Scalable Sonochemical Synthetic Strategy for Pyrazolo[1,5-a]pyridine Derivatives: First Catalyst-Free Concerted [3 + 2] Cycloaddition of Alkyne and Alkene Derivatives to 2-Imino-1H-pyridin-1-amines.

A highly efficient and convenient one-pot sonochemical synthetic strategy has been sophisticated for synthesizing a novel class of polysubstituted pyrazolo[1,5-a]pyridines via [3 + 2] cycloaddition of dialkyl acetylenedicarboxylates, ethyl propiolate, and alkenes to 2-imino-1H-pyridin-1-amines under catalyst-free conditions. A series of uniquely substituted pyrazolo[1,5-a]pyridines has been synthesized with a very good to excellent yield, and the mechanistic pathway that involves a [3 + 2] annulation process was also proposed. In this study, several spectroscopic tools of analyses were employed for structure elucidation, and the X-ray single-crystal technique was utilized to confirm the proposed mechanism and the regioselectivity.

Introduction

The pyrazolopyridine derivatives and their analogues represent a remarkable category among the pharmaceutically active compounds, for example, the pyrazolo[1,5-a]pyridine heterocyclic system, which was found as a part of the skeletal backbone of many therapeutic drugs today.[1] This class of compounds has various pharmacological and biological activities including antiplatelet,[2] melatonin receptor agonist,[3] antipsychotic, antiherpetic,[4] and a D4 and D3 receptor antagonist and agonist.[5] Consequently, they are applicable in the treatment of several neurological disorders including anxiety, schizophrenia, attention deficit disorder, drug dependency, and Parkinson’s disease.[5−7] Moreover, members of this family like the pyrazolo[1,5-a]pyridine derivative 1 (Figure ) has been shown to serve as a potent and selective 5HT3 antagonist, which has been clinically applied to treat vomiting caused by cancer chemotherapy.[8] In addition, pyrazolo[1,5-a]pyridine derivatives 2 and 3 (Figure ) are adenosine A1 receptor antagonists with potent diuretic activity.[9,10]

Figure 1

Some biologically active pyrazolo[1,5-a]pyridine derivatives 1–3.

As a result of these interesting characteristics and applications, the fused pyridine derivatives are of notable structures; consequently, they have attracted continuing attention of the synthetic organic chemists and pharmaceutical industry. Recently, numerous protocols have been evaluated for the synthesis of pyrazolo[1,5-a]pyridines; the most common and popular route involves the intermolecular cyclization reactions of N-iminopyridinium ylides with a dipolarophile like alkynes and alkenes.[2,11−17] Moreover the intramolecular rearrangement reactions have also given rise to the formation of pyrazolo[1,5-a]pyridine derivatives, for example, the intramolecular cyclization of ethynylpyridines[18,19] and transient nitrenes.[20,21] Recently, in our laboratory, we developed various protocols for synthesizing the pyridine derivatives and their utility as valuable precursors to synthesize a novel pyrazolo[3,4-c]pyridine derivatives through a new distinctive [4 + 1] cycloaddition process.[22,23] In a commitment of our research aimed at developing new approaches for polyfunctionally substituted pyrazolopyridines, this investigation was aimed to develop a novel route for polysubstituted pyrazolo[1,5-a]pyridines via [3 + 2] cycloaddition reaction of acetylenedicarboxylate, ethyl propiolate, and alkenes to 2-imino-1H-pyridin-1-amines under catalyst-free conditions via a sonochemical approch. Herein, the X-ray single-crystal technique was utilized as a distinctive tool of analysis for structure elucidation and to confirm the proposed mechanism and the regioselectivity for the reaction products.

Results and Discussion

The synthetic strategy of our study to obtain the targeted polysubstituted pyrazolo[1,5-a]pyridine compounds begins by preparing the starting material 1-amino-2(1H)-pyridine-2-imine derivatives 3a–g. These were synthesized in two sequential steps: (i) the reaction of the arylethylidenemalononitriles 1a–g with DMF-DMA (dimethylformamide dimethyl acetal) afforded the enaminonitriles 2a–g then (ii) the reaction of the latter with hydrazine hydrate in refluxing ethanol obtained the enamines (cf. Scheme and Figure ).

Scheme 1

Preparation of 1-Amino-2(1H)-pyridine-2-imine Derivatives (3)

Figure 2

Thermal ellipsoid crystal structure of compound 3f.

Now, the utlity of 1-amino-2(1H)-pyridine-2-imine derivatives 3 as valuable precursors for synthesizing novel uniquely substituted pyrazolo[1,5-a]pyridine derivatives will be investigated to explore the limitations and opportunity of this conversion. However, to the best of our knowledge and after an extensive literature survey, it was noted that this is the first synthesis of pyrazolo[1,5-a]pyridine from the 1-amino-2(1H)-pyridine-2-imine derivatives 3, and the synthetic route for the pyrazolo[1,5-a]pyridines involving the asymmetric N-aminopyridine salts has some disadvantages like having poor yields and lacking regioselectivity, since it is usually accompanied by the formation of unfavorable two regioisomers.[2,11] Thus, in this study, we try to overcome these synthetic drawbacks by selecting the asymmetric 1-amino-2(1H)-pyridine-2-imines as a novel precursor for synthesizing pyrazolo[1,5-a]pyridine derivatives as a regioselective product with high yield. The first stage in this study was aimed to explore a general protocol and establish the best reaction conditions for the synthesis of pyrazolo[1,5-a]pyridine derivatives via an eco-friendly green synthetic methodology. Thus, the reaction of an equimolar mixture of 1-amino-2(1H)-pyridine-2-imine derivative (3a) and dimethyl acetylenedicarboxylate (DMAD) (4a) was selected as a model reaction; intially, this reaction was examined in the presence of different types of solvents without any addition of a catalyst or additive. In the beginning, the reaction between 1-amino-2(1H)-pyridine-2-imine derivative (3a) (5 mmol) and dimethyl acetylenedicarboxylate (4a) (5 mmol) was conducted in ethanol (25 mL) under both thermal heating and sonication at (85 °C) to study the effect of an energy source on this model reaction. This reaction generates a novel single product in 54% yield under conventional heating and 69% under sonication, and the results are outlined in Table (entries 1 and 2). The structure of this product was assigned as 7-amino-6-cyano-5-phenylpyrazolo[1,5-a]pyridine-2,3-dicarboxylic acid dimethyl ester (5a) and not pyrido[1,2-b]1,2,4-triazine 6 (Scheme ) on the basis of the data obtained from diversified spectrometric tools. The 1H NMR data of the obtained product in DMSO exhibited two singlet signals at δ 8.48 ppm for NH2 protons and δ 7.18 ppm for pyridine hydrogen (H4), and the two methyl groups of the two ester groups manifested as two singlets at δ 3.95 and 3.81 ppm, respectively, in addition to the aromatic protons signals at δ 7.52–7.62 ppm. Moreover, all the data obtained from 13C NMR, IR, and mass and accurate mass determination support the pyrazolo[1,5-a]pyridine structure. This structure was definitely confirmed via X-ray single crystallography for some representative examples as shown later (cf. Figures –6). Then, we applied different solvents to conduct the above model reaction like methanol, acetonitrile, propanol, isopropanol, dioxane, N,N-dimethylformamide, water, and toluene. The obtained results for this solvent screening study showed that acetonitrile is the most efficacious solvent for conducting this reaction (70% yield under conventional heating and 92% under sonication), in comparison with the other used solvents as illustrated in Table ( entries 3–18). Furthermore, improvement was noted in both the reaction yield and rate when this model reaction was carried out under sonication (at 85 °C, 110 W) as a substitutional energy source. The use of ultrasonic irradiation along with thermal activation for conducting chemical reactions in solution has many specifications like increasing and improving the reactivities and reaction rate in a dramatic way, which proceeds by the generation, growth, and collapse of acoustic bubbles in the reaction mixture. These directly help in decreasing the reaction time and considerably improve the reaction yield.[24−26] Meanwhile, to check the effect of the catalyst on the outcome of the above model reaction, we first conducted this reaction in the presence 10 mol % of palladium(II) acetate Pd(OAc)2, utlizing the most effective solvent acetonitrile. The results summarized in Table (entries 19 and 20) showed that the obtained yields, either thermally or under sonication, are very close to the results obtained without using the catalytic agent. Moreover, the same reaction was conducted using Cu(OAc)2 as a catalyst but also had a moderate effect on this reaction, since the obtained yields were almost the same. This means that the catalyst has no effect on the reaction yield.

Table 1

Optimization of Conditions for the Synthesis of 5aa

entry	catalyst	solvent	method	time (min)	yield (%)
1		EtOH	heating	180	54
2		EtOH	sonication	20	69
3		MeOH	heating	180	49
4		MeOH	sonication	20	67
5		CH3CN	heating	180	70
6		CH3CN	sonication	20	92
7		propanol	heating	180	45
8		propanol	sonication	20	66
9		isopropanol	heating	180	49
10		isopropanol	sonication	20	67
11		1,4-dioxane	heating	120	55
12		1,4-dioxane	sonication	15	73
13		DMF	heating	90	43
14		DMF	sonication	15	65
15		water	heating	180	NRb
16		water	sonication	30	NRb
17		toluene	heating	180	NRb
18		toluene	sonication	30	NRb
19	Pd(OAc)2	CH3CN	heating	180	70
20	Pd(OAc)2	CH3CN	sonication	20	91
21	Cu(OAc)2	CH3CN	heating	180	71
22	Cu(OAc)2	CH3CN	sonication	20	90

Reaction conditions: 1-amino-2(1H)-pyridine-2-imine derivatives (3a) (5 mmol), dimethyl acetylenedicarboxylate (4a) (5 mmol), solvent (25 mL), and catalyst (10 mol %) (in the case of sonication, the temperature was 85 °C at 110 W).

NR, no reaction.

Scheme 2

Reaction of 1-Amino-2(1H)-pyridine-2-imine 3a with DMAD 4a

Figure 3

Thermal ellipsoid crystal structure of compound 5i.

Figure 6

Thermal ellipsoid crystal structure of compound 5r.

Thermal ellipsoid crystal structure of compound 5j.

Thermal ellipsoid crystal structure of compound 5l.

With the optimized set of the reaction conditions in our hand, we were enthusiastic to explore the scope and limitations of the abovementioned reaction. Moreover, in order to investigate the scalable synthetic approach of this reaction, we conducted the reaction using 10 mmol of each starting material instead of 5 mmol. Thus, the reactions of an equimolar mixture of 1-amino-2(1H)-pyridine-2-imine derivatives (3a–g) and acetylene derivatives like dimethyl acetylenedicarboxylate (4a), diethyl acetylenedicarboxylate (4b), and ethyl propiolate (4c) in refluxing acetonitrile only without any additives were scrutinized thermally and under ultrasonic irradiation to compare the reaction yields. The outlined data depicted in Scheme showed that all the above suggested interactions gave the same reaction output in excellent yields via ultrasonic irradiation, which evidenced to be the corresponding pyrazolo[1,5-a]pyridine derivatives 5a–s (cf. Scheme ). All the proposed pyrazolo[1,5-a]pyridine structures for the reaction products have been confirmed based on various tools of spectrometric analysis, such as 1H NMR and 13C NMR, in addition to the mass and accurate mass assignment. Moreover, the above structure was assured without any doubt through the X-ray single-crystal structure determination in some representative examples (cf. Figures –6).

Scheme 3

Reaction of 1-Amino-2(1H)-pyridine-2-imine Derivatives (3) with Acetylenedicarboxylate 4

A conceivable mechanistic pathway for the synthesis of 5a–s was proposed as a concerted [3 + 2] annulation process as outlined in Scheme . First, in this route, the exocyclic amino group in the 1-amino-2(1H)-pyridine-2-imine derivatives (3) underwent Michael-type addition to the acetylenedicarboxylate derivatives 4 in a domino-like pathway to yield the congruent nonseparated cyclic intermediate 6, which was then converted to the corresponding intermediate 7 by means of 1,4-hydrogen shift; eventually, the intermediate 7 underwent aromatization through losing one hydrogen molecule to form the corresponding pyrazolo[1,5-a]pyridines 5 (cf. Scheme ).

Scheme 4

Mechanistic Pathway for the Formation of Pyrazolo[1,5-a]pyridines 5

Now, we will test the reaction of the abovementioned 1-aminopyridine-2-imine derivatives 3a–g with ethyl acrylate (8) as a representative example of an alkene. Thus, reacting an equimolar ratio from 1-aminopyridine-2-imine derivatives 3a–g with ethyl acrylate (8) in acetonitrile without any additives leads to the formation of compounds with structures assigned as pyrazolo[1,5-a]pyridines 5m–s based on various spectrometric analyses, which is the same product that was obtained from the reaction of ethyl propiolate. During the course of this reaction, it is believed that the intermediate 9 has been first formed through the cycloaddition of aminopyridine 3 with ethyl acrylate (8), which underwent losing two molecules of hydrogen to furnish the final product pyrazolopyridines 5 (cf. Scheme ).

Scheme 5

Reaction of 1-Aminopyridine-2-imine Derivatives 3 with Ethyl Acrylate (8)

In order to confirm the above mechanistic sequence and to prove that the 1,4-hydrogen shift step occurred before the aromatization by losing hydrogen, we endeavored to isolate one of the above intermediates by using various examples of alkynes and alkenes, and finally we succeeded to isolate the intermediate of type 9. Therefore, reacting of the aminopyridine 3d with acrylonitrile 10 afforded the corresponding tetrahydropyrazolopyridine derivative 11, and the structure of this tetrahydro product was exclusively evidenced via the X-ray single-crystal analysis as shown in Figure . Then, the tetrahydropyrazolopyridine derivative 11 was successfully converted to the corresponding pyrazolopyridine derivative 12 via boiling in dimethylformamide (DMF) (cf. Scheme ).

Figure 7

Thermal ellipsoid crystal structure of compound 11.

Scheme 6

Reaction of 1-Aminopyridine-2-imine 3d with Acrylonitrile 10

The obtained pyrazolopyridine 5 was found as a versatile substrate for synthesizing a novel and uniquely substituted tricyclic system pyrazolo[2′,3′:1,6]pyrido[2,3-d]pyrimidine by condensing pyrazolopyridines 5i and 5p with N,N-dimethylformamide dimethyl acetal (DMF-DMA) to afford the corresponding amidine derivatives 13, which underwent heterocyclization with the cyano moiety upon boiling in acetic acid containing ammonium acetate to afford the corresponding pyrazolo[2′,3′:1,6]pyrido[2,3-d]pyrimidine derivatives 14 (cf. Scheme ).

Scheme 7

Synthesis of Pyrazolo[2′,3′:1,6]pyrido[2,3-d]pyrimidine Derivatives 14

Conclusions

In the abovementioned study, a convenient novel sonochemical synthetic strategy for multisubstituted pyrazolo[1,5-a]pyridine derivatives has been explored through the reaction of 1-amino-2(1H)-pyridine-2-imine derivatives 3a–g with dialkyl acetylenedicarboxylate or alkenyl derivatives. This synthetic route has more inherent merits like high regioselectivity and yields, in comparison to the aforementioned procedures, which used asymmetric N-aminopyridines that gave two regioisomers with poor selectivity and yields. The X-ray crystallography was successfully utilized in this research for affirmation of the regioselectivity and the [3 + 2] cycloaddition mechanism.

Experimental Section

General

Melting points were recorded on a Griffin melting point apparatus and are uncorrected. IR spectra were recorded using KBr disks using Jasco FT-IR-6300 spectrophotometer. 1H NMR (400 MHz) or (600 MHz) and 13C NMR (100 MHz) or (150 MHz) spectra were recorded at 25 °C using DMSO-d6 or CDCl3 as a solvent with TMS as internal standard on a Bruker DPX 400 or 600 superconducting NMR spectrometer. Chemical shifts are reported in parts per million (ppm). Low-resolution electron impact mass spectra [MS (EI)] and high-resolution electron impact mass spectra [HRMS (EI)] were performed using a high-resolution GC-MS (DFS) thermospectrometer at 70.1 eV and a magnetic sector mass analyzer. Follow up of the reactions and checking the homogeneity of the prepared compounds were made by using thin-layer chromatography (TLC). The X-ray crystal structures were determined by using a Rigaku R-AXIS RAPID diffractometer and Bruker X8 Prospector, and the collection of single-crystal data was made at room temperature by using Cu Kα radiation. The structures were solved by using direct methods and expanded using Fourier techniques. The nonhydrogen atoms were refined anisotropically. The structures were solved and refined using the Bruker SHELXTL software package (structure solution program SHELXS-97 and refinement program SHELXL-97).[27] Data were corrected for the absorption effects using the multiscan method (SADABS). Sonication was performed in MKC6, Guyson ultrasonic bath (model MKC6, operating frequency of 38 kHz ± 10%, and an output power of 110 W). The arylethylidenemalononitriles 1a–g[28] and enaminonitriles 2a–g[29] were prepared according to the literature procedures.

General Procedure for the Preparation of 1-Amino-2-imino-4-aryl-1,2-dihydropyridine-3-carbonitrile 3a–g

An equimolar mixture of the enaminonitriles 2a–g (20 mmol) and hydrazine hydrate (1.5 mL, 30 mmol) in 60 mL of ethanol was refluxed for 1 h. The reaction mixture was evaporated in vacuo, and the residual solid was crystallized from the appropriate solvent to give 3a–g as pure products.

1-Amino-2-imino-4-phenyl-1,2-dihydropyridine-3-carbonitrile (3a)[30]

Yellow crystals; yield: 3.7 g (89%); mp 165–166 °C, IR (KBr) ν (cm–1): 3318, 3226 (NH2), 3137 (NH), 2211 (CN); 1H NMR (DMSO-d6, δ): 5.90 (d, J = 7.2 Hz, 1H, C-H6), 6.16 (s, 2H, NH2), 6.53 (brs, 1H, imine NH), 7.52–7.59 (m, 5H, Ar-H), 7.81 ppm (d, J = 7.2 Hz, 1H, C-H5); 13C NMR (DMSO-d6, δ): 97.22, 101.63, 117.06, 127.76, 128.79, 136.25, 143.12, 154.58, 155.10 ppm (Ar-C and CN); MS (EI) m/z (%): 211 (M+ + 1, 118.25), 210 (M+, 100.0); HRMS (EI): m/z calcd for C12H10N4 (M+) 210.0899; found, 210.0899.

1-Amino-2-imino-4-p-tolyl-1,2-dihydropyridine-3-carbonitrile (3b)

Yellow crystals; yield: 4.3 g (90%); mp 223–224 °C, IR (KBr) ν (cm–1): 3315, 3262 (NH2), 3171 (NH), 2207 (CN); 1H NMR (DMSO-d6), δ: 3.35 (s, 3H, CH3), 5.88 (d, J = 7.2 Hz, 1H, C-H6), 6.13 (s, 2H, NH2), 6.58 (brs, 1H, imine NH), 7.34 (d, J = 8.0 Hz, 2H, Ar-H), 7.48 (d, J = 8.0 Hz, 2H, Ar-H), 7.78 ppm (d, J = 7.2 Hz, 1H, C-H5); 13C NMR (DMSO-d6, δ): 20.88 (CH3), 101.59, 117.15, 127.69, 129.32, 133.33, 140.00, 142.64, 142.95, 154.63, 155.03 ppm (Ar-C and CN); MS (EI) m/z (%): 225 (M+ + 1, 13.19), 224 (M+, 72.89); HRMS (EI): m/z calcd for C13H12N4 (M+) 224.1056; found, 224.1055.

1-Amino-2-imino-4-(4-methoxyphenyl)-1,2-dihydropyridine-3-carbonitrile (3c)

Yellow crystals; yield: 4.2 g (88%); mp 225–226 °C, IR (KBr) ν (cm–1): 3316, 3248 (NH2), 3167 (NH), 2206 (CN); 1H NMR (DMSO-d6, δ): 3.83 (s, 3H, OCH), 5.89 (d, J = 6.8 Hz, 1H, C-H6), 6.11 (s, 2H, NH2), 6.55 (brs, 1H, imine NH), 7.08 (d, J = 8.4 Hz, 2H, Ar-H), 7.56 (d, J = 8.4 Hz, 2H, Ar-H), 7.76 ppm (d, J = 6.8 Hz, 1H, C-H5); 13C NMR (DMSO-d6, δ): 55.84 (OCH), 101.99, 102.02, 114.65, 117.83, 128.66, 129.91, 143.27, 155.06, 155.23, 161.23 ppm (Ar-C and CN); MS (EI) m/z (%): 241 (M+ + 1, 19.27), 240 (M+, 100); HRMS (EI): m/z calcd for C13H12N4O (M+) 240.1005; found, 240.1005.

1-Amino-4-(4-chlorophenyl)-2-imino-1,2-dihydropyridine-3-carbonitrile (3d)[31]

Bright yellow crystals; yield: 4.35 g (89%); mp 234–235 °C, IR (KBr) ν (cm–1): 3314, 3267 (NH2), 3178 (NH), 2210 (CN); 1H NMR (DMSO-d6, δ): 5.89 (d, J = 6.8 Hz, 1H, C-H6), 6.16 (s, 2H, NH2), 6.61 (brs, 1H, imine NH), 7.61–7.63 (m, 4H, Ar-H), 7.81 ppm (d, J = 6.8 Hz, 1H, C-H5); 13C NMR (DMSO-d6, δ): 101.34, 116.80, 128.81, 129.67, 134.84, 135.01, 143.09 143.18, 153.85, 154.27 ppm (Ar-C and CN); MS (EI) m/z (%): 246 (M+ + 2, 34.29), 245 (M+ + 1, 17.94), 244 (M+, 100); HRMS (EI): m/z calcd for C12H9N4Cl (M+) 244.0510; found, 244.0510.

1-Amino-4-(4-bromophenyl)-2-imino-1,2-dihydropyridine-3-carbonitrile (3e)

Yellow crystals; yield: 5.3 g (92%); mp 239–240 °C, IR (KBr) ν (cm–1): 3311, 3263 (NH2), 3176 (NH), 2208 (CN); 1H NMR (DMSO-d6, δ): 5.90 (d, J = 6.8 Hz, 1H, C-H6), 6.17 (s, 2H, NH2), 6.73 (brs, 1H, imine NH), 7.54 (d, J = 8.4 Hz, 2H, Ar-H), 7.74 (d, J = 8.4 Hz, 2H, Ar-H) and 7.82 ppm (d, J = 6.8 Hz, 1H, C-H5); 13C NMR (DMSO-d6, δ): 102.16, 116.58, 123.73, 129.96, 131.80, 135.26, 143.39, 143.43, 154.16 and 154.29 ppm (Ar-C and CN); MS (EI): m/z (%) 290 (M++2, 97.06), 289 (M++1, 18.49), 288 (M+, 100); HRMS (EI): m/z Calcd. for C12H9N4Br(M+) 288.0005, found 288.0005.

1-Amino-2-imino-4-(4-nitrophenyl)-1,2-dihydropyridine-3-carbonitrile (3f)

Yellow crystals; yield: 4.4 g (87%); mp 207–208 °C, IR (KBr) ν (cm–1): 3312, 3255 (NH2), 3161 (NH), 2206 (CN); 1H NMR (DMSO-d6, δ): 5.94 (d, J = 7.2 Hz, 1H, C-H6), 6.23 (brs, 2H, NH2), 6.74 (brs, 1H, imine NH), 7.85–7.87 (m, 3H, 2Ar-H and C-H5), 8.36 ppm (d, J = 7.6 Hz, 2H, Ar-H); 13C NMR (DMSO-d6, δ): 97.70, 101.29, 116.53, 123.91, 129.48, 142.53, 143.59, 148.22, 153.06, 154.02 ppm (Ar-C and CN); MS (EI) m/z (%): 256 (M+ + 1, 17.92), 255 (M+, 100); HRMS (EI): m/z calcd for C12H9N5O2 (M+) 255.0751; found, 255.0750. Crystal data, moiety formula: C12H9N5O2, M = 255.24, tetragonal, a = 35.87(2) Å, b = 35.87(13) Å, c = 3.8092(8) Å, V = 4900(3) Å3, α = β = γ = 90°, space group I41/a, Z = 2, Dcalc = 1.384 g·cm–3, no. of reflection measured, 2195, 2θmax = 50.6°, R1 = 0.1088 (CCDC 1889192).[32]

1-Amino-2-imino-4-thiophen-2-yl-1,2-dihydropyridine-3-carbonitrile (3g)

Yellow crystals; yield: 3.60 g (84%); mp 218–219 °C, IR (KBr) ν (cm–1): 3321, 3273 (NH2), 3181 (NH), 2214 (CN); 1H NMR (DMSO-d6, δ): 5.91 (d, J = 6.8 Hz, 1H, C-H6), 6.22 (s, 2H, NH2), 6.67 (brs, 1H, imine NH), 6.81 (d, J = 6.6 Hz, 1H, Ar-H), 7.34 (d, J = 6.6 Hz, 1H, Ar-H), 7.88 (d, J = 6.8 Hz, 1H, C-H5), 8.06 ppm (t, J = 6.6 Hz, 1H, Ar-H); 13C NMR (DMSO-d6, δ): 101.86, 114.89, 123.90, 125.75, 128.87, 133.50, 136.27, 145.31, 145.69, 158.35 ppm (Ar-C and CN); MS (EI) m/z (%): 217 (M+ + 1, 17.94), 216 (M+, 100); HRMS (EI): m/z calcd for C10H8N4S (M+) 216.0464; found, 216.0464.

General Procedure for the Preparation of the Pyrazolo[1,5-a]pyridine Derivatives 5a–s

Independent mixtures of 1-amino-2-iminopyridine derivatives 3a–g (10 mmol) and the appropriate acetylene derivatives 4a-c (10 mmol) in acetonitrile (30 mL) were heated at the refluxing temperature for 3 h or sonicated for 20 min at 85 °C, and the reaction was followed up by TLC. The mixtures were cooled to room temperature. The solid products that formed were filtered off, washed with ethanol, dried, and recrystallized from the indicated solvents to give 5a–s as pure products. The reported yields here are from the sonication procedure.

7-Amino-6-cyano-5-phenylpyrazolo[1,5-a]pyridine-2,3-dicarboxylic Acid Dimethyl Ester (5a)

Recrystallized from acetonitrile as yellow crystals; yield: 3.2 g (92%); mp 220–221 °C; IR (KBr) ν (cm–1): 3373, 3304 (NH2), 2217 (CN), 1736, 1712 (2CO); 1H NMR (DMSO-d6, δ): 3.81 (s, 3H, OCH), 3.95 (s, 3H, OCH), 7.18 (s, 1H, pyridine H4), 7.52–7.62 (m, 5H, Ar-H), 8.48 ppm (s, 2H, NH2); 13C NMR (DMSO-d6, δ): 51.76, 53.06 (2CH3), 76.98 (pyridine C6), 101.92, 103.76, 116.11, 128.43, 128.69, 129.28, 137.22, 141.33, 144.65, 148.57, 148.97, 161.65, 163.22 ppm (Ar-C and CN); MS (EI) m/z (%): 351 (M+ + 1, 19.14), 350 (M+, 100); HRMS (EI): m/z calcd for C18H14N4O4 (M+) 350.1009; found, 350.1009.

7-Amino-6-cyano-5-p-tolylpyrazolo[1,5-a]pyridine-2,3-dicarboxylic Acid Dimethyl Ester (5b)

Recrystallized from acetonitrile as buff crystals; yield: 3.4 g (93%); mp 215–216 °C; IR (KBr) ν (cm–1): 3410, 3326 (NH2), 2213 (CN), 1738, 1717 (2CO); 1H NMR (DMSO-d6, δ): 2.40 (s, 3H, CH3), 3.81 (s, 3H, OCH), 3.95 (s, 3H, OCH), 7.16 (s, 1H, pyridine H4), 7.35 (d, J = 8.0 Hz, 2H, Ar-H), 7.50 (d, J = 8.0 Hz, 2H, Ar-H), 8.45 ppm (s, 2H, NH2); 13C NMR (DMSO-d6, δ): 20.84, 51.73, 53.04 (3CH3), 76.99 (pyridine C6), 101.75, 103.52, 116.15, 128.31, 129.25, 134.33, 138.96, 141.37, 144.69, 148.55, 148.95, 161.65, 163.22 ppm (Ar-C and CN); MS (EI) m/z (%): 366 (M+ + 1, 25.84), 365 (M+, 100); HRMS (EI): m/z calcd for C19H17N4O4 (M+) 365.1244; found, 365.1244.

7-Amino-6-cyano-5-(4-methoxyphenyl)pyrazolo[1,5-a]pyridine-2,3-dicarboxylic Acid Dimethyl Ester (5c)

Recrystallized from acetonitrile as orange crystals; yield: 3.4 g (90%); mp 195–196 °C; IR (KBr) ν (cm–1): 3410, 3326 (NH2), 2213 (CN), 1738, 1717 (2CO); 1H NMR (DMSO-d6, δ): 3.82 (s, 3H, OCH), 3.84 (s, 3H, OCH), 3.95 (s, 3H, OCH), 7.10 (d, J = 8.4 Hz, 2H, Ar-H), 7.16 (s, 1H, pyridine H4), 7.57 (d, J = 8.4 Hz, 2H, Ar-H), 8.43 ppm (s, 2H, NH2); 13C NMR (DMSO-d6, δ): 51.71, 53.02, 55.32 (3CH3), 77.01 (pyridine C6), 101.59, 103.33, 114.12, 116.25, 129.32, 129.85, 141.41, 144.42, 148.55, 148.96, 160.12, 161.66, 163.23 ppm (Ar-C and CN); MS (EI) m/z (%): 381 (M+ + 1, 24.88), 380 (M+, 100); HRMS (EI): m/z calcd for C19H16N4O5 (M+) 380.1115; found, 380.1114.

7-Amino-5-(4-chlorophenyl)-6-cyanopyrazolo[1,5-a]pyridine-2,3-dicarboxylic Acid Dimethyl Ester (5d)

Recrystallized from acetonitrile as creamy white crystals; yield: 3.7 g (96%); mp 230–231 °C; IR (KBr) ν (cm–1): 3388, 3309 (NH2), 2216 (CN), 1739, 1718 (2CO); 1H NMR (DMSO-d6, δ): 3.81 (s, 3H, OCH), 3.94 (s, 3H, OCH), 7.17 (s, 1H, pyridine H4), 7.59–7.64 (m, 4H, Ar-H), 8.53 ppm (s, 2H, NH2); 13C NMR (DMSO-d6, δ): 51.79, 53.08 (2CH3), 76.78 (pyridine C6), 102.10, 103.80, 116.00, 128.73, 130.35, 134.22, 136.03, 141.27, 143.33, 148.54, 148.95, 161.60, 163.16 ppm (Ar-C and CN); MS (EI) m/z (%): 386 (M+ + 2, 50.64), 385 (M+ + 1, 24.68), 384 (M+, 100); HRMS (EI): m/z calcd for C18H13ClN4O4 (M+) 384.0619; found, 384.0619.

7-Amino-5-(4-bromophenyl)-6-cyanopyrazolo[1,5-a]pyridine-2,3-dicarboxylic Acid Dimethyl Ester (5e)

Recrystallized from acetonitrile as creamy white crystals; yield: 4.0 g (94%); mp 234–235 °C; IR (KBr) ν (cm–1): 3442, 3322 (NH2), 2215 (CN), 1742, 1716 (2CO); 1H NMR (DMSO-d6, δ): 3.82 (s, 3H, OCH), 3.95 (s, 3H, OCH), 7.18 (s, 1H, pyridine H4), 7.56 (d, J = 8.4 Hz, 2H, Ar-H), 7.76 (d, J = 8.4 Hz, 2H, Ar-H), 8.53 ppm (s, 2H, NH2); 13C NMR (DMSO-d6, δ): 52.22, 53.51 (2CH3), 77.18 (pyridine C6), 102.57, 104.20, 116.41, 123.34, 131.04, 132.12, 136.87, 141.73, 143.85, 148.99, 149.41, 162.05, 163.59 ppm (Ar-C and CN); MS (EI) m/z (%): 430 (M+ + 2, 100), 429 (M+ + 1, 19.83), 428 (M+, 98.46); HRMS (EI): m/z calcd for C18H13BrN4O4 (M+) 428.0114; found, 428.0112.

7-Amino-6-cyano-5-(4-nitrophenyl)pyrazolo[1,5-a]pyridine-2,3-dicarboxylic Acid Dimethyl Ester (5f)

Recrystallized from acetonitrile as yellow crystals; yield: 3.5 g (89%); mp 288–289 °C; IR (KBr) ν (cm–1): 3406, 3307 (NH2), 2220 (CN), 1735, 1709 (2CO); 1H NMR (DMSO-d6, δ): 3.81 (s, 3H, OCH), 3.94 (s, 3H, OCH), 7.21 (s, 1H, pyridine H4), 7.87 (d, J = 8.4 Hz, 2H, Ar-H), 7.36 (d, J = 8.4 Hz, 2H, Ar-H), 8.60 ppm (s, 2H, NH2); 13C NMR (DMSO-d6, δ): 51.84, 53.10 (2CH3), 76.38 (pyridine C6), 102.56, 104.23, 115.81, 123.74, 130.05, 141.11, 142.29, 143.54, 147.81, 148.59, 148.92, 161.53, 163.06 ppm (Ar-C and CN); MS (EI) m/z (%): 396 (M+ + 1, 28.16), 395 (M+, 100); HRMS (EI): m/z calcd for C18H13N5O6 (M+) 395.0860; found, 395.0860.

7-Amino-6-cyano-5-phenylpyrazolo[1,5-a]pyridine-2,3-dicarboxylic Acid Diethyl Ester (5g)

Recrystallized from acetonitrile as white crystals; yield: 3.4 g (90%); mp 160–161 °C; IR (KBr) ν (cm–1): 3431, 3397 (NH2), 2221 (CN), 1741, 1709 (2CO); 1H NMR (DMSO-d6, δ): 1.27 (t, J = 7.2 Hz, 3H, CHCH2), 1.35 (t, J = 7.2 Hz, 3H, CHCH2), 4.27 (q, 2H, J = 7.2 Hz, CH3CH), 4.41 (q, 2H, J = 7.2 Hz, CH3CH), 7.19 (s, 1H, pyridine H4), 7.53–7.62 (m, 5H, Ar-H), 8.48 ppm (s, 2H, NH2); 13C NMR (DMSO-d6, δ): 13.92, 14.10 (2CH3), 60.29, 62.13 (2CH2), 76.87 (pyridine C6), 101.82, 103.67, 116.15, 128.40, 128.72, 129.30, 137.23, 141.44, 144.56, 148.60, 149.20, 161.20, 162.89 ppm (Ar-C, CO, and CN); MS (EI) m/z (%): 379 (M+ + 1, 20.54), 378 (M+, 100); HRMS (EI): m/z calcd for C20H18N4O4 (M+) 378.1322; found, 378.1322.

7-Amino-6-cyano-5-p-tolylpyrazolo[1,5-a]pyridine-2,3-dicarboxylic Acid Diethyl Ester (5h)

Recrystallized from acetonitrile as yellowish white crystals; yield: 3.5 g (89%); m.p. 175–176 °C; IR (KBr) ν (cm–1): 3416, 3311 (NH2), 2219 (CN), 1740, 1698 (2CO); 1H NMR (DMSO-d6, δ): 1.21 (t, J = 7.2 Hz, 3H, CHCH2), 1.30 (t, J = 7.2 Hz, 3H, CHCH2), 2.33(s, 3H, CH3), 4.20 (q, 2H, J = 7.2 Hz, CH3CH), 4.36 (q, 2H, J = 7.2 Hz, CH3CH), 7.11 (s, 1H, pyridine H4), 7.28 (d, J = 8.4 Hz, 2H, Ar-H), 7.40 (d, J = 8.4 Hz, 2H, Ar-H), 8.23 ppm (brs, 2H, NH2); 13C NMR (DMSO-d6, δ): 14.26, 14.42, 21.19 (3CH3), 60.87, 62.76 (2CH2), 77.31 (pyridine C6), 102.20, 104.01, 116.66, 128.59, 129.70, 134.51, 139.60, 141.87, 144.87, 148.89, 149.55, 161.73, 162.35 ppm (Ar-C and CN); MS (EI) m/z (%): 393 (M+ + 1, 25.12), 392 (M+, 100); HRMS (EI): m/z calcd for C21H20N4O4 (M+) 392.1479; found, 392.1479.

7-Amino-6-cyano-5-(4-methoxyphenyl)pyrazolo[1,5-a]pyridine-2,3-dicarboxylic Acid Diethyl Ester (5i)

Recrystallized from acetonitrile as creamy white crystals; yield: 3.7 g (91%); mp 204–205 °C; IR (KBr) ν (cm–1): 3400, 3308 (NH2), 2220 (CN), 1739, 1712 (2CO); 1H NMR (DMSO-d6, δ): 1.27 (t, J = 7.2 Hz, 3H, CHCH2), 1.35 (t, J = 7.2 Hz, 3H, CHCH2), 3.84 (s, 3H, OCH), 4.27 (q, 2H, J = 7.2 Hz, CH3CH), 4.40 (q, 2H, J = 7.2 Hz, CH3CH), 7.10 (d, J = 8.8 Hz, 2H, Ar-H), 7.16 (s, 1H, pyridine H4), 7.56 (d, J = 8.8 Hz, 2H, Ar-H), 8.41 ppm (s, 2H, NH2); 13C NMR (DMSO-d6, δ): 13.90, 14.08 (2CH3), 55.30 (OCH3), 60.21, 62.07 (2CH2), 76.90 (pyridine C6), 101.51, 103.24, 114.13, 116.30, 129.32, 129.79, 141.50, 144.30, 148.57, 149.19, 160.13, 161.20, 162.90 ppm (Ar-C and CN); MS (EI) m/z (%): 409 (M+ + 1, 23.84), 408 (M+, 100); HRMS (EI): m/z calcd. for C21H20N4O5 (M+) 408.1428; found, 408.1429. Crystal data, moiety formula: C21H20N4O5, M = 408.41, monoclinic, a = 11.251(2) Å, b = 10.026(2) Å, c = 17.905(4) Å, V = 2019.7(7) Å3, α = γ = 90°, β = 90.013(7)°, space group P21/n, Z = 4, Dcalc = 1.343 g·cm–3, no. of reflection measured, 10,853, θmax = 50.0°, R1 = 0.0518 (CCDC 1889193).[32]

7-Amino-5-(4-chlorophenyl)-6-cyanopyrazolo[1,5-a]pyridine-2,3-dicarboxylic Acid Diethyl Ester (5j)

Recrystallized from acetonitrile as canary yellow crystals; yield: 3.9 g (94%); mp 217–218 °C; IR (KBr) ν (cm–1): 3457, 3317 (NH2), 2219 (CN), 1739, 1708 (2CO); 1H NMR (DMSO-d6, δ): 1.27 (t, J = 7.2 Hz, 3H, CHCH2), 1.35 (t, J = 7.2 Hz, 3H, CHCH2), 4.27 (q, 2H, J = 7.2 Hz, CH3CH), 4.41 (q, 2H, J = 7.2 Hz, CH3CH), 7.18 (s, 1H, pyridine H4), 7.63–7.64 (m, 4H, Ar-H), 8.53 ppm (s, 2H, NH2); 13C NMR (DMSO-d6, δ): 13.94, 14.11 (2CH3), 60.34, 62.16 (2CH2), 76.70 (pyridine C6), 102.04, 103.74, 116.06, 128.78, 130.32, 134.26, 136.07, 141.40, 143.24, 148.60, 149.21, 161.17, 162.86 ppm (Ar-C and CN); MS (EI) m/z (%): 414 (M+ + 2, 41.56), 413 (M+ + 1, 25.14), 412 (M+, 100); HRMS (EI): m/z calcd for C20H17ClN4O4 (M+) 412.0932; found, 412.0932. Crystal data, moiety formula: C20H17ClN4O4, M = 412.83, triclinic, a = 7.155(2) Å, b = 15.769(3) Å, c = 19.040(4) Å, V = 1953.3(6) Å3, α = 66.725(5)°, β = 83.623(6)°, γ = 82.812(6)°, space group P1, Z = 4, Dcalc = 1.404 g·cm–3, no. of reflection measured, 15,634, θmax = 50.7°, R1 = 0.0927 (CCDC 1889194).[32]

7-Amino-5-(4-bromophenyl)-6-cyanopyrazolo[1,5-a]pyridine-2,3-dicarboxylic Acid Diethyl Ester (5k)

Recrystallized from acetonitrile as orange crystals; yield: 4.2 g (92%); mp 205–206 °C; IR (KBr) ν (cm–1): 3455, 3316 (NH2), 2218 (CN), 1737, 1707 (2CO); 1H NMR (DMSO-d6, δ): 1.27 (t, J = 7.2 Hz, 3H, CHCH2), 1.35 (t, J = 7.2 Hz, 3H, CHCH2), 4.27 (q, 2H, J = 7.2 Hz, CH3CH), 4.41 (q, 2H, J = 7.2 Hz, CH3CH), 7.19 (s, 1H, pyridine H4), 7.57 (d, J = 8.4 Hz, 2H, Ar-H), 7.76 (d, J = 8.4 Hz, 2H, Ar-H), 8.51 ppm (s, 2H, NH2); 13C NMR (DMSO-d6, δ): 13.89, 14.07 (2CH3), 60.30, 62.11 (2CH2), 76.59 (pyridine C6), 101.99, 103.62, 115.99, 122.89, 130.53, 131.68, 136.41, 141.35, 143.28, 148.55, 149.17, 161.13, 162.79 ppm (Ar-C and CN); MS (EI) m/z (%): 458 (M+ + 2, 98.05), 457 (M+ + 1, 26.87), 456 (M+, 100); HRMS (EI): m/z calcd for C20H17BrN4O4 (M+) 456.0427; found, 456.0426.

7-Amino-6-cyano-5-(4-nitrophenyl)pyrazolo[1,5-a]pyridine-2,3-dicarboxylic Acid Diethyl Ester (5l)

Recrystallized from acetonitrile as creamy white crystals; yield: 3.7 g (88%); mp 231–232 °C; IR (KBr) ν (cm–1): 3449, 3303 (NH2), 2221 (CN), 1747, 1703 (2CO); 1H NMR (DMSO-d6, δ): 1.27 (t, J = 7.2 Hz, 3H, CHCH2), 1.35 (t, J = 7.2 Hz, 3H, CHCH2), 4.28 (q, 2H, J = 7.2 Hz, CH3CH), 4.41 (q, 2H, J = 7.2 Hz, CH3CH), 7.25 (s, 1H, pyridine H4), 7.90 (d, J = 8.8 Hz, 2H, Ar-H), 8.39 (d, J = 8.8 Hz, 2H, Ar-H), 8.61 ppm (s, 2H, NH2); 13C NMR (DMSO-d6, δ): 13.91, 14.08 (2CH3), 60.41, 62.18 (2CH2), 76.32 (pyridine C6), 102.45, 104.10, 115.84, 123.82, 130.04, 141.23, 142.29, 143.59, 147.85, 148.63, 149.17, 161.10, 162.74 ppm (Ar-C and CN); MS (EI) m/z (%): 424 (M+ + 1, 48.26), 423 (M+, 100); HRMS (EI): m/z calcd for C20H17N5O6 (M+) 423.1173; found, 423.1173. Crystal data, moiety formula: C20H17N5O6, M = 423. 38, monoclinic, a = 14.503(1) Å, b = 19.468(2) Å, c = 7.1357(7) Å, V = 1995.7(3) Å3, α = γ = 90°, β = 97.882(6)°, space group P21/c (#14), Z = 4, Dcalc = 1.409 g·cm–3, no. of reflection measured, 11,313, 2θmax = 50.6°, R1 = 0.0822 (CCDC 1889195).[32]

7-Amino-6-cyano-5-phenylpyrazolo[1,5-a]pyridine-3-carboxylic Acid Ethyl Ester (5m)

Recrystallized from acetonitrile as creamy white crystals; yield: 2.6 g (85%); mp 211–212 °C; IR (KBr) ν (cm–1): 3431, 3397 (NH2), 2216 (CN), 1709 (CO); 1H NMR (DMSO-d6, δ): 1.30 (t, J = 7.2 Hz, 3H, CHCH2), 4.29 (q, 2H, J = 7.2 Hz, CH3CH), 7.19 (s, 1H, pyridine H4), 7.52–7.62 (m, 5H, Ar-H), 8.35 (s, 2H, NH2), 8.56 ppm (s, 1H, pyrazole H2); 13C NMR (DMSO-d6, δ): 14.35 (CH3), 59.80 (CH2), 75.68 (pyridine C6), 103.63, 104.47, 116.45, 128.39, 128.70, 129.15, 137.47, 141.21, 143.53, 145.68, 148.56, 162.32 ppm (Ar-C, CO, and CN); MS (EI) m/z (%): 307 (M+ + 1, 18.99), 306 (M+, 100); HRMS (EI): m/z calcd for C17H14N4O2 (M+) 306.1111; found, 306.1111.

7-Amino-6-cyano-5-p-tolylpyrazolo[1,5-a]pyridine-3-carboxylic Acid Ethyl Ester (5n)

Recrystallized from acetonitrile as creamy white crystals; yield: 2.8 g (88%); mp 205–206 °C; IR (KBr) ν (cm–1): 3455, 3312 (NH2), 2218 (CN), 1707 (CO); 1H NMR (DMSO-d6, δ): 1.31 (t, J = 7.2 Hz, 3H, CHCH2), 2.40 (s, 3H, CH3), 4.29 (q, 2H, J = 7.2 Hz, CH3CH), 7.18 (s, 1H, pyridine H4), 7.36 (d, J = 8.0 Hz, 2H, Ar-H), 7.50 (d, J = 8.0 Hz, 2H, Ar-H), 8.33 (s, 2H, NH2), 8.57 ppm (s, 1H, pyrazole H2); 13C NMR (DMSO-d6, δ): 14.34, 20.83 (2CH3), 59.77 (CH2), 75.70 (pyridine C6), 103.40, 104.31, 116.52, 128.27, 129.26, 134.59, 138.78, 141.25, 143.56, 145.65, 148.56, 162.33 ppm (Ar-C, CO, and CN); MS (EI) m/z (%): 321 (M+ + 1, 20.08), 320 (M+, 100); HRMS (EI): m/z calcd for C18H16N4O2 (M+) 320.1267; found, 320.1268.

7-Amino-6-cyano-5-(4-methoxyphenyl)pyrazolo[1,5-a]pyridine-3-carboxylic Acid Ethyl Ester (5o)

Recrystallized from acetonitrile as canary yellow crystals; yield: 2.9 g (87%); mp 201–202 °C; IR (KBr) ν (cm–1): 3459, 3306 (NH2), 2218 (CN), 1703 (CO); 1H NMR (DMSO-d6, δ): 1.31 (t, J = 7.2 Hz, 3H, CHCH2), 3.84 (s, 3H, OCH), 4.28 (q, 2H, J = 7.2 Hz, CH3CH), 7.09 (d, J = 8.4 Hz, 2H, Ar-H), 7.16 (s, 1H, pyridine H4), 7.54 (d, J = 8.4 Hz, 2H, Ar-H), 8.27 (s, 2H, NH2), 8.54 ppm (s, 1H, pyrazole H2); 13C NMR (DMSO-d6, δ): 14.80 (CH3), 55.76 (OCH), 60.20 (CH2), 76.23 (pyridine C6), 103.73, 104.65, 114.59, 117.07, 130.05, 130.22, 141.76, 143.75, 146.10, 149.00, 160.47, 162.80 ppm (Ar-C, CO, and CN); MS (EI) m/z (%): 337 (M+ + 1, 21.18), 336 (M+, 100); HRMS (EI): m/z calcd for C18H16N4O3 (M+) 336.1216; found, 336.1216.

7-Amino-5-(4-chlorophenyl)-6-cyanopyrazolo[1,5-a]pyridine-3-carboxylic Acid Ethyl Ester (5p)

Recrystallized from acetonitrile as white crystals; yield: 3.0 g (90%); mp 238–239 °C; IR (KBr) ν (cm–1): 3474, 3359 (NH2), 2209 (CN), 1719 (CO); 1H NMR (DMSO-d6, δ): 1.31 (t, J = 7.2 Hz, 3H, CHCH2), 4.28 (q, 2H, J = 7.2 Hz, CH3CH), 7.18 (s, 1H, pyridine H4), 7.62–764 (m, 4H, Ar-H), 8.38 (s, 2H, NH2), 8.56 ppm (s, 1H, pyrazole H2); 13C NMR (DMSO-d6, δ): 14.69 (CH3), 60.19 (CH2), 76.47 (pyridine C6), 104.62, 105.46, 116.44, 129.11, 130.61, 134.61, 136.83, 141.60, 142.49, 146.06, 148.98, 162.64 ppm (Ar-C, CO, and CN); MS (EI) m/z (%): 342 (M+ + 2, 37.81), 341 (M+ + 1, 20.98), 340 (M+, 100); HRMS (EI): m/z calcd for C17H13ClN4O2 (M+) 340.0721; found, 340.0721.

7-Amino-5-(4-bromophenyl)-6-cyanopyrazolo[1,5-a]pyridine-3-carboxylic Acid Ethyl Ester (5q)

Recrystallized from acetonitrile as white crystals; yield: 3.3 g (86%); mp 238–239 °C; IR (KBr) ν (cm–1): 3474, 3360 (NH2), 2213 (CN), 1715 (CO); 1H NMR (DMSO-d6, δ): 1.31 (t, J = 7.2 Hz, 3H, CHCH2), 4.29 (q, 2H, J = 7.2 Hz, CH3CH), 7.20 (s, 1H, pyridine H4), 7.57 (d, J = 8.4 Hz, 2H, Ar-H), 7.76 (d, J = 8.4 Hz, 2H, Ar-H), 8.40 (s, 2H, NH2), 8.59 ppm (s, 1H, pyrazole H2); 13C NMR (DMSO-d6, δ): 12.35 (CH3), 57.87 (CH2), 73.46 (pyridine C6), 101.66, 102.70, 114.35, 120.76, 128.57, 129.70, 134.69, 139.16, 140.30, 143.73, 146.56, 160.32 ppm (Ar-C, CO, and CN); MS (EI) m/z (%): 386 (M+ + 2, 97.12), 385 (M+ + 1, 22.54), 384 (M+, 100); HRMS (EI): m/z calcd for C17H13BrN4O2 (M+) 384.0216; found, 384.0217.

7-Amino-6-cyano-5-(4-nitrophenyl)pyrazolo[1,5-a]pyridine-3-carboxylic Acid Ethyl Ester (5r)

Recrystallized from acetonitrile as canary yellow crystals and from DMSO to generate the crystals for X-ray; yield: 3.0 g (87%); mp 306–307 °C; IR (KBr) ν (cm–1): 3469, 3357 (NH2), 2214 (CN), 1722 (CO); 1H NMR (DMSO-d6, δ): 1.31 (t, J = 7.2 Hz, 3H, CHCH2), 4.29 (q, 2H, J = 7.2 Hz, CH3CH), 7.24 (s, 1H, pyridine H4), 7.89 (d, J = 8.8 Hz, 2H, Ar-H), 8.38 (d, J = 8.8 Hz, 2H, Ar-H), 8.48 (s, 2H, NH2), 8.60 ppm (s, 1H, pyrazole H2); 13C NMR (DMSO-d6, δ): 14.32 (CH3), 59.91 (CH2), 75.07 (pyridine C6), 104.09, 105.11, 116.16, 123.78, 130.00, 140.96, 141.21, 143.84, 145.72, 147.75, 148.59, 162.21 ppm (Ar-C, CO, and CN); MS (EI) m/z (%): 352 (M+ + 1, 18.76), 351 (M+, 100); HRMS (EI): m/z calcd for C17H13N5O4 (M+) 351.0962; found, 351.0962. Crystal data, moiety formula: C17H13N5O4, C2H6OS, sum formula: C19H19N5O5S, M = 429.45, monoclinic, a = 11.135(2) Å, b = 8.1060(14) Å, c = 22.476(4) Å, V = 2012.1(6) Å3, α = γ = 90°, β = 97.338(9)°, space group P121/c1, Z = 4, Dcalc = 1.418 g·cm–3, no. of reflection measured, 11,492, θmax = 66.69°, R1 = 0.0637 (CCDC 1889196).[32]

7-Amino-6-cyano-5-(thiophen-2-yl)pyrazolo[1,5-a]pyridine-3-carboxylic Acid Ethyl Ester (5s)

Recrystallized from acetonitrile as yellow crystals; yield: 2.60 g (84%); mp 225–226 °C; IR (KBr) ν (cm–1): 3435, 3323 (NH2), 2211 (CN), 1718 (CO); 1H NMR (DMSO-d6, δ): 1.33 (t, J = 7.2 Hz, 3H, CHCH2), 4.30 (q, 2H, J = 7.2 Hz, CH3CH), 7.26 (t, J = 6.6 Hz, 1H, Ar-H), 7.35 (s, 1H, pyridine H4), 7.66 (d, J = 6.6 Hz, 1H, Ar-H), 7.79 (d, J = 6.6 Hz, 1H, Ar-H), 8.37 (s, 2H, NH2), 8.56 ppm (s, 1H, pyrazole H2); 13C NMR (DMSO-d6, δ): 14.26 (CH3), 59.82 (CH2), 74.28 (pyridine C6), 102.92, 104.60, 116.58, 128.22, 128.42, 128.57, 135.20, 138.25, 141.03, 145.67, 148.88, 162.19 ppm (Ar-C, CO, and CN); MS (EI) m/z (%): 313 (M+ + 1, 27.95), 312 (M+, 100); HRMS (EI): m/z calcd for C15H12N4O2S (M+) 312.0675; found, 312.0676.

7-Amino-5-(4-chlorophenyl)-1,2,3,3a-tetrahydropyrazolo[1,5-a]pyridine-3,6-dicarbonitrile (11)

A mixture of 1-amino-2-iminopyridine derivative 3d (2.44 g, 10 mmol) and acrylonitrile (0.53 g, 10 mmol) in acetonitrile (30 mL) were heated at the refluxing temperature, and the reaction was followed up by TLC and continued for 3 h. The mixture was cooled to room temperature. The solid products that formed was filtered off, washed with cold ethanol, dried, and recrystallized from ethanol as white crystals; yield: 2.4 g (82%); mp 210–211 °C; IR (KBr) ν (cm–1): 3453, 3342, 3270 (NH2 and NH), 2242, 2166 (CN); 1H NMR (DMSO-d6, δ): 2.63–2.67 (m, 1H, pyrazole H), 3.45–3.49 (m, 1H, pyrazole H), 3.73–3.77 (m, 1H, pyrazole H), 4.32–4.34 (m, 1H, NH), 4.99 (d, J = 4.2 Hz, 1H, H-4), 5.49–5.52 (m, 1H, pyrazole H3a), 6.78 (s, 2H, NH2) 7.36 (d, J = 8.4 Hz, 2H, Ar-H), 7.45 ppm (d, J = 8.4 Hz, 2H, Ar-H); 13C NMR (DMSO-d6, δ): 38.09, 47.84, 56.67, 61.31, 101.72, 120.08, 120.83, 128.09, 129.11, 132.39, 136.04, 138.05, 158.66 ppm (Ar-C, CO, and CN); MS (EI) m/z (%): 298 (M+ + 1, 2.76), 297 (M+, 9.25); HRMS (EI): m/z calcd for C15H12N5Cl (M+) 297.0776; found, 297.0776. Crystal data, moiety formula: C15H12N5Cl, M = 297.75, monoclinic, a = 7.2408(2) Å, b = 24.7912(6) Å, c = 8.5046(2) Å, V = 1441.96(6) Å3, α = γ = 90°, β = 109.173(2)°, space group P121/c1, Z = 4, Dcalc = 1.372 g·cm–3, no. of reflection measured, 9000, θmax = 66.33°, R1 = 0.0439 (CCDC 1889197).[32]

7-Amino-5-(4-chlorophenyl)pyrazolo[1,5-a]pyridine-3,6-dicarbonitrile (12)

A solution of tetrahydropyrazolopyridine derivative 11 (1.48 g, 5 mmol) in dimethylformamide (DMF) (10 mL) was heated at the refluxing temperature for 3 h. The mixtures were cooled to room temperature and poured over ice-cold water. The solid products that formed were filtered off, washed with ethanol, dried, and recrystallized to give 12 as a pure product. Yield: 1.0 g (72%); mp 276–277 °C; IR (KBr) ν (cm–1): 3434, 3302 (NH2), 2215 (CN); 1H NMR (DMSO-d6, δ): 7.09 (s, 1H, H-4), 7.63 (d, J = 7.6 Hz, 2H, Ar-H), 7.69 (d, J = 7.6 Hz, 2H, Ar-H), 8.54 (s, 2H, NH2), 8.79 ppm (s, 1H, H-2); 13C NMR (DMSO-d6, δ): 76.03, 101.90, 113.56, 116.06, 128.58, 130.43, 134.17, 135.63, 142.65, 143.12, 146.89, 148.69, 162.24 ppm (Ar-C, CO, and CN); MS (EI) m/z (%): 294 (M+ + 1, 26.35), 293 (M+, 100); HRMS (EI): m/z calcd for C15H8N5Cl (M+) 293.0463; found, 293.0462.

General Procedure for the Preparation of Formamidine Derivatives 13a,b

Independent mixtures of pyrazolopyridines 5i,p (5 mmol) in dry toluene (20 mL) containing N,N-dimethylformamide dimethyl acetal (DMF-DMA) (0.6 mL, 5 mmol) were stirred at reflux under nitrogen for 8 h. The separated solid products obtained upon standing at room temperature were collected by filtration, washed with petroleum ether, and recrystallized from the proper solvent.

6-Cyano-7-[(dimethylamino)methyleneamino]-5-(4-methoxyphenyl)pyrazolo[1,5-a]pyridine-2,3-dicarboxylic Acid Diethyl Ester (13a)

Recrystallized from ethanol as white crystals; yield: 1.7 g (74%); mp 162–163 °C; IR (KBr) ν (cm–1): 2217 (CN), 1735, 1714 (2CO); 1H NMR (DMSO-d6, δ): 1.27 (t, J = 7.2 Hz, 3H, CHCH2), 1.34 (t, J = 7.2 Hz, 3H, CHCH2), 3.16 (s, 3H, NCH), 3.22 (s, 3H, NCH), 3.85 (s, 3H, OCH), 4.27 (q, 2H, J = 7.2 Hz, CH3CH), 4.40 (q, 2H, J = 7.2 Hz, CH3CH), 7.11 (d, J = 8.8 Hz, 2H, Ar-H), 7.44 (s, 1H, pyridine H4), 7.60 (d, J = 8.8 Hz, 2H, Ar-H), 8.84 ppm (s, 1H, amidine CH); 13C NMR (DMSO-d6, δ): 13.89, 14.10 (2CH3), 34.30, 40.61 (2CH3), 55.33 (OCH3), 60.26, 62.02 (2CH2), 89.02 (pyridine C6), 101.46, 107.84, 114.18, 117.33, 129.12, 129.90, 142.33, 143.83, 149.01, 151.66, 158.24, 160.15, 161.23, 162.92 ppm (Ar-C and CN); MS (EI) m/z (%): 464 (M+ + 1, 27.15), 463 (M+, 100); HRMS (EI): m/z calcd for C24H25N5O5 (M+) 463.1850; found, 463.1850.

5-(4-Chlorophenyl)-6-cyano-7-[(dimethylamino)methyleneamino]pyrazolo[1,5-a]pyridine-3-carboxylic Acid Ethyl Ester (13b)

Recrystallized from ethanol as white crystals; yield: 1.40 g (70%); mp 230–231 °C; IR (KBr) ν (cm–1): 2216 (CN), 1717 (CO); 1H NMR (CDCl3, δ): 1.40 (t, J = 7.2 Hz, 3H, CHCH2), 3.25 (s, 3H, NCH), 3.29 (s, 3H, NCH), 4.38 (q, 2H, J = 7.2 Hz, CH3CH), 7.26 (s, 1H, pyridine H4), 7.47 (d, J = 8.8 Hz, 2H, Ar-H), 7.57 (d, J = 8.8 Hz, 2H, Ar-H), 8.42 (s, 1H, pyrazole H2), 8.91 ppm (s, 1H, amidine CH); 13C NMR (CDCl3, δ): 14.71 (CH3), 35.19, 41.41 (2CH3), 60.48 (CH2), 88.99 (pyridine C6), 105.41, 110.12, 117.83, 129.13, 130.20, 135.54, 136.06, 142.55, 142.92, 146.32, 151.31, 157.47, 163.39 ppm (Ar-C and CN); MS (EI) m/z (%): 396 (M+ + 1, 30.85), 395 (M+, 100); HRMS (EI): m/z calcd for C20H18ClN5O2 (M+) 395.1144; found, 395.1142.

General Procedure for the Preparation of Pyrazolo[2′,3′:1,6]pyrido[2,3-d]pyrimidine Derivatives 14a,b

A solution of amidine derivatives 13a,b (2 mmol) in AcOH (10 mL) containing ammonium acetate (0.77 g, 10 mmol) was stirred at reflux for 4 h. The mixture was cooled to room temperature and poured into ice-cold water. The formed solid product was collected by filtration, washed with water, and recrystallized from EtOH/dioxane mixture (2:1) to furnish compounds 14a,b as pure products.

4-Amino-5-(4-methoxyphenyl)pyrazolo[2′,3′:1,6]pyrido[2,3-d]pyrimidine-7,8-dicarboxylic Acid Diethyl Ester (14a)

Beige crystals, yield: 0.55 g, ( 63%), mp 160–161 °C; IR (KBr) ν (cm–1): 3367, 3293 (NH2), 1733, 1712 (2CO); 1H NMR (DMSO-d6, δ): 1.27 (t, J = 7.2 Hz, 3H, CHCH2), 1.36 (t, J = 7.2 Hz, 3H, CHCH2), 3.86 (s, 3H, OCH), 4.29 (q, 2H, J = 7.2 Hz, CH3CH), 4.42 (q, 2H, J = 7.2 Hz, CH3CH), 7.16 (d, J = 8.4 Hz, 2H, Ar-H), 7.49 (d, J = 8.4 Hz, 2H, Ar-H), 7.60 (s, 1H, H-5), 5.16, 8.19 (two br, 2H, NH2), 8.59 ppm (s, 1H, H-2); 13C NMR (DMSO-d6, δ): 13.95, 14.06 (2CH3), 55.36 (OCH3), 60.47, 61.91 (2CH2), 99.95, 103.62, 114.71, 115.93, 129.65, 129.90, 139.28, 140.63, 148.09, 148.56, 157.83, 160.01, 161.27 ,161.52, 162.75 ppm (Ar-C and CN); MS (EI) m/z (%): 436 (M+ + 1, 26.55), 435 (M+, 100); HRMS (EI): m/z calcd for C22H21N5O5 (M+) 435.1537; found, 435.1537.

4-Amino-5-(4-chlorophenyl)pyrazolo[2′,3′:1,6]pyrido[2,3-d]pyrimidine-7-carboxylic Acid Ethyl Ester (14b)

Pale yellow crystals, yield: 0.45 g, ( 61%), mp 212–213 °C; IR (KBr) ν (cm–1): 3385, 3293 (NH2), 1715 (CO); 1H NMR (DMSO-d6, δ): 1.39 (t, J = 7.2 Hz, 3H, CHCH2), 4.35 (q, 2H, J = 7.2 Hz, CH3CH), 7.41 (d, J = 8.4 Hz, 2H, Ar-H), 7.51 (d, J = 8.4 Hz, 2H, Ar-H), 7.65 (s, 1H, H-5), 5.22, 8.18 (two br, 2H, NH2), 8.38 (s, 1H, H-8), 8.65 ppm (s, 1H, H-2); 13C NMR (DMSO-d6, δ): 14.05 (CH3), 60.42 (CH2), 99.83, 104.01, 111.25, 116.98, 129.24, 130.87, 135.77, 136.17, 142.28, 143.02, 146.52, 151.35, 157.88, and 163.62 ppm (Ar-C and CN); MS (EI) m/z (%): 368 (M+ + 1, 27.85), 367 (M+, 100); HRMS (EI): m/z calcd for C18H14ClN5O2 (M+) 367.0831; found, 367.0830.