Synthesis of trifluoromethyl-substituted pyrazolo[4,3-c]pyridines - Sequential versus multicomponent reaction approach

Article abstract of DOI:10.3762/bjoc.10.183

A straightforward synthesis of 6-substituted 1-phenyl-3-trifluoromethyl-1H- pyrazolo[4,3-c]pyridines and the corresponding 5-oxides is presented. Hence, microwave-assisted treatment of 5-chloro-1-phenyl-3-trifluoromethylpyrazole-4- carbaldehyde with vario

Full text of DOI:10.3762/bjoc.10.183

Synthesis of trifluoromethyl-substituted
pyrazolo[4,3-c]pyridines – sequential versus
multicomponent reaction approach
Barbara Palka1, Angela Di Capua1,2, Maurizio Anzini2, Gyté Vilkauskaité1,3,
Algirdas Šačkus3 and Wolfgang Holzer*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2014, 10, 1759–1764.
1Division of Drug Synthesis, Department of Pharmaceutical
Chemistry, Faculty of Life Sciences, University of Vienna,
Althanstrasse 14, A-1090 Vienna, Austria, 2Department of
Biotechnology, Chemistry and Pharmacy, University of Siena,
I-53100, Siena, Italy and 3Institute of Synthetic Chemistry, Kaunas
University of Technology, LT-50254 Kaunas, Lithuania
doi:10.3762/bjoc.10.183
Received: 29 April 2014
Accepted: 11 July 2014
Published: 31 July 2014
This article is part of the Thematic Series "Multicomponent reactions II".
Guest Editor: T. J. J. Müller
Email:
Wolfgang Holzer* - wolfgang.holzer@univie.ac.at
* Corresponding author
© 2014 Palka et al; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
microwave-assisted reactions; multicomponent reactions; NMR (1H;
13C; 15N; 19F); Sonogashira coupling; trifluoromethylpyrazoles
Abstract
A straightforward synthesis of 6-substituted 1-phenyl-3-trifluoromethyl-1H-pyrazolo[4,3-c]pyridines and the corresponding
5-oxides is presented. Hence, microwave-assisted treatment of 5-chloro-1-phenyl-3-trifluoromethylpyrazole-4-carbaldehyde with
various terminal alkynes in the presence of tert-butylamine under Sonogashira-type cross-coupling conditions affords the former
title compounds in a one-pot multicomponent procedure. Oximes derived from (intermediate) 5-alkynyl-1-phenyl-3-trifluoro-
methyl-1H-pyrazole-4-carbaldehydes were transformed into the corresponding 1H-pyrazolo[4,3-c]pyridine 5-oxides by silver
triflate-catalyzed cyclization. Detailed NMR spectroscopic investigations (1H, 13C, 15N and 19F) were undertaken with all obtained
products.
Introduction
Fluorine-containing compounds play an important role in medi- leads to a higher metabolic stability and can modulate some
cinal and pharmaceutical chemistry as well as in agrochemistry physicochemical properties such as basicity or lipophilicity
[1-4]. A popular approach for the modulation of activity [1,2]. Moreover, incorporation of fluorine often results in an
consists in the introduction of one or more fluorine atoms into increase of the binding affinity of drug molecules to the target
the structure of a bioactive compound. This variation frequently protein [1,2]. As a consequence, a considerable amount –
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approximately 20% – of all the pharmaceuticals being currently 5-alkynylpyrazole-4-carbaldehydes can be transformed into the
on the market contain at least one fluorine substituent, including corresponding 1-phenylpyrazolo[4,3-c]pyridine 5-oxides [17].
important drug molecules in different pharmaceutical classes
[5]. Keeping in mind the above facts, the synthesis of fluori- For the synthesis of the title compounds a similar approach was
nated heterocyclic compounds, which can act as building blocks envisaged. As starting material the commercially available
for the construction of biologically active fluorine-containing 1-phenyl-3-trifluoromethyl-1H-pyrazol-5-ol (1) was employed
molecules, is of eminent interest. In the field of pyrazoles, which, after Vilsmaier formylation [18] and concomitant trans-
pyridines and condensed systems thereof trifluoromethyl-substi- formation of the hydroxy function into a chloro substituent by
tuted congeners can be found as partial structures in several treatment with excessive POCl3, gave the chloroaldehyde 2 [19]
pharmacologically active compounds. In the pyridine series the (Scheme 1). Although Sonogashira-type cross-coupling reac-
HIV protease inhibitor Tipranavir (Aptivus®) [6] may serve as tions are preferably accomplished with iodo(hetero)arenes –
an example, within the pyrazole-derived compounds the COX-2 considering the general reactivity I > Br/OTf >> Cl [20] – from
inhibitor Celecoxib (Celebrex®) is an important representative related examples it was known that the chloro atom in
(Figure 1) [7].
5-chloropyrazole-4-aldehydes is sufficiently activated to act as
the leaving group in such kind of C–C linkages [17]. Indeed,
In continuation of our program regarding the synthesis of reaction of chloroaldehyde 2 with different alkynes 3a–c under
fluoro- and trifluoromethyl-substituted pyrazoles and annulated typical Sonogashira reaction conditions afforded the corres-
pyrazoles [8,9] we here present the synthesis of trifluoromethyl- ponding cross-coupling products 4a–c in good yields
substituted pyrazolo[4,3-c]pyridines. The latter heterocyclic (Scheme 1). In some runs compounds of type 8 were deter-
system represents the core of several biologically active com- mined as byproducts in differing yields, but mostly below 10%,
pounds, acting, for instance, as SSAO inhibitors [10], or inhibi- obviously resulting from addition of water to the triple bond of
tors of different kinases (LRRK2 [11,12], TYK2 [13], JAK 4 under the reaction conditions (or during work-up) and subse-
[14,15]).
quent tautomerization of the thus formed enoles into the corres-
ponding ketones. The hydration of C–C triple bonds under the
influence of various catalytic systems, including also Pd-based
catalysts, is a well-known reaction [21,22]. It should be empha-
Results and Discussion
Chemistry
The construction of the pyrazolo[4,3-c]pyridine system can be sized that NMR investigations with compounds 8a,c unambigu-
mainly achieved through two different approaches. One strategy ously revealed the methylene group adjacent to the pyrazole
involves the annelation of a pyrazole ring onto an existing, suit- nucleus and the carbonyl moiety attached to the substituent R
able pyridine derivative [16]. Alternatively, the bicyclic system originating from the employed alkyne.
can be accessed by pyridine-ring formation with an accordant
pyrazole precursor. Employing the latter approach we recently In the next reaction step, alkynylaldehydes 4a,b were cyclized
presented a novel method for the synthesis of the pyrazolo[4,3- into the target pyrazolo[4,3-c]pyridines 5a,b in 71%, resp. 52%
c]pyridine system by Sonogashira-type cross-coupling reaction yield by reaction with tert-butylamine under microwave assis-
of easily obtainable 5-chloro-1-phenyl-1H-pyrazole-4-carbalde- tance [17]. In view of the fact, that the two-step conversion
hydes with various alkynes and subsequent ring-closure reac- 2→4a,b→5a,b was characterized by only moderate overall
tion of the thus obtained 5-alkynyl-1H-pyrazole-4-carbalde- yields (59%, resp. 43%) it was considered to merge these two
hydes in the presence of tert-butylamine [17]. Furthermore, we steps into a one-pot multicomponent reaction. The latter type of
showed that the oximes derived from the before mentioned reaction attracts increasing attention in organic chemistry due to
Figure 1: Important drug molecules containing a trifluoromethylpyridine, respectively a trifluoromethylpyrazole moiety.
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Scheme 1: Synthesis of the title compounds.
its preeminent synthetic efficiency, also in the construction of high yields. Moreover, we tested an alternative approach to
heterocyclic and condensed heterocyclic systems [23-27]. After access compounds 7 through multicomponent reactions (MCR).
testing different reaction conditions we found that microwave Attempts to react chloroaldehyde 2 with hydroxylamine
heating of the chloroaldehyde 2 with tert-butylamine in the hydrochloride and an alkyne 3 in the presence of a suitable
presence of 6 mol % of Pd(PPh3)2Cl2 afforded the desired pyra- catalytic system were not successful. However, after conver-
zolopyridines 5a–c in high (5a: 89%, 5c: 92%) respectively sion of 2 into the corresponding aldoxime 9 the latter could be
acceptable yields (5b: 51%) in a single one-pot and copper-free transformed into the N-oxides 7a and 7b by reaction with
reaction step (Scheme 1). It should be mentioned that com- alkynes 3a and 3b, respectively, employing Pd(OAc)2 as the
pounds 5 are also accessible by heating of ketones 8 with am- catalyst and under microwave irradiation (Scheme 1). Although
monium acetate in acetic acid according to a procedure a number of different reaction conditions were tested, we were
described in [28]. Following this way, 5a and 5c were obtained not able to increase the yields in excess of 30%. Thus, with
in 70% yield from the corresponding ketones 8a and 8c. respect to the overall yields the successive approach
Although ketones 8 were only obtained as byproducts, the latter 2→4→6→7 (overall yields: 6a: 62%, 6b: 43%) here is still ad-
transformation allowed increasing the overall yield of com- vantageous compared to the multicomponent reaction following
pounds 5 through this ‘bypass’.
the path 2→9→7. Azine N-oxides of type 7 are estimated to be
of particular interest due to the possibility of further functional-
In order to gain access to the corresponding N-oxides of type 7, ization adjacent to the nitrogen atom (position 4), for instance
aldehydes 4a–c were transformed into the corresponding by palladium-catalyzed direct arylation reactions [31].
oximes 6a–c by reaction with hydroxylamine hydrochloride in
ethanol in the presence of sodium acetate (Scheme 1). Subse- NMR spectroscopic investigations
quent treatment of the oximes with AgOTf in dichloromethane In Supporting Information File 1 the NMR spectroscopic data
[29] finally afforded the corresponding pyrazolo[4,3-c]pyridine of all compounds treated within this study are indicated. Full
5-oxides 7a–c by a regioselective 6-endo-dig cyclisation [30] in and unambiguous assignment of all 1H, 13C, 15N and 19F NMR
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resonances was achieved by combining standard NMR tech- (15.6–18.3 ppm), being typical for the changeover from pyri-
niques [32], such as fully 1H-coupled 13C NMR spectra, APT, dine to pyridine N-oxide [33].
HMQC, gs-HSQC, gs-HMBC, COSY, TOCSY, NOESY and
NOE-difference spectroscopy.
NMR experiments also allowed the determination of the stereo-
chemistry of oximes 6: considering the size of 1J(N=C-H)
In compounds 4–7 the trifluoromethyl group exhibits very which is strongly dependent on lone-pair effects [34] as well as
consistent chemical shifts, ranging from δ(F) −60.8 to the comparison of chemical shifts with those of related, unam-
−61.9 ppm. The fluorine resonance is split into a doublet by a biguously assigned oximes [17] reveals E-configuration at the
small coupling (0.5–0.9 Hz) due to a through-space (or possibly C=N double bond.
5J) interaction with spatially close protons (4: CHO; 6: CH=N;
5 and 7: H-4). Reversely, the signals of the latter protons are With byproduct 8a the position of the carbonyl group unequivo-
split into a quartet (not always well resolved). The corres- cally follows from the correlations between phenyl protons and
ponding carbon resonance of CF3 is located between 120.2 and the carbonyl C-atom and, reversely, from those between the
121.2 ppm with the relevant 1J(C,F) coupling constants being methylene protons with pyrazole C-4 and pyrazole C-5 (deter-
approximately 270 Hz (269.6–270.6 Hz). As well, the signal of mined by 13C,1H HMBC).
C-3 is always split into a quartet (J ~ 40 Hz) due to the 2J(C,F3)
coupling.
In Figure 2 essential NMR data for the complete series of type c
(4c, 5c, 6c, 7c) are displayed, which easily enables to compare
As the 15N NMR chemical shifts were determined by 15N,1H the notable chemical shifts and allows following the trends
HMBC experiments the resonance of (pyrazole) N-2 was not described above.
captured owing to the fact that this nitrogen atom lacks of suffi-
cient couplings to protons, thus disabling the necessary coher- Full experimental details as well as spectral and microanalyt-
ence transfer (19F,15N HMBC spectra were not possible with ical data of the obtained compounds are presented in Supporting
the equipment at hand). For N-1, with pyrazole derivatives 4 Information File 1.
and 6 remarkably larger 15N chemical shifts were detected
(−158.8 to −160.2 ppm) compared to the corresponding signals Conclusion
for pyrazolopyridines 5 and 7 (−182.2 to −185.9 ppm). When To sum up, the presented approach represents a simple method
switching from an azine to an azine oxide partial structure for the synthesis of 6-substituted 1-phenyl-3-trifluoromethyl-
(5→7) the N-5 resonance exhibits an explicit upfield shift 1H-pyrazolo[4,3-c]pyridines 5 and the analogous 5-oxides 7
Figure 2: 1H (in italics, red), 13C (black), 15N (in blue) and 19F NMR (green) chemical shifts of compounds 4c, 5c, 6c and 7c (in CDCl3).
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13.Blench, T.; Goodacre, S.; Lai, Y.; Liang, Y.; MacLeod, C.;
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methyl-1H-pyrazol-5-ol (1). In the case of the former (5) the
described multicomponent reaction approach is superior
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yields. In addition, in-depth NMR studies with all synthesized
compounds were performed, affording full and unambiguous
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