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Article

K2CO3-Promoted Formal [3+3]-Cycloaddition of N-Unsubstituted Isatin N,N′-Cyclic Azomethine Imine 1,3-Dipoles with Knoevenagel Adducts

by
Guosheng Yang
1,†,
Sicheng Li
2,†,
Qiumi Wang
1,†,
Huabao Chen
3,
Chunping Yang
3,
Zhongqiong Yin
4,
Xu Song
4,
Li Zhang
1,
Cuifen Lu
5 and
Guizhou Yue
1,*
1
College of Science, Sichuan Agricultural University, Ya’an 625014, China
2
The Yingjing County Emergency Management Agency, Ya’an 625200, China
3
College of Agronomy, Sichuan Agricultural University, Chengdu 611130, China
4
College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
5
Hubei Collaborative Innovation Center for Advanced Organochemical Materials & Ministry-of-Education Key Laboratory for the Synthesis and Application of Organic Functional Molecules, Hubei University, Wuhan 430062, China
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Molecules 2023, 28(3), 1034; https://doi.org/10.3390/molecules28031034
Submission received: 27 December 2022 / Revised: 13 January 2023 / Accepted: 17 January 2023 / Published: 19 January 2023
(This article belongs to the Special Issue Chemistry of Nitrogen Heterocyclic Compounds)
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Abstract

:
The synthesis of dicyclic spiropyridazine oxoindole derivatives by using [3+3]-cycloaddition of N-unsubstituted isatin N,N′-cyclic azomethine imine 1,3-dipoles was reported. The products bearing two consecutive stereocenters, including spiroquaternary stereocenters in one ring structure, can be effectively obtained in moderate to excellent yields (20–93%) and low to moderate diastereoselectivities (1:9–10:1 dr). The synthesized compounds (>35 examples) were characterized by single-crystal XRD, FTIR, NMR, and mass spectral analysis.

1. Introduction

Heterocycles are common structural units that are widely found in natural products, pharmaceuticals, and agrochemicals [1]. In particular, dinitrogen-fused heterocycles are the core moieties in many biologically active compounds. The N,N-bicyclic pyridazinylpyrazolidinone skeletons are structurally interesting, and have been investigated as a herbicide CGA 271,312 (I) [2], camptothecin mimics (II) as a DNA topoisomerase (Top1) inhibitor [3], a potent drug to inhibit acetyl-CoA carboxylase (ACC) (III) [4], and β-sheet mimetic as a protease inhibitor (IV) [5] (Figure 1). Therefore, the exploration of practical and efficient methods for the synthesis of dinitrogen-fused heterocycles has attracted extensive attention in the field of organic chemistry and pharmacology. Various methods for the construction of N,N-bicyclic pyridazinylpyrazolidinone skeletons have been reported, including the double acylation of pyrazolidine [2]; the double alkylation of pyrazolidinone [4] and indazole [6]; the annulation by Rh-catalyzed C-H activation [7,8]; Rh-catalyzed [4+1] cyclization of N-arylphthalazine-1,4-dione with 2-diazo carbonyl compounds [9] or vinylene carbonate [10]; and the cycloaddition of 1,3-dipolar azomethine imines with various partners [11,12,13]. There is no doubt that the [3+3]-cycloaddition of azomethine imines with various dipolarophile precursors is one of the most popular methods in various protocols (Scheme 1).
Very recently, Moghaddam and co-workers [14] reported an unexpected abnormal tandem Michael addition/N-cyclization of isatin N,N′-cyclic azomethine imine 1,3-dipole with 2-arylidenemalononitriles for the synthesis of spiropyridazine oxindoles with good yields (77–91%) and excellent diastereoselectivities (>20:1 dr), under the condition of DABCO as the base and DCM as the solvent at room temperature (Scheme 1). However, the result of the reaction of N-unsubstituted isatin N,N′-cyclic azomethine imines with 2-arylidenemalononitriles was not exhibited under their optimal condition in this work. We found that the desired products of the reaction of N-unsubstituted isatin N,N′-cyclic azomethine imines with 2-benzylidenemalononitrile were not observed in the above optimal condition, even under reflux conditions (Table 1, Entry 1).
To date, the reactions of isatin N,N′-cyclic azomethine imines have rarely been studied and demonstrated by a few examples [15,16,17,18,19,20,21,22,23,24,25,26,27,28]. So, it is urgent to explore the new 1,3-dipolar cycloaddition of isatin N,N′-cyclic azomethine imines. Knoevenagel adducts, easily prepared from aromatic aldehydes and malononitrile in the presence of a base, were valuable substrates for various types of reactions such as Michael addition, cycloaddition reaction, reductive reaction, domino reaction, etc. [29,30,31,32,33,34,35,36,37]. Although the above work is excellent, it is still necessary to further expand the reaction range of istain N,N′-cyclic azomethine imines by using N-unsubstituted azomethine imines and 2-arylidenemalononitriles. Based on our previous studies of the reactions of azomethine imines and ylides 1,3-dipoles [38,39,40,41,42,43,44,45], herein we report the synthesis of spiropyridazinylpyrazolidinone oxoindole derivatives via the K2CO3-promoted formal [3+3]-cycloaddition of N-unsubstituted isatin N,N′-cyclic azomethine imines with Knoevenagel adducts under the condition of the DCE as the solvent at reflux.

2. Results and Discussion

At the beginning of our study, N-unsubstituted isatin N,N′-cyclic azomethine imine 1a and 2-benzylidenemalononitrile 2a were chosen as model substrates to search for the reaction optimal condition (Table 1). We discovered that isatin N,N′-cyclic azomethine imine 1a could react with 2a to give the desired product in 45% yield and with 2.5:1 dr value with K2CO3 as the base in dimethylsulfoxide (DMSO) in our previous work [43]. Inspired by the above result, we decided to develop an efficient method for the synthesis of N-unsubstituted spiropyridazinylpyrazolidinone oxoindoles as an important supplement to Moghaddam’s work. Initially, we screened various solvents in the presence of 2.0 equiv. K2CO3. Except for DMSO, other aprotic polar solvents (N,N-dimethylforammide (DMF), N,N-dimethylacetamide (DMA), pyrrolidone) could improve the product yields (47–76%) (Entries 3–5), while the products could be afforded in unsatisfied results with the yields of 32% and 42%, respectively, when N-methylpyrrolidone (NMP) and hydroxylethylpyrrolidone (HEP) were chosen as the reaction solvents. We also found that the results of protic solvents (EtOH, MeOH, and H2O) and aprotic solvents (THF, ACN, dioxane, and toluene) were inferior to those of DMSO. We turned our attention to chlorinated solvents and found that DCE used as the solvent could greatly enhance the product yield (77%) and diastereoselectivity (7.2:1 dr) (Entry 17). Next, we chose DCE as a solvent and tested a variety of bases to improve the diastereoselectivity of the reaction. The results demonstrated that the inorganic base Na2CO3 provided the product with 41% yield, but no product was formed with Li2CO3 and Cs2CO3 as the bases at reflux (Entries 18 and 20). Stronger bases NaOH, KOH, MeONa, and EtONa cannot improve the product yield (Entries 21–24). Additionally, the products could be acquired with lower yields or could not be observed when common organic bases (TEA, DIPEA, DBU, and DABCO) were used. According to the above experiments, K2CO3 was an optimal base. Then, we changed the amount of base, 2-benzylidenemalononitrile, and the concentration of the reaction. We found that the yield of the product did not change significantly, but diastereoselectivities were reduced when the amount of K2CO3 was changed compared with 2.0 equivalent K2CO3 (Entries 31–36, except for Entry 34). When the amount of 2-benzylidenemalononitrile 2a was added up to 2.2–3.3 equivalent, all the yields were greatly increased, but the diastereoselectivities dropped off (Entries 37–39). Finally, the concentration of the reaction had little effect on yields and selectivities (Entries 40–41). The optimal reaction condition for 1,3-dipolar cycloaddition was established, and the desired product could be obtained in 77% yield and 7.2:1 dr value when using isatin N,N′-cyclic azomethine imine 1a (1 equiv.), 2-benzylidenemalononitrile 2a (1.1 equiv.), and K2CO3 (2.0 equiv.) as the solvent in DCE at reflux for 1.8 h (Entry 17).
After the optimal reaction condition was established, a wide scope of different substituted 2-benzylidenemalononitrile 2 was explored for this [3+3]-cycloaddition. As outlined in Table 2, various substituted groups on the phenyl ring of 2 could be tolerated, with the desired products afforded in low to excellent yields (26–89%) and low to moderate diastereoselectivities (1.6:1–10:1 dr) (Table 2, Entries 2–23). The reaction of 1a with 2a could be carried out at 1.0 mmol scale, with the product obtained in 86% yield with a 6.3:1 dr value under the optimal reaction condition.
It is worth mentioning that the progress of the reaction was monitored by TLC with visible light, UV, ninhydrin, and the color change of the reaction solution (Figure 2). Substrate 2 bearing electron-donating or electron-withdrawing groups led to inferior results in contrast with 2a. The position of substituents on the benzene ring had a great impact on the yields, and the 2-substituted phenyl ring of 2a usually gave the best yields (Entries 2, 5, 8, and 11), except for 2-BrPh (Entry 14). It was regrettable that isomers 3 and 3′ were not separated by column chromatography. Fortunately, in most reactions, a single isomer with sufficient purity can be obtained by using EtOH recrystallization, which can be characterized by different spectroscopic techniques, such as FTIR, 1H and 13C NMR, and mass spectrometry (see Supplementary Materials).
Subsequently, various substituents on the benzene ring of isatin N,N′-cyclic azomethine imines can also be well tolerated, which further proves the universality of the cycloaddition reaction. Unfortunately, the diastereoselectivities (3.3:1–1:2 dr) of the desired product with electron-donating groups (5-Me, 5-OMe) or electron-withdrawing groups (5-F, 5-Cl, 6-Br, 5-I, 5-NO2, and 7-CF3) on the benzene ring of the compound 1 was lower than that of the model reaction, as shown in Table 3. The reaction of 5-methyl isatin N,N′-cyclic azomethine imine was scaled up to 5.0 mmol, and the products 4a/4′a could be obtained in 75% yield. The structure of 4a was clearly confirmed by single-crystal X-ray diffraction (Figure 3) [46]. The strong electron-drawing group NO2 significantly impacted the product yield (Entry 7). The 4g/4′g was only obtained in 20% yield with 2.5:1 dr under the optimal reaction condition (Table 1, Entry 18) and obtained in 40% yield with 1:1.4 dr under the suboptimal condition (Table 1, Entry 38), while 7-trifluoromethylisatin N,N′-cyclic azomethine imine led to a satisfying yield of 74% with 1.6:1 dr (Entry 8). To our delight, the single isomers 4 could also be obtained through the recrystallization from EtOH in all reactions except for 4a/4′a and 4h/4′h.
To expand the application scope of the reaction, α-methyl isatin N,N′-cyclic azomethine imines 1 reacted with 2 in the standard condition to afford cycloadducts 5/5′ in 58–93% yields with 1.3:1–2.8:1 dr under the optimal condition (Table 4). However, only a trace amount of desired products could be observed when the R2 group of isatin N,N′-cyclic azomethine imines was replaced by methyl or phenyl (Entries 8 and 9). In most reactions, the single isomers 5a, 5d, 5e, and 5f were also afforded by recrystallization from EtOH.
The dicyclic spiropyridazine oxoindole product exhibited potentially wide application in organic synthesis (Scheme 2). For example, the N-allylation of 3a reacted with Morita–Baylis–Hillman carbonate to provide the compound 6 in 76% yield in the presence of DABCO. 3a reacted with Boc2O to give the N,N,N-triBoc-protected product 7 in 71% yield. The diazotization and hydrolysis of the amino group of 3′b could generate the enol 8 in 25% yield under NaNO2/p-TsOH [47]. Finally, 5a can be converted into N-acetyl product 9 with a high yield (86%).
On the basis of the literature reports [14], experimental results, and X-ray analysis, a plausible reaction pathway is proposed in Scheme 3. The intermediate I could be obtained by resonance form of the compound 1. The intermediate I was tautomerized under the condition of the base to form the delocalized intermediate II, which can be added with Knoevenagel adducts 2 through Michael addition to give the intermediate III. Subsequently, the nucleophilic addition of the nitrogen atom of the intermediate III to the cyano group could give the formal [3+3]-cycloadduct IV. The final products 3/3′, 4/4′, and 5/5′ were formed via the enamination of the imine group of the compound IV.

3. Materials and Methods

3.1. General Methods

All reactions were carried out without strict water-free and oxygen-free conditions, except for using NaH, MeONa, and EtONa as bases. All reagents and reagents were obtained from commercial suppliers and were directly used for reactions without further purification unless otherwise stated. When the reactions preformed at the condition of NaH, MeONa, and EtONa, solvent DCE was predried with CaH2. Flash chromatography was performed using silica gel (200−300 mesh). Reactions were monitored by TLC or/and color changes of the reaction solution. Visualization was achieved under a UV lamp (254 nm and 365 nm), I2, and by developing the plates with ninhydrin. 1H and 13C NMR were recorded on 400 and 600 MHz NMR spectrometers with tetramethylsilane (TMS) as the internal standard. IR spectra were acquired on an FTIR spectrometer and were reported in wavenumbers (cm−1). High-resolution mass spectra were obtained using electrospray ionization (ESI). 1H NMR splitting patterns are designated as singlet (s), broad singlet (brs), double (d), triplet (t), false triplet (ψt), quartet (q), doublet of doublets (dd), multiples (m), etc. Coupling constants (J) are reported in Hertz (Hz).

3.2. Preparation of Intermediates

Pyrazolidine-3-ones were obtained by the reaction of hydrazine monohydrate with methyl acrylate in ethanol under the refluxing condition [15]. All isatin N,N′-cyclic azomethine imines 1 were prepared by the condensation of isatins and the above pyrazolidone in menthol under 45 °C or the refluxing condition [15]. All Knoevenagel adducts 2 were prepared by a one-step reaction (0.2 equiv. KOH, 1.0 equiv. aldehyde, 1.0 equiv. malononitrile, and EtOH/H2O at room temperature for 2–3 h) [48], except for 2w (0.1 equiv. DABCO and MeOH).

3.3. General Procedure for Condition Optimization

A 10.0 mL tube was charged with isatin N,N′-cyclic azomethine imine 1a (0.5 mmol, 1.0 equiv.), Knoevenagel adduct 2a (0.55–1.65 mmol, 1.1–3.3 equiv.), base (0.5–2.0 mmol, 0.5–4.0 equiv.), and solvent (1.0–4.0 mL). The suspended solution was vigorously stirred at rt or reflux, and then the base was added. The reaction finished when the suspension reaction liquid gradually changed from red to brown and then to green. The solution was purified by flash silica gel chromatography eluted with EtOAc-petroleum ether (1:3 to 1:0) to afford the corresponding products 3a and 3′a.

3.4. General Procedure for Typical Procedure for [3+3]-Cycloaddition

A tube (25.0 mL) was charged with isatin N,N′-cyclic azomethine imine 1a (1.0 mmol, 1.0 equiv.), Knoevenagel adduct 2 (1.1 mmol, 1.1 equiv.), K2CO3 (276.4 mg, 2.0 mmol, 2.0 equiv.), and DCE (4.0 mL). The suspended solution was vigorously stirred at reflux. When the reaction mixture became clear and the color of the reaction solution changed, the reaction finished (1–18 h). The solution was purified by flash silica gel chromatography eluted with EtOAc-petroleum ether (1:3 to 1:0) to afford the corresponding cycloaddition products 3/3′, 4/4′, and 5/5′.

3.5. Synthesis of the Products 6, 7, 8, and 9

DABCO (2.2 mg, 0.2 mmol, 0.1 equiv.) was added to a solution of 3a (43 mg, 0.2 mmol, 1.0 equiv.) and ethyl 2-(((tert-butoxycarbonyl)oxy)methyl)acrylate (92 mg, 0.4 mmol, 2.0 equiv.) in DCM (3.0 mL) at rt. The mixture was stirred at rt for 5.0 h. The resulting mixture was washed with saturated NH4Cl solution (10.0 mL). The aqueous solution was extracted with EtOAc (3 × 10.0 mL). The combined organic layers were dried and concentrated. The crude product was purified by flash column chromatography on silica gel with petroleum ether-EtOAc (3:1 to 1:1) to obtain the compound 6.
Boc2O (175 mg, 0.8 mmol, 4.0 equiv.) was added to a solution of 3a (74 mg, 0.2 mmol, 1.0 equiv.) and DMAP (5.0 mg, 0.04 mmol, 0.2 equiv.) in DCM (3.0 mL) at 0 °C. The mixture was stirred at rt for 5.0 h. The resulting mixture was washed with saturated NH4Cl solution (10 mL). The aqueous solution was extracted with EtOAc (3 × 10 mL). The combined organic layers were dried and concentrated. The crude product was purified by flash column chromatography on silica gel with petroleum ether-EtOAc (3:1 to 1:1) to give the adduct 7.
To a solution of p-TsOH·H2O (114 mg, 0.6 mmol) in MeCN (1.5 mL) was added with 3′b (76 mg, 0.2 mmol. 1.0 equiv.). The resulting suspension of amine salt was cooled to 5 °C and was gradually added with a solution of NaNO2 (28 mg, 0.4 mmol) in H2O (0.2 mL). The reaction mixture was stirred for 10 min, then allowed to warm to rt. The mixture was stirred at rt for 3.0 h. The reaction mixture was then added with H2O (2.0 mL), NaHCO3 (1 M; until pH = 9–10), and Na2S2O3 (2 M, 1.0 mL). The aqueous solution was extracted with EtOAc (3 × 15.0 mL). The combined organic layers were dried and concentrated. The crude product was purified by flash column chromatography on silica gel with petroleum ether-EtOAc (2:1 to 1:2) to form the compound 8.
Ac2O (41 mg, 0.4 mmol, 2.0 equiv.) was added to a solution of 5a (76 mg, 0.2 mmol, 1.0 equiv.) and DMAP (5.0 mg, 0.04 mmol, 0.2 equiv) in DCM (3.0 mL) at 0 °C. The mixture was stirred at rt for 5.0 h. The resulting mixture was washed with saturated NH4Cl solution (10 mL). The aqueous solution was extracted with EtOAc (3 × 15.0 mL). The combined organic layers were dried and concentrated. The crude product was purified by flash column chromatography on silica gel with petroleum ether-EtOAc (3:1 to 1:1) to afford the compound 9.

3.6. Data for All New Compounds

(±)-(3R,6′R)-8′-amino-1′,2-dioxo-6′-phenyl-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (3a)
Molecules 28 01034 i001
[Reaction time: 4.0 h], 318 mg, 86%, a white solid, m.p. 214.5–216.5 °C; IR (thin film): νmax 3367, 3275, 3147, 3062, 3026, 2183, 1712, 1684, 1625, 1572, 1432, 1285, 1048, 752 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 10.40 (s, 1 H), 7.74–7.71 (m, 3 H), 7.32 (d, J = 4.0 Hz, 1 H), 7.30 (td, J = 7.6, 0.8 Hz, 1 H), 7.18–7.11 (m, 4 H), 6.97 (brs, 2 H), 6.61 (d, J = 7.6 Hz, 1 H), 5.67 (d, J = 4.0 Hz, 1 H), 4.64 (s, 1 H); 13C NMR (100 MHz, DMSO-d6): δ 171.1, 165.4, 150.2, 142.8, 142.6, 142.6, 134.7, 131.9, 130.1, 128.4, 128.2, 126.0, 123.1, 122.9, 119.6, 119.6, 110.6, 101.0, 67.4, 58.4, 46.6; HRMS (ESI): m/z calcd. for C21H15N5O2 [M + H]+ 370.1304 found 370.1380.
(±)-(3R,6′S)-8′-amino-1′,2-dioxo-6′-(o-tolyl)-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (3′b)
Molecules 28 01034 i002
[Reaction time: 2.0 h], 249 mg, 65%, a white solid, m.p. 210.3–212.1 °C; IR (thin film): νmax 3369, 3282, 3146, 3116, 3026, 2189, 1724, 1662, 1530, 1331, 1159, 1047, 758 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 10.88 (s, 1 H), 7.73 (brs, 2 H), 7.39(d, J = 4.0 Hz, 1 H), 7.31 (td, J = 7.6, 0.8 Hz, 1 H), 7.21–7.10 (m, 2 H), 7.03 (d, J = 6.8 Hz, 1 H), 6.96 (d, J = 7.6 Hz, 1 H), 6.87 (d, J = 8.0 Hz, 1 H), 6.76 (ψt, J = 7.6 Hz, 1 H), 5.83 (d, J = 7.6 Hz, 1 H), 5.62 (d, J = 4.0 Hz, 1 H), 4.28 (s, 1 H), 1.71 (s, 3 H); 13C NMR (100 MHz, DMSO-d6): δ 172.1, 165.2, 149.8, 142.7, 142.4, 138.1, 135.7, 131.6, 130.4, 128.7, 128.4, 126.4, 126.0, 122.2, 121.7, 120.0, 111.0, 100.2, 66.6, 58.3, 40.9, 19.2; HRMS (ESI): m/z calcd. forC22H17N5O2 [M + H]+ 384.1460, found 384.1468.
(±)-(3R,6′S)-8′-amino-1′,2-dioxo-6′-(m-tolyl)-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (3′c)
Molecules 28 01034 i003
[Reaction time: 4.0 h], 228 mg, 59%,a white solid, m.p. 211.1–212.9 °C; IR (thin film): νmax 3481, 3321, 3252, 3147, 2185, 1735, 1686, 1604, 1560, 1466, 1426, 1286, 1200, 1175, 762 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 10.86 (s, 1 H), 7.77–7.76 (m, 2 H), 7.62 (d, J = 4.0 Hz, 1 H), 7.24 (ψt, J = 7.6 Hz, 1 H), 7.06–7.02 (m, 2 H), 6.91 (ψt, J = 7.6 Hz, 1 H), 6.73 (d, J = 8.0 Hz, 1 H), 6.68 (brs, 2 H), 6.53 (d, J = 7.6 Hz, 1 H), 5.64 (d, J = 4.0 Hz, 1 H), 4.26 (s, 1 H), 2.13 (s, 3 H); 13C NMR (100 MHz, DMSO-d6): δ 171.1, 165.4, 150.1, 142.8, 142.6, 137.1, 134.7, 131.8, 130.8, 129.1, 128.1, 127.2, 126.0, 123.1, 122.9, 119.6, 110.6, 100.9, 67.4, 58.6, 46.5, 21.4; HRMS (ESI): m/z calcd. for C22H17N5O2 [M + H]+ 384.1460, found 384.1464.
(±)-(3R,6′R)-8′-amino-1′,2-dioxo-6′-(p-tolyl)-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (3d)
Molecules 28 01034 i004
[Reaction time: 4.0 h], 230 mg, 60%, a yellow solid, m.p. 210.5–212.5 °C; IR (thin film): νmax 3440, 3363, 3230, 3146, 2197, 1724, 1688, 1613, 1570, 1542, 1518, 1468, 1257, 1194, 752 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 10.39 (s, 1 H), 7.72 (d, J = 7.2 Hz, 1 H), 7.68 (s, 2 H), 7.32–7.28 (m, 2 H), 7.16 (ψt, J = 7.4 Hz, 1 H), 6.94 (d, J = 7.6 Hz, 2 H), 6.85 (br s, 2 H), 6.62 (d, J = 8.0 Hz, 1 H), 5.66 (d, J = 4.0 Hz, 1 H), 4.61 (s, 1 H), 2.18 (s, 3 H); 13C NMR (100 MHz, DMSO-d6): δ 171.1, 165.4, 150.1, 142.8, 142.5, 137.5, 131.8, 131.7, 130.0, 128.9, 126.0, 123.1, 123.0, 119.6, 110.7, 100.9, 67.4, 58.7, 46.2, 21.1; HRMS (ESI): m/z calcd. for C22H17N5O2 [M + H]+ 384.1460, found 384.1461.
(±)-(3R,6′R)-8′-amino-1′,2-dioxo-6′-(2-methoxyphenyl)-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (3e)
Molecules 28 01034 i005
[Reaction time: 2.0 h], 275 mg, 69%, a white solid, m.p. 238.9–240.2 °C; IR (thin film): νmax 3369, 3270, 3136, 2186, 1714, 1677, 1620, 1569, 1509, 1471, 1426, 1253, 1189, 744 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 10.39 (s, 1 H), 7.71 (d, J = 7.2 Hz, 1 H), 7.67 (s, 2 H), 7.31 (ψt, J = 7.6 Hz, 1 H), 7.30 (d, J = 4.0 Hz, 1 H), 7.16 (ψt, J = 7.6 Hz, 1 H), 6.87 (brs, 2 H), 6.69 (d, J = 8.0 Hz, 2 H), 6.63 (d, J = 7.6 Hz, 1 H), 5.66 (d, J = 4.0 Hz, 1 H), 4.60 (s, 1 H), 3.66 (s, 3 H); 13C NMR (100 MHz, DMSO-d6): δ 171.2, 165.4, 159.2, 150.0, 142.9, 142.5, 131.2, 126.4, 126.0, 123.1, 123.0, 119.6, 113.6, 100.6, 100.9, 67.4, 58.9, 55.4, 45.8; HRMS (ESI): m/z calcd. for C22H17N5O3 [M + H]+ 400.1410, found 400.1405.
(±)-(3R,6′R)-8′-amino-1′,2-dioxo-6′-(3-methoxyphenyl)-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (3f)
Molecules 28 01034 i006
[Reaction time: 7.0 h], 171 mg, 43%, a white solid, m.p. 242.5–243.9 °C; IR (thin film): νmax 3440, 3363, 3230, 3146, 2197, 1724, 1688, 1613, 1570, 1542, 1518, 1468, 1257, 1194, 752 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 10.45 (s, 1 H), 7.73 (d, J = 8.0 Hz, 1 H), 7.72 (s, 2 H), 7.34 (d, J = 4.0 Hz, 1 H), 7.32 (ψt, J = 7.6 Hz, 1 H), 7.18 (ψt, J = 7.6 Hz, 1 H), 7.06 (ψt, J = 7.6 Hz, 1 H), 6.73 (dd, J = 8.0, 2.0 Hz, 1 H), 6.63 (d, J = 7.6 Hz, 1 H), 6.53 (brs, 2 H), 5.67 (d, J = 4.0 Hz, 1 H), 4.64 (s, 1 H), 3.55 (s, 3 H); 13C NMR (100 MHz, DMSO-d6): δ 171.1, 165.4, 158.8, 150.1, 142.9, 142.6, 136.2, 131.8, 129.2, 126.0, 123.1, 122.9, 122.3, 119.6, 115.8, 113.8, 110.6, 101.0, 67.3, 58.4, 55.2, 46.5; HRMS (ESI): m/z calcd. for C22H17N5O3 [M + H]+ 400.1410, found 400.1410.
(±)-(3R,6′R)-8′-amino-1′,2-dioxo-6′-(4-methoxyphenyl)-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (3g)
Molecules 28 01034 i007
[Reaction time: 2.0 h], 263 mg, 66%, a yellow solid, m.p. 245.2–247.1 °C; IR (thin film): νmax 3684, 3987, 1710, 1694, 1573, 1383, 1267, 1128, 761 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 10.39 (s, 1 H), 7.71 (d, J = 7.6 Hz, 1 H), 7.67 (s, 2 H), 7.31 (ψt, J = 8.0 Hz, 1 H), 7.30 (d, J = 4.0 Hz, 1 H), 7.16 (ψt, J = 7.6 Hz, 1 H), 6.87 (brs, 2 H), 6.69 (d, J = 8.0 Hz, 2 H), 6.63 (d, J = 7.6 Hz, 1 H), 5.66 (d, J = 4.0 Hz, 1 H), 4.60 (s, 1 H), 3.65 (s, 3 H); 13C NMR (100 MHz, DMSO-d6): δ 171.2, 165.4, 159.2, 150.0, 142.9, 142.6, 131.8, 131.2, 126.4, 126.0, 123.1, 123.0, 119.7, 113.6, 110.7, 100.9, 67.4, 58.8, 55.4, 45.7; HRMS (ESI): m/z calcd. for C22H17N5O3 [M + H]+ 400.1410, found 400.1419.
(±)-(3R,6′R)-8′-amino-1′,2-dioxo-6′-(2-fluorophenyl)-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (3h)
Molecules 28 01034 i008
[Reaction time: 1.0 h], 302 mg, 78%, a yellow solid, m.p. 192.7–193.2 °C; IR (thin film): νmax 3479, 3313, 2188, 1734, 1687, 1618, 1563, 1471, 1428, 1333, 1192, 1097, 758 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 10.60 (s, 1 H), 7.78 (s, 2 H), 7.65 (d, J = 7.6 Hz, 1 H), 7.35 (td, J = 7.6, 1.6 Hz, 1 H), 7.33 (d, J = 4.0 Hz, 1 H), 7.31 (td, J = 7.6, 0.8 Hz, 1 H), 7.27–7.21 (m, 1 H), 7.17 (td, J = 7.6, 0.8 Hz, 1 H), 7.13 (ψt, J = 7.6 Hz, 1 H), 6.91 (ψt, J = 9.2 Hz, 1 H), 6.66 (d, J = 7.6 Hz, 1 H), 5.67 (d, J = 4.0 Hz, 1 H), 4.98 (s, 1 H); 13C NMR (100 MHz, DMSO-d6): δ 171.0, 165.4, 150.5, 142.6, 142.4, 132.0, 131.2, 130.6 (d), 126.3, 124.8, 124.7, 123.1, 122.5, 121.9 (d), 119.4, 115.4 (d), 110.6, 100.9, 66.9, 57.5, 38.1; 19F NMR (376 MHz, DMSO-d6): δ −114.5; HRMS (ESI): m/z calcd. for C21H14FN5O2 [M + H]+ 388.1210, found 388.1216.
(±)-(3R,6′R)-8′-amino-1′,2-dioxo-6′-(2-fluorophenyl)-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (3i)
Molecules 28 01034 i009
[Reaction time: 2.0 h], 256 mg, 66%, a yellow solid, m.p. 246.3–248.1 °C; IR (thin film): νmax 3365, 3269, 3147, 2184, 1717, 1682, 1623, 1572, 1550, 1476, 1431, 1269, 1194, 893, 748 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 10.52 (s, 1 H), 7.76 (s, 2 H), 7.73 (d, J = 7.6 Hz, 1 H), 7.36 (d, J = 4.0 Hz, 1 H), 7.33 (td, J = 7.6, 0.8 Hz, 1 H), 7.18 (ψt, J = 7.4 Hz, 2 H), 7.03 (td, J = 8.4, 2.4 Hz, 1 H), 6.78 (brs, 2 H), 6.65 (d, J = 7.6 Hz, 1 H), 5.69 (d, J = 4.0 Hz, 1 H), 4.73 (s, 1 H); 13C NMR (100 MHz, DMSO-d6): δ 171.0, 165.4, 150.3, 142.8, 142.7, 137.8 (d), 132.0, 130.2 (d), 126.3, 126.0, 123.3, 122.6, 119.5, 116.7 (d), 115.5, 115.3, 110.8, 101.2, 66.7, 57.8, 46.1; 19F NMR (376 MHz, DMSO-d6): δ −113.5; HRMS (ESI): m/z calcd. for C21H14FN5O2 [M + H]+ 388.1210, found 388.1219.
(±)-(3R,6′R)-8′-amino-1′,2-dioxo-6′-(2-fluorophenyl)-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (3j)
Molecules 28 01034 i010
[Reaction time: 3.0 h], 225 mg, 58%, a yellow solid, m.p. 249.6–250.2 °C; IR (thin film): νmax 3375, 3271, 3146, 2184, 1716, 1678, 1623, 1572, 1541, 1507, 1474, 1278, 1068, 907, 742 cm−; 1H NMR (400 MHz, DMSO-d6): δ 10.89 (s, 1 H), 7.81 (s, 2 H), 7.64 (d, J = 4.0 Hz, 1 H), 7.25 (td, J = 7.6, 0.8 Hz, 1 H), 7.02 (ψt, J = 8.8 Hz, 1 H), 6.94 (ψt, J = 7.6 Hz, 3 H), 6.75 (d, J = 8.0 Hz, 1 H), 6.53 (d, J = 7.6 Hz, 1 H), 5.65 (d, J = 4.0 Hz, 1 H), 4.36 (s, 1 H); 13C NMR (100 MHz, DMSO-d6): δ 171.0, 165.4, 150.2, 142.8, 142.7, 132.1, 132.0, 131.0 (d), 126.0, 123.2, 122.7, 119.6, 115.3, 115.1, 110.7, 101.0, 67.3, 58.2, 45.8; 19F NMR (376 MHz, DMSO-d6): δ −119.6; HRMS (ESI): m/z calcd. for C21H14FN5O2 [M + H]+ 388.1210, found 388.1217.
(±)-(3R,6′S)-8′-amino-6′-(2-chlorophenyl)-1′,2-dioxo-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (3′k)
Molecules 28 01034 i011
[Reaction time:3.0 h], 360 mg, 89%, a white solid, m.p. 240.9–241.6 °C; IR (thin film): νmax 3402, 3271, 3136, 2183, 1736, 1683, 1626, 1575, 1540, 1473, 1257, 1042, 853, 752 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 10.95 (s, 1 H), 7.85 (s, 2 H), 7.40–7.27 (m, 6 H), 6.90 (d, J = 8.0 Hz, 1 H), 6.74 (ψt, J = 7.4 Hz, 1 H), 5.65 (d, J = 4.0 Hz, 1 H), 4.40 (s, 1 H); 13C NMR (100 MHz, DMSO-d6): δ 172.0, 165.3, 150.0, 143.0, 142.5, 135.3, 131.8, 130.6, 130.4, 129.5, 128.0, 127.7, 125.8, 122.4, 121.0, 120.0, 111.2, 100.6, 65.9, 56.6, 41.7; HRMS (ESI): m/z calcd. for C21H14ClN5O2 [M + H]+ 404.0914, found 404.0914.
(±)-(3R,6′R)-8′-amino-1′,2-dioxo-6′-(2-chlorophenyl)-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (3l)
Molecules 28 01034 i012
[Reaction time:2.0 h], 239 mg, 59%, a yellow solid, m.p. 243.6–244.8 °C; IR (thin film): νmax 3488, 3324, 3243, 2186, 1734, 1687, 1614, 1565, 1469, 1428, 1333, 1197, 753, 697 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 10.54 (s, 1 H), 7.77 (s, 2 H), 7.72 (d, J = 7.2 Hz, 1 H), 7.36 (d, J = 4.0 Hz, 1 H), 7.33 (td, J = 7.6, 1.2 Hz, 1 H), 7.27–7.24 (m, 1 H), 7.19 (td, J = 7.6, 0.8 Hz, 1 H), 7.01 (brs, 1 H), 6.90 (brs, 1 H), 6.65 (d, J = 8.0 Hz, 1 H), 5.69 (d, J = 4.0 Hz, 1 H), 4.73 (s, 1 H); 13C NMR (100 MHz, DMSO-d6): δ 170.9, 165.4, 150.3, 142.9, 142.7, 137.4, 132.8, 132.0, 130.1, 129.9, 128.9, 128.5, 126.1, 123.3, 122.6, 119.5, 110.8, 101.2, 67.2, 57.7, 46.1; HRMS (ESI): m/z calcd. for C21H14ClN5O2 [M + H]+ 404.0914, found 404.0918.
(±)-(3R,6′R)-8′-amino-1′,2-dioxo-6′-(2-chlorophenyl)-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (3m)
Molecules 28 01034 i013
[Reaction time: 4.0 h], 219 mg, 54%, a yellow solid, m.p. 259.7–261.7 °C; IR (thin film): νmax 3452, 3240, 3136, 2192, 1725, 1685, 1613, 1570, 1536, 1489, 1465, 1282, 1206, 838, 759 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 10.49 (s, 1 H), 7.77 (s, 2 H), 7.73 (d, J = 7.6 Hz, 1 H), 7.36 (d, J = 4.0 Hz, 1 H), 7.33 (ψt, J = 7.6 Hz, 1 H), 7.25 (d, J = 7.6 Hz, 2 H), 7.18 (ψt, J = 7.6 Hz, 1 H), 6.97 (brs, 2 H), 6.66 (d, J = 8.0 Hz, 1 H), 5.69 (d, J = 4.0 Hz, 1 H), 4.72 (s, 1 H); 13C NMR (100 MHz, DMSO-d6): δ 170.9, 165.4, 150.2, 142.8, 142.7, 133.9, 133.1, 132.0, 131.9, 128.4, 126.0, 123.3, 122.6, 119.6, 110.8, 101.1, 67.2, 57.9, 45.9; HRMS (ESI): m/z calcd. for C21H14ClN5O2 [M + H]+ 404.0914, found. 404.0915.
(±)-(3R,6′S)-8′-amino-1′,2-dioxo-6′-(2-bromophenyl)-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (3′n)
Molecules 28 01034 i014
[Reaction time: 3.0 h], 265 mg, 59%, a yellow solid, m.p. 259.7–261.2 °C; IR (thin film): νmax 3365, 3143, 2194, 1725, 1659, 1580, 1527, 1470, 1426, 1216, 1050, 745, 587 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 10.96 (s, 1 H), 7.85 (s, 2 H), 7.49–7.44 (m, 2 H), 7.35–7.27 (m, 4 H), 6.91 (d, J = 8.0 Hz, 1 H), 6.73 (ψt, J = 7.6 Hz, 1 H), 5.66 (d, J = 4.0 Hz, 1 H), 5.64 (d, J = 8.8 Hz, 1 H), 4.36 (s, 1 H); 13C NMR (100 MHz, DMSO-d6): δ 172.0, 165.3, 150.0, 143.1, 142.4, 137.0, 132.7, 131.9, 130.7 (2C), 128.6, 126.9, 126.0, 122.4, 120.8, 120.0, 111.2, 100.5, 65.8, 56.7, 44.4; HRMS (ESI): m/z calcd. for C21H14BrN5O2 [M + H]+ 448.0409, found 448.0430.
(±)-(3R,6′R)-8′-amino-1′,2-dioxo-6′-(3-bromophenyl)-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (3o)
Molecules 28 01034 i015
[Reaction time: 1.0 h], 319 mg, 71%, a yellow solid, m.p. 259.9–261.6 °C; IR (thin film): νmax 3362, 3268, 3146, 2182, 1718, 1682, 1624, 1570, 1542, 1473, 1281, 1189, 749, 591 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 10.54 (s, 1 H), 7.77 (s, 2 H), 7.72 (d, J = 7.6 Hz, 1 H), 7.40–7.32 (m, 3 H), 7.21–7.12 (m, 3 H), 6.94 (brs, 1 H), 6.66 (d, J = 7.6 Hz, 1 H), 5.69 (d, J = 4.0 Hz, 1 H), 4.71 (s, 1 H); 13C NMR (100 MHz, DMSO-d6): δ 170.9, 165.4, 150.3, 142.9, 142.7, 137.6, 132.8, 132.0, 131.4, 130.4, 129.2, 126.1, 123.3, 122.6, 121.4, 119.5, 110.8, 101.8, 101.2, 67.2, 57.7, 46.0; HRMS (ESI): m/z calcd. for C21H14BrN5O2 [M + H]+ 448.0409, found 448.0410.
(±)-(3R,6′S)-8′-amino-1′,2-dioxo-6′-(4-bromophenyl)-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (3′p)
Molecules 28 01034 i016
[Reaction time: 1.5 h], 319 mg, 71%, a yellow solid, m.p. 260.5–262.5 °C; IR (thin film): νmax 3361, 3269, 2189, 1720, 1681, 1626, 1570, 1535, 1476, 1279, 1105, 750, 608 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 10.96 (s, 1 H), 7.85 (s, 2 H), 7.49–7.44 (m, 2 H), 7.35–7.27 (m, 4 H), 6.91 (d, J = 7.6 Hz, 1 H), 6.73 (ψt, J = 7.6 Hz, 1 H), 5.66 (d, J = 4.0 Hz, 1 H), 5.64 (d, J = 7.6 Hz, 1 H), 4.37 (s, 1 H); 13C NMR (100 MHz, DMSO-d6): δ 170.9, 165.4, 150.2, 142.8, 142.7, 134.4, 132.2, 131.3, 126.0, 123.3, 122.6, 121.8, 119.6, 110.8, 101.8, 101.1, 67.2, 57.8, 45.9; HRMS (ESI): m/z calcd. for C21H14BrN5O2 [M + H]+ 448.0409, found 448.0425.
(±)-(3R,6′R)-8′-amino-1′,2-dioxo-6′-(4-nitrophenyl)-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (3q) and (±)-(3R,6′S)-8′-amino-1′,2-dioxo-6′-(4-nitrophenyl)-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (3′q)
Molecules 28 01034 i017
[Reaction time: 15.0 h], 108 mg, 26%, a yellow solid, m.p. 239.5–241.5 °C; IR (thin film): νmax 3442, 3351, 3262, 2193, 1726, 1679, 1622, 1570, 1521, 1471, 1344, 1110, 857 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 3q: 10.57 (s, 1 H), 8.08 (d, J = 8.8 Hz, 2 H), 7.85 (s, 2 H), 7.75 (d, J = 7.6 Hz, 1 H), 7.61 (d, J = 4.0 Hz, 1 H), 7.40 (d, J = 4.0 Hz, 1 H), 7.28–7.23 (m, 1 H), 7.20 (ψt, J = 7.6 Hz, 1 H), 6.90 (ψt, J = 7.6 Hz, 1 H), 6.66 (d, J = 8.0 Hz, 1 H), 5.72 (d, J = 4.0 Hz, 1 H), 4.92 (s, 1 H); 3′q: 10.97 (s, 1 H), 8.08 (d, J = 8.8 Hz, 2 H), 7.90 (s, 2 H), 7.34 (ψt, J = 7.6 Hz, 1 H), 7.28–7.23 (m, 4 H), 6.78 (d, J = 8.0 Hz, 1 H), 6.41 (d, J = 7.6 Hz, 1 H), 5.69 (d, J = 4.0 Hz, 1 H), 4.55 (s, 1 H); 13C NMR (100 MHz, DMSO-d6): δ 171.0, 170.7, 165.4 (2C), 150.4, 150.0, 147.6, 144.1, 143.7, 143.0, 142.9, 142.5, 142.0, 132.2, 131.6, 126.0, 125.6, 123.5, 123.4, 122.6, 122.4, 122.0, 119.5 (2C), 111.3, 110.9, 101.4, 101.3, 67.3, 67.0, 57.3, 57.2, 46.2, 45.7; HRMS (ESI): m/z calcd. forC21H14N6O4 [M + H]+ 415.1155, found 415.12316.
(±)-(3R,6′R)-8′-amino-1′,2-dioxo-6′-(naphthalen-1-yl)-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (3r)
Molecules 28 01034 i018
[Reaction time: 4.0 h], 140 mg, 28%, a yellow solid, m.p. 248.8–250.8 °C; IR (thin film): νmax 3366, 3268, 3125, 2188, 1723, 1676, 1647, 1625, 1564, 1531, 1517, 1463, 1333, 1193, 743 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 10.43 (s, 1 H), 7.84 (s, 4 H), 7.71 (s, 2 H), 7.54–7.20 (m, 7 H), 6.55 (d, J = 7.2 Hz, 1 H), 5.71 (s, 1 H), 4.89 (s, 1 H); 13C NMR (100 MHz, DMSO-d6): δ 171.2, 165.4, 150.4, 142.7 (2C), 132.9, 132.8, 132.5, 131.9, 129.6, 128.2, 127.9, 127.7 (2C), 126.8, 126.7, 126.1, 123.2, 122.9, 119.7, 110.7, 101.0, 67.4, 58.5, 46.7; HRMS (ESI): m/z calcd. for C25H17N5O2 [M + H]+ 420.1460, found 420.15148.
(±)-(3R,6′R)-8′-amino-1′,2-dioxo-6′-(3,4-dimethylphenyl)-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (3s)
Molecules 28 01034 i019
[Reaction time: 2.5 h], 216 mg, 54%, a white solid, m.p. 236.6–237.9 °C; IR (thin film): νmax 3485, 3369, 3274, 3145, 2183, 1719, 1684, 1604, 1562, 1468, 1200, 752 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 10.43 (s, 1 H), 7.73 (d, J = 7.6 Hz, 1 H), 7.69 (s, 2 H), 7.33–7.29 (m, 2 H), 7.17 (ψt, J = 7.6 Hz, 1 H), 6.88 (d, J = 6.8 Hz, 1 H), 6.75 (brs, 1 H), 6.64 (brs, 1 H), 6.63 (d, J = 8.0 Hz, 1 H), 5.66 (d, J = 4.0 Hz, 1 H), 4.58 (s, 1 H), 2.09 (s, 3 H), 2.03 (s, 3 H); 13C NMR (100 MHz, DMSO-d6): δ 171.2, 165.4, 150.4, 142.9, 142.5, 136.2, 135.8, 132.1, 131.8, 131.2, 129.3, 127.6, 126.0, 123.1, 123.0, 119.7, 110.7, 101.0, 67.4, 58.9, 46.1, 19.9, 19.4; HRMS (ESI): m/z calcd. for C23H19N5O2 [M + H]+ 398.1617, found 398.1625.
(±)-(3R,6′S)-8′-amino-6′-(3,4-dimethoxyphenyl)-1′,2-dioxo-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (3′t)
Molecules 28 01034 i020
[Reaction time: 7.0 h], 171 mg, 43%, a white solid, m.p. 242.5–243.9 °C; IR (thin film): νmax 3277, 3140, 2188, 1733, 1678, 1620, 1574, 1544, 1515, 1469, 1266, 1024, 755 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 10.85 (s, 1 H), 7.79 (s, 2 H), 7.71 (d, J = 4.0 Hz, 1 H), 7.26 (d, J = 7.6 Hz, 1 H), 6.70 (ψt, J = 7.6 Hz, 1 H), 6.78–6.72 (m, 3 H), 6.56 (d, J = 7.6 Hz, 1 H), 6.20 (brs, 1 H), 5.64 (d, J = 4.0 Hz, 1 H), 4.30 (s, 1 H), 3.67 (s, 3 H), 3.34 (s, 3 H); 13C NMR (100 MHz, DMSO-d6): δ 171.0, 165.3, 149.8, 148.9, 148.0, 143.9, 141.8, 131.1, 126.9, 124.9, 123.6, 122.8, 122.4, 119.4, 113.3, 111.2 (2C), 100.9, 68.4, 59.0, 55.7, 55.5, 46.5; HRMS (ESI): m/z calcd. for C23H20N5O4 [M + H]+ 430.1515, found 430.15274.
(±)-(3R,6′R)-8′-amino-1′,2-dioxo-6′-(2,4-dichloroxyphenyl)-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (3u) and (±)-(3R,6′S)-8′-amino-1′,2-dioxo-6′-(2,4-dichloroxyphenyl)-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (3′u)
Molecules 28 01034 i021
[Reaction time: 1.5 h], 382 mg, 87%, a yellow solid, m.p. 260.2–262.2 °C; IR (thin film): νmax 3450, 3304, 2150, 2192, 1719, 1685, 1617, 1565, 1473, 1433, 1280, 1105, 837, 752 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 3u: 10.84 (s, 1 H), 7.86 (d, J = 7.2 Hz, 2 H), 7.51–7.46 (m, 2 H), 7.43–7.41 (m, 1 H), 7.39–7.36 (m, 2 H), 7.34–7.30 (m, 2 H), 6.77 (d, J = 8.0 Hz, 1 H), 5.67 (d, J = 4.0 Hz, 1 H), 4.93 (s, 1 H); 3′u: 10.97 (s, 1 H), 7.86 (d, J = 7.2 Hz, 2 H), 7.56 (d, J = 7.2 Hz, 1 H), 7.51–7.46 (m, 2 H), 7.34–7.30 (m, 1 H), 7.11 (ψt, J = 7.6, 0.8 Hz, 1 H), 6.91 (d, J = 8.0 Hz, 1 H), 6.83 (ψt, J = 7.6, 0.8 Hz, 1 H), 5.86 (d, J = 7.2 Hz, 1 H), 5.68 (d, J = 4.0 Hz, 1 H), 4.38 (s, 1 H); 13C NMR (100 MHz, DMSO-d6): δ 171.8, 170.6, 165.4 (2C), 150.2, 150.1, 143.1, 142.9, 142.7, 142.0, 136.1, 135.4, 134.5, 124.0, 133.9, 132.7, 132.4, 132.1, 132.0, 131.9, 129.0, 128.8, 128.3, 128.0, 126.2, 125.7, 123.0, 122.9, 122.6, 120.9, 119.8, 119.3, 111.3, 110.9, 101.1, 100.8, 66.8, 65.8, 57.3, 56.2, 42.2, 41.5; HRMS (ESI): m/z calcd. for C21H13Cl2N5O2 [M + H]+ 438.0525, found 438.06128.
(±)-(3R,6′R)-8′-amino-1′,2-dioxo-6′-(3,4-dichlorophenyl)-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (3v)
Molecules 28 01034 i022
[Reaction time: 4.0 h], 183 mg, 42%, a yellow solid, m.p. 259.8–261.6 °C; IR (thin film): νmax 3358, 3176, 3150, 2191, 1736, 1655, 1627, 1580, 1536, 1469, 1429, 1295, 1030, 830, 750 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 10.61 (s, 1 H), 7.83 (s, 2 H), 7.71 (d, J = 6.4 Hz, 1 H), 7.48 (s, 1 H), 7.39–7.33 (m, 2 H), 7.19 (d, J = 6.4 Hz, 2 H), 6.94 (brs, 1 H), 6.70 (d, J = 6.8 Hz, 1 H), 5.71 (s, 1 H), 4.76 (s, 1 H); 13C NMR (100 MHz, DMSO-d6): δ 170.8, 165.4, 150.3, 143.0, 142.6, 136.2, 132.2, 132.0, 121.2, 130.9, 130.6, 126.0, 123.4, 122.4, 119.5, 110.9, 101.3, 67.0, 57.2, 45.5; HRMS (ESI): m/z calcd. for C21H13Cl2N5O2 [M + H]+ 438.0525, found 438.06011.
(±)-(3R,6′R)-8′-amino-1′,2-dioxo-6′-((E)-styryl)-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (3w) and (±)-(3R,6′S)-8′-amino-1′,2-dioxo-6′-((E)-styry)-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (3′w)
Molecules 28 01034 i023
[Reaction time: 18 h], 246 mg, 62%, a yellow solid, m.p. 251.3–253.1 °C; IR (thin film): νmax 3354, 3273, 3229, 2188, 1724, 1689, 1626, 1566, 1541, 1515, 1472, 1206, 1170, 11003, 968, 747 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 3w: 10.40 (s, 1 H), 7.74–7.56 (m, 3 H), 7.57 (d, J = 7.2 Hz, 1 H), 7.39–7.16 (m, 7 H), 6.96 (brs, 2 H), 6.60 (d, J = 7.6 Hz, 1 H), 5.67–5.65 (m, 1 H), 4.07–4.02 (m, 1 H); 3′w: 10.78 (s, 1 H), 7.74–7.56 (m, 2 H), 7.39–7.16 (m, 9 H), 6.83 (d, J = 7.6 Hz, 1 H), 6.23 (d, J = 15.6 Hz, 1 H), 5.81–5.74 (m, 1 H), 5.67–5.65 (m, 1 H), 4.66 (s, 1 H); 13C NMR (100 MHz, DMSO-d6): δ 171.2, 171.1, 165.4, 165.3, 150.2, 149.3, 142.8, 142.6 (2C), 136.2, 135.8, 134.7, 131.8 (2C), 130.1 (2C), 129.2, 128.6, 128.4, 128.2, 126.7 (2C), 126.0, 125.6, 123.6, 123.5, 123.3, 123.1, 122.9, 119.8, 119.6, 110.9, 110.6, 101.0, 100.9, 100.5, 67.4, 66.2, 58.5, 57.4, 46.5, 44.4, 14.2; HRMS (ESI): m/z calcd. for C23H17N5O2 [M + H]+ 396.1460, found 396.1524.
(±)-(3R,6′R)-8′-amino-5-methyl-1′,2-dioxo-6′-phenyl-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (4a)
Molecules 28 01034 i024
[Reaction time: 3.0 h], 307 mg, 80%, a white solid, m.p. 238.8–240.2 °C; IR (thin film): νmax 3364, 3306, 3279, 3155, 2185, 1715, 1681, 1625, 1579, 1550, 1494, 1284, 1163, 742 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 10.28 (s, 1 H), 7.69 (s, 2 H), 7.56 (s, 1 H), 7.31 (d, J = 4.0 Hz, 1 H), 7.15–7.09 (m, 4 H), 6.98 (brs, 2 H), 6.49 (d, J = 8.0 Hz, 1 H), 5.66 (d, J = 4.0 Hz, 1 H), 4.61 (s, 1 H), 2.34 (s, 3 H); 13C NMR (100 MHz, DMSO-d6): δ 171.1, 165.4, 150.1, 142.6, 140.4, 134.8, 132.1 (2C), 130.1, 128.4, 128.2, 126.4, 122.9, 119.6, 110.4, 100.9, 67.5, 58.5, 46.6, 21.3; HRMS (ESI): m/z calcd. for C22H17N5O2 [M+Na]+ 406.1280, found 406.13334.
(±)-(3R,6′R)-8′-amino-5-methoxy-1′,2-dioxo-6′-phenyl-1′H,6′H-spiro[indoline-3,5′-pyrazolo [1,2-a]pyridazine]-7′-carbonitrile (4b) and (±)-(3R,6′S)-8′-amino-5-methoxy-1′,2-dioxo-6′-phenyl-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (4′b)
Molecules 28 01034 i025
[Reaction time: 7.0 h], 280 mg, 70%, a brown solid, m.p. 239.6–241.2 °C; IR (thin film): νmax 3363, 3245, 3214, 2172, 1732, 1683, 1624, 1576, 1539, 1494, 1431,1300, 1200, 781 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 4b: 10.21 (s, 1 H), 7.69 (s, 2 H), 7.44 (d, J = 2.4 Hz, 1 H), 7.36 (d, J = 4.0 Hz, 1 H), 7.28–7.20 (m, 2 H), 7.16–7.15 (m, 1H), 7.01 (brs, 2 H), 6.87–6.81 (m, 1 H), 6.52 (d, J = 8.4 Hz, 1 H), 5.67 (d, J = 4.0 Hz, 1 H), 4.70 (s, 1 H), 3.79 (s, 3 H); 4′b: 10.97 (s, 1 H), 7.77 (s, 2 H), 7.55 (d, J = 4.0 Hz, 1 H), 7.28–7.20 (m, 2 H), 7.16–7.15 (m, 1 H), 6.96 (d, J = 6.8 Hz, 2 H), 6.87–6.81 (m, 1 H), 6.69 (d, J = 8.8 Hz, 1 H), 5.83 (d, J = 1.6 Hz, 1 H), 5.64 (d, J = 4.0 Hz, 1 H), 4.22 (s, 1 H), 3.49 (s, 3 H); 13C NMR (100 MHz, DMSO-d6): δ 171.2, 171.1, 165.4, 165.3, 155.9, 154.7, 150.1, 149.7, 143.4, 142.7, 136.5, 135.9, 135.2, 134.8, 130.1, 128.6, 128.4 (2C), 128.3, 123.9, 123.5, 119.8, 119.6, 117.1, 115.9, 112.4, 112.3, 111.6, 111.3, 100.9, 100.8, 67.8, 58.5, 56.5, 56.1, 55.7, 46.4; HRMS (ESI): m/z calcd. for C22H17N5O3 [M+K]+ 438.0968, found 438.10269.
(±)-(3R,6′R)-8′-amino-5-fluoro-1′,2-dioxo-6′-phenyl-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (4c)
Molecules 28 01034 i026
[Reaction time: 8.5 h], 237 mg, 61%, a white solid, m.p. 231.4–233.4 °C; IR (thin film): νmax 3431, 3270, 3146, 2189, 1727, 1658, 1622, 1574, 1543, 1488, 1428, 1275, 1175, 1071, 802 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 10.43 (s, 1 H), 7.75–7.70 (m, 2 H), 7.48 (d, J = 4.0 Hz, 1 H), 7.18–7.12 (m, 4 H), 7.00 (brs, 2 H), 6.60 (dd, J = 8.8, 4.4 Hz, 1 H), 5.71 (d, J = 4.0 Hz, 1 H), 4.69 (s, 1 H); 13C NMR (100 MHz, DMSO-d6): δ 171.1, 165.4, 150.1, 143.0, 139.1 (d), 134.5, 130.1, 128.5, 128.4, 124.4 (2C), 119.5, 118.4 (d), 114.2, 114.0, 111.7 (d), 101.2, 67.6, 58.3, 46.5; 19F NMR (376 MHz, DMSO-d6): δ -119.6; 19F NMR (376 MHz, DMSO-d6): δ −119.6; HRMS (ESI): m/z calcd. for C21H14FN5O2 [M+Na]+ 410.1029, found 410.10951.
(±)-(3R,6′R)-8′-amino-5-chloro-1′,2-dioxo-6′-phenyl-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (4d)
Molecules 28 01034 i027
[Reaction time: 6.0 h], 331 mg, 82%, a brown solid, m.p. 231.0–232.9 °C; IR (thin film): νmax 3435, 3270, 3141, 2191, 1722, 1654, 1627, 1559, 1527, 1477, 1427, 1276, 1211, 909, 703 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 10.54 (s, 1 H), 7.90 (d, J = 1.6 Hz, 1 H), 7.70 (d, J = 5.6 Hz, 1 H), 7.51 (d, J = 4.0 Hz, 1 H), 7.36–7.33 (m, 1 H), 7.18–7.15 (m, 3 H), 6.98 (brs, 2 H), 6.61 (d, J = 7.6 Hz, 1 H), 5.57 (d, J = 4.0 Hz, 1 H), 4.71 (s, 1 H); 13C NMR (100 MHz, DMSO-d6): δ 170.9, 165.4, 150.1, 143.0, 141.8, 134.5, 131.8, 130.1, 128.6, 128.4, 127.1, 126.4, 124.8, 119.5, 112.1, 101.2, 67.4, 58.3, 46.4; HRMS (ESI): m/z calcd. for C21H14ClN5O2 [M + H]+ 404.0914, found 404.09140.
(±)-(3R,6′R)-8′-amino-6-bromo-1′,2-dioxo-6′-phenyl-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (4e)
Molecules 28 01034 i028
[Reaction time: 12 h], 213 mg, 47%, a brown solid, m.p. 230.8–232.7 °C; IR (thin film): νmax 3426, 3395, 3365, 3138, 2188, 1733, 1682, 1655, 1618, 1577, 1543, 1482, 1455, 1278, 1175, 742, 593 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 10.57 (s, 1 H), 7.71 (s, 2 H), 7.69 (s, 1 H), 7.48 (d, J = 4.0 Hz, 1 H), 7.37 (d, J = 8.0 Hz, 1 H), 7.19 (s, 3 H), 6.98 (brs, 2 H), 6.77 (s, 1 H), 5.69 (d, J = 4.0 Hz, 1 H), 4.68 (s, 1 H); 13C NMR (100 MHz, DMSO-d6): δ 170.9, 165.4, 150.1, 143.0, 141.8, 134.5, 131.8, 130.1, 128.6, 128.4, 127.1, 126.4, 124.8, 119.5, 112.1, 101.2, 67.4, 58.3, 46.4; HRMS (ESI): m/z calcd. for C21H14BrN5O2 [M + H]+ 448.0409, found 448.04897.
(±)-(3R,6′R)-8′-amino-5-iodo-1′,2-dioxo-6′-phenyl-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2 -a]pyridazine]-7′-carbonitrile (4f)
Molecules 28 01034 i029
[Reaction time: 8.0 h], 207 mg, 42%, a brown solid, m.p. 234.2–235.6 °C; IR (thin film): νmax 3144, 2190, 1735, 1687, 1616, 1568, 1544, 1468, 1427, 1319, 1206, 750, 527 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 10.51 (s, 1 H), 8.12 (d, J = 1.6 Hz, 1 H), 7.70 (s, 2 H), 7.63 (dd, J = 8.0, 1.6 Hz, 1 H), 7.47 (d, J = 4.0 Hz, 1 H), 7.18–7.16 (m, 3 H), 6.98 (brs, 2 H), 6.44 (d, J = 8.0 Hz, 1 H), 5.69 (d, J = 4.0 Hz, 1 H), 4.69 (s, 1 H); 13C NMR (100 MHz, DMSO-d6): δ 170.6, 165.3, 150.1, 143.0, 142.6, 140.3, 134.5, 134.4, 130.0, 128.5, 128.4, 125.3, 119.5, 112.9, 101.1, 85.8, 67.2, 58.3, 46.3; HRMS (ESI): m/z calcd. for C21H14IN5O2 [M + H]+ 496.0270, found 496.03396.
(±)-(3R,6′R)-8′-amino-5-nitro-1′,2-dioxo-6′-phenyl-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (4g)
Molecules 28 01034 i030
[Reaction time: 4.0 h], 83 mg, 20%, a yellow solid, m.p. 234.5–236.5 °C; IR (thin film): νmax 3466, 3376, 3344, 3134, 2193, 1745, 1683, 1622, 1560, 1526, 1481, 1427, 1279, 1176, 841 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 11.10 (s, 1 H), 8.73 (d, J = 6.0 Hz, 1 H), 8.25 (dd, J = 8.8, 2.0 Hz, 1 H), 7.74 (s, 2 H), 6.98 (brs, 2 H), 6.79 (d, J = 8.8 Hz, 2 H), 5.76 (d, J = 4.0 Hz, 1 H), 4.87 (s, 1 H); 13C NMR (100 MHz, DMSO-d6): δ 171.5, 165.4, 150.1, 149.1, 143.4, 143.2, 134.1, 130.1, 128.8, 128.7, 128.5, 123.9, 122.6, 119.4, 111.0, 101.4, 67.1, 58.0, 46.3; HRMS (ESI): m/z calcd. for C21H14N6O4 [M + H]+ 415.1155, found 415.12022.
(±)-(3R,6′S)-8′-amino-1′,2-dioxo-6′-phenyl-7-(trifluoromethyl)-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (4′h) and (±)-(3R,6′R)-8′-amino-1′,2-dioxo-6′-phenyl-7-(trifluoromethyl)-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (4h)
Molecules 28 01034 i031
[Reaction time: 6.0 h], 324 mg, 74%, a yellow solid, m.p. 235.4–236.7 °C; IR (thin film): νmax 3456, 3280, 3121, 2187, 1736, 1H NMR (400 MHz, DMSO-d6): δ 4′h: 11.37 (s, 1 H), 7.83 (s, 2 H), 7.67 (d, J = 4.0 Hz, 1 H), 7.55 (d, J = 8.4 Hz, 1 H), 7.28–7.14 (m, 3 H), 7.05 (ψt, J = 8.0 Hz, 1 H), 6.92 (d, J = 6.4 Hz, 2 H), 6.56 (d, J = 7.6 Hz, 1 H), 5.74 (d, J = 4.0 Hz, 1 H), 4.35 (s, 1 H); 4h: 10.91 (s, 1 H), 8.03 (d, J = 7.6 Hz, 1 H), 7.77 (s, 2 H), 7.60 (d, J = 8.0 Hz, 1 H), 7.55 (d, J = 8.4 Hz, 1 H), 7.36 (ψt, J = 7.6 Hz, 1 H), 7.28–7.14 (m, 3 H), 6.92 (d, J = 6.4 Hz, 2 H), 5.70 (d, J = 4.0 Hz, 1 H), 4.71 (s, 1 H); 13C NMR (100 MHz, DMSO-d6): δ 172.0, 171.6, 165.4, 165.3, 150.2, 149.7, 150.1, 143.7, 143.2, 139.5, 135.7, 134.0, 129.9, 129.4, 128.7, 128.6, 128.4, 128.3, 127.7, 124.9, 124.8, 124.5, 123.3, 122.5, 122.1, 119.6, 112.2, 111.9, 101.3, 101.1, 66.4, 66.3, 58.1, 58.0, 46.9, 46.3; 19F NMR (376 MHz, DMSO-d6): δ −60.2, −60.4; HRMS (ESI): m/z calcd. for C22H14F3N5O2 [M + H]+ 438.1178, found 438.1179.
(±)-(3R,6′R)-8′-amino-2′-methyl-1′,2-dioxo-6′-phenyl-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (5a)
Molecules 28 01034 i032
[Reaction time: 1.0 h], 299 mg, 78%, a yellow solid, m.p. 257.5–259.4 °C; IR (thin film): νmax 3465, 3276, 3095, 2189, 1733, 1679, 1614, 1575, 1468, 1425, 1245, 1160, 746 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 10.34 (s, 1 H), 7.73 (d, J = 7.6 Hz, 1 H), 7.67 (s, 2 H), 7.30 (ψt, J = 7.6 Hz, 1 H), 7.18–7.12 (m, 4 H), 6.97 (brs, 2 H), 6.60 (d, J = 7.6 Hz, 1 H), 4.63 (s, 1 H), 1.69 (s, 3 H); 13C NMR (100 MHz, DMSO-d6): δ 171.2, 165.7, 150.8, 142.8, 139.6, 135.0, 131.7, 130.1, 128.3, 128.2, 125.9, 123.3, 123.0, 119.7, 110.2, 100.6, 67.3, 58.7, 46.7, 7.5; HRMS (ESI): m/z calcd. for C22H17N5O2 [M+Na]+ 406.1280, found 406.13367.
(±)-(3R,6′S)-8′-amino-2′-methyl-1′,2-dioxo-6′-(p-tolyl)-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (5′b) and (±)-(3R,6′R)-8′-amino-2′-methyl-1′,2-dioxo-6′-(p-tolyl)-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (5b)
Molecules 28 01034 i033
[Reaction time: 3.5 h], 346 mg, 87%, a white solid, m.p. 240.1–242.0 °C; IR (thin film): νmax 3376, 3210, 3101, 2193, 1717, 1673, 1624, 1570, 1515, 1473, 1427, 1250, 1161, 1047, 739 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 5′b: 10.84 (s, 1 H), 7.76 (s, 2 H), 7.43 (s, 1 H), 7.22 (ψt, J = 7.6 Hz, 1 H), 6.96–6.90 (m, 2 H), 6.85 (brs, 1 H), 6.78 (d, J = 7.2 Hz, 2 H), 6.71 (d, J = 7.6 Hz, 1 H), 6.57 (d, J = 7.6 Hz, 1 H), 4.27 (s, 1 H), 2.20 (s, 3 H), 1.65 (s, 3 H); 5b: 10.35 (s, 1 H), 7.72 (d, J = 7.6 Hz, 1 H), 7.65 (s, 2 H), 7.30 (ψt, J = 7.6 Hz, 1 H), 7.16 (ψt, J = 7.6 Hz, 1 H), 7.11 (s, 1 H), 6.96–6.90 (m, 4 H), 6.62 (d, J = 8.0 Hz, 1 H), 4.59 (s, 1 H), 2.18 (s, 3 H), 1.69 (s, 3 H); 13C NMR (100 MHz, DMSO-d6): δ 171.4, 171.2, 165.6, 150.0, 142.8, 141.8, 140.5, 139.5, 137.6, 137.4, 132.6, 131.9, 131.6, 131.0, 130.0, 128.8, 125.9, 125.2, 123.4, 123.0, 122.3, 119.7, 119.6, 111.2, 111.0 (2C), 110.6, 68.1, 67.3, 59.0, 58.9, 46.3, 46.2, 21.1 (2C), 19.0, 7.5; HRMS (ESI): m/z calcd. for C23H19N5O2 [M + H]+ 398.1617, found.398.16345.
(±)-(3R,6′R)-8′-amino-6′-(4-methoxylphenyl)-2′-methyl-1′,2-dioxo-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (5c) and (±)-(3R,6′S)-8′-amino-6′-(4-methoxylphenyl)-2′-methyl-1′,2-dioxo-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazinee]-7′-carbonitrile (5′c)
Molecules 28 01034 i034
[Reaction time: 4.0 h], 290 mg, 73%, a yellow solid, m.p. 241.5–242.7 °C; IR (thin film): νmax 3369, 3259, 3208, 2178, 1716, 1672, 1624, 1598, 1567, 1510, 1470, 1428, 1247, 1175, 738 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 5c: 10.35 (s, 1 H), 7.75 (s, 1 H), 7.65 (s, 2 H), 7.31 (ψt, J = 7.6 Hz, 1 H), 7.16 (ψt, J = 7.6 Hz, 1 H), 7.11 (s, 1 H), 6.94–6.80 (m, 3 H), 6.74–6.63 (m, 1 H), 6.63 (d, J = 7.6 Hz, 1 H), 4.58 (s, 1 H), 3.65 (s, 3 H), 1.69 (s, 3 H); 5′c: 10.84 (s, 1 H), 7.71 (d, J = 7.2 Hz, 2 H), 7.43 (s, 1 H), 7.23 (ψt, J = 7.6 Hz, 1 H), 6.94–6.80 (m, 3 H), 6.74–6.63 (m, 3 H), 6.56 (d, J = 7.2 Hz, 1 H), 4.25 (s, 1 H), 3.67 (s, 3 H), 1.65 (s, 3 H); 13C NMR (100 MHz, DMSO-d6): δ 171.3, 165.6, 159.1, 150.0 (2C), 142.8, 141.8, 140.5, 139.5, 131.6, 131.2, 131.0, 127.4, 126.6, 125.9, 125.2, 123.4, 123.0, 122.4, 119.8, 119.6, 113.6, 111.1, 111.0, 110.9, 110.6, 68.2, 67.3, 59.1 (2C), 55.4 (2C), 45.9, 45.8, 19.0, 7.5; HRMS (ESI): m/z calcd. for C23H19N5O3 [M + H]+ 414.1566, found 414.12751.
(±)-(3R,6′R)-8′-amino-6′-(4-fluorophenyl)-2′-methyl-1′,2-dioxo-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (5d)
Molecules 28 01034 i035
[Reaction time: 2.0 h], 297 mg, 91%, a white solid, m.p. 260.8–262.4 °C; IR (thin film): νmax 3372, 3333, 3213, 3104, 2181, 1720, 1670, 1628, 1590, 1509, 1476, 1427, 1251, 1191, 737 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 10.39 (s, 1 H), 7.71 (d, J = 7.2 Hz, 1 H), 7.69 (s, 2 H), 7.32 (ψt, J = 8.0, 1.2 Hz, 1 H), 7.17 (ψt, J = 8.8, 0.8 Hz, 1 H), 7.14 (d, J = 1.2 Hz, 1 H), 6.99 (d, J = 6.0 Hz, 4 H), 6.64 (d, J = 7.6 Hz, 1 H), 4.67 (s, 1 H), 1.69 (d, J = 0.8 Hz, 3 H); 13C NMR (100 MHz, DMSO-d6): δ 171.1, 165.7, 150.1, 142.7, 139.6, 132.1, 132.0, 131.8, 131.2, 125.9, 123.2 (2C), 119.7, 115.2, 115.0, 111.2, 110.6, 67.2, 58.4, 45.8, 7.5; 19F NMR (376 MHz, DMSO-d6): −114.3; HRMS (ESI): m/z calcd. for C22H16FN5O2 [M+K]+ 440.0925, found 440.09885.
(±)-(3R,6′R)-8′-amino-6′-(4-chlorophenyl)-2′-methyl-1′,2-dioxo-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (5e)
Molecules 28 01034 i036
[Reaction time: 3.5 h], 243 mg, 58%, a yellow solid, m.p. 260.1–262.0 °C; IR (thin film): νmax 3472, 3373, 3344, 2182, 1725, 1652, 1624, 1567, 1471, 1427, 1277, 1161, 832, 742 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 10.41 (s, 1 H), 7.72 (s, 1 H), 7.71 (s, 2 H), 7.32 (ψt, J = 7.6 Hz, 1 H), 7.24–7.14 (m, 4 H), 6.99 (brs, 2 H), 6.66 (d, J = 7.6 Hz, 1 H), 4.68 (s, 1 H), 1.69 (s, 3 H); 13C NMR (100 MHz, DMSO-d6): δ 171.0, 165.7, 150.1, 142.7, 139.7, 134.2, 133.1, 131.9, 131.8, 128.3, 125.9, 123.2, 123.0, 119.7, 111.3, 110.7, 67.1, 58.1, 45.8, 7.5; HRMS (ESI): m/z calcd. for C22H16ClN5O2 [M + H]+ 418.1071, found 429.11331.
(±)-(3R,6′R)-8′-amino-6′-(4-bromophenyl)-2′-methyl-1′,2-dioxo-1′H,6′H-spiro[indoline-3,5′ -pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (5f)
Molecules 28 01034 i037
[Reaction time: 1.5 h], 305 mg, 66%, a yellow solid, m.p. 263.7–265.7 °C; IR (thin film): νmax 3472, 3342, 3190, 3131, 3098, 2188, 1733, 1651, 1619, 1561, 1472, 1413, 1277, 1157, 744, 516 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 10.41 (s, 1 H), 7.72 (s, 1 H), 7.70 (s, 1 H), 7.32 (ψt, J = 7.6 Hz, 1 H), 7.23 (d, J = 7.6 Hz, 1 H), 7.17 (ψt, J = 7.6 Hz, 1 H), 7.15 (s, 1 H), 6.97 (s, 2 H), 6.65 (d, J = 8.0 Hz, 1 H), 4.68 (s, 1 H), 1.69 (s, 3 H); 13C NMR (100 MHz, DMSO-d6): δ 171.1, 165.7, 150.1, 142.7, 139.7, 134.6, 132.2, 131.8, 131.3, 125.9, 123.2, 123.0, 121.8, 119.7, 111.3, 110.7, 67.0, 58.0, 45.9, 7.5; HRMS (ESI): m/z calcd. for C22H16BrN5O2 [M + H]+ 462.0566, found 462.06279.
(±)-(3R,6′S)-8′-amino-6′-(4-nitrophenyl)-2′-methyl-1′,2-dioxo-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (5′g) and (±)-(3R,6′R)-8′-amino-6′-(4-nitrophen-yl)-2′-methyl-1′,2-dioxo-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (5g)
Molecules 28 01034 i038
[Reaction time: 16.0 h], 301 mg, 70%, a yellow solid, m.p. 261.7–263.3 °C; IR (thin film): νmax 3368, 3260, 3217, 2188, 1722, 1675, 1619, 1571, 1521, 1473, 1428, 1251, 1165, 848, 748 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 5′g: 10.94 (s, 1 H), 8.09 (s, 2 H), 7.87 (s, 2 H), 7.38–7.19 (m, 4 H), 6.88 (ψt, J = 7.6 Hz, 1 H), 6.77 (d, J = 8.0 Hz, 1 H), 6.66 (d, J = 7.6 Hz, 1 H), 4.51 (s, 1 H), 1.66 (s, 3 H); 5g: 10.50 (s, 1 H), 8.07 (s, 2 H), 7.81 (s, 2 H), 7.74 (d, J = 7.6 Hz, 1 H), 7.38–7.19 (m, 5 H), 6.36 (d, J = 7.2 Hz, 1 H), 4.89 (s, 1 H), 1.70 (s, 3 H); 13C NMR (100 MHz, DMSO-d6): δ 171.3, 170.7, 165.7, 165.7, 150.3, 149.9, 147.6, 144.4, 143.2, 142.5, 142.0, 140.3, 139.8, 132.0, 131.5, 131.4, 125.9, 125.6, 123.4, 123.3, 122.8, 122.5, 122.0, 119.6, 111.6, 111.3, 111.2, 110.8, 67.2, 67.0, 57.5, 57.4, 46.2, 45.8, 21.2, 7.5; HRMS (ESI): m/z calcd. for C22H16N6O4 [M + H]+ 429.1311, found 429.13739.
(±)-Ethyl 2-(((3R,6′R)-8′-amino-7′-cyano-1′,2-dioxo-6′-phenyl-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazin]-1-yl)methyl)acrylate (6)
Molecules 28 01034 i039
[Reaction time: 5.0 min], 73 mg, 76%, a white solid m.p. 206.0–207.3 °C; IR (thin film): νmax 3370, 2981, 2189, 1725, 1683, 1492, 1382, 1172, 1027, 754 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 7.85 (d, J = 7.2 Hz, 1 H), 7.72 (s, 2 H), 7.40 (td, J = 8.0–7.6, 0.8 Hz, 1 H), 7.32 (d, J = 4.0 Hz, 1 H), 7.28 (ψt, J = 7.6–7.2 Hz 1 H), 7.20–7.30 (m, 3 H), 6.91 (brs, 2 H), 6.77 (d, J = 7.8 Hz, 1 H), 5.76 (s, 1 H), 5.67 (d, J = 4.0 Hz, 1 H), 4.77 (s, 1 H), 4.20 (d, J = 16.8 Hz, B of AB, 1 H), 4.14–4.04 (m, 2 H), 1.18 (t, J = 7.2 Hz, 3 H); 13C NMR (100 MHz, DMSO-d6): δ 169.3, 165.4, 165.0, 150.2, 143.3, 142.8, 134.4, 133.3, 132.0, 130.2, 128.6, 128.4, 126.0, 125.2, 124.1, 122.0, 119.5, 110.6, 101.4, 67.1, 61.2, 58.5, 46.4, 14.4; HRMS (ESI): m/z calcd. for C27H24N5O4 [M + H]+ 482.1828, found 482.1689.
(±)-tert-butyl (3R,6′R)-8′-(bis(tert-butoxycarbonyl)amino)-7′-cyano-1′,2-dioxo-6′-phenyl-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-1-carboxylate (7)
Molecules 28 01034 i040
[Reaction time: 5.0 h], 95 mg, 71%, a white solid, m.p. 159.2–160.3 °C; IR (thin film): νmax 2980, 2926, 2855, 2221, 1775, 1741, 1708, 1647, 1551, 1465, 1043, 914, 857 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 7.81 (d, J = 7.6 Hz, 1 H), 7.57 (ψt, J = 7.6 Hz, 1 H), 7.53 (ψt, J = 7.6 Hz, 1 H), 7.47–7.43 (m, 2 H), 7.28–7.19 (m, 3 H), 6.83 (s, 2 H), 5.75 (d, J = 4.0 Hz, 1 H), 4.91 (s, 1 H), 1.60 (s, 9 H), 1.44 (s, 9 H), 1.38 (s, 9 H); 13C NMR (100 MHz, DMSO-d6): δ 1670.1, 162.3, 148.4, 147.8 (2C), 145.3, 140.4, 139.5, 132.5, 132.0, 129.8, 129.2, 128.6, 126.2, 125.9, 121.1, 115.4, 115.1, 103.7, 91.9, 84.5 (2C), 84.2, 67.2, 66.6, 48.9, 29.8, 28.2, 27.9, 27.8; HRMS (ESI): m/z calcd. for C36H39N5NaO8 [M+Na]+ 692.2696, found 692.2679.
(±)-(3R,6′S)-1′,2,8′-trioxo-6′-(o-tolyl)-7′,8′-dihydro-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (8)
Molecules 28 01034 i041
[Reaction time: 5.0 h], 19 mg, 25%, a yellow solid, m.p. 270.7–272.7 °C; IR (thin film): νmax 3533, 3365, 3175, 2923, 2852, 2187, 1751, 1718, 1677, 1577, 1430, 1343, 1169, 1014, 887, 740 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 10.90 (s, 1 H), 8.37 (s, 1 H), 7.34–7.30 (m, 2 H), 7.28–7.19 (m, 2 H), 7.08 (d, J = 6.4 Hz, 1 H), 7.01 (d, J = 6.8 Hz, 1 H), 6.90 (d, J = 7.6 Hz, 1 H), 6.72 (ψt, J = 7.2 Hz, 1 H), 5.74 (d, J = 7.2 Hz, 1 H), 5.64 (d, J = 4.0 Hz, 1 H), 4.44 (s, 1 H), 1.71 (s, 3 H), 1.70 (s, 3 H); 13C NMR (100 MHz, DMSO-d6): δ 172.3, 161.8, 143.8, 143.0, 138.8, 133.5, 131.8, 130.7, 130.1, 129.0, 128.4, 126.6, 126.2, 122.3, 121.2, 118.4, 111.0, 101.1, 89.2, 65.7, 41.9, 19.3; HRMS (ESI): m/z calcd. for C22H16N4NaO3 [M+Na]+ 407.1120, found 407.0876.
(±)-(3R,6′R)-1-acetyl-8′-amino-2′-methyl-1′,2-dioxo-6′-phenyl-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (9)
Molecules 28 01034 i042
[Reaction time: 5.0 h], 73 mg, 86%, a white solid, m.p. 252.5–254.4 °C; IR (thin film): νmax 3414, 3015, 2924, 2219, 1728, 1666, 1626, 1571, 1529, 1471, 1372, 1197, 897, 755 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 7.88–7.78 (m, 4 H), 7.51–7.48 (m, 2 H), 7.25 (s, 1 H), 7.20–7.16 (m, 3 H), 6.84 (brs, 2 H), 4.67 (s, 1 H), 2.29 (s, 3 H), 1.70 (s, 3 H); 13C NMR (100 MHz, DMSO-d6): δ 170.6, 169.6, 165.6, 150.1, 140.4, 140.1, 133.7, 129.6, 131.4, 125.9, 125.6, 123.4, 123.3, 122.8, 122.5, 122.0, 119.6, 111.6, 111.3, 111.2, 110.8, 67.2, 67.0, 57.5, 57.4, 46.2, 45.8, 21.2, 7.5; HRMS (ESI): m/z calcd. for C24H19N5NaO3 [M+Na]+ 448.1386, found 448.1376.

4. Conclusions

In summary, we have developed an abnormally formal [3+3]-cycloaddition of N-unsubstituted isatin N,N′-cyclic azomethine imine 1,3-dipoles with Knoevenagel adducts to form novel dicyclic spiropyridazine oxindole derivatives in moderate to excellent yields (20–93%) and low to high diastereoselectivities (1:9–10:1 dr) under the optimized reaction condition. All the synthesized spiro-oxindole derivatives 3/3′, 4/4′, and 5/5′ were confirmed by 1H and 13C NMR, IR, and HMRS technologies. The relative stereochemistry of products was determined by the single-crystal X-ray of 4a and the single-crystal X-ray of the compound reported by Moghaddam [14].

Supplementary Materials

The supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules28031034/s1.

Author Contributions

Writing—original draft preparation, G.Y. (Guizhou Yue); writing—review and editing, C.Y. and H.C.; methodology, G.Y. (Guizhou Yue) and S.L.; conducting the experiments, G.Y. (Guosheng Yang) and S.L.; validation, Q.W.; supervision, G.Y. (Guizhou Yue), L.Z. and Z.Y.; funding acquisition, G.Y. (Guizhou Yue) and X.S.; mass spectrometry, C.L. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by Sichuan Science and Technology Program (No. 2020YFH0129), the National Key R&D Program of China (No. 2019YFD1002100), and the Program Sichuan Veterinary Medicine and Drug Innovation Group of China Agricultural Research System (No. SCCXTD-2020-18).

Data Availability Statement

Not applicable.

Acknowledgments

We thank Guizhou Covalent Bond Bochuang Technology Co. Ltd. for the NMR analysis.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Cederbaum, F.; Brunner, H.G.; Boeger, M. Novel Herbicidally, Acaricidally and Insecticidally Active Compounds. Patent WO199216510, 1 October 1992. [Google Scholar]
  2. Muehlebach, M.; Boeger, M.; Cederbaum, F.; Cornes, D.; Friedmann, A.A.; Glock, J.; Niderman, T.; Stoller, A.; Wagner, T. Aryldiones incorporating a [1,4,5] oxadiazepane ring. part I: Discovery of the novel cereal herbicide pinoxaden. Bioorg. Med. Chem. 2009, 17, 4241–4256. [Google Scholar] [CrossRef]
  3. Bertozzi, D.; Marinello, J.; Manzo, S.G.; Fornari, F.; Gramantieri, L.; Capranico, G. The natural inhibitor of DNA topoisomerase 1. Camptothecin, modulates HIF-1α activity by changing miR expression pattern in human cancer cells. Mol. Cancer Ther. 2014, 13, 239–248. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  4. Kamata, M.; Yamashita, T.; Kina, A.; Tawada, M.; Endo, S.; Mizukami, A.; Sasaki, M.; Tani, A.; Nakano, Y.; Watanabe, Y.; et al. Symmetrical approach of spiro-pyrazolidinediones as acetyl-CoA carboxylase inhibitors. Bioorg. Med. Chem. Lett. 2012, 22, 4769–4772. [Google Scholar] [CrossRef] [PubMed]
  5. Kamata, M.; Yamashita, T. Pyrazolidinedione Derivative. JP Patent 2009196966A, 3 September 2009. [Google Scholar]
  6. Lam, B.V.; Berhault, Y.; Stiebing, S.; Fossey, C.; Cailly, T.; Collot, V.; Fabis, F. Iodoindazoles with selective magnesiation at position 3: A route to highly functionalized indazoles. Chem. Eur. J. 2016, 22, 4440–4446. [Google Scholar] [CrossRef]
  7. Wu, X.; Ji, H.J. Rhodium-catalyzed [4+1] cyclization via C–H activation for the synthesis of divergent heterocycles bearing a quaternary carbon. J. Org. Chem. 2018, 83, 4650–4656. [Google Scholar] [CrossRef]
  8. Yang, C.; Song, F.; Chen, J.; Huang, Y. Construction of pyridazine analogues via rhodium-mediated C-H activation. Adv. Synth. Catal. 2017, 359, 3496–3502. [Google Scholar] [CrossRef]
  9. Karishma, P.; Mahesha, C.K.; Agarwal, D.S.; Mandal, S.K.; Sakhuja, R.J. Additive-Driven Rhodium-catalyzed [4+1]/[4+2] annulations of N-arylphthalazine-1,4-dione with α-diazo carbonyl compounds. J. Org. Chem. 2018, 83, 11661–11673. [Google Scholar] [CrossRef] [PubMed]
  10. Kim, S.; Choi, S.B.; Kang, J.Y.; An, W.; Lee, S.H.; Oh, H.; Ghosh, P.; Mishra, N.K.; Kim, I.S. Synthesis of cinnolines via Rh(III)-catalyzed annulation of N-aryl heterocycles with vinylene carbonate. Asian J. Org. Chem. 2021, 10, 3005–3014. [Google Scholar] [CrossRef]
  11. Eicher, T.; Hauptmann, S. The Chemistry of Heterocycles, 2nd ed.; Wiley-VCH: Weinheim, Germany, 2003. [Google Scholar]
  12. Varvounis, G.; Fiamegos, Y.; Pilidis, G. Pyrazol-3-ones part 1: Synthesis and applications. Adv. Heterocycl. Chem. 2001, 80, 75–165. [Google Scholar]
  13. Elguero, J. Pyrazoles: Comprehensive Heterocyclic Chemistry II; Katritzky, A.R., Rees, C.W., Scriven, E.F.V., Eds.; Elsevier: Oxford, UK, 1996; Volume 3, pp. 1–75. [Google Scholar]
  14. Moghaddam, F.M.; Eslami, M.; Siahpoosh, A.; Golfam, H. A diastereoselective construction of functionalized dihydro-pyridazine based spirooxindole scaffold via C-3 umpolung of isatin N,N′-cyclic azomethine imine. New J. Chem. 2019, 43, 10318–10323. [Google Scholar] [CrossRef]
  15. Wang, X.; Yang, P.; Zhang, Y.; Tang, C.-Z.; Tian, F.; Peng, L.; Wang, L.-X. Isatin N,N′-cyclic azomethine imine 1,3-dipole and abnormal [3 + 2]-cycloaddition with maleimide in the presence of 1,4-diazabicyclo[2.2.2]octane. Org. Lett. 2017, 19, 646–649. [Google Scholar] [CrossRef] [PubMed]
  16. Wang, X.; Wu, L.; Yang, P.; Song, X.-J.; Ren, H.-X.; Peng, L.; Wang, L.-X. Isatin N,N′-cyclic azomethine imine 1,3-dipole and base catalyzed Michael addition with β-nitrostyrene via C3 umpolung of oxindole. Org. Lett. 2017, 19, 3051–3054. [Google Scholar] [CrossRef] [PubMed]
  17. Hu, S.; Zhang, J.; Jin, Q. DMAP-catalyzed alkylation of isatin N,N′-cyclic azomethine imine 1,3-dipoles with Morita-Baylis-Hillman carbonates. New J. Chem. 2018, 42, 7025–7029. [Google Scholar] [CrossRef]
  18. Jin, Q.; Zhang, J.; Jiang, C.; Zhang, D.; Gao, M.; Hu, S. Self [3 + 4] cycloadditions of isatin N,N′-cyclic azomethine imine 1,3-dipole with N-(o-chloromethyl)aryl amides. J. Org. Chem. 2018, 83, 8410–8416. [Google Scholar] [CrossRef] [PubMed]
  19. Wang, Q.-H.; Zhu, Z.-X.; Huang, T.; Wu, M.-S. Base catalyzed unexpected rearrangement of isatin-derived N,N′-cyclic azomethine imines and Michael addition to hindered vinylidene bisphosphonates: Access to 3,3-disubstituted oxindole-fused pyrazolidin-3-one derivatives containing bisphosphonates. Tetrahedron 2019, 75, 416–421. [Google Scholar] [CrossRef]
  20. Shi, Y.; Wang, G.; Chen, Z.; Wu, M.; Wang, J.; Trigoura, L.; Guo, H.; Xing, Y.; Sun, S. Synthesis of spiro(indoline-3,1-pyrazolo[1,2-a ]pyrazoles) by 1,3-dipolar cycloadditions of isatin N,N′-cyclic azomethine imines with alkynes. J. Heterocycl. Chem. 2020, 57, 2044–2047. [Google Scholar] [CrossRef]
  21. Song, X.J.; Ren, H.X.; Xiang, M.; Li, C.Y.; Tian, F.; Wang, L.X. Base catalyzed abnormal [3+2]-cycloaddition between isatin N,N′-cyclic azomethine imine 1,3-dipole and 3-methyleneoxindole for the one-step construction of tetracyclic bispirooxindoles. J. Org. Chem. 2020, 85, 3921–3928. [Google Scholar] [CrossRef] [PubMed]
  22. Song, X.J.; Ren, H.X.; Xiang, M.; Li, C.Y.; Zou, Y.; Li, X.; Huang, Z.C.; Tian, F.; Wang, L.X. Organocatalytic enantioselective Michael addition between 3-(3-hydroxy-1H-pyrazol-1-yl)oxindole and β-nitrostyrene for the preparation of chiral disubstituted oxindoles. J. Org. Chem. 2020, 85, 9290–9300. [Google Scholar] [CrossRef] [PubMed]
  23. Fang, Q.-Y.; Jin, H.-S.; Wang, R.-B.; Zhao, L.-M. A role for isatin azomethine imines as a dipolarphile in cycloaddition reactions. Org. Lett. 2020, 22, 7358–7362. [Google Scholar] [CrossRef]
  24. Jin, Q.; Zhang, D.; Zhang, J. A [3 + 2] cycloaddition/C-arylation of isatin N,N′-cyclic azomethine imine 1,3-dipole with arynes. RSC Adv. 2020, 10, 30620–30623. [Google Scholar] [CrossRef] [PubMed]
  25. Wang, Z.-Y.; Yang, T.; Chen, R.; Ma, X.; Liu, H.; Wang, K.-K. 1,3-dipolar cycloaddition of isatin N,N′-cyclic azomethine imines with α,β-unsaturated aldehydes catalyzed by DBU in water. RSC Adv. 2020, 10, 24288–24292. [Google Scholar] [CrossRef]
  26. Kartikey, K.D.D.; Reddy, M.S.; Chowhan, L.R. Isatin N,N′-cyclic azomethine imine 1, 3-dipole mediated regio and diastereoselective synthesis of isoxazole-containing spirooxindoles by an abnormal [3+2] cycloaddition. Tetrahedron Lett. 2020, 61, 152664. [Google Scholar] [CrossRef]
  27. Meerakrishna, R.S.; Suresh, S.S.; Athira, M.; Choutipalli, V.S.K.; Shanmugam, P. Diverse reactivity of isatin based N,N′-cyclic azomethine imine dipoles with arynes: Synthesis of 1′-methyl-2′-oxospiro [indene-1,3′-indolines] and 3-aryl-3-pyrazol-2-oxindoles. New. J. Chem. 2020, 44, 11593–11601. [Google Scholar] [CrossRef]
  28. Borah, B.; Chowhan, R.L. Recent updates on the stereoselective synthesis of structurally functionalized spiro-oxindoles mediated by isatin N,N′-cyclic azomethine imine 1, 3-dipoles. Tetrahedron Lett. 2022, 104, 154014. [Google Scholar] [CrossRef]
  29. Bian, Y.-J.; Qin, Y.; Xiao, L.-W.; Li, J.-T. New advances of Knoevenagel condensation reactions. Chin. J. Org. Chem. 2006, 26, 1165–1172. (In Chinese) [Google Scholar]
  30. Han, Y.F.; Xia, M. Multicomponent synthesis of cyclic frameworks on Knoevenagel-initiated domino reactions. Curr. Org. Chem. 2010, 14, 379–413. [Google Scholar] [CrossRef]
  31. Scherrmann, M.C. Knoevenagel reaction of unprotected sugars. In Carbohydrates in Sustainable Development II: A Mine for Functional Molecules and Materials; Rauter, A.P., Vogel, P., Queneau, Y., Eds.; Springer: Berlin/Heidelberg, Germany, 2010; Volume 295, pp. 1–18. [Google Scholar]
  32. Zanin, L.L.; Jimenez, D.E.Q.; Fonseca, L.P.; Porto, A.L.M. Knoevenagel condensation reactions of cyano malononitrile-derivatives under microwave radiation. Curr. Org. Chem. 2018, 22, 519–532. [Google Scholar] [CrossRef]
  33. Khare, R.; Pandey, J.; Smriti; Rupanwar, R. The importance and applications of Knoevenagel reaction (brief review). Orient. J. Chem. 2019, 35, 423–429. [Google Scholar] [CrossRef]
  34. Bugaenko, D.I.; Karchava, A.V.; Yurovskaya, M.A. The versatility of DABCO: Synthetic applications of its basic, nucleophilic, and catalytic properties part 1. catalysis of Morita-Baylis-Hillman and Knoevenagel reactions. Chem. Heterocycl. Comp. 2020, 56, 128–144. [Google Scholar] [CrossRef]
  35. Heravi, M.M.; Janati, F.; Zadsirjan, V. Applications of Knoevenagel condensation reaction in the total synthesis of natural products. Monatsh. Chem. 2020, 151, 439–482. [Google Scholar] [CrossRef]
  36. Beurden, K.; Koning, S.; Molendijk, D.; Schijndel, J. The Knoevenagel reaction: A review of the unfinished treasure map to forming carbon-carbon bonds. Green Chem. Lett. Rev. 2020, 13, 85–100. [Google Scholar] [CrossRef]
  37. Johari, S.; Johan, M.R.; Khaligh, N.G. An overview of metal-free sustainable nitrogen-based catalytic Knoevenagel condensation reaction. Org. Biomol. Chem. 2022, 20, 2164–2186. [Google Scholar] [CrossRef] [PubMed]
  38. Chen, Z.; Yue, G.; Lu, C.; Yang, G. Synthesis of a library of indolizines using poly (ethylene glycol) as soluble support. Synlett 2004, 2004, 1231–1234. [Google Scholar] [CrossRef]
  39. Yue, G.; Wan, Y.; Song, S.; Yang, G.; Chen, Z. Synthesis of a library of benzoindolizines using poly (ethylene glycol) as soluble support. Bioorg. Med. Chem. Lett. 2005, 15, 453–458. [Google Scholar] [CrossRef]
  40. Yue, G.; Chen, Z.; Yang, G. Synthesis of a library of 1,2,3,7-tetrasubstituted indolizines using poly(ethylene glycol) as soluble support. J. Heterocycl. Chem. 2006, 43, 781–786. [Google Scholar] [CrossRef]
  41. Yue, G.-Z.; Huang, Q.-M.; Zou, P. Recent development in the synthesis of indolizines. Chin. J. Org. Chem. 2007, 27, 1060–1068. (In Chinese) [Google Scholar]
  42. Yue, G.; Wu, Y.; Dou, Z.; Chen, H.; Yin, Z.; Song, X.; He, C.; Wang, X.; Feng, J.; Zhang, Z.; et al. Synthesis of spiropyrrolidine oxindoles via Ag-catalyzed stereo- and regioselective 1,3-diploar cycloaddition of indole-based azomethine ylides with chalcones. New J. Chem. 2018, 42, 20024–20031. [Google Scholar] [CrossRef]
  43. Yue, G.; Dou, Z.; Zhou, Z.; Zhang, L.; Feng, J.; Chen, H.; Yin, Z.; Song, X.; Liang, X.; Wang, X.; et al. Rapid abnormal [3+2]-cycloaddition of isatin N,N′-cyclic azomethine imine 1,3-dipoles with chalcones. New J. Chem. 2020, 44, 8813–8817. [Google Scholar] [CrossRef]
  44. Yue, G.; Liu, B. Research progress on [3+n] (n≥3) cycloaddition of 1,3-diploes. Chin. J. Org. Chem. 2020, 40, 3132–3153. (In Chinese) [Google Scholar] [CrossRef]
  45. Yue, G.; Jiang, D.; Dou, Z.; Li, S.; Feng, J.; Zhang, L.; Chen, H.; Yang, C.; Yin, Z.; Song, X.; et al. Rapid umpolung Michael addition of isatin N,N′-cyclic azomethine imine 1,3-dipoles with chalcones. New J. Chem. 2021, 45, 11712–11718. [Google Scholar] [CrossRef]
  46. CCDC 2151254 Contain the Supplementary Crystallographic Data for Compound 4a. Cambridge Crystallographic Data Centre. Available online: www.Ccdc.cam.ac.uk/data_request/cif (accessed on 10 February 2022).
  47. Biswas, S.; Balha, M.; Das, S.; Pan, C.S. Organocatalytic asymmetric reaction between α-cyano enones and dioxindoles: Synthesis of dihydrofuran-spirooxindoles. Asian J. Org. Chem. 2022, 11, e202200359. [Google Scholar] [CrossRef]
  48. Nirschl, A.A.; Hamann, L.G. Method of Using 3-cyano-4-arylpyridine Derviatives as Modulators of Androgen Receptor Fuction. U.S. Patent 20050182105, 18 August 2005. [Google Scholar]
Molecules 28 01034 g001 550
Figure 1. Representatives of bioactive pyridazine-fused heterocycles (I–IV).
Figure 1. Representatives of bioactive pyridazine-fused heterocycles (I–IV).
Molecules 28 01034 g001
Molecules 28 01034 sch001 550
Scheme 1. [3+3]-cycloaddition of N,N′-cyclic azomethine imine 1,3-dipoles with Knoevenagel adducts.
Scheme 1. [3+3]-cycloaddition of N,N′-cyclic azomethine imine 1,3-dipoles with Knoevenagel adducts.
Molecules 28 01034 sch001
Molecules 28 01034 g002 550
Figure 2. The phenomenon of the reaction for 1a and 2a under K2CO3 in DCE at reflux and TLC analysis: (a) no K2CO3 (0 h) (a light red cloudy solution); (b) added K2CO3 (3 h) (a clarified luminous yellow solution); (c): reaction finished (4 h) (a dark green solution).
Figure 2. The phenomenon of the reaction for 1a and 2a under K2CO3 in DCE at reflux and TLC analysis: (a) no K2CO3 (0 h) (a light red cloudy solution); (b) added K2CO3 (3 h) (a clarified luminous yellow solution); (c): reaction finished (4 h) (a dark green solution).
Molecules 28 01034 g002
Molecules 28 01034 g003 550
Figure 3. X-ray crystal structure of 4a (CCDC: 2151254).
Figure 3. X-ray crystal structure of 4a (CCDC: 2151254).
Molecules 28 01034 g003
Molecules 28 01034 sch002 550
Scheme 2. Transformation of the dicyclic spiropyridazine oxoindole products.
Scheme 2. Transformation of the dicyclic spiropyridazine oxoindole products.
Molecules 28 01034 sch002
Molecules 28 01034 sch003 550
Scheme 3. The plausible reaction mechanism.
Scheme 3. The plausible reaction mechanism.
Molecules 28 01034 sch003
Table
Table 1. The condition optimization of model reaction a.
Table 1. The condition optimization of model reaction a.
Molecules 28 01034 i043
EntryReaction ConditionYield (%) bRatio of 3a:3a′ d
1DABCO, DCM, rt to refluxNR c- e
2K2CO3, DMSO, 0.5 h, rt452.5:1
3K2CO3, DMF, 0.8 h, rt471.5:1
4K2CO3, DMA, 0.8 h, rt671.6:1
5K2CO3, pyrrolidone, 0.8 h, rt552.5:1
6K2CO3, NMP, 0.2 h, rt32- e
7K2CO3, HEP, 0.8 h, rt421:1
8K2CO3, H2O, 2 h, rt11- e
9K2CO3, MeOH, 0.5 h, rt37- e
10K2CO3, EtOH, 0.2 h, rt25- e
11K2CO3, THF, 1 h, rt37- e
12K2CO3, ACN, 1 h, rt36- e
13K2CO3, dioxane, 1 h, rt25- e
14K2CO3, PhMe, 0.5 h, rt39- e
15K2CO3, DCM, 4 h, refluxNR c- e
16K2CO3, CHCl3, 4 h, refluxNR c- e
17K2CO3, DCE, 1.8 h, reflux777.2:1
18Li2CO3, DCE, 4 h, refluxNR c- e
19Na2CO3, DCE, 4 h, reflux41- e
20Cs2CO3, DCE, 4 h, refluxNR c- e
21NaOH, DCE, 2.5 h, reflux35- e
22KOH, DCE, 2.5 h, reflux35- e
23MeONa, DCE, 1 h, reflux37- e
24EtONa, DCE, 4 h, refluxNR c- e
25NaH, DCE, 2 h, reflux733.5:1
26TEA, DCE, 1 h, reflux41- e
27DABCO, DCE, 1 h, reflux14- e
28DIPEA, DCE, 2 h, reflux50- e
29DMAP, DCE, 0.5 h, reflux35- e
30DBU, DCE, 12 min, reflux26- e
310.5 eq K2CO3, DCE, 1.8 h, reflux653.3:1
321.0 eq K2CO3, DCE, 2.0 h, reflux553.6:1
331.5 eq K2CO3, DCE, 1.7 h, reflux755.6:1
342.5 eq K2CO3, DCE, 2.3 h, reflux677.1:1
353.0 eq K2CO3, DCE, 2 h, reflux754.8:1
364.0 eq K2CO3, DCE, 2.5 h, reflux612.7:1
37K2CO3, 2.2 eq. 2a, DCE, 0.8 h, reflux891.9:1
38K2CO3, 2.5 eq. 2a, DCE, 0.9 h, reflux822.9:1
39K2CO3, 3.3 eq. 2a, DCE, 1.5 h, reflux864.4:1
40K2CO3, 1 mL DCE, 0.7 h, reflux712.7:1
41K2CO3, 4 mL DCE, 2.2 h, reflux656.3:1
a Unless otherwise indicated, the reaction was performed at the 0.5 mmol scale in a solvent (2.0 mL) with base (2.0 equiv.) at rt, and the molar ratio of 1a:2a was 1.0:1.1. b Isolated yield. c NR: No Reaction. d The selectivity was determined by 1H NMR. e ND: not determined.
Table
Table 2. Synthesis of tricyclic spiropyridazine oxindoles 3 and 3′ from isatin N,N′-cyclic azomethine imine 1a and Knoevenagel adducts 2 a.
Table 2. Synthesis of tricyclic spiropyridazine oxindoles 3 and 3′ from isatin N,N′-cyclic azomethine imine 1a and Knoevenagel adducts 2 a.
Molecules 28 01034 i044
EntryCompoundArYield (%)of 3/3′ b Ratio of 3:3′ c
13a/3′aPh866.3:1
23b/3′b2-MeC6H4651:7.1
33c/3′c3-MeC6H4591:3
43d/3′d4-MeC6H4601:4.6
53e/3′e2-MeOC6H4691:2.5
63f/3′f3-MeOC6H443(49) d1:2.4(1.2:1)
73g/3′g4-MeOC6H4662.5:1
83h/3′h2-FC6H4783:1
93i/3′i3-FC6H4663:1
103j/3′j4-FC6H45810:1
113k/3′k2-ClC6H4891:1.3
123l/3′l3-ClC6H4591:2
133m/3′m4-ClC6H4541:3.3
143n/3′n2-BrC6H4591.6:1
153o/3′o3-BrC6H4711:8.3
163p/3′p4-BrC6H4712.9:1
173q/3′q4-NO2C6H426(38) d1:1.4(1.2:1)
183r/3′r2-naphthyl35(58) d1:2(1.3:1)
193s/3′s3,4-Me2C6H4541:3
203t/3′t3,4-(MeO)2C6H437(53) d1:9.2(1:5)
213u/3′u2,4-Cl2C6H4875:1
223v/3′v3,4-Cl2C6H442(45) d2.3:1(1.2:1)
233w/3′w(E)-PhCH = CH402.5:1
a Reaction conditions: 1a (1.0 mmol), 2a (1.1 mmol) and K2CO3 (2.0 mmol), DCE (4.0 mL), reflux, 1–18 h. b Isolated yield via recrystallization or column chromatography. c The selectivity was determined by 1 H NMR. d The reaction condition: only instead of 2a (1.1 mmol) with 2a (2.2 mmol) (Table 1, Entry 38).
Table
Table 3. Synthesis of dicyclic spiropyridazine oxindoles 4 and 4′ from isatin N,N′-cyclic azomethine imines 1b–g and Knoevenagel adducts 2a a.
Table 3. Synthesis of dicyclic spiropyridazine oxindoles 4 and 4′ from isatin N,N′-cyclic azomethine imines 1b–g and Knoevenagel adducts 2a a.
Molecules 28 01034 i045
EntryCompoundRYield (%) b of 4/4′Ratio of 4/4′ c
14a/4′a5-Me80(75) d1.6:1
24b/4′b5-OMe701:2
34c/4′c5-F613:1
44d/4′d5-Cl821:1
54e/4′e6-Br47(50) e3.3:1(2:1)
64f/4′f5-I421.7:1
74g/4′g5-NO220(42) e2.5:1(1:1.4)
84h/4′h7-CF3741.6:1
a Reaction conditions: 1a (1.0 mmol), 2a (1.1 mmol) and K2CO3 (2.0 mmol), DCE (4.0 mL), reflux, 3–12 h. b Isolated yield via column chromatography. c The selectivity was determined by 1H NMR. d The reaction was scaled up to 5.0 mmol, and obtained the products 4a/4′a with a total quality of 1.44 g. e Reaction condition: only instead of 2a (1.1 mmol) with 2a (2.2 mmol) (Table 1, Entry 38).
Table
Table 4. Synthesis of dicyclic spiropyridazine oxindoles 5 and 5′ from isatin N,N′-cyclic azomethine imines 1h–m and Knoevenagel adducts 2 a.
Table 4. Synthesis of dicyclic spiropyridazine oxindoles 5 and 5′ from isatin N,N′-cyclic azomethine imines 1h–m and Knoevenagel adducts 2 a.
Molecules 28 01034 i046
EntryCompoundR1R2ArYield (%) of 5/5′ b Ratio of 5/5′ c
15a/5′aMeHPh781.5:1
25b/5′bMeH4-MeC6H4871.7:1
35c/5′cMeH4-MeOC6H4732.1:1
45d/5′dMeH4-FC6H4932.8:1
55e/5′eMeH4-ClC6H4581.3:1
65f/5′fMeH4-BrC6H4661.6:1
75g/5′gMeH4-NO2C6H4701.3:1
85h/5′hHMePhtrace-
95i/5′iHPhPhtrace-
a Reaction conditions: 1a (1.0 mmol), 2a (1.1 mmol) and K2CO3 (2.0 mmol), DCE (4.0 mL), reflux, 1–16 h. b Isolated yield via column chromatography. c The selectivity was determined by 1H NMR.
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MDPI and ACS Style

Yang, G.; Li, S.; Wang, Q.; Chen, H.; Yang, C.; Yin, Z.; Song, X.; Zhang, L.; Lu, C.; Yue, G. K2CO3-Promoted Formal [3+3]-Cycloaddition of N-Unsubstituted Isatin N,N′-Cyclic Azomethine Imine 1,3-Dipoles with Knoevenagel Adducts. Molecules 2023, 28, 1034. https://doi.org/10.3390/molecules28031034

AMA Style

Yang G, Li S, Wang Q, Chen H, Yang C, Yin Z, Song X, Zhang L, Lu C, Yue G. K2CO3-Promoted Formal [3+3]-Cycloaddition of N-Unsubstituted Isatin N,N′-Cyclic Azomethine Imine 1,3-Dipoles with Knoevenagel Adducts. Molecules. 2023; 28(3):1034. https://doi.org/10.3390/molecules28031034

Chicago/Turabian Style

Yang, Guosheng, Sicheng Li, Qiumi Wang, Huabao Chen, Chunping Yang, Zhongqiong Yin, Xu Song, Li Zhang, Cuifen Lu, and Guizhou Yue. 2023. "K2CO3-Promoted Formal [3+3]-Cycloaddition of N-Unsubstituted Isatin N,N′-Cyclic Azomethine Imine 1,3-Dipoles with Knoevenagel Adducts" Molecules 28, no. 3: 1034. https://doi.org/10.3390/molecules28031034

APA Style

Yang, G., Li, S., Wang, Q., Chen, H., Yang, C., Yin, Z., Song, X., Zhang, L., Lu, C., & Yue, G. (2023). K2CO3-Promoted Formal [3+3]-Cycloaddition of N-Unsubstituted Isatin N,N′-Cyclic Azomethine Imine 1,3-Dipoles with Knoevenagel Adducts. Molecules, 28(3), 1034. https://doi.org/10.3390/molecules28031034

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