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Abstract

The synthesis of spiro[chromeno[4,3-b]pyrazolo[4,3-e]pyridine-7,3ʹ-indoline]s is achieved via three-component reactions of 5-amino-3-methylpyrazole, 4-aminocoumarin, and isatin derivatives. This protocol provides expedient synthesis of 10-unsubstituted derivatives of the parent heterocyclic spiro framework and does not lead to coumarin ring opening. The synthesis is highly convergent as no by-products are present in the reaction mixtures. The spiro products show violet fluorescence emissions depending on the nature of their substituents.

Keywords

homogeneous catalysis sonochemistry spirooxindoles substituent-directed synthesis pyrazolopyridine

Introduction

Multicomponent reactions (MCRs) are very convenient and rapid approaches to complex molecules from three or more simple starting materials compared to multi-step conventional methods.¹ Owing to being performed in one pot and avoiding unnecessary workup steps, MCRs are associated with advantages such as the flexibility to deliver diverse products simply by changing the reacting components, atom economy, and less requirements for solvents or other reagents.^2–6 Therefore, the development of MCRs is an important strategy to fulfill the demands of green chemistry in organic synthesis. As a continuation of our ongoing program toward the development of multicomponent synthetic methods,^7–10 herein, we introduce an efficient route to the synthesis of several novel spiro[chromeno[4,3-b]pyrazolo[4,3-e]pyridine-7,3ʹ-indoline]s. The products consist of an oxindole moiety spiro-fused to a 1,4-dihydropyridine core, which itself is fused on two sides with 1H-pyrazole and coumarin ring systems. Pyrazolopyridine is a privileged heterocyclic core existing in many synthetic compounds exhibiting inhibition of enterovirus replication¹¹ and angiogenesis,¹² and shows potential for the treatment of autoimmune diseases and leukocyte malignancies via PI3K inhibition.¹³ Pyrazolopyridine-based compounds have also shown antileishmanial,¹⁴ antimicrobial, antiquorum-sensing, and antitumor activities.¹⁵ On the other hand, pyridocoumarin is the common scaffold of many compounds exhibiting a broad spectrum of diverse pharmaceutical properties, including antitumor, antimalarial, antiviral, central nervous system (CNS) depressant, antimicrobial, and anti-inflammatory activities.¹⁶ Moreover, they have shown photochemical properties which are interesting for applications as luminescence intensifiers¹⁷ and laser dyestuffs.¹⁸ Therefore, synthetic methods that allow the merging of these valuable pharmacophoric heterocyclic elements into a spiro-oxindole structural architecture would be helpful in the discovery of drug-like lead compounds. Spiro-oxindoles are common in natural alkaloids (horsfiline),¹⁹ mammalian cell cycle inhibitors (spirotryprostatins A and B),²⁰ and in many synthetic drugs and drug-like compounds exhibiting diverse pharmacological activities.²¹ Hence, significant efforts have been devoted to their synthesis.^21–29 Bazgir et al.³⁰ were the first to attempt the synthesis of spiro[chromeno[4,3-b]pyrazolo[4,3-e]pyridine-7,3ʹ-indoline]s in water using p-toluenesulfonic acid (p-TSA) as the catalyst. However, their method based on the three-component reaction of 4-hydroxycoumarin, isatins, and 5-amino-3-methylpyrazole did not give the target product due to unexpected cyclization of the key reaction intermediate leading to aminopyrazole-mediated coumarin ring opening (Scheme 1(a)). Several years later, Choudhury et al.³¹ succeeded to synthesize spiro[chromeno[4,3-b]pyrazolo[4,3-e]pyridine-7,3’-indoline]s from the same combination of substrates, however, under the drastic conditions of microwave heating at 130^oC in acetic acid. They showed that the efficiency of their method significantly depends on the solvent of reaction. Recently, we developed a reliable route to spiro[chromeno[4,3-b]pyrazolo[4,3-e]pyridine-7,3ʹ-indoline]s via the three-component reaction of 4-aminocoumarin, isatins, and 1-phenyl-1H-pyrazol-5(4H)-ones, in which the cyclization of the key intermediate proceeded through cyclocondensation of the coumarin-bound amino group and the pyrazolone ring.⁷ Based on this success, we aimed at modifying Bazgir’s route by replacing 4-hydroxycoumarin with 4-aminocoumarin to synthesize 10-unsubstituted spiro[chromeno[4,3-b]pyrazolo[4,3-e]pyridine-7,3ʹ-indoline]s (Scheme 1(b)). Here, we describe the efficiency of the modified synthetic approach under two sets of optimized conditions.

Scheme 1.

Derivatization-directed synthesis of spiro[chromeno[4,3-b]pyrazolo[4,3-e]pyridine-7,3ʹ-indoline]s (part b) versus the previously reported formation of spiro[indoline-3,4ʹ-pyrazolo[3,4-b]pyridine]s (part a).

Results and discussion

We planned to examine our protocol on the model synthe-sis of spiro[chromeno[4,3-b]pyrazolo[4,3-e]pyridine-7,3ʹ-indoline] 4a via the reaction of 4-aminocoumarin (1), isatin (2a), and 5-amino-3-methylpyrazole (3). Initial tests of the model reaction in some common solvents and in the presence of p-TSA were encouraging but gave poor yields of the product 4a (Table 1, entries 2–5). However, the best results in terms of yield and reaction time were obtained by performing the model reaction in ethyl alcohol (EtOH) at 80 °C (entry 6). The viability of the model reaction was also examined in the presence of different organic bases and other acids. In contrast to p-TSA, the applied Lewis acid (entry 11) and tertiary amines (entries 12 and 13) gave low or trace yields in EtOH. Of note is the acidic salt, 1-methyl-3-sulfonylimidazolium chloride ([MSIm]Cl), which despite having a structure similar to p-TSA and liquefaction at the reaction temperature (80 °C), gave only a moderate yield in EtOH (entry 8) and a trace amount of 4a under solvent-free conditions (entry 9) within comparable reaction times. Therefore, it is reasonable to rationalize the catalytic efficiency of p-TSA.H₂O in terms of its acidic character, enabling it to activate isatin and other intermediate electrophilic species toward nucleophilic addition reactions. That is, the synthetic reaction appears to proceed via a proton catalysis pathway giving better yields in the ethanol/acid solution.

Table 1.

Optimization of the model three-component reaction.


Entry^a	Solvent	Catalyst	Time (h)	Yield (%)^b
1	–	p-TSA (10 mol%)	3	Trace^c
2	CH₃CN	p-TSA (10 mol%)	3	33
3	CCl₄	p-TSA (10 mol%)	3	25
4	H₂O	p-TSA (10 mol%)	3	59
5	EtOH_aq 50%	p-TSA (10 mol%)	3	72
6	EtOH	p-TSA (10 mol%)	2	84
7	EtOH	p-TSA (20 mol%)	2	84
8	EtOH	[MSIm]Cl (10 mol%)	3	68
9	–	[MSIm]Cl (10 mol%)	3	Trace^c
10	–	LiClO₄ (10 mol%)	3	Trace^c
11	EtOH	LiClO₄ (10 mol%)	3	19
12	EtOH	DABCO	3	Trace^c
13	EtOH	Et₃N	3	Trace^c

EtOH: ethyl alcohol; p-TSA: p-toluenesulfonic acid; [MSIm]Cl: 1-methyl-3-sulfonylimidazolium chloride; DABCO: 1,4-diazabicyclo[2.2.2]octane. The parameters of the bold entry (6) were identified optimal.

With 1 mmol of each reactant at 80 °C in 3 mL of solvent (if present).

Isolated yields.

Mostly two-component products were formed.

Further advancements in terms of yield and reaction time were realized by performing the three-component reaction under sonication. As shown in Table 2, a remarkable reduction in reaction time along with an increase in the yield of product 4a was achieved by performing the model three-component synthesis under sonication in the acidic ethanol.

Table 2.

Further optimization of the model synthesis of 4a under sonication.

Entry^a	solvent	Catalyst (10 mol%)	Temperature (°C)^b	Yield (%)^c
1	EtOH	none	80	Trace
2	EtOH	p-TSA	80	88
3	EtOH	p-TSA	60	73
4	EtOH	p-TSA	50	61
5	H₂O	p-TSA	80	68
6	H₂O	p-TSA	60	39

EtOH: ethyl alcohol; p-TSA: p-toluenesulfonic acid.

Reaction conditions: 1 mmol of each reactant and 4 mL of solvent, 10 min.

Temperature of the sonication bath.

Isolated yields.

It is evident from Table 2 that sonication remarkably promotes the model synthesis in an ethanolic solution of p-TSA at 80 °C (entry 2). This fact can be ascribed to the occurrence of ultrasound-induced cavitations. Collapse of the micro-bubbles generated at locations of these cavitations creates local high temperature and high pressure spots within which the key energy-demanding step-reactions and those associated with negative entropy changes become more feasible.

After optimizing the reaction conditions, we set out to synthesize a set of spiro[chromeno[4,3-b]pyrazolo[4,3-e]pyridine-7,3ʹ-indoline]s 4 via the reaction of isatin derivatives with 4-aminocoumarin and 5-amino-3-methylpyrazole. See the Supplemental Materials for the (NMR and Mass) spectra of the products and their selected physical data. As Table 3 shows, different substituted isatins were used in this synthetic route to yield the desired spiro-products 4a–f. The reaction tolerates various substituents on the aromatic ring of the isatin to give fairly high yields of the corresponding products. However, our attempts to extend the scope of the reactants by using 6-aminouracils in place of 4-aminocoumarin proved unsuccessful.

Table 3.

Synthesis of products 4a–f under the optimized conditions.


Product	X	Under sonication^a	Classical heating^a
Product	X	Yield (%)^b	Yield (%)^b
4a	H	88	84
4b	Cl	86	83
4c	Br	85	79
4d	NO₂	84	81
4e	OCH₃	81	77
4f	F	88	82

p-TSA: p-toluenesulfonic acid.

With 1 mmol of each reactant in ethanol (4 mL) and p-TSA·H₂O (0.1 mmol), at 80 °C; 10 min for sonication or 2 h for classical heating.

Yields of isolated products.

A plausible cascade of reactions resulting in the formation of product 4 is outlined in Scheme 2. Possibly, the synthesis proceeds by two alternative pathways, namely, A and B, which converge at the formation of the product 4. Each path involves the condensation of isatin with one of the two amino components and nucleophilic addition of the resulting condensates with the other amino compound. Condensation of isatin (2) with 4-aminocoumarin (1) (path A) or 5-amino-3-methylpyrazole (3) (path B) leads to formation of the intermediates 6 and 5, respectively. The intermediates 6 and 5 then undergo nucleophilic addition at their reactive imino groups with, respectively, 5-amino-3-methylpyrazole (3) (path A) and 4-aminocoumarin (1) (path B) to give the adducts 7 and 8. These adducts immediately undergo a [3,3]-sigmatropic rearrangement, followed by liberation of ammonia via a cyclocondensation reaction to form a dihydropyridine ring, which subsequently tautomerizes to give the product 4. It is worth noting that no product other than 4 was resolved from the reaction mixtures. This observation implies that the condensation of isatin with one of the amino components (likely 3, according to thin layer chromatography (TLC) monitoring) is much faster than with the other. Moreover, unlike in Bazgir’s experiments, the coumarin ring remains intact in this route. The chemoselectivity of this synthesis lies in the greater reactivity of the intermediate imino groups compared with the lactone ring of the coumarin toward nucleophilic attack of the amino group.

Scheme 2.

A plausible mechanism for the formation of the spiro-product 4.

Scheme 3 illustrates the key steps suspected to control the kinetics of path B. As can be seen, these representative reaction steps, involving the formation of intermediate 5 and its nucleophilic addition with 4-aminocoumarin, are associated with protonation of the electrophilic carbonyl and imine groups. Of these reaction steps with the two enamine components (3 and 1), the first step occurs at the C-terminus of 3 to give the thermodynamic product 5 and is expected to be slower than the formation of 7 that proceeds via the kinetically more favored addition of 1 at its N-terminus onto the imino group of 5.

Scheme 3.

The key steps of the p-TSA-mediated catalysis of the reaction.

Interestingly, the products 4a–f show broad fluorescence emissions with peaks close to 428 nm. As can be seen in Figure 1, no significant shifts of the emission peak occurred due to the nature of the substituents on the oxindole moiety, except for compound 4e, which showed a dual emissive behavior by exhibiting an emission maximum at 498 nm in addition to a broad emission hump at 428 nm. The 70-nm red-shifted emission peak can be attributed to involvement of the MeO group in an additional local excited state of 4e. However, all the oxindole substituents show considerable effects on the intensity of the fluorescence peak at 428 nm. Compounds 4c and 4d, due to quenching effects of their Br and NO₂ substituents, displayed the minimum emission intensities. It is well known that fluorescence emissions can be quenched by nitroaromatics³² and that the intensity of fluorescence largely diminishes according to the so-called internal heavy atom effect. Substitution of heavy atoms such as Br on aromatic molecules usually results in fluorescence quenching due to the increased probability of radiationless transitions (intersystem crossing). The efficiency of this effect is favored by spin-orbit coupling and directly depends on the atomic number of the substituent atom by a power of 4.³³

Figure 1.

The fluorescence spectra of 4a–f as solutions (5 × 10⁻⁴ M) in DMSO. The slit width was set to 4 nm and the molecules were excited at 348 nm.

Conclusion

Novel 10-unsubstituted spiro[chromeno[4,3-b]pyrazolo[4,3-e]pyridine-7,3ʹ-indoline]s 4a–f have been synthesized for the first time via a domino reaction of 4-aminocoumarin, 5-amino-3-methylpyrazole, and isatin derivatives under acid catalysis using p-TSA in ethanol. Further investigations showed that a remarkable reduction in reaction time and increased yields were obtained by performing the reactions under sonication. Noteworthy, unlike in previous reports,^30,31 the present protocol does not furnish any product resulting from coumarin ring opening and gives fairly high yields of the desired products under mild conditions and in shorter times. The products have shown low to relatively high fluorescence emissions depending on the nature of the substituent on the aromatic ring of the oxindole moiety.

Experimental

Typical procedure for the synthesis of 4a under sonication

A mixture of isatin (2) (0.147 g, 1 mmol), 5-amino-3-methylpyrazole (3) (0.097 g, 1 mmol), 4-aminocoumarin (1) (0.161 g, 1 mmol), and p-TSA monohydrate (0.1 mmol, 0.02 g) was added to a flask (25 mL) containing ethanol 95% (5 mL). The flask was equipped with an air-cooled condenser, placed in a preheated sonication bath (80 °C), and sonicated until completion of the reaction (monitored by TLC on silica gel using a 1:1 mixture of ethyl acetate/n-hexane). At this stage, the reaction mixture was kept at 5 °C in a refrigerator for about 4 h, and the virtually pure creamy powder precipitate of the product was collected by filtration, washed with cold ethanol (95%, 2 mL), and dried at 50 °C to give 4a in 88% (0.327 g) yield.

8-Methyl-10,11-dihydro-6H-spiro[chromeno[4,3-b]pyrazolo[4,3-e]pyridine-7,3′-indoline]-2′,6-dione (4a)

Creamy powder (0.327 g, 88%), m.p.: 357–359 °C. IR (KBr): 3360, 3307, 3217, 3120, 3069, 2816, 1699, 1614, 1556, 1508, 1468, 1325, 1223, 1114, 1069, 759 cm⁻¹.¹H NMR (400 MHz, DMSO-d₆): δ 12.24 (1H, s, NH), 10.82 (1H, s, NH), 10.5 (1H, s, NH), 8.42 (1H, d, J = 7.6 Hz, 10–H), 7.66 (1H, dt, J = 7.8 and 1.2 Hz), 7.43 (1H, t, J = 7.2 Hz), 7.38 (1H, dd, J = 8.4 and 0.8 Hz), 7.15 (1H, dt, J = 7.6 and 1.2 Hz), 6.93–6.84 (3H, m), 1.64 (3H, s, CH₃).¹³C NMR (100 MHz, DMSO-d₆): δ 8.6 (CH₃), 48.9 (C_spiro), 94.8, 100.1, 108.8, 113.6, 116.7, 121.7, 123.2, 123.3, 124.0, 127.6, 132.2, 134.6, 136.5, 141.6, 145.6, 146.1, 152.0, 159.5 (CO), 179.0 (CO). MS (EI, 70 eV): m/z = 370 (M⁺, 5), 368 (M–2, 11), 246 (6), 236 (10), 152 (7), 123 (13), 111 (14), 97 (40), 83 (55), 69 (76), 57 (96), 43 (100). Anal. calcd for C₂₁H₁₄N₄O₃ (370.36): C, 68.10; H, 3.81; N, 15.13; found: C, 67.93; H, 3.92; N, 15.19.

Supplemental Material

Electronic_supporting_Information – Supplemental material for A derivatization-directed three-component synthesis of fluorescent spiro [dihydropyridine-4,3ʹ-indoline]s

Supplemental material, Electronic_supporting_Information for A derivatization-directed three-component synthesis of fluorescent spiro [dihydropyridine-4,3ʹ-indoline]s by Faranak Najafizadeh, Kurosh Rad-Moghadam and Soraya Yaghoubi Kalurazi in Journal of Chemical Research

Footnotes

Acknowledgements

Support of this work from the Research Council of University of Guilan is gratefully acknowledged.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Kurosh Rad-Moghadam

Supplemental material

Supplemental material for this article is available online.

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