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Article

Synthesis of Spirocyclopropane-Containing 4H-Pyrazolo[1,5-a]indoles via Alkylative Dearomatization and Intramolecular N-Imination of an Indole–O-(Methylsulfonyl)oxime

by
Jiann-Jyh Huang
1,2,*,†,
Hung-Chun Liao
2,
Cheng-En Hsu
2,
Yan-Ru Liu
2,
Yi-Fu Chang
2 and
Shan-Yen Chou
3,*,†
1
Institute of BioPharmaceutical Sciences, National Sun Yat-sen University, Kaohsiung 80424, Taiwan
2
Department of Applied Chemistry, National Chiayi University, Chiayi City 600, Taiwan
3
Development Center for Biotechnology, National Biotechnology Research Park, Taipei City 115, Taiwan
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Molecules 2023, 28(17), 6374; https://doi.org/10.3390/molecules28176374
Submission received: 9 August 2023 / Revised: 26 August 2023 / Accepted: 29 August 2023 / Published: 31 August 2023
(This article belongs to the Special Issue Feature Papers in Organic Chemistry (Volume II))
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Versions Notes

Abstract

:
In this paper, we report the synthesis of spirocyclopropane-containing 4H-pyrazolo[1,5-a]indoles 6a–e via alkylative dearomatization and intramolecular N-imination of indole–O-(methylsulfonyl)oxime 11. Starting materials tryptophol (7) and 2-bromocyclopetanone (8) were reacted in the presence of HBF4·OEt2, providing 1,2,3,5,6,11-hexahydrocyclopenta[2,3]oxepino[4,5-b]indole (9) in a 63% yield. Compound 9 was reacted with hydroxylamine hydrochloride to afford oxime 10 (65% yield), which was subsequently bis-methanesulfonated to form 11 in a 85% yield. Heating 11 with various alcohols in the presence of N,N-diisopropylethylamine (DIPEA) triggered the alkylative dearomatization and intramolecular N-imination, forming the spirocyclopropane and 4H-pyrazolo[1,5-a]indole structures in the targets 6a–e with 67–84% yields.

Graphical Abstract

1. Introduction

Pyrazolo[1,5-a]indole, a condensed type of pyrazoloindole, has three possible isomers. The 4H-Pyrazolo[1,5-a]indole (1, Figure 1) is the most stable isomer as the 1H-isomer is isoelectronic to azulene [1,2], and the 3H-isomer is readily converted to 1 [3,4]. As a result, pyrazoloindole 1 and its derivatives are more frequently reported. Representative examples using 1 as their scaffold or substructure are also 199shown in Figure 1, including diester 2 with a benzo-fused structure [5], salt 3 substituted with an exocyclic 4-methylene [6,7,8], benzo-fused 4 with a 4-spirosuccinimide [9], and Siamese-twin-type porphyrin 5 [10]. Among them, compound 3 shows potent anti-cancer activity through inhibiting topoisomerase I [2], and compound 5 has an interesting folded structure [10].
Reported methods for the synthesis of 4H-pyrazolo[1,5-a]indole 1 are reviewed in Scheme 1. Katayama and his colleagues first reported the intramolecular cycloaddition of 2-allylphenylhydrazones to form the dihydropyrazoloindoles [11], followed by oxidation with DDQ [12] to synthesize 2-substituted 1 (Scheme 1A). Intramolecular cyclization of 1-(2′-carboethoxyphenyl)pyrazoles and subsequent reductive decarbonylation were also accomplished by Katayama to prepare 2-substituted 1 (Scheme 1B) [12]. The same group later reported the cyclization of hydrozone-containing indolines in the presence of Lewis acid (Scheme 1C) [13,14] and the use of Boulton–Katritzky rearrangement as the key step to synthesize 2-substituted 1 (Scheme 1D) [15]. Dougherty and his colleagues found the thermal decomposition of a diazide-generated benzo-fused 1 (Scheme 1E), which was the synthetic method for compound 2 shown in Figure 1 [5]. Pd-catalyzed [16] and Cu-catalyzed [17] aromatic amination of indolines were also reported by the Katayama group to prepare the benzo-fused derivatives of 1 (Scheme 1F). In another approach (Scheme 1G), Zhu and his colleagues applied Cu-catalyzed intramolecular N-arylation to pyrazoles to synthesize various 2- and/or 3-substituted derivatives of 1 [18], and the reaction could start from 1,3-diketones and hydrazine in tandem conditions [19]. Spiro 4 and its derivatives were prepared via the dehydrogenative annulation reaction of 2-arylindazoles with maleimides (Scheme 1H) [9]. As shown in Scheme 1I, salt 3 (Figure 1) was prepared by reacting the corresponding 1 with MeOTf and benzaldehyde [6,7]. Porphyrin 5 was prepared from the oxidation of its precedent Siamese-twin porphyrin [10].
We are interested in synthesizing novel heterocyclic compounds as they are often biologically active and possibly developed as pharmaceuticals [20]. In our discovering indolo[3,2-c]quinolinones as topoisomerase-I inhibitors [21], we found that spirocyclopropane-containing 4H-pyrazolo[1,5-a]indoles 6a–e could be readily prepared from indole–O-(methylsulfonyl)oxime 11 through double cyclization reactions (Scheme 2). Substrate 11 was synthesized from tryptophol (7) and 2-bromocyclopentanone (8) through intermediates 9 and 10. Compared with the synthetic methods from the literature (Scheme 1), our method has the advantage of using simple starting materials (indole and cycloalkanone) and avoiding the use of expensive or toxic metal catalysts to form 6a–e having complex structures in good yields. In addition, 6a–e are new compounds and have a characteristic cyclopropyl fragment that frequently appears in preclinical/clinical drug molecules [22], which might render them biologically active. Furthermore, the functional groups in 6a–e, such as the alkoxy and spirocyclopropane, could further be modified to give derivatives with more diverse substituents.
Herein, we report the detailed reaction conditions for the transformations shown in Scheme 2. Based on the results, we also provided a tentative reaction mechanism to account for the cyclization of 11 to form 6a–e.

2. Results and Discussion

We first found that the reaction of 7 with 2-chlorocyclopentanone (12) in the presence of pyridinium p-toluenesulfonate (PPTS, 20 mol %) in refluxing toluene for 2.0 h formed a trace amount of 1,2,3,5,6,11-hexahydrocyclopenta[2,3]oxepino[4,5-b]indole (9, entry 1, Table 1). As this reaction should take place through hemiacetal formation and Friedel–Crafts-like alkylation, the more reactive bromo substrate 8 was tried as the substrate. Nevertheless, the yield for 9 was not improved (entry 2). Using more acidic toluenesulfonic acid (TsOH) did not form the product regardless of using 8 or 12 (entries 3 and 4). Application of BF3·OEt2 (150 mol %) for the reaction with elongation of the reaction time to 3.0 h in CH2Cl2 at 0 °C gave the target 9 in 20% and 26% yields from substrates 12 and 8, respectively (entries 5 and 6). When HBF4·OEt2 was used, the yields of 9 increased to 56% and 63% from the corresponding 12 and 8 (entries 7 and 8). Reduction of the amount of HBF4·OEt2 (75 mole %) decreased the yields of 9 (entries 9 and 10).
We then treated 9 with hydroxylamine hydrochloride (NH2OH·HCl) in EtOH and calculated the isolated yields of oxime 10 and enone 13 (Table 2). The reaction was found not to take place at room temperature (entry 1). At 55 °C, the reaction gave 10 and 13 in 63% and 27% yields, respectively (entry 2). Increasing the reaction temperature, the amount of NH2OH·HCl and the reaction time showed similar results (entries 3–5). As a result, enone 13 and its oxime 10 might be interconverted in equilibrium. The transformation comprised a benzylic oxidative reaction as a conjugated double bond was formed in 10 and 13.
Mesylation of 10 with methanesulfonyl chloride (MsCl) and N,N-diisopropylethylamine (DIPEA) in CH2Cl2 afforded indole–O-(methylsulfonyl)oxime 11 (85% yield, Scheme 2), which was then reacted with various alcoholic solvents to afford the target spirocyclopropane-containing 4H-pyrazolo[1,5-a]indoles 6a–e. Ethoxy analog 6a was generated with an 81% yield. Propoxy analog 6b had a better 84% yield. Tert-butoxy analog 6c and benzyloxy analog 6d showed slightly reduced yields (67% and 72%). The reaction of 11 with (E)-but-2-enol afforded the target 6e an 81% yield with the retention of the trans configuration in the alkoxy group. When DIPEA for the reaction was replaced with secondary amines (e.g., Me2NH, Et2NH), a messy mixture was formed without the expected amino product. This might come from the reaction of the strong nucleophilic amines with the O-(methylsulfonyl)oxime or the cyclopropane moiety, which would result in the formation of multiple by-products.
The structures of the synthesized compounds 9, 10, 11, 13, and 6a–e were fully characterized by spectroscopic methods (see Supplementary Materials). First, their molecular formulas were consistent with those suggested by high-resolution mass spectrometry. For the structure of 9, five separated CH2 multipletes at 1.96–4.41 ppm in the 1H NMR spectrum suggested the presence of a cyclopentaoxepino moiety, in which the peaks at 4.28–4.41 ppm corresponded to the CH2 adjacent to the oxygen atom. A broad singlet at 7.68 ppm revealed an indolyl NH. The five most downfield peaks at 69.41 (OCH2), 34.12 (OCCH2), 30.32 (OC=CCH2), 27.74 (OCH2CH2), and 19.98 (CH2CH2CH2) ppm in the 13C NMR spectrum of 9 further supported the structure of a cyclopentaoxepino moiety.
For the structure of 10, the presence of an oxime functionality was revealed by the stretching vibration bands at 3572 cm–1 (O–H), 1645 cm–1 (C=N), and 922 cm–1 (N–O) in the IR spectrum. Protons of the two CH2 in the cyclopentenone oxime moiety produced two multipletes at 2.72–2.77 and 2.85–2.89 ppm in the NMR spectrum, and the sole olefinic proton resided at 7.53–7.70 ppm. Protons of the two CH2 connected to the indole showed two tripletes centered at 3.23 and 3.96 ppm. In the 13C NMR spectrum of 10, the β-carbon of the enone oxime showed a peak at 143.60 ppm. On the other hand, the spectra of 13 were similar to those of 10, except that the carbonyl carbon showed a peak at 210.56 ppm. For 11, similar 1H NMR patterns were observed. The two CH3 in the mesylate were located at 2.82 and 3.15 ppm in the 1H NMR spectrum and at 36.90 and 37.55 ppm in the 13C NMR spectrum.
For the final product 6a, its ethoxy peaks were found at 1.21 ppm (triplet) and 3.51–3.40 ppm (multiplet) in the 1H NMR spectrum. Peaks at 1.63–1.87 ppm (multiplet) indicated the presence of a cyclopropane moiety, which was further confirmed by 13C NMR and DEPT spectrometry. The two methylene carbons were found at 17.81 and 16.79 ppm, and the quaternary carbon was found at 23.56 ppm. These results supported the structures of 6a and could be referred to as the structures of 6b–e bearing different alkoxy groups.
For reaction mechanisms of the transformations shown in Scheme 2, we presume that the condensation of 7 and 8 to afford 9 took place by a hemiacetal formation and Friedel–Crafts-like alkylation, both promoted by the strong acid HBF4·OEt2 (step 1). The enol-ether-containing seven-membered ring in 9 should be opened by highly nucleophilic hydroxylamine followed by benzylic oxidation to form 10 (step 2). This step might be a novel tandem oximation/oxidation reaction that can be further investigated. Compound 10 was then converted to bis-methanesulfonated 11 by reacting with MsCl (step 3). The intriguing cyclization of 11 to 6a–e (step 4) was accounted for in a tentative reaction mechanism presented in Scheme 3. DIPEA first deprotonated 11, and the formed amide anion pushed the conjugated π electrons to expel the methanesulfonate anion (MsO–), forming the spirocyclopropane structure in 14. This alkylative dearomatization reaction (11 → 14) might take place first as similar reactions were reported to proceed fast [23,24]. Intermediate 14, having a cross-conjugation system, was attacked by alcohols to form anion 15 with a more stable N-anion, C=C, and C=N conjugation. Finally, the N-imination reaction occurred in 15 when the amide anion attacked the nitrogen atom of the oxime sulfonate ester to form the pyrazole moiety in the final products 6a–e. The mechanism of this N–N formation was supported by the similar reactions reported by Stambuli and his colleagues for the synthesis of indazoles [25,26] and should be thermodynamically favored because of the formation of aromatic structure.
Oxime and its O-substituted derivative (i.e., the oxime sulfonate in 11, Scheme 2 and Scheme 3) can be used as electron-deficient N-imination or amination agents [27]. In addition to the transformation of 11 to 6a–e (Scheme 3) and the synthesis of indazole previously mentioned [25,26], an intramolecular reaction of O-(arylsulfonyl)oximes with a nearby amino group was applied to the synthesis of 1,2,3-triazoles [28]. Oximes activated by N,N’-dicyclohexylcarbodiimide were also used to synthesize pyrrolidines [29]. The intermolecular reaction of O-(arylsulfonyl)oximes with arylamines forms the corresponding arylhydrazones [30,31]. Arylamines, alkylamines, and sulfonamides can couple with 2-bromoaryl oxime acetates catalyzed by Cu(I) to afford various 1H-indazoles [32]. Therefore, the transformation of 11 to 6a–e reported herein was a new application of N-imination with activated oximes for the synthesis of 4H-pyrazolo[1,5-a]indoles.

3. Materials and Methods

3.1. General Procedure

Reagents and starting materials were used as purchased without further purification. Purification by column chromatography was conducted using Merck Reagents Silica Gel 60 (particle size of 0.063–0.200 mm, 70–230 mesh ASTM). The melting point was recorded on a STUART SMP3 apparatus. Proton (300 MHz) and carbon-13 (75 MHz) NMR spectra were recorded on a Varian Mercury-300 spectrometer using CDCl3 as the solvent. Multiplicities are abbreviated as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; J, coupling constant (hertz). Infrared (IR) spectra were measured on a PerkinElmer ONE FT-IR spectrometer with an ATR accessory. High-resolution mass spectra were obtained on an LTQ Orbitrap XL mass spectrometer (Thermo Fisher Scientific).

3.2. Synthesis of Compounds 9–11

3.2.1. 1,2,3,5,6,11-Hexahydrocyclopenta[2,3]oxepino[4,5-b]indole (9)

A solution of tryptophol (7, 5.50 g, 34.1 mmol) and freshly prepared 2-bromocyclopentanone (8, 7.11 g, 43.6 mmol) [33] in anhydrous CH2Cl2 (90 mL) was added with HBF4·OEt2 (11.04 g, 68.2 mmol) in a period of 5.0 min at 0 °C under N2. The reaction mixture was stirred at 0 °C for 10 h. The solution was diluted with CH2Cl2 (90 mL), quenched with icy water (100 mL), neutralized with saturated aqueous K2CO3, and filtered through Celite. The filtrate was washed with water, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of EtOAc and hexanes (1:5) as the eluent to give the target 9 (4.83 g, 21.4 mmol) in 63% yield: brown oil; 1H NMR δ 7.68 (brs, 1 H), 7.47–7.40 (m, 1 H), 7.33–7.27 (m, 1 H), 7.13–7.06 (m, 1 H), 4.41–4.28 (m, 2 H), 3.21 (t, J = 4.4 Hz, 2 H), 2.82–2.71 (m, 2 H), 2.66–2.55 (m, 2 H), and 2.10–1.96 (m, 2 H); 13C NMR δ 157.70, 135.05, 132.13, 128.50, 120.84, 119.52, 117.10, 110.66, 110.48, 103.36, 69.41, 34.12, 30.32, 27.74, 19.98; IR 3443, 3386, 2961, 2924, 2889, 1629, 1460, 1327, 1274, 1098, and 731 cm–1; HRMS Calcd for [C15H15NO + H+]: 226.1226; Found: 226.1224; new compound.

3.2.2. (E)-2-[3-(2-Hydroxyethyl)-1H-indol-2-yl]cyclopent-2-en-1-one Oxime (10)

A solution of 9 (2.70 g, 12.0 mmol) and hydroxylamine hydrochloride (1.80 g, 25.9 mmol) in 95% EtOH (100 mL) was heated under reflux for 15 h under N2. The solution was concentrated, re-dissolved in CH2Cl2 (20 mL), washed with 5% aqueous Na2CO3 (10 mL) and water (10 mL), and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of EtOAc and hexanes (1:2) as the eluent to give 10 (2.00 g, 7.80 mmol) as white solids in 65% yield: mp 140.5–141.5 °C; 1H NMR δ 9.97 (brs, 1 H), 7.70–7.53 (m, 1 H), 7.36 (dt, J = 8.1, 1.0 Hz, 1 H), 7.23–7.07 (m, 3 H), 3.96 (t, J = 6.6 Hz, 2 H), 3.23 (t, J = 6.6 Hz, 2 H), 2.89–2.85 (m, 2 H), and 2.77–2.72 (m, 2 H); 13C NMR δ 168.37, 143.60, 135.05, 130.97, 128.60, 128.41, 122.50, 119.45, 118.61, 111.21, 110.40, 62.47, 29.97, 28.45, and 25.25; IR 3572, 3341, 3077, 2873, 1645, 1453, 1434, 1304, 1004, 922, and 740 cm–1; HRMS calculated for [C15H16N2O2 + H+]: 257.1285; Found: 257.1283; new compound.

3.2.3. 2-[3-(2-Hydroxyethyl)-1H-indol-2-yl]cyclopent-2-en-1-one (13)

Compound 13 was purified by column chromatography from the reaction mixture to prepare 10; white solids; mp 141.0–141.5 °C; 1H NMR δ 10.32 (brs, 1 H), 8.19 (t, J = 3.2 Hz, 1 H), 7.64–7.58 (m, 1 H), 7.41 (dt, J = 8.1, 1.1 Hz, 1 H), 7.22 (ddd, J = 8.1, 7.0, 1.1 Hz, 1 H), 7.12 (ddd, J = 8.0, 7.0, 1.1 Hz, 1 H), 3.95 (t, J = 6.5 Hz, 2 H), 3.23 (t, J = 6.5 Hz, 2 H), 2.88–2.79 (m, 2 H), and 2.65–2.57 (m, 2 H); 13C NMR δ 210.56, 158.05, 135.34, 134.59, 128.04, 127.52, 123.16, 119.82, 118.79, 111.76, 111.13, 62.79, 35.00, 28.68, and 27.41; IR 3401, 3093, 3080, 2840, 1742, 1622, 1354, 1268, 1125, and 1118 cm–1; HRMS calculated for [C15H15NO2 + H+]: 242.1176; Found: 242.1172; new compound.

3.2.4. (E)-2-[2-(5-{[(Methylsulfonyl)oxy]imino}cyclopent-1-en-1-yl)-1H-indol-3-yl]ethyl Methanesulfonate (11)

An anhydrous CH2Cl2 solution (240 mL) of 10 (6.31 g, 24.6 mmol) and DIPEA (7.72 g, 59.7 mmol) in an ice bath was added with methanesulfonyl chloride (6.25 g, 54.6 mmol). The reaction mixture was stirred in an ice bath under N2 for 12 h. The solution was quenched with water (100 mL) and extracted with CH2Cl2 (50 mL × 2). The organic layer was washed with 1.0 N HCl (80 mL), water (80 mL), 10% NaHCO3 (80 mL), and brine. The solution was dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of EtOAc and hexanes (1:2) as the eluent to give 11 (8.63 g, 20.9 mmol) as a brown oil in 85% yield: 1H NMR δ 9.44 (brs, 1 H), 7.57 (d, J = 7.8 Hz, 1 H), 7.39 (d, J = 7.8 Hz, 1 H), 7.28–7.22 (m, 2 H), 7.15–7.13 (m, 1 H), 4.42 (t, J = 7.5 Hz, 2 H), 3.36 (t, J = 7.5 Hz, 2 H), 3.15 (s, 3 H), 3.00–2.96 (m, 2 H), 2.82 (s, 3 H), and 2.80–2.78 (m, 2 H); 13C NMR δ 175.83, 150.43, 135.40, 130.04, 127.87, 127.11, 123.49, 120.35, 118.53, 111.80, 109.31, 69.20, 37.55, 36.90, 30.59, 27.75, and 25.67; IR 3491, 3096, 3085, 1668, 1303, 1299, 1286, 1138, 1130, and 1027; HRMS calculated for [C17H20N2O6S2 + H+]: 413.0836; Found: 413.0833; new compound.

3.3. Synthesis of 1-Alkoxy-2,3-dihydro-1H-spiro[cyclopenta[3,4]pyrazolo[1,5-a]indole-10,1′-cyclopropanes] 6a–e

3.3.1. Standard Procedure

A reaction mixture of 11 (~200 mg, 1.0 equiv) and DIPEA (5.0 equiv) in an anhydrous alcoholic solvent (12 mL) was heated at 45–50 °C for 2.0 h. The solution was concentrated under reduced pressure, re-dissolved in CH2Cl2, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of EtOAc and hexanes (1:6) as the eluent to give 6a–e as liquids in 67–84% yields.

3.3.2. 1-Ethoxy-2,3-dihydro-1H-spiro[cyclopenta[3,4]pyrazolo[1,5-a]indole-10,1′-cyclopropane] (6a)

Using EtOH as the solvent; 81% yield; yellow liquid; 1H NMR δ 7.59 (d, J = 7.4 Hz, 1 H), 7.35–7.30 (m, 1 H), 7.16–7.09 (m, 1 H), 6.96 (d, J = 7.4 Hz, 1 H), 4.92–4.80 (m, 1 H), 3.54–3.42 (m, 2 H), 3.07–2.97 (m, 1 H), 2.81–2.64 (m, 2 H), 2.47–2.34 (m, 1 H), 1.91–1.71 (m, 4 H), and 1.22 (t, J = 7.0 Hz, 3 H); 13C NMR δ 166.06, 145.69, 140.50, 138.48, 127.14, 123.83, 119.46, 115.57, 110.12, 75.17, 63.37, 37.32, 23.81, 23.56, 17.81, 16.79, and 15.80; IR 3097, 3007, 2884, 1609, 1468, 1409, 1310, 1301, 1108, and 778 cm–1; HRMS calculated for [C17H18N2O + H+]: 267.1492; Found: 267.1488; new compound.

3.3.3. 1-Propoxy-2,3-dihydro-1H-spiro[cyclopenta[3,4]pyrazolo[1,5-a]indole-10,1′-cyclopropane] (6b)

Using PrOH as the solvent;: 84% yield; brown liquid; 1H NMR δ 7.61–7.57 (m, 1 H), 7.35–7.30 (m, 1 H), 7.17–7.10 (m, 1 H), 6.98–6.94 (m, 1 H), 4.86 (dd, J = 6.6, 3.2 Hz, 1 H), 3.48–3.40 (m, 1 H), 3.37–3.29 (m, 1 H), 3.07–2.98 (m, 1 H), 2.82–2.67 (m, 2 H), 2.44–2.34 (m, 1 H), 1.85–1.64 (m, 6 H), and 0.96 (t, J = 7.3 Hz, 3 H); 13C NMR δ 165.94, 145.64, 140.45, 138.44, 127.07, 123.77, 119.42, 115.51, 110.05, 75.31, 69.83, 37.16, 23.79, 23.47, 23.37, 17.86, 16.67, and 10.91; IR 3098, 3041, 3006, 2885, 1468, 1460, 1375, 1310, 1302, and 1109, cm–1; HRMS calculated for [C18H20N2O + H+]: 281.1648; Found: 281.1654; new compound.

3.3.4. 1-(Tert-butoxy)-2,3-dihydro-1H-spiro[cyclopenta[3,4]pyrazolo[1,5-a]indole-10,1′-cyclopropane] (6c)

Using t-BuOH and THF (3:1) as the solvent; 67% yield; brown liquid; 1H NMR δ 7.54 (d, J = 7.8 Hz, 1 H), 7.31–7.24 (m, 1 H), 7.11–7.06 (m, 1 H), 6.92 (d, J = 7.8 Hz, 1 H), 5.04 (t, J = 2.1 Hz, 1 H), 2.98–2.94 (m, 1 H), 2.77–2.70 (m, 2 H), 2.26 (m, 1 H), 1.94–1.91 (m, 1 H), 1.72–1.64 (m, 3 H), and 1.26 (s, 9 H); 13C NMR δ 164.77, 145.29, 140.60, 138.51, 127.19, 123.72, 119.54, 117.28, 110.09, 73.87, 68.76, 41.47, 31.42, 28.95, 24.31, 17.72, and 17.18; IR 3103, 3047, 3044, 3000, 1608, 1462, 1408, 1308, 1205, and 1077 cm–1; HRMS calculated for [C19H22N2O + H+]: 295.1805; Found: 295.1804; new compound.

3.3.5. 1-(Benzyloxy)-2,3-dihydro-1H-spiro[cyclopenta[3,4]pyrazolo[1,5-a]indole-10,1′-cyclopropane] (6d)

Using BnOH and THF (1:1) as the solvent; 72% yield; yellow liquid; 1H NMR δ 7.60 (d, J = 7.5 Hz, 1 H), 7.40–7.31 (m, 6 H), 7.14 (t, J = 7.5 Hz, 1 H), 6.95 (d, J = 7.5 Hz, 1 H), 4.99 (dd, J = 6.5, 3.2 Hz, 1 H), 4.55 (d, J = 11.6 Hz, 1 H), 4.47 (d, J = 11.6 Hz, 1 H), 3.10–3.01 (m, 1 H), 2.82–2.68 (m, 2 H), 2.55–2.41 (m, 1 H), 1.92–1.85 (m, 1 H), and 1.78–1.68 (m, 3 H); 13C NMR δ 166.08, 145.78, 140.45, 138.62, 138.44, 128.59, 127.87, 127.60, 127.05, 123.89, 119.46, 110.20, 74.76, 70.05, 37.07, 23.82, 23.58, 17.95, and 16.79; IR 3087, 3072, 2850, 1678, 1608, 1470, 1309, 1085, 1407, and 1370 cm–1; HRMS calculated for [C22H20N2O + H+]: 329.1648; Found: 329.1655; new compound.

3.3.6. (E)-1-(But-2-en-1-yloxy)-2,3-dihydro-1H-spiro[cyclopenta[3,4]pyrazolo[1,5-a]indole-10,1′-cyclopropane] (6e)

Using (E)-but-2-en-1-ol as the solvent; 81% yield; yellow liquid; 1H NMR δ 7.53 (d, J = 7.5 Hz, 1 H), 7.29–7.22 (m, 1 H), 7.09–7.06 (m, 1 H), 6.90 (d, J = 7.5 Hz, 1 H), 5.69–5.63 (m, 1 H), 5.58–5.50 (m, 1 H), 4.85–4.82 (m, 1 H), 3.86–3.82 (m, 2 H), 3.00–2.93 (m, 1 H), 2.75–2.57 (m, 2 H), 2.40–2.32 (m, 1 H), and 1.86–1.63 (m, 7 H); 13C NMR δ 166.16, 145.63, 140.47, 138.47, 129.43, 127.87, 127.13, 123.81, 119.43, 115.43, 110.12, 74.57, 68.76, 37.32, 23.76, 23.55, 17.95, 17.85, and 16.79; IR 2994, 2769, 2759, 1611, 1478, 1471, 1367, 1306, 1133, and 1081 cm–1; HRMS calculated for [C19H20N2O + H+]: 293.1648; Found: 293.1647; new compound.

4. Conclusions

We report a synthetic method for the preparation of spirocyclopropane-containing 4H-pyrazolo[1,5-a]indoles 6a–e from indole–O-(methylsulfonyl)oxime 11. Double cyclizations involving alkylative dearomatization and intramolecular N-imination were proposed as the reaction mechanism for the transformation. Currently, we are investigating intramolecular N-imination on simple indole substrates and the topoisomerase-I inhibitory activity of 6a–e. The results will be reported in due course.

Supplementary Materials

The following supporting information can be downloaded at https://www.mdpi.com/article/10.3390/molecules28176374/s1, 1H and 13C NMR spectra of compounds 9, 10, 11, and 6a–e.

Author Contributions

Conceptualization, J.-J.H. and S.-Y.C.; synthesis, H.-C.L., C.-E.H., Y.-R.L. and Y.-F.C.; writing—original draft preparation, J.-J.H. and S.-Y.C.; writing—review and editing, all authors; project administration, J.-J.H. and S.-Y.C. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the National Science and Technology Council (NSTC) of Taiwan, grant number NSTC 111-2113-M-110-017.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

The authors would like to thank the National Science and Technology Council (NSTC) of Taiwan for financial support.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Samples of the compounds are available from the authors.

References

  1. Shen, J.-K.; Katayama, H. 1H-Pyrazolo[l,5-a]indoles: Isoelectronic analogues of azulene (pseudoazulene). Chem. Pharm. Bull. 1992, 40, 2879–2881. [Google Scholar] [CrossRef]
  2. Shen, J.-K.; Katayama, H. Preparation and reaction of 1H-pyrazolo[l,5-a]indoles as isoelectronic analogues of azulene (pseudoazulene). J. Chem. Soc. Perkin Trans. 1 1994, 1871–1877. [Google Scholar] [CrossRef]
  3. Shen, J.-K.; Katayama, H. Preparation and reactions of 3H-pyrazolo[l,5-a]indole derivatives. Chem. Pharm. Bull. 1994, 42, 214–221. [Google Scholar] [CrossRef]
  4. Katayama, H.; Tagawa, N.; Kawada, Y.; Shiobara, K.; Kaneko, K.; Honda, Y.; Kondo, N.; Ikeda, Y. Heterocyclic analogues of quinone methide: Preparation and cytotoxicity of 3-oxo-3H-pyrazolo[1,5-a]indole derivatives. Chem. Pharm. Bull. 1997, 45, 143–147. [Google Scholar] [CrossRef]
  5. Kaszynski, P.; Dougherty, D.A. Synthesis and properties of diethyl 5,10-dihetera-5,10-dihydroindeno[2,1-a]indene-2,7-dicarboxylates. J. Org. Chem. 1993, 58, 5209–5220. [Google Scholar] [CrossRef]
  6. Katayama, H.; Kawada, Y.; Kaneko, K.; Oshiyama, T.; Takatsu, N. Synthetic inhibitors of DNA topoisomerase I and II. Chem. Pharm. Bull. 1999, 47, 48–53. [Google Scholar] [CrossRef]
  7. Katayama, H.; Kiryu, Y.; Kaneko, K.; Ohshima, R. Anti-cancer activities of pyrazolo[1,5-a]indole derivatives. Chem. Pharm. Bull. 2000, 48, 1628–1633. [Google Scholar] [CrossRef]
  8. Ji, Y.Y.; Zhu, Y.M.; Wang, J.W. GS-2, a pyrazolo[1,5-a]indole derivative with inhibitory activity of topoisomerases, exerts its potent cytotoxic activity by ROS generation. Environ. Toxicol. Pharmacol. 2013, 36, 1186–1196. [Google Scholar] [CrossRef]
  9. Guo, C.; Li, B.; Liu, H.; Zhang, X.; Zhang, X.; Fan, X. Synthesis of fused or spiro polyheterocyclic compounds via the dehydrogenative annulation reactions of 2-arylindazoles with maleimides. Org. Lett. 2019, 21, 7189–7193. [Google Scholar] [CrossRef]
  10. Vogel, A.; Dechert, S.; John, M.; Brückner, C.; Meyer, F. Siamese-twin porphyrin origami: Oxidative fusing and folding. Chem. Eur. J. 2016, 22, 2307–2316. [Google Scholar] [CrossRef]
  11. Katayama, H.; Takatsu, N.; Kitano, H.; Shimaya, Y. Intramolecular cycloaddition of 2-allylphenylhydrazones. Chem. Pharm. Bull. 1990, 38, 1129–1135. [Google Scholar] [CrossRef]
  12. Katayama, H.; Sakurada, M.; Herath, W.H.H.; Takatsu, N.; Shen, J.-K. Preparation of 4H-pyrazolo[1,5-a]indole. Chem. Pharm. Bull. 1992, 40, 2267–2269. [Google Scholar] [CrossRef]
  13. Shen, J.-K.; Katayama, H. Preparation of pyrazole and pyrazoline derivatives by intramolecular reaction of hydrazones. Chem. Lett. 1992, 21, 451–452. [Google Scholar] [CrossRef]
  14. Shen, J.-K.; Katayama, H.; Takatsu, N.; Shiro, I. Intramolecular reaction of the hydrazonyl group with formyl and oxo groups: Preparation of pyrazolo[1,5-a]indoles and related pyrazolo compounds. J. Chem. Soc. Perkin Trans. 1 1993, 2087–2097. [Google Scholar] [CrossRef]
  15. Katayama, H.; Takatsu, N.; Sakurada, M.; Kawada, Y. Preparation of 2-amino-4H-pyrazolo[1,5-a]indole derivatives by Boulton-Katritzky rearrangement. Heterocycles 1993, 35, 453–459. [Google Scholar] [CrossRef]
  16. Zhu, Y.-m.; Kiryu, Y.; Katayama, H. Intramolecular aromatic amination by a hydrazino group for the synthesis of indolo[1,2-b]indazole derivatives. Tetrahedron Lett. 2002, 43, 3577–3580. [Google Scholar] [CrossRef]
  17. Chi, J.; Hang, C.; Zhu, Y.; Katayama, H. Synthesis of indolo[1,2-b]indazole derivatives via copper(I)-catalyzed intramolecular amination reaction. Synth. Commun. 2010, 40, 1123–1133. [Google Scholar] [CrossRef]
  18. Zhu, Y.-M.; Qin, L.-N.; Liu, R.; Ji, S.-J.; Katayama, H. Synthesis of pyrazolo[1,5-a]indoles via copper(I)-catalyzed intramolecular amination. Tetrahedron Lett. 2007, 48, 6262–6266. [Google Scholar] [CrossRef]
  19. Hang, C.; Li, Q.; Zhu, Y.; Katayama, H. Copper(I)-catalyzed tandem cyclization/condensation reaction to novel 4,5-dihydropyrazolo[1,5-a]quinolines and pyrazolo[1,5-a]indoles. Synth. Commun. 2011, 41, 3318–3324. [Google Scholar] [CrossRef]
  20. Taylor, A.P.; Robinson, R.P.; Fobian, Y.M.; Blakemore, D.C.; Jones, L.H.; Fadeyi, O. Modern advances in heterocyclic chemistry in drug discovery. Org. Biomol. Chem. 2016, 14, 6611–6637. [Google Scholar] [CrossRef]
  21. Hsueh, W.-Y.; Lee, Y.-S.E.; Huang, M.-S.; Lai, C.-H.; Gao, Y.-S.; Lin, J.-C.; Chen, Y.-F.; Chang, C.-L.; Chou, S.-Y.; Chen, S.-F.; et al. Copper(I)-catalyzed nitrile-addition/N-arylation ring-closure cascade: Synthesis of 5,11-dihydro-6H-indolo[3,2-c]quinolin-6-ones as potent topoisomerase-I inhibitors. J. Med. Chem. 2021, 64, 1435–1453. [Google Scholar] [CrossRef] [PubMed]
  22. Talele, T.T. The “cyclopropyl fragment” is a versatile player that frequently appears in preclinical/clinical drug molecules. J. Med. Chem. 2016, 59, 8712–8756. [Google Scholar] [CrossRef] [PubMed]
  23. Johansen, J.E.; Christie, B.D.; Rapoport, H. Iminium salts from α-amino acid decarbonylation. Application to the synthesis of octahydroindolo[2,3-a]quinolizines. J. Org. Chem. 1981, 46, 4914–4920. [Google Scholar] [CrossRef]
  24. Arumugam, S.; Verkade, J.G. P(CH3NCH2CH2)3N: A nonionic superbase for efficient dehydrohalogenation. J. Org. Chem. 1997, 62, 4827–4828. [Google Scholar] [CrossRef]
  25. Counceller, C.M.; Eichman, C.C.; Wray, B.C.; Stambuli, J.P. A practical, metal-free synthesis of 1H-indazoles. Org. Lett. 2008, 10, 1021–1023. [Google Scholar] [CrossRef] [PubMed]
  26. Wray, B.C.; Stambuli, J.P. Synthesis of N-arylindazoles and benzimidazoles from a common intermediate. Org. Lett. 2010, 12, 4576–4579. [Google Scholar] [CrossRef]
  27. Yan, X.; Yang, X.; Xi, C. Recent progress in copper-catalyzed electrophilic amination. Catal. Sci. Technol. 2014, 4, 4169–4177. [Google Scholar] [CrossRef]
  28. Sączewski, J.; Gdaniec, M. Synthesis of heterocycles by intramolecular nucleophilic substitution at an electron-deficient sp2 nitrogen atom. Eur. J. Org. Chem. 2010, 2387–2394. [Google Scholar] [CrossRef]
  29. Hassner, A.; Michelson, M.J. The formation of the N–N bond in pyrazolines. J. Org. Chem. 1962, 27, 298–301. [Google Scholar] [CrossRef]
  30. Stankevicius, A.P.; Janushene, L.N.; Terentiev, P.B.; Vitkevicius, K.T. Cleavage of 9,10-phenanthrenequinone monooxime O-arenesulfonates in the presence of amines. Russ. J. Org. Chem. 2006, 42, 1725–1726. [Google Scholar] [CrossRef]
  31. Stankjavicius, A.P.; Yanusiene, L.N.; Zablockaite, D.P.; Pechura, R.B. Synthesis of aliphatic amides of 2-(2(-cyanophenyl)benzoic acid. Pharm. Chem. J. 2007, 41, 646–647. [Google Scholar] [CrossRef]
  32. Tang, X.; Gao, H.; Yang, J.; Wu, W.; Jiang, H. Efficient access to 1H-indazoles via copper-catalyzed cross-coupling/cyclization of 2-bromoaryl oxime acetates and amines. Org. Chem. Front. 2014, 1, 1295–1298. [Google Scholar] [CrossRef]
  33. Meshram, H.M.; Reddy, P.N.; Sadashiv, K.; Yadav, J.S. Amberlyst-15®-promoted efficient 2-halogenation of 1,3-keto-esters and cyclic ketones using N-halosuccinimides. Tetrahedron Lett. 2005, 46, 623–626. [Google Scholar] [CrossRef]
Molecules 28 06374 g001
Figure 1. The structures of 4H-pyrazolo[1,5-a]indole (1), representative examples 2–5 containing 1, and spirocyclopropane-containing 4H-pyrazolo[1,5-a]indole 6 reported in this study.
Figure 1. The structures of 4H-pyrazolo[1,5-a]indole (1), representative examples 2–5 containing 1, and spirocyclopropane-containing 4H-pyrazolo[1,5-a]indole 6 reported in this study.
Molecules 28 06374 g001
Molecules 28 06374 sch001
Scheme 1. Reported methods for the synthesis of 4H-pyrazolo[1,5-a]indoles 1 [5,6,7,9,11,12,13,14,15,16,17,18,19].
Scheme 1. Reported methods for the synthesis of 4H-pyrazolo[1,5-a]indoles 1 [5,6,7,9,11,12,13,14,15,16,17,18,19].
Molecules 28 06374 sch001
Molecules 28 06374 sch002
Scheme 2. Synthesis of spirocyclopropane-containing 4H-pyrazolo[1,5-a]indoles 6a–e.
Scheme 2. Synthesis of spirocyclopropane-containing 4H-pyrazolo[1,5-a]indoles 6a–e.
Molecules 28 06374 sch002
Molecules 28 06374 sch003
Scheme 3. Tentative reaction mechanism for the conversion of 11 to 6a–e.
Scheme 3. Tentative reaction mechanism for the conversion of 11 to 6a–e.
Molecules 28 06374 sch003
Table 1. Optimization of the reaction conditions for the synthesis of 9 a.
Table 1. Optimization of the reaction conditions for the synthesis of 9 a.
Molecules 28 06374 i001
EntryXAcid (mol %)SolventT (°C) bTime (h)Yield (%) c
1ClPPTS (20) dtoluenereflux2.0Trace e
2BrPPTS (20) dtoluenereflux2.0Trace e
3ClTsOH (20)toluenereflux2.00 f
4BrTsOH (20)toluenereflux2.00 f
5ClBF3·OEt2 (150)CH2Cl203.020
6BrBF3·OEt2 (150)CH2Cl203.026
7ClHBF4·OEt2 (150) CH2Cl201056
8BrHBF4·OEt2 (150)CH2Cl201063
9ClHBF4·OEt2 (75)CH2Cl201025
10BrHBF4·OEt2 (75)CH2Cl201030
a The reaction was carried out using 7 (~200 mg, 1.0 equiv), 8, or 12 (1.2 equiv), and acids in 4.0 mL of solvents. b Bath temperature. c Isolated yield. d PPTS, pyridinium p-toluenesulfonate. e The [M + 1]+ peak of 9 was detected in ESI-MS. f The peaks related to 9 were not observed in ESI-MS.
Table 2. Optimization of the reaction conditions for oxime 10 a.
Table 2. Optimization of the reaction conditions for oxime 10 a.
Molecules 28 06374 i002
EntryEquivalent of NH2OH·HClT (°C) bTime (h)Yield (%) c
1013
12.2r.t.150 d0 d
22.255156327
32.2reflux156525
43.2reflux306220
53.2reflux456318
a The reaction was carried out using 9 (~200 mg, 1.0 equiv) with NH2OH·HCl in 10 mL of 95% EtOH. b Bath temperature. c I solated yield. d No reaction with the recovery of starting material.
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MDPI and ACS Style

Huang, J.-J.; Liao, H.-C.; Hsu, C.-E.; Liu, Y.-R.; Chang, Y.-F.; Chou, S.-Y. Synthesis of Spirocyclopropane-Containing 4H-Pyrazolo[1,5-a]indoles via Alkylative Dearomatization and Intramolecular N-Imination of an Indole–O-(Methylsulfonyl)oxime. Molecules 2023, 28, 6374. https://doi.org/10.3390/molecules28176374

AMA Style

Huang J-J, Liao H-C, Hsu C-E, Liu Y-R, Chang Y-F, Chou S-Y. Synthesis of Spirocyclopropane-Containing 4H-Pyrazolo[1,5-a]indoles via Alkylative Dearomatization and Intramolecular N-Imination of an Indole–O-(Methylsulfonyl)oxime. Molecules. 2023; 28(17):6374. https://doi.org/10.3390/molecules28176374

Chicago/Turabian Style

Huang, Jiann-Jyh, Hung-Chun Liao, Cheng-En Hsu, Yan-Ru Liu, Yi-Fu Chang, and Shan-Yen Chou. 2023. "Synthesis of Spirocyclopropane-Containing 4H-Pyrazolo[1,5-a]indoles via Alkylative Dearomatization and Intramolecular N-Imination of an Indole–O-(Methylsulfonyl)oxime" Molecules 28, no. 17: 6374. https://doi.org/10.3390/molecules28176374

APA Style

Huang, J. -J., Liao, H. -C., Hsu, C. -E., Liu, Y. -R., Chang, Y. -F., & Chou, S. -Y. (2023). Synthesis of Spirocyclopropane-Containing 4H-Pyrazolo[1,5-a]indoles via Alkylative Dearomatization and Intramolecular N-Imination of an Indole–O-(Methylsulfonyl)oxime. Molecules, 28(17), 6374. https://doi.org/10.3390/molecules28176374

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