 2JC-3a,4-H = 4.8, 3JC-3a,7-H = 6.0 Hz, C-3a), 122.4 (Ph C-2,6),
127.7 (Ph C-4), 129.8 (Ph C-3,5), 131.9 (1JC-4,4-H = 188.4 Hz, C-4),
133.4 (1JC-3,3-H = 194.7, 3JC-3,4-H = 2.1 Hz, C-3), 134.8 (2JC-7a,7-H
=
3
3
1.7, JC-7a,4-H = 7.1, JC-7a,3-H = 3.3 Hz, C-7a), 138.7 (Ph C-1),
151.5 (C-6) ppm. 15N NMR (50 MHz, CDCl3): δ = –184.8 (N-1),
–104.2 (N-5), –55.9 (N-2) ppm. MS: m/z (%) = 267 (9) [M]+, 225
(71), 209 (33), 208 (100), 77 (58), 69 (22), 51 (32). C16H17N3O
(267.33)·0.16H2O: calcd. C 71.12, H 6.46, N 15.55; found C 71.11,
H 6.58, N 15.37.
General Procedure for the Preparation of 7-Iodo-pyrazolo[4,3-c]pyr-
idine 5-Oxides (7b and 7e): Iodine (1.27 g, 5 mmol) was added un-
der argon to a solution of the appropriate oxime (5b or 5e, 1 mmol)
in dry ethanol (4 mL) and the reaction mixture was stirred at room
temp. for 3 h. Saturated aq. Na2S2O3 was added and stirring was
continued for 5 min. The mixture was extracted with dichlorometh-
ane (3ϫ 20 mL). The organic layers were combined and dried with
sodium sulfate. The solvent was evaporated and the residue was
purified by column chromatography (SiO2, eluent ethyl acetateǞ
DCM/MeOH 9:1, v/v).
3-Methyl-1,6-diphenyl-1H-pyrazolo[4,3-c]pyridine 5-Oxide (6d):
Yield 223 mg, 74%; yellowish solid, m.p. 188–189 °C. 1H NMR
(500 MHz, CDCl3): δ = 2.63 (s, 3 H, CH3), 7.37 (m, 1 H, NPh 4-
H), 7.46 (m, 3 H, CPh 3,4,5-H), 7.52 (m, 2 H, NPh 3,5-H), 7.63 (s,
1 H, 7-H), 7.64 (m, 2 H, NPh 2,6-H), 7.76 (m, 2 H, CPh 2,6-H),
8.83 (s, 1 H, 4-H) ppm. 13C NMR (125 MHz, CDCl3): δ = 11.9 7-Iodo-1-phenyl-6-(3-thienyl)-1H-pyrazolo[4,3-c]pyridine
5-Oxide
4
1
(1J3-Me = 129.0 Hz, CH3), 108.1 (1JC-7,7-H = 169.4, JC-7,4-H
=
(7b): Yield 209 mg, 50%; brown solid, m.p. 238–240 °C. H NMR
3
4
1.1 Hz, C-7), 121.7 (C-3a), 122.1 (NPh C-2,6), 127.4 (NPh C-4), (500 MHz, CDCl3): δ = 7.16 (dd, JTh4-H,Th5-H = 4.5, JTh2-H,Th4-H
128.2 (CPh C-3,5), 129.5 (CPh C-4), 129.6 (CPh C-2,6), 129.7 (NPh = 1.8 Hz, 1 H, Th 4-H), 7.45 (m, 2 H, Th 2,5-H), 7.47 (m, 2 H, Ph
Eur. J. Org. Chem. 2011, 5123–5133
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5131

ˇ
G. Vilkauskaite, A. Sacˇkus, W. Holzer
˙
FULL PAPER
[8]
[9]
M. Pal, Y. K. Rao, I. Khanna, N. K. Swamy, V. Subramanian,
V. R. Batchu, J. Iqbal, S. Pillarisetti, U. S. Pattent Application,
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L. Commeiras, S. C. Woodcock, J. E. Baldwin, R. M. Adling-
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938.
V. I. Tyvorskii, D. N. Bobrov, O. G. Kulinkovich, K. A.
Tehrani, N. De Kimpe, Tetrahedron 2001, 57, 2051–2055.
R. V. Fucini, E. J. Hanan, M. J. Romanowski, R. A. Elling, W.
Lew, K. J. Barr, J. Zhu, J. C. Yoburn, Y. Liu, B. T. Fahr, J. Fan,
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H. E. Purkey, M. J. Evanchik, W. Yang, Bioorg. Med. Chem.
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2,6-H), 7.52 (m, 2 H, Ph 3,5-H), 7.55 (m, 1 H, Ph 4-H), 8.20 (s, 1
H, 3-H), 8.84 (s, 1 H, 4-H) ppm. 13C NMR (125 MHz, CDCl3): δ
2
= 77.1 (4JC-7,4-H = 1.9 Hz, C-7), 120.5 (2JC-3a,3-H = 11.4, JC-3a,4-H
2
= 5.1 Hz, C-3a), 125.8 (1JThC-5,Th5-H = 187.3, JThC-5,Th4-H = 7.2,
3JThC-5,Th2-H = 5.6 Hz, Th C-5), 127.7 (1JThC-2,Th2-H = 187.0,
3
3JThC-2,Th4-H
=
8.7, JThC-2,Th5-H
=
4.8 Hz, Th C-2), 128.1
[10]
[11]
2
3
(1JThC-4,Th4-H = 169.5, JThC-4,Th5-H = 6.1, JThC-4,Th2-H = 8.3 Hz,
Th C-4), 128.7 (Ph C-3,5), 129.4 (Ph C-2,6), 130.1 (Ph C-4), 131.5
3
(1JC-4,4-H = 189.8 Hz, C-4), 132.5 (1JC-3,3-H = 195.7, JC-3,4-H
=
2.2 Hz, C-3), 135.9 (2JThC-3,Th4-H = 4.7 Hz, Th C-3), 137.4 (Ph C-
1), 137.8 (3JC-7a,4-H = 7.0, JC-7a,3-H = 3.3 Hz, C-7a), 148.3
3
(3JC-6,4-H = 5.2 Hz, C-6) ppm. 15N NMR (50 MHz, CDCl3): δ =
–181.2 (N-1), –102.0 (N-5), –44.0 (N-2) ppm. MS: m/z (%) = 419
(3) [M]+, 292 (27), 264 (26), 77 (100), 69 (27), 63 (25), 57 (27), 51
[12]
G. M. Shutske, K. J. Kapples, J. D. Tomer, U. S. Patent
5264576, 1993.
(78), 45 (41). C16H10IN3OS (419.24): calcd. C 45.84, H 2.40, N [13]
10.02; found C 46.22, H 2.63, N 10.20.
R. C. Gupta, V. V. Jagtap, A. B. Mandhare, T. Perkins, D. PCT
Int. Appl., WO 2007/100295, 2007.
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[15]
E. Savory, I. Simpson, D. PCT Int. Appl. WO 2010/031791.
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M. Schnürch, R. Flasik, A. F. Khan, M. Spina, M. D. Mihovi-
lovic, P. Stanetty, Eur. J. Org. Chem. 2006, 3283–3307.
M. M. Heravi, S. Sadjadi, Tetrahedron 2009, 65, 7761–7775.
G. Kirsch, S. Hesse, A. Comel, Curr. Org. Synth. 2004, 1, 47–
63.
7-Iodo-3-methyl-1-phenyl-6-(3-thienyl)-1H-pyrazolo[4,3-c]pyridine
5-Oxide (7e): Yield 359 mg, 83%; yellowish solid, m.p. 235–237 °C.
1H NMR (500 MHz, CDCl3): δ = 2.60 (s, 3 H, CH3), 7.15 (dd,
[16]
4
3JTh4-H,Th5-H = 4.6, JTh2-H,Th4-H = 1.7 Hz, 1 H, Th 4-H), 7.44 (m,
4 H, Ph 2,6-H, Th 2,5-H), 7.50 (m, 2 H, Ph 3,5-H), 7.51 (m, 1 H,
[17]
[18]
Ph 4-H), 8.76 (s, 1 H, 4-H) ppm. 13C NMR (125 MHz, CDCl3): δ
= 11.8 (1J3-Me = 129.1 Hz, CH3), 76.8 (4JC-7,4-H = 1.9 Hz, C-7),
3
120.1 (2JC-3a,4-H
=
5.0, JC-3a,3-Me
=
3.1 Hz, C-3a), 125.8
[19]
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G. Zeni, R. C. Larock, Chem. Rev. 2006, 106, 4644–4680.
(1JThC-5,Th5-H = 187.3, JThC-5,Th4-H = 7.2, JThC-5,Th2-H = 5.6 Hz,
2
3
ˇ
E. Arbacˇiauskiene, G. Vilkauskaite, A. Sacˇkus, W. Holzer, Eur.
J. Org. Chem. 2011, 10, 1880–1890.
˙
˙
Th C-5), 127.6 (1JThC-2,Th2-H
=
187.0, JThC-2,Th4-H
=
8.7,
3
3JThC-2,Th5-H = 4.8 Hz, Th C-2), 128.1 (1JThC-4,Th4-H = 169.1,
[21]
a) S. F. Vasilevsky, E. V. Mshvidobadze, J. Elguero, J. Hetero-
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Vasilevsky, J. Elguero, Tetrahedron 2004, 60, 11875–11878.
2JThC-4,Th5-H = 6.5, JThC-4,Th2-H = 8.2 Hz, Th C-4), 128.7 (Ph C-
3
3,5), 129.3 (Ph C-2,6), 129.8 (Ph C-4), 131.3 (1JC-4,4-H = 188.4 Hz,
C-4), 135.9 (Th C-3), 137.3 (Ph C-1), 138.7 (3JC-7a,4-H = 7.0 Hz, C-
[22]
[23]
[24]
D. R. Gorja, V. R. Batchu, A. Ettam, M. Pal, Beilstein J. Org.
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3
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(3JC-6,4-H = 5.0 Hz, C-6) ppm. 15N NMR (50 MHz, CDCl3): δ =
–187.0 (N-1), –104.2 (N-5), –50.3 (N-2) ppm. MS: m/z (%) = 433
(32) [M]+, 417 (37), 307 (23), 306 (100), 278 (77), 234 (32), 139 (21),
77 (65), 51 (41). C17H12IN3OS (433.27)·0.5H2O: calcd. C 46.17, H
2.96, N 9.50; found C 46.02, H 3.06, N 9.15.
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Gyte Vilkauskaite acknowledges a PhD Research Fellowship
˙
˙
Award from the Lithuanian Science Council. We are grateful to Dr.
L. Jirovetz for recording the mass spectra.
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