Dipyrazolo[1,5-a:4',3'-c]pyridines - A new heterocyclic system accessed via multicomponent reaction

Article abstract of DOI:10.3762/bjoc.8.251

The synthesis of dipyrazolo[1,5-a:4',3'-c]pyridines is described. Easily obtainable 5-alkynylpyrazole-4-carbaldehydes, p-toluenesulfonyl hydrazide, and an aldehyde or ketone containing an α-hydrogen atom were reacted in a silver triflate catalyzed multicomponent reaction affording new tricyclic compounds with a dipyrazolo[1,5-a:4',3'-c]pyridine core. Detailed NMR spectroscopic investigations (¹H, ¹³C and ¹⁵N) were undertaken with all obtained compounds.

Full text of DOI:10.3762/bjoc.8.251

Dipyrazolo[1,5-a:4',3'-c]pyridines – a new
heterocyclic system accessed via
multicomponent reaction
Wolfgang Holzer*1, Gytė Vilkauskaitė1,2, Eglė Arbačiauskienė2
and Algirdas Šačkus2
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2012, 8, 2223–2229.
1Department of Drug and Natural Product Synthesis, Faculty of Life
Sciences, University of Vienna, Althanstrasse 14, A-1090 Vienna,
Austria and 2Institute of Synthetic Chemistry, Kaunas University of
Technology, Radvilėnų pl. 19, 50254 Kaunas, Lithuania
doi:10.3762/bjoc.8.251
Received: 02 October 2012
Accepted: 13 December 2012
Published: 27 December 2012
Email:
Wolfgang Holzer* - wolfgang.holzer@univie.ac.at
Associate Editor: J. P. Wolfe
* Corresponding author
© 2012 Holzer et al; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
cyclization; nitrogen heterocycles; NMR spectroscopy;
multicomponent reaction; pyrazole
Abstract
The synthesis of dipyrazolo[1,5-a:4',3'-c]pyridines is described. Easily obtainable 5-alkynylpyrazole-4-carbaldehydes, p-toluenesul-
fonyl hydrazide, and an aldehyde or ketone containing an α-hydrogen atom were reacted in a silver triflate catalyzed multicompo-
nent reaction affording new tricyclic compounds with a dipyrazolo[1,5-a:4',3'-c]pyridine core. Detailed NMR spectroscopic investi-
gations (1H, 13C and 15N) were undertaken with all obtained compounds.
Introduction
Condensed pyrazole scaffolds are important substructures of core, which can closely mimic the purine system of adenosine
compounds with biological activity and can be found in some and, thus, has been incorporated in various compounds
well-known drug molecules, such as, for example, Sildenafil (a impairing protein kinases and ATPases [7-9]. Moreover, a large
pyrazolo[4,3-d]pyrimidine) [1,2], Allopurinol (a pyrazolo[3,4- variety of additional fused pyrazoles exhibit interesting bio-
d]pyrimidin-4-one) [3], Zaleplon (a pyrazolo[1,5-a]pyrimidine) logical activities, such as, pyrazolo[1,5-a]quinolones [10], pyra-
[4], and Zolazepam (a pyrazolo[3,4-e][1,4]diazepine derivative, zolo[4,3-c]quinolones [11], pyrazolo[5,1-a]isoquinolines [12],
used in veterinary medicine) [5]. Particularly pyrazolopyrimi- and thieno[2,3-c]pyrazoles [13]. In view of these facts as well
dines are a very frequently accessed class of compounds [6] as due to our continuing interest in the exploration of useful but
with the particular importance of the pyrazolo[3,4-d]pyrimidine unused chemical space, which has become a paradigm of
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Beilstein J. Org. Chem. 2012, 8, 2223–2229.
Scheme 1: Intermediate reactions of pyrazole-4-carbaldehyde 1a.
contemporary medicinal chemistry [14], we have devoted some In order to test the reaction conditions, firstly each step of the
effort to the construction of novel condensed heterocyclic multicomponent reaction was carried out separately. According
systems containing pyrazole substructures. Apart from a series to the strategy, pyrazole-4-carbaldehyde 1a was primarily
of publications dealing with the construction of pyrazole condensed with p-toluenesulfonyl hydrazide affording
analogues of xanthones and related systems [15-20] we hydrazide 2a in 97% yield (Scheme 1). Secondly, two steps of
recently described the synthesis of pyrano[4,3-c]pyrazol-4(1H)- the applied strategy were performed at once: condensation of 1a
ones and -4(2H)-ones [21], 1,5-dihydro- resp. 2,5-dihydro- with p-toluenesulfonyl hydrazide and subsequent 6-endo-dig
4 H - p y r a z o l o [ 4 , 3 - c ] p y r i d i n - 4 - o n e s [ 2 0 ] , a n d cyclization [28] of intermediate 2a in the presence of silver
pyrazolo[4,3-c]pyridines [22]. In continuation of these studies triflate produced p-toluenesulfonylazamide 3a in 91% yield
we herein present the synthesis and detailed NMR spectro- (Scheme 1). The reaction of intermediate 3a with CH-acidic
scopic characterization of the new heterocyclic system aldehydes or ketones in the presence of base would lead to
dipyrazolo[1,5-a:4',3'-c]pyridine. The access to the latter was various dipyrazolo[1,5-a:4',3'-c]pyridines 5.
achieved by a multicomponent reaction (MCR) starting from
5-alkynylpyrazole-4-carbaldehydes. Such MCRs, although Thus, after these results, we decided to explore the one-pot
being present since the early days of organic chemistry, nowa- tandem reaction with various 5-alkynylpyrazole-4-carbalde-
days attract an increasing interest because of their unmatched hydes 1, p-toluenesulfonyl hydrazide and butyraldehyde (4a).
synthetic efficiency, which permits the construction of complex As alkynyl functions, phenylethynyl (1a,b), 3-thienylethynyl
molecules in an elegant and sufficient manner [23-26].
(1c,d) and hex-1-ynyl (1e,f) were employed; silver triflate was
used as the catalyst and K3PO4 as a base, needed for the forma-
tion of the second pyrazole ring. In this way, the
dipyrazolo[1,5-a:4',3'-c]pyridines 5a–f were achieved in yields
Results and Discussion
Chemistry
The starting compounds for the construction of the title com- of 44–83% (Table 1, entries 1–6). Replacement of butyralde-
pounds are the 5-alkynylpyrazole-4-carbaldehydes 1. Their syn- hyde by propionaldehyde (4b) or 3-phenylpropanal (4c)
thesis from easily accessible 2-pyrazolin-5-ones through afforded the corresponding tricyclic products 5g, 5h and 5i in
Vilsmeier formylation (with concomitant transformation of the 59–73% yield, respectively (Table 1, entries 7–9). Lastly, appli-
oxygen into a chlorine substituent), followed by Sonogashira cation of the cyclic ketones cyclopentanone (4d), cyclohexa-
cross-coupling reaction of the obtained 5-chloropyrazole-4- none (4e) and 2-methylcyclohexanone (4f) as carbonyl compo-
carbaldehydes with appropriate alkynes, has been described by nents resulted in the formation of tetracycles 5j–l in acceptable
us in a former publication [21]. Compounds 1 containing an yields (Table 1, entries 10–12).
alkyne function and a nucleophilic substituent in the ortho pos-
ition of the pyrazole system are valuable precursors for the NMR spectroscopic investigations
construction of corresponding annulated systems. In order to The NMR spectroscopic data of all compounds described in this
employ this arrangement of functionalities for the latter study are given in Supporting Information File 1. Unequivocal
purpose, we adapted the approach of Wu and co-workers, who assignment of resonances was carried out by the combined
described the synthesis of H-pyrazolo[5,1-a]isoquinolines by a application of various standard NMR spectroscopic techniques,
one-pot tandem reaction of 2-alkynylbenzaldehydes, sulfonohy- such as 1H coupled 13C NMR spectra, APT, HMQC, gs-HSQC,
drazide, and ketones or aldehydes [27]. In our case, application gs-HMBC, COSY, TOCSY, NOESY and NOE-difference spec-
of pyrazolecarbaldehydes 1 should enable access to the desired troscopy [29]. In some cases experiments with selective excita-
dipyrazolo[1,5-a:4',3'-c]pyridines 5.
tion of certain 1H resonances were performed, such as long-
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Beilstein J. Org. Chem. 2012, 8, 2223–2229.
Table 1: Multicomponent reaction of various 5-alkynyl-1-phenyl-1H-pyrazole-4-carbaldehydes 1 with p-toluenesulfonyl hydrazide and aldehydes or
ketones 4.
Entry
Compound 1
Compound 4
Product 5
Yield, %
1
83
4a
1a
5a
5b
5c
5d
2
3
4
47
73
73
4a
4a
4a
1b
1c
1d
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Beilstein J. Org. Chem. 2012, 8, 2223–2229.
Table 1: Multicomponent reaction of various 5-alkynyl-1-phenyl-1H-pyrazole-4-carbaldehydes 1 with p-toluenesulfonyl hydrazide and aldehydes or
ketones 4. (continued)
5
44
4a
1e
5e
6
79
4a
1f
5f
7
59
4b
1a
5g
8
73
4c
1a
5h
9
59
4c
1b
5i
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Beilstein J. Org. Chem. 2012, 8, 2223–2229.
Table 1: Multicomponent reaction of various 5-alkynyl-1-phenyl-1H-pyrazole-4-carbaldehydes 1 with p-toluenesulfonyl hydrazide and aldehydes or
ketones 4. (continued)
10
46
4d
4e
4f
1a
5j
11
64
1a
5k
12
38
1a
5l
range INEPT [30] and 2D(δ,J) long-range INEPT [31], the signals due to H-1 and H-4 are split due to a small long-
the latter experiments having been used for the range coupling (5J(H-1,H-4) ~ 0.8 Hz). The signal of H-4 is
unambiguous determination of long-range 13C,1H coupling located within a relatively small range, namely between 6.85
constants.
and 7.20 ppm. Those compounds unsubstituted at position 8
show the H-8 signal at 7.75–7.91 ppm. Characteristic core
With compound 2a, the tosylhydrazone of starting aldehyde 1a, signals in the 13C NMR spectra are those of C-3a (134.8–136.7
(E)-configuration at the C=N double bond follows from an ppm), C-4 (95.1–98.3 ppm), C-9 (5j: C-10a, 5k,l: C-11a)
NOE between the iminyl-H (7.96 ppm) and NH (8.22 ppm) as (105.6–114.6 ppm), C-9a (5j: C-10b, 5k,l: C-11b)
well from the size of 1J(N=C–H) (160.7 Hz). In contrast, the (130.4–134.2) and C-9b (5j: C-10c, 5k,l: C-11c) (111.2–112.7
(Z)-configuration and thus cis-position of the lone pair of the ppm). The other carbon resonances (C-1, C-5, C-8) are influ-
nitrogen and the coupled proton with respect to the C=N double enced by the attached substituents to a somewhat larger extent.
bond should result in a considerably larger 1J-coupling due to Also the 15N NMR spectra show a uniform pattern: the reso-
lone-pair effects, which strongly influence such spin couplings nances of N-2 and N-3 are slightly influenced by the substituent
[32,33].
at position 1 with the 1-H derivatives having slightly larger
chemical shifts than those of the corresponding 1-methyl
The target products 5a–l show very consistent signal sets congeners. The 15N chemical shifts of N-6 and N-7 are some-
regarding the invariable part of the molecules. In the 1H NMR what smaller with derivatives 5j–5l having a cycloaliphatic ring
spectra of congeners unsubstituted at position 1 (5b, 5d, 5f, 5i) anellated to the concerning pyrazole ring. In Figure 1 the 1H,
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Beilstein J. Org. Chem. 2012, 8, 2223–2229.
Acknowledgements
Grant financed by the Scholarship Council of the Scholarship
Foundation of the Republic of Austria is gratefully acknowl-
edged by Gytė Vilkauskaitė.
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