Intramolecular Aminolactonization for Synthesis of Furoindolin-2-One

Propellanes are polycyclic compounds in which tricyclic systems share one carbon–carbon single bond. Propellane frameworks that consist of larger sized rings are found in a variety of natural products. As an approach to the stereoselective synthesis of the propellane framework, one of the efficient methods is forming several rings in a single operation. Lapidilectine B (1) is composed of a propellane framework and was synthesized through the oxidative cyclization of trisubstituted alkenes. When the alkene with an ester moiety was treated with N-iodosuccinimide (NIS), iodocyclization proceeded to give the cyclic carbamate. On the other hand, when PhI(OAc)2 was allowed to react in the carboxyl form, a furoindolin-2-one structure corresponding to the A-B-C ring of lapidilectine B (1) was produced. Furthermore, when Pd(OAc)2 catalyst was used for cyclization under oxidative conditions, the product yield was improved.

The structural feature of 1 is possessing a unique propellane structure composed of indoline, γ-lactone, and azocane. In addition, the cyclohexane ring is connected to two pyrrolidine rings via two spirocenters. The first total synthesis of 1 was achieved by Pearson in 2001, where the Smalley cyclization was used to construct the framework of the B and C rings [3,4]. The optically active form of 1 was synthesized by Nishida in 2016 via desymmetrization of the spiro center using enantioselective deprotonation with a chiral lithium amide [5]. In 2018, Ma utilized manganese (III) mediated oxidative cyclization of 2-alkylindole to form the B-C-D rings of 1 in one operation [6]. We focused on the anticonfiguration between oxygen and nitrogen atoms in the B-C-E propellane moiety, and postulated that the simultaneous functionalization of the alkene is a key reaction for ring construction in 1.  The structural feature of 1 is possessing a unique propellane structure composed of indoline, γ-lactone, and azocane. In addition, the cyclohexane ring is connected to two pyrrolidine rings via two spirocenters. The first total synthesis of 1 was achieved by Pearson in 2001, where the Smalley cyclization was used to construct the framework of the B and C rings [3,4]. The optically active form of 1 was synthesized by Nishida in 2016 via desymmetrization of the spiro center using enantioselective deprotonation with a chiral lithium amide [5]. In 2018, Ma utilized manganese (III) mediated oxidative cyclization of 2-alkylindole to form the B-C-D rings of 1 in one operation [6]. We focused on the anti-configuration between oxygen and nitrogen atoms in the B-C-E propellane moiety, and postulated that the simultaneous functionalization of the alkene is a key reaction for ring construction in 1.
As a methodology for double functionalization with heteroatoms on C-C double bond, Baran indicated the oxidative coupling reaction of o-iodoaniline and tryptamine 2 of 11 using NIS to form the 3a substituted pyrroindoline motif in the synthesis of psychotrimine (Scheme 1A) [7,8]. The electrophilic N-haloaniline and the nucleophilic carbamate of the tryptamine side chain were introduced into the 2,3-positions of the indole. One of promising methods for introducing of two heteroatoms onto an alkene with a transition metal catalyst is Sharpless's asymmetric aminohydroxylation [9]. In 2007, Muñiz reported the palladium-catalyzed aminoalkoxylation of internal alkene bearing aniline and phenol moieties with PhI(OAc) 2 (Scheme 1B) [10,11]. Interestingly in this method, a furoindoline skeleton is assembled by closing two rings of a disubstituted alkene at once. To construct the 5-5 bicyclo B-C ring system in lapidilectine B (1), the Z trisubstituted alkene 2 was selected as the precursor for the ring closing reaction (Scheme 1C). Here, we report the efficient synthesis of furoindolin-2-one 3 by the successive cyclization of trisubstituted alkene 2 with the goal of developing a method for synthesizing the polycyclic skeleton of 1. As a methodology for double functionalization with heteroatoms on C-C double bond, Baran indicated the oxidative coupling reaction of o-iodoaniline and tryptamine using NIS to form the 3a substituted pyrroindoline motif in the synthesis of psychotrimine (Scheme 1A) [7,8]. The electrophilic N-haloaniline and the nucleophilic carbamate of the tryptamine side chain were introduced into the 2,3-positions of the indole. One of promising methods for introducing of two heteroatoms onto an alkene with a transition metal catalyst is Sharpless's asymmetric aminohydroxylation [9]. In 2007, Muñiz reported the palladium-catalyzed aminoalkoxylation of internal alkene bearing aniline and phenol moieties with PhI(OAc)2 (Scheme 1B) [10,11]. Interestingly in this method, a furoindoline skeleton is assembled by closing two rings of a disubstituted alkene at once. To construct the 5-5 bicyclo B-C ring system in lapidilectine B (1), the Z trisubstituted alkene 2 was selected as the precursor for the ring closing reaction (Scheme 1C). Here, we report the efficient synthesis of furoindolin-2-one 3 by the successive cyclization of trisubstituted alkene 2 with the goal of developing a method for synthesizing the polycyclic skeleton of 1. Scheme 1. Oxidative cyclization of alkenes.

Results and Discussion
We synthesized trisubstituted alkenes 2 and 6 bearing an alkoxycarbonyl group on the aniline nitrogen (Scheme 2). Aniline, its hydrochloride, and 4-oxopentanoic acid were condensed under heating at 200 °C to obtain lactam 4 according to the literature [12]. Thereafter, lactam 4 was transformed to imides 5a-e by treating n-butyllithium with alkyl chloroformate or triethylamine with Boc2O, after which imides 5 were hydrolyzed with NaOH in THF-water to prepare carboxylic acids 2a-e. Boc form 5c was solvolyzed with sodium methoxide in MeOH to obtain methyl ester 6. Scheme 1. Oxidative cyclization of alkenes.

Results and Discussion
We synthesized trisubstituted alkenes 2 and 6 bearing an alkoxycarbonyl group on the aniline nitrogen (Scheme 2). Aniline, its hydrochloride, and 4-oxopentanoic acid were condensed under heating at 200 • C to obtain lactam 4 according to the literature [12]. Thereafter, lactam 4 was transformed to imides 5a-e by treating n-butyllithium with alkyl chloroformate or triethylamine with Boc 2 O, after which imides 5 were hydrolyzed with NaOH in THF-water to prepare carboxylic acids 2a-e. Boc form 5c was solvolyzed with sodium methoxide in MeOH to obtain methyl ester 6. First, we investigated a key cyclization using compounds 2c and 6 bearing a Boc group (Scheme 3). The treatment of carboxylic acid 2c with NIS in a solution of MeCN and MeOH resulted in a complex mixture. On the other hand, when methyl ester 6 was treated under the same conditions as above, cyclic carbamate 7 was obtained in 89% yield as a single diastereomer. Iodocyclization triggered by the activation of the alkene with NIS, accompanied by the elimination of isobutylene from the Boc group, gave 7. Trisubstituted alkene 2a possessing a carboxylic acid moiety was then subjected to halogenating and oxidizing agents ( Table 1). The reaction yielded many products when NIS was added to 2a (entry 1), whereas the reaction did not proceed with NCS (entry 2). When 2a was treated with CAN in MeCN solution, the trace amount of the desired cyclized product 3a was produced (entry 3). When the reaction was carried out with PhI(OAc)2 under refluxing MeCN, product 3a was obtained in 43% yield, along with many First, we investigated a key cyclization using compounds 2c and 6 bearing a Boc group (Scheme 3). The treatment of carboxylic acid 2c with NIS in a solution of MeCN and MeOH resulted in a complex mixture. On the other hand, when methyl ester 6 was treated under the same conditions as above, cyclic carbamate 7 was obtained in 89% yield as a single diastereomer. Iodocyclization triggered by the activation of the alkene with NIS, accompanied by the elimination of isobutylene from the Boc group, gave 7. First, we investigated a key cyclization using compounds 2c and 6 bearing a Boc group (Scheme 3). The treatment of carboxylic acid 2c with NIS in a solution of MeCN and MeOH resulted in a complex mixture. On the other hand, when methyl ester 6 was treated under the same conditions as above, cyclic carbamate 7 was obtained in 89% yield as a single diastereomer. Iodocyclization triggered by the activation of the alkene with NIS, accompanied by the elimination of isobutylene from the Boc group, gave 7. Trisubstituted alkene 2a possessing a carboxylic acid moiety was then subjected to halogenating and oxidizing agents ( Table 1). The reaction yielded many products when NIS was added to 2a (entry 1), whereas the reaction did not proceed with NCS (entry 2). When 2a was treated with CAN in MeCN solution, the trace amount of the desired cyclized product 3a was produced (entry 3). When the reaction was carried out with PhI(OAc)2 under refluxing MeCN, product 3a was obtained in 43% yield, along with many Trisubstituted alkene 2a possessing a carboxylic acid moiety was then subjected to halogenating and oxidizing agents ( Table 1). The reaction yielded many products when NIS was added to 2a (entry 1), whereas the reaction did not proceed with NCS (entry 2). When 2a was treated with CAN in MeCN solution, the trace amount of the desired cyclized product 3a was produced (entry 3). When the reaction was carried out with PhI(OAc) 2 under refluxing MeCN, product 3a was obtained in 43% yield, along with many decompo-sition products (entry 4). Other hypervalent iodine reagents, PhI(OCOCF 3 ) 2 , PhI(OH)OTs, and PhIO were tested, product 3a was slightly detected on TLC, however substrate 2a was mainly decomposed (entries 5-7). The fused ring structure of product 3a was confirmed by the correlation between the methyl proton at position 8b and the 3a carbon in the HMBC experiment, and between the methyl proton at position 8b and the 3a proton in the nOe experiment. decomposition products (entry 4). Other hypervalent iodine reagents, PhI(OCOCF3)2, PhI(OH)OTs, and PhIO were tested, product 3a was slightly detected on TLC, however substrate 2a was mainly decomposed (entries 5-7). The fused ring structure of product 3a was confirmed by the correlation between the methyl proton at position 8b and the 3a carbon in the HMBC experiment, and between the methyl proton at position 8b and the 3a proton in the nOe experiment. A plausible reaction mechanism is shown in Scheme 4. In conjunction with the oxidative activation of the aniline nitrogen atom in 2a by PhI(OAc)2, the nitrogen atom undergoes nucleophilic attack by the π-electron of the alkene, after which the carboxylic acid cyclized to give furoindolin-2-one 3a. The conditions for palladium(II) mediated oxidative difunctionalization of alkenes reported by Muñiz were applied to trisubstituted alkene 2a (Table 2). When 1 equivalent of the palladium reagent with 1.5 equivalents of PhI(OAc)2 treated with 2a in DMF at room temperature, product 3a was obtained in 19% yield with PdCl2, in 29% yield with Pd(OCOCF3)2, and in 58% yield with Pd(OAc)2 (entries 1-3). Using Pd(OAc)2 in MeCN, 3a was obtained in 50% yield (entry 4). Based on the above results, a catalytic amount of Pd(OAc)2 was examined using DMF or MeCN. First, when 0.2 equivalent of Pd(OAc)2 was reacted at room temperature for 24 h, the yield of 3a decreased to 14% in DMF and was maintained at 51% in MeCN (entries 5 and 6). When the reaction was performed under refluxing MeCN, the reaction time was shortened and the yield of 3a increased to 78% (entry 7). Further reduction the amount of Pd(OAc)2 to 0.1 equivalent decreased the product yield to 47% (entry 8). With the optimum conditions in hand, the substituent effect on A plausible reaction mechanism is shown in Scheme 4. In conjunction with the oxidative activation of the aniline nitrogen atom in 2a by PhI(OAc) 2 , the nitrogen atom undergoes nucleophilic attack by the π-electron of the alkene, after which the carboxylic acid cyclized to give furoindolin-2-one 3a.
Molecules 2022, 27, x FOR PEER REVIEW 4 of 12 decomposition products (entry 4). Other hypervalent iodine reagents, PhI(OCOCF3)2, PhI(OH)OTs, and PhIO were tested, product 3a was slightly detected on TLC, however substrate 2a was mainly decomposed (entries 5-7). The fused ring structure of product 3a was confirmed by the correlation between the methyl proton at position 8b and the 3a carbon in the HMBC experiment, and between the methyl proton at position 8b and the 3a proton in the nOe experiment. A plausible reaction mechanism is shown in Scheme 4. In conjunction with the oxidative activation of the aniline nitrogen atom in 2a by PhI(OAc)2, the nitrogen atom undergoes nucleophilic attack by the π-electron of the alkene, after which the carboxylic acid cyclized to give furoindolin-2-one 3a. The conditions for palladium(II) mediated oxidative difunctionalization of alkenes reported by Muñiz were applied to trisubstituted alkene 2a (Table 2). When 1 equivalent of the palladium reagent with 1.5 equivalents of PhI(OAc)2 treated with 2a in DMF at room temperature, product 3a was obtained in 19% yield with PdCl2, in 29% yield with Pd(OCOCF3)2, and in 58% yield with Pd(OAc)2 (entries 1-3). Using Pd(OAc)2 in MeCN, 3a was obtained in 50% yield (entry 4). Based on the above results, a catalytic amount of Pd(OAc)2 was examined using DMF or MeCN. First, when 0.2 equivalent of Pd(OAc)2 was reacted at room temperature for 24 h, the yield of 3a decreased to 14% in DMF and was maintained at 51% in MeCN (entries 5 and 6). When the reaction was performed under refluxing MeCN, the reaction time was shortened and the yield of 3a increased to 78% (entry 7). Further reduction the amount of Pd(OAc)2 to 0.1 equivalent decreased the product yield to 47% (entry 8). With the optimum conditions in hand, the substituent effect on The conditions for palladium(II) mediated oxidative difunctionalization of alkenes reported by Muñiz were applied to trisubstituted alkene 2a (Table 2). When 1 equivalent of the palladium reagent with 1.5 equivalents of PhI(OAc) 2 treated with 2a in DMF at room temperature, product 3a was obtained in 19% yield with PdCl 2 , in 29% yield with Pd(OCOCF 3 ) 2 , and in 58% yield with Pd(OAc) 2 (entries 1-3). Using Pd(OAc) 2 in MeCN, 3a was obtained in 50% yield (entry 4). Based on the above results, a catalytic amount of Pd(OAc) 2 was examined using DMF or MeCN. First, when 0.2 equivalent of Pd(OAc) 2 was reacted at room temperature for 24 h, the yield of 3a decreased to 14% in DMF and was maintained at 51% in MeCN (entries 5 and 6). When the reaction was performed under refluxing MeCN, the reaction time was shortened and the yield of 3a increased to 78% (entry 7). Further reduction the amount of Pd(OAc) 2 to 0.1 equivalent decreased the product yield to 47% (entry 8). With the optimum conditions in hand, the substituent effect on nitrogen atom was examined. The ethoxycarbonyl compound 2b gave the corresponding product 3b in 56% yield (entry 9). Even with 2c possessing a bulky Boc group, product 3c was obtained in 38% yield (entry 10). Even when the Cbz and Alloc substituents attached to nitrogen, products 3d and 3e were obtained in 33% and 29% yields, respectively (entries 11 and 12). nitrogen atom was examined. The ethoxycarbonyl compound 2b gave the corresponding product 3b in 56% yield (entry 9). Even with 2c possessing a bulky Boc group, product 3c was obtained in 38% yield (entry 10). Even when the Cbz and Alloc substituents attached to nitrogen, products 3d and 3e were obtained in 33% and 29% yields, respectively (entries 11 and 12). A reaction mechanism for the cyclization was proposed based on the report by Muñiz.  A reaction mechanism for the cyclization was proposed based on the report by Muñiz.

General Information
All melting points were measured on a Yanagimoto micro melting po IR spectra were recorded on a JASCO FT/IR-4100 spectrometer and absorba reported in wavenumber (cm −1 ). 1 H NMR spectra were recorded on JEOL and 400 (300 and 400 MHz) spectrometer or JEOL JNM-ECS 400 (400 MHz) Chemical shifts are reported relative to internal standard (tetramethylsila CDCl3 at δH 7.26). Data are presented as follows: chemical shift (δ, ppm), m singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling constan tion. 13 C NMR spectra were recorded on JEOL JNM-ECA 400 (100 MHz) Chemical shifts are reported relative to internal standard (CDCl3 at δ 77.00) were recorded on a JEOL JMS 700 instrument with a direct inlet system. Co tography was carried out on Kanto silica gel 60 N (40-50 mesh). Analytical t matography (TLC) was carried out on Merck Kieselgel 60 F254 plates with vi ultraviolet, anisaldehyde stain solution or phosphomolybdic acid stain solu aqueous reactions were carried out in flame-dried glassware under argon a less otherwise noted. Reagents were purchased from TCI, nacalai tesque, K FUJIFILM Wako chemicals or Sigma-Aldrich. Reagents and solvents were purification. Substrate 4 was synthesized by a reported method [12], and agreed with the literature values.

General Information
All melting points were measured on a Yanagimoto micro melting point apparatus. IR spectra were recorded on a JASCO FT/IR-4100 spectrometer and absorbance bands are reported in wavenumber (cm −1 ). 1 H NMR spectra were recorded on JEOL JNM-AL 300 and 400 (300 and 400 MHz) spectrometer or JEOL JNM-ECS 400 (400 MHz) spectrometer. Chemical shifts are reported relative to internal standard (tetramethylsilane at δ H 0.00, CDCl 3 at δ H 7.26). Data are presented as follows: chemical shift (δ, ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling constant and integration. 13 C NMR spectra were recorded on JEOL JNM-ECA 400 (100 MHz) spectrometer. Chemical shifts are reported relative to internal standard (CDCl 3 at δ 77.00). Mass spectra were recorded on a JEOL JMS 700 instrument with a direct inlet system. Column chromatography was carried out on Kanto silica gel 60 N (40-50 mesh). Analytical thin layer chromatography (TLC) was carried out on Merck Kieselgel 60 F 254 plates with visualization by ultraviolet, anisaldehyde stain solution or phosphomolybdic acid stain solution. All non-aqueous reactions were carried out in flame-dried glassware under argon atmosphere unless otherwise noted. Reagents were purchased from TCI, nacalai tesque, Kanto chemical, FUJIFILM Wako chemicals or Sigma-Aldrich. Reagents and solvents were used without purification. Substrate 4 was synthesized by a reported method [12], and spectra data agreed with the literature values. the mixture was stirred for 20 min at same temperature. After confirming the disappearance of substrate 4 by TLC, saturated the NH 4 Cl aqueous solution was added. The reaction mixture was extracted with CH 2 Cl 2 . The organic layer was washed with a saturated aqueous NaCl solution, dried with anhydrous MgSO 4 , filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 5.     (6) A solution of 5c (0.27 g, 1.0 mmol) in MeOH (10 mL) was added NaOMe (54 mg, 5.0 mmol) and stirred at rt for 1.5 h. After confirming the consumption of substrate 5c by TLC, the reaction mixture was acidified with 10% HCl and extracted with AcOEt, the organic layer was washed with brine, dried with anhydrous MgSO 4 , filtered, and the filtrate was concentrated under reduced pressure to obtain 6 (0.28 g, 93%).   (7) To a solution of 6 (30 mg, 0.10 mmol) in a mixture of MeCN/MeOH (1.2 mL, 20/1) was added a solution of NIS (3.4 mg, 0.15 mmol) in MeCN (0.30 mL) at −45 • C. The reaction mixture was stirred and allowed to room temperature for 5 h. After confirming the consumption of substrate 6 by TLC, the reaction was quenched with aqueous solution of Na 2 S 2 O 3 . After extraction with AcOEt, the organic layer was washed with brine, dried with anhydrous MgSO 4 , filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/n-hexane = 1/2) to obtain 7 (33 mg, 89%) as a pale yellow oil. IR To a solution of 2 in MeCN was added Pd(OAc) 2 and PhI(OAc) 2 . The reaction mixture was stirred under reflux for 6 h. After confirming the consumption of substrate 2 by TLC, the reaction was quenched with aqueous solution of Na 2 S 2 O 3 . After extraction with AcOEt, the organic layer was washed with brine, dried with anhydrous MgSO 4 , filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 3.

Data Availability Statement:
The data presented in this study are available in this article.