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

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.

acid (Scheme 1C) [13,14] and the use of Boulton-Katritzky rearrangement as the key s to synthesize 2-substituted 1 (Scheme 1D) [15].Dougherty and his colleagues found thermal decomposition of a diazide-generated benzo-fused 1 (Scheme 1E), which was synthetic method for compound 2 shown in Figure 1 [5].Pd-catalyzed [16] and catalyzed [17] aromatic amination of indolines were also reported by the Katayama gro to prepare the benzo-fused derivatives of 1 (Scheme 1F).In another approach (Sche 1G), Zhu and his colleagues applied Cu-catalyzed intramolecular N-arylation to pyrazo to synthesize various 2-and/or 3-substituted derivatives of 1 [18], and the reaction co start from 1,3-diketones and hydrazine in tandem conditions [19].Spiro 4 and derivatives were prepared via the dehydrogenative annulation reaction of 2-arylindazo with maleimides (Scheme 1H) [9].As shown in Scheme 1I, salt 3 (Figure 1) was prepa by reacting the corresponding 1 with MeOTf and benzaldehyde [6,7].Porphyrin 5 w prepared from the oxidation of its precedent Siamese-twin porphyrin [10].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 Cucatalyzed [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.
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.

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).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.
We then treated 9 with hydroxylamine hydrochloride (NH 2 OH•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 NH 2 OH•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.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.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 CH 2 Cl 2 afforded indole-O-(methylsulfonyl)oxime 11 (85% yield, Scheme 2), which was then reacted with various alcoholic solvents to afford the target spirocyclopropanecontaining 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., Me 2 NH, Et 2 NH), 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 CH 2 multipletes at 1.96-4.41ppm in the 1 H NMR spectrum suggested the presence of a cyclopentaoxepino moiety, in which the peaks at 4.28-4.41ppm corresponded to the CH 2 adjacent to the oxygen atom.A broad singlet at 7.68 ppm revealed an indolyl NH.The five most downfield peaks at 69.41 (OCH 2 ), 34.12 (OCCH 2 ), 30.32 (OC=CCH 2 ), 27.74 (OCH 2 CH 2 ), and 19.98 (CH 2 CH 2 CH 2 ) ppm in the 13 C 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 CH 2 in the cyclopentenone oxime moiety produced two multipletes at 2.72-2.77and 2.85-2.89ppm in the NMR spectrum, and the sole olefinic proton resided at 7.53-7.70ppm.Protons of the two CH 2 connected to the indole showed two tripletes centered at 3.23 and 3.96 ppm.In the 13 C 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 1 H NMR patterns were observed.The two CH 3 in the mesylate were located at 2.82 and 3.15 ppm in the 1 H NMR spectrum and at 36.90 and 37.55 ppm in the 13 C NMR spectrum.
For the final product 6a, its ethoxy peaks were found at 1.21 ppm (triplet) and 3.51-3.40ppm (multiplet) in the 1 H NMR spectrum.Peaks at 1.63-1.87ppm (multiplet) indicated the presence of a cyclopropane moiety, which was further confirmed by 13 C 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 HBF 4 •OEt 2 (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.
Molecules 2023, 28, x FOR PEER REVIEW 6 of 10 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, Schemes 2 and 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'-dicy- Oxime and its O-substituted derivative (i.e., the oxime sulfonate in 11, Schemes 2 and 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 2bromoaryl 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.

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 0.063-0.200mm, 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 CDCl 3 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).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 CH 2 Cl 2 (90 mL) was added with HBF 4 •OEt 2 (11.04 g, 68.2 mmol) in a period of 5.0 min at 0 • C under N 2 .The reaction mixture was stirred at 0 • C for 10 h.The solution was diluted with CH 2 Cl 2 (90 mL), quenched with icy water (100 mL), neutralized with saturated aqueous K 2 CO 3 , and filtered through Celite.The filtrate was washed with water, dried over MgSO 4 , and concentrated under reduced pressure.The residue was purified by column chromatography on silica gel using a mixture of EtOAc and hexanes (1:5)

(E
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 N 2 .The solution was concentrated, re-dissolved in CH 2 Cl 2 (20 mL), washed with 5% aqueous Na 2 CO 3 (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 An anhydrous CH 2 Cl 2 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 N 2 for 12 h.The solution was quenched with water (100 mL) and extracted with CH 2 Cl 2 (50 mL × 2).The organic layer was washed with 1.0 N HCl (80 mL), water (80 mL), 10% NaHCO 3 (80 mL), and brine.The solution was dried over anhydrous MgSO 4 , 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: 1   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 CH 2 Cl 2 , dried over anhydrous MgSO 4 , 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.

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.

a
The reaction was carried out using 9 (~200 mg, 1.0 equiv) with NH 2 OH•HCl in 10 mL of 95% EtOH.b Bath temperature.c I solated yield.d No reaction with the recovery of starting material.

Scheme 3 .
Scheme 3. Tentative reaction mechanism for the conversion of 11 to 6a-e.

Scheme 3 .
Scheme 3. Tentative reaction mechanism for the conversion of 11 to 6a-e.

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 .

Table 2 .
Optimization of the reaction conditions for oxime 10 a .
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.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 .
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 .

HCl T (°C) b Time (h) Yield (%) c 10 13
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.