A General and Scalable Synthesis of Polysubstituted Indoles

A consecutive 2-step synthesis of N-unprotected polysubstituted indoles bearing an electron-withdrawing group at the C-3 position from readily available nitroarenes is reported. The protocol is based on the [3,3]-sigmatropic rearrangement of N-oxyenamines generated by the DABCO-catalyzed reaction of N-arylhydroxylamines and conjugated terminal alkynes, and delivers indoles endowed with a wide array of substitution patterns and topologies.


Introduction
The indole moiety occupies a privileged place in the realm of heterocyclic chemistry [1]. It constitutes the core structure of many natural products and synthetic bioactive compounds exhibiting a wide array of biological activities [2][3][4][5][6], and has also found use as structural parts of material science devices [7][8][9] and chiral catalysts [10][11][12]. Recent studies have shown that the substitution at the C-3 position with electron-withdrawing groups (3-EWG-indoles) not only endows these structures with important pharmaceutical/therapeutic activities [13][14][15][16][17][18][19][20][21], but also it converts them into versatile synthetic molecular platforms in heterocyclic chemistry, such as, in dearomatization-based synthetic disconnections [22]. The catalytic asymmetric dearomatization of 3-nitroindoles constitutes an iconic example of this synthetic potential [23][24][25][26][27][28][29][30][31][32][33][34]. The most traditional synthetic approach to these functionalized indoles relies on the Friedel-Crafts acylation of preformed indoles [35][36][37]. This transformation suffers important drawbacks such as mandatory nitrogen protection, regioselectivity control, stoichiometric use of metal salts and Lewis acid promoters, and strict exclusion of moisture. Although modern alternatives using metal-catalysis [38][39][40][41][42] or photocatalysis [43][44][45][46] have overcome some of these difficulties, the implementation of real-world strategies to prepare these heterocycles from simple and widely accessible starting materials remains a synthetic challenge in medicinal and synthetic chemistry. In spite of the many advances achieved in the synthesis of indoles during the last 100 years [47], the de novo synthesis of 3-EWG-indoles remains largely unexplored. A large number of strategies for the synthesis of indoles use alkynes and a convenient nitrogen source as substrates [48] and the annelation of the five-membered ring to an existing functionalized benzene ring as the main synthetic disconnection [49]. The inherent alkyne reactivity and the broad access to nitrogen sources constitute practical advantages for these strategies. Among them, the [3,3]-sigmatropic rearrangement of N-oxyenamines [50] or 1-aryl-2-vinylhydrazines [51,52] have been objects of profuse research (Scheme 1a). Prototypical examples of these strategies constitute the Bartoli [53,54] (N-oxyenamines) and the Fischer [55] (1-aryl-2-vinylhydrazines) syntheses of indoles. Although both reactions have been largely used in the preparation of indoles [47], they present We envisioned that a simpler and general methodology using the N-oxyenamine disconnection could be arranged on the basis of the well-established addition of nucleophiles onto terminal conjugated alkynes catalyzed by tertiary amines (Scheme 1c) [58][59][60][61]. When searching for precedents for this disconnection, we found a reduced number of reported examples, all of them circumscribed to the synthesis of alkyl indole-3-carboxyates [62][63][64][65][66], and with important drawbacks for a practical and general application. They mostly use N-arylhydroxylamine salts or N-protected Narylhydroxylamines to force the O-addition reaction, and require large excesses of alkyne and long reaction times to deliver the indole-3-carboxylates in low to moderate yields. Therefore, a general and practical protocol for accessing NH-free 3-EWG-indoles based on this disconnection remains to be established. In terms of sustainability, such protocol should be direct, operationally simple and scalable, avoiding non-productive N-protection/N-deprotection steps. We report herein our results on the implementation of a strategy fulfilling these requirements and overcoming the practical shortcomings found in previous reports. The strategy delivers NH-free multisubstituted 3-EWG- We envisioned that a simpler and general methodology using the N-oxyenamine disconnection could be arranged on the basis of the well-established addition of nucleophiles onto terminal conjugated alkynes catalyzed by tertiary amines (Scheme 1c) [58][59][60][61]. When searching for precedents for this disconnection, we found a reduced number of reported examples, all of them circumscribed to the synthesis of alkyl indole-3-carboxyates [62][63][64][65][66], and with important drawbacks for a practical and general application. They mostly use N-arylhydroxylamine salts or N-protected N-arylhydroxylamines to force the O-addition reaction, and require large excesses of alkyne and long reaction times to deliver the indole-3-carboxylates in low to moderate yields. Therefore, a general and practical protocol for accessing NH-free 3-EWG-indoles based on this disconnection remains to be established. In terms of sustainability, such protocol should be direct, operationally simple and scalable, avoiding non-productive N-protection/N-deprotection steps. We report herein our results on the implementation of a strategy fulfilling these requirements and overcoming the practical shortcomings found in previous reports. The strategy delivers NH-free multisubstituted 3-EWG-indoles through a consecutive 2-step reaction manifold, and it uses nitroarenes and activated terminal alkynes as building blocks (Scheme 1c). The reaction manifold takes advantage of the O-reactivity of N-arylhydroxylamines toward terminal conjugated alkynes and of the rich arsenal of commercially available functionalized nitroarenes. Whereas the first one avoids unnecessary N-protection/N-deprotection steps (step-economy, reagent-economy), the second one offers an almost countless catalogue of functional diversity on the benzene ring (general outcome). These properties make this reaction manifold a convenient, instrumentally simple, robust and reliable synthetic tool for the exploration/annotation of the chemical space of 3-EWG-indoles.

Initial Experiments and Optimization of the Reaction Conditions for a Consecutive 2-Step Protocol
The initial studies began using commercially available N-benzoyl-N-phenylhydroxylamine (4a-N-Bz) as the nitrogen species needed for the synthesis of indoles and the standard conditions reported by our group for the DABCO-catalyzed synthesis of propargyl vinyl ethers [59] (Scheme 2). Although the addition of the hydroxylamine to methyl propiolate (5a) took place in the presence of DABCO, and this was followed by the desired cyclization, the hydroxyindoline intermediate HI was isolated instead of the expected indole 6a-N-Bz. Furthermore, a side-product incorporating a second unit of methyl propiolate was also obtained (DVE). It forms from the DABCO-catalyzed addition of methyl propiolate (5a) on the enol ether generated on the [3,3] indoles through a consecutive 2-step reaction manifold, and it uses nitroarenes and activated terminal alkynes as building blocks (Scheme 1c). The reaction manifold takes advantage of the O-reactivity of N-arylhydroxylamines toward terminal conjugated alkynes and of the rich arsenal of commercially available functionalized nitroarenes. Whereas the first one avoids unnecessary N-protection/Ndeprotection steps (step-economy, reagent-economy), the second one offers an almost countless catalogue of functional diversity on the benzene ring (general outcome). These properties make this reaction manifold a convenient, instrumentally simple, robust and reliable synthetic tool for the exploration/annotation of the chemical space of 3-EWG-indoles.

Initial Experiments and Optimization of the Reaction Conditions for a Consecutive 2-Step Protocol
The initial studies began using commercially available N-benzoyl-N-phenylhydroxylamine (4a-N-Bz) as the nitrogen species needed for the synthesis of indoles and the standard conditions reported by our group for the DABCO-catalyzed synthesis of propargyl vinyl ethers [59] (Scheme 2). Although the addition of the hydroxylamine to methyl propiolate (5a) took place in the presence of DABCO, and this was followed by the desired cyclization, the hydroxyindoline intermediate HI was isolated instead of the expected indole 6a-N-Bz. Furthermore, a side-product incorporating a second unit of methyl propiolate was also obtained (DVE). It forms from the DABCO-catalyzed addition of methyl propiolate (5a) on the enol ether generated on the [3,3]  At this time, we decided to question the need for the protecting group on the nitrogen atom. Indeed, when starting from N-phenylhydroxylamine (4a) and methyl propiolate (5a) (1.2 equiv) as the reactants, the reaction proceeded smoothly to the desired unprotected indole 6a (Table 1, entry 1). The observed outcome was different to that reported by Hwu et al. [64] in which N-vinyl protected indoles were obtained when N-phenylhydroxylamine (4a) reacted with an excess of methyl propiolate (5a) in the presence of a catalytic amount of DMAP. Strikingly, the report by Hwu et al.. claims that DABCO and Et3N did not give significant amounts of the desired indoles under their reaction conditions. Once the feasibility of the reaction using free N-phenylhydroxylamine (4a) was established, we next undertook the optimization of the reaction (Table 1). Under all assayed conditions, the formation of the desired indole 6a was accompanied by the formation of very small amounts of side-product DVE. Based on these results, and taking into consideration the simplicity of the experimental procedure, we chose the reaction conditions depicted in entry 4 as the standardized conditions for the formation of the desired indoles 6 from the appropriate N-arylhydroxylamines 4. Once this reaction was optimized, we coupled this reaction with the reduction of the nitrobenzene (3a) to set up a consecutive 2-step reaction manifold (Scheme 3). Thus, reduction of nitrobenzene (3a) with hydrazine monohydrate and Rh on activated charcoal (5%) in THF gave Nphenylhydroxylamine (4a), which, after filtration of the reaction mixture and concentration, was directly submitted to the next reaction step to deliver indole 6a in 80% overall yield. Under these conditions, the overall yield of indole 6a was comparable to that obtained directly from 4a (80% vs 82%).

Scheme 3.
Coupling reduction and cascade condensation/rearrangement/elimination reactions in a consecutive 2-step protocol.

Scope of the Consecutive 2-Step Protocol
With a convenient protocol in hand, we next explored its scope with regard to the alkyne using N-phenylhydroxylamine (4a) as the nitrogen component (Scheme 4). The reaction was well suited to prepare 3-EWG-indoles incorporating carboxylates (6a-c), aroyl (acyl) groups (6d,e), or carboxamides (6f,g). In the case of N,N-disubstituted propionamides 5f and 5g, the poorest Michael acceptors of the series, the reaction needed more time (overnight) to deliver the corresponding N,Ndisubstituted indole-3-carboxamides 6f and 6g in synthetically relevant 52% and 58% yields respectively. The efficiency and simplicity of this transformation are emphasized when compared with the current multistep methodologies to prepare these indole-3-carboxamides [67].
Red: To highlight that these are the best conditions.
Once the feasibility of the reaction using free N-phenylhydroxylamine (4a) was established, we next undertook the optimization of the reaction (Table 1). Under all assayed conditions, the formation of the desired indole 6a was accompanied by the formation of very small amounts of side-product DVE. Based on these results, and taking into consideration the simplicity of the experimental procedure, we chose the reaction conditions depicted in entry 4 as the standardized conditions for the formation of the desired indoles 6 from the appropriate N-arylhydroxylamines 4.
Once this reaction was optimized, we coupled this reaction with the reduction of the nitrobenzene (3a) to set up a consecutive 2-step reaction manifold (Scheme 3). Thus, reduction of nitrobenzene (3a) with hydrazine monohydrate and Rh on activated charcoal (5%) in THF gave N-phenylhydroxylamine (4a), which, after filtration of the reaction mixture and concentration, was directly submitted to the next reaction step to deliver indole 6a in 80% overall yield. Under these conditions, the overall yield of indole 6a was comparable to that obtained directly from 4a (80% vs 82%).

Molecules 2020, 25, x FOR PEER REVIEW 4 of 16
Once the feasibility of the reaction using free N-phenylhydroxylamine (4a) was established, we next undertook the optimization of the reaction (Table 1). Under all assayed conditions, the formation of the desired indole 6a was accompanied by the formation of very small amounts of side-product DVE. Based on these results, and taking into consideration the simplicity of the experimental procedure, we chose the reaction conditions depicted in entry 4 as the standardized conditions for the formation of the desired indoles 6 from the appropriate N-arylhydroxylamines 4. Once this reaction was optimized, we coupled this reaction with the reduction of the nitrobenzene (3a) to set up a consecutive 2-step reaction manifold (Scheme 3). Thus, reduction of nitrobenzene (3a) with hydrazine monohydrate and Rh on activated charcoal (5%) in THF gave Nphenylhydroxylamine (4a), which, after filtration of the reaction mixture and concentration, was directly submitted to the next reaction step to deliver indole 6a in 80% overall yield. Under these conditions, the overall yield of indole 6a was comparable to that obtained directly from 4a (80% vs 82%).

Scope of the Consecutive 2-Step Protocol
With a convenient protocol in hand, we next explored its scope with regard to the alkyne using N-phenylhydroxylamine (4a) as the nitrogen component (Scheme 4). The reaction was well suited to prepare 3-EWG-indoles incorporating carboxylates (6a-c), aroyl (acyl) groups (6d,e), or carboxamides (6f,g). In the case of N,N-disubstituted propionamides 5f and 5g, the poorest Michael acceptors of the series, the reaction needed more time (overnight) to deliver the corresponding N,Ndisubstituted indole-3-carboxamides 6f and 6g in synthetically relevant 52% and 58% yields respectively. The efficiency and simplicity of this transformation are emphasized when compared with the current multistep methodologies to prepare these indole-3-carboxamides [67].

Scope of the Consecutive 2-Step Protocol
With a convenient protocol in hand, we next explored its scope with regard to the alkyne using N-phenylhydroxylamine (4a) as the nitrogen component (Scheme 4). The reaction was well suited to prepare 3-EWG-indoles incorporating carboxylates (6a-c), aroyl (acyl) groups (6d,e), or carboxamides (6f,g). In the case of N,N-disubstituted propionamides 5f and 5g, the poorest Michael acceptors of the series, the reaction needed more time (overnight) to deliver the corresponding N,N-disubstituted indole-3-carboxamides 6f and 6g in synthetically relevant 52% and 58% yields respectively. The efficiency and simplicity of this transformation are emphasized when compared with the current multistep methodologies to prepare these indole-3-carboxamides [67]. The scope of the consecutive 2-step manifold with regard to the substitution at the benzene ring was explored using methyl propiolate (5a) as the alkyne component and differently substituted nitroarenes 3 (Scheme 5). The manifold tolerated a diverse substitution pattern on the benzene ring to deliver the corresponding methyl indole-3-carboxylates 6 with overall good efficiency and broad functional/structural diversity. A convenient grade of topological diversity could be generated, spanning from the simple monosubstituted derivatives (e.g., 6h-r, 52-90% yield) to more complex polycyclic (6w, 57%) or fused aromatic systems (6ac, 83%). Meta-substituted N-arylhydroxylamines afforded separable mixtures of the corresponding C-4/C-6 regioisomers in excellent yields (80-90%) and with a slight substituent-dependent regioselectivity (Scheme 5, compounds 6n-r). A balance between steric and electronic effects of the substituent seems to steer the outcome of the [3,3]sigmatropic rearrangement, in line with the reported results in the Fischer synthesis of indoles endowed with this substitution pattern [52,65,68]. Thus, electron-donating substituents (R = OMe) unbalanced the chemical outcome towards the less crowed isomer (6r, 1.7:1 / C-6: C-4 ratio) whereas electron-withdrawing groups did it in the opposite direction (6o-q; from 1:1 to 2.3:1 / C-4:C-6 ratio). It is remarkable that the [3,3]-sigmatropic rearrangement of benzyl ketene acetals bearing a meta-OMe substituent on the aromatic ring preponderantly delivers the C-4 isomer. Theoretical studies pointed to a stabilizing interaction between the lone pair of the substituent and the LUMO orbital of the transition state as being responsible for the observed regioselectivity [69]. The observed inverted regioselectivity in our reaction seems to rule out the existence of this kind of stabilizing interactions. The scope of the consecutive 2-step manifold with regard to the substitution at the benzene ring was explored using methyl propiolate (5a) as the alkyne component and differently substituted nitroarenes 3 (Scheme 5). The manifold tolerated a diverse substitution pattern on the benzene ring to deliver the corresponding methyl indole-3-carboxylates 6 with overall good efficiency and broad functional/structural diversity. A convenient grade of topological diversity could be generated, spanning from the simple monosubstituted derivatives (e.g., 6h-r, 52-90% yield) to more complex polycyclic (6w, 57%) or fused aromatic systems (6ac, 83%). Meta-substituted N-arylhydroxylamines afforded separable mixtures of the corresponding C-4/C-6 regioisomers in excellent yields (80-90%) and with a slight substituent-dependent regioselectivity (Scheme 5, compounds 6n-r). A balance between steric and electronic effects of the substituent seems to steer the outcome of the [3,3]-sigmatropic rearrangement, in line with the reported results in the Fischer synthesis of indoles endowed with this substitution pattern [52,65,68]. Thus, electron-donating substituents (R = OMe) unbalanced the chemical outcome towards the less crowed isomer (6r, 1.7:1 / C-6: C-4 ratio) whereas electron-withdrawing groups did it in the opposite direction (6o-q; from 1:1 to 2.3:1 / C-4:C-6 ratio). It is remarkable that the [3,3]-sigmatropic rearrangement of benzyl ketene acetals bearing a meta-OMe substituent on the aromatic ring preponderantly delivers the C-4 isomer. Theoretical studies pointed to a stabilizing interaction between the lone pair of the substituent and the LUMO orbital of the transition state as being responsible for the observed regioselectivity [69]. The observed inverted regioselectivity in our reaction seems to rule out the existence of this kind of stabilizing interactions. As expected, substitution at the ortho-position posed a regioselectivity problem in the [3,3]sigmatropic rearrangement, since the C-C bond formation at the most substituted ortho-position becomes a competitive pathway (Scheme 6). Indeed, in some cases, we were able to isolate the product 10 obtained from this pathway. The effect of this mechanistic divergence was mainly reflected in a diminished efficiency in the reactions of nitroarenes bearing a good leaving group at that position (6x-z, 6aa-ab). In the case of simple alkyl substituents (6s-u) or fused bicycles (6w), the manifold mostly afforded the expected C-7 substituted indole derivatives in moderate to good yields. The versatility of this methodology is highlighted when compared with Zhangs' protocol [56] (Scheme 1B), which is sensitive to steric impediments and shows a reduced tolerance to alkyl substitution at this position [70]. However, the easy access to ortho-substituted nitroarenes together with the simplicity of the 2-step reaction manifold compensate for these deficiencies and make this methodology a viable synthetic alternative to prepare C-7 substituted 3-EWG indoles.  The reaction manifold was well suited to scale up. As a proof of concept, we carried out the synthesis of methyl 6-acetylindole-3-carboxylate (6m) at 50 mmol scale from 4-acetylnitrobenzene (3m) and methyl propiolate (5a). The scaled manifold afforded indole 6m in an excellent 84% yield As expected, substitution at the ortho-position posed a regioselectivity problem in the [3,3]-sigmatropic rearrangement, since the C-C bond formation at the most substituted ortho-position becomes a competitive pathway (Scheme 6). Indeed, in some cases, we were able to isolate the product 10 obtained from this pathway. The effect of this mechanistic divergence was mainly reflected in a diminished efficiency in the reactions of nitroarenes bearing a good leaving group at that position (6x-z, 6aa-ab). In the case of simple alkyl substituents (6s-u) or fused bicycles (6w), the manifold mostly afforded the expected C-7 substituted indole derivatives in moderate to good yields. The versatility of this methodology is highlighted when compared with Zhangs' protocol [56] (Scheme 1B), which is sensitive to steric impediments and shows a reduced tolerance to alkyl substitution at this position [70]. However, the easy access to ortho-substituted nitroarenes together with the simplicity of the 2-step reaction manifold compensate for these deficiencies and make this methodology a viable synthetic alternative to prepare C-7 substituted 3-EWG indoles.

General Information
1 H-NMR and 13 C-NMR spectra (see supplementary materials) of DMSO-d6 or CDCl 3 solutions were recorded either at 400 and 100 MHz or at 500 and 125 MHz (Bruker Ac 200 and AMX2-500 respectively). Mass spectra (low resolution) (EI/CI) were obtained with a Hewlett-Packard 5995 gas chromatograph/mass spectrometer. High-resolution mass spectra were recorded with a Micromass Autospec mass spectrometer. Analytical thin-layer chromatography plates used were E. Merck Brinkman UV-active silica gel (Kieselgel 60 F254) on aluminum. Flash column chromatography was carried out with E. Merck silica gel 60 (particle size less than 0.020 mm) using appropriate mixtures of ethyl acetate and hexanes, or ethyl acetate and dichloromethane as eluents. All reactions were performed in oven-dried glassware. All materials were obtained from commercial suppliers and used as received. N-phenylhydroxylamine (4a) was prepared on a multigram scale following a standard experimental procedure [71].

General Procedure for the Synthesis of Indoles 6 Directly from N-phenylhydroxylamine (4a). Preparation of Methyl Indol-3-carboxylate (6a)
To a solution of N-phenylhydroxylamine (4a) (436 mg, 4.0 mmol) in dichloromethane (20 mL) was added the activated alkyne 5 (4.2 mmol) and the resulting solution was cooled to 0 • C using an ice bath. DABCO (22 mg, 0.2 mmol) was added all at once and the reaction mixture was stirred for 1 h. The solvent was removed under reduced pressure, and the residue was purified by flash column chromatography (silica gel; n-hexane/ethyl acetate: 70/30 v/v) to give indole 6a (565.2 mg, 80%).

Conclusions
In summary, we reported a practical (scalable) and instrumentally simple methodology to synthesize N-unprotected polysubstituted indoles endowed with an electron-withdrawing group at C-3 position. The importance of these N-unprotected heterocycles in organic synthesis (molecular platforms), asymmetric catalysis (chiral catalysts), medicinal chemistry (therapeutics) and materials sciences (molecular devices) ensures the practical use of this methodology in different fields of organic chemistry. Studies aimed at the use of these 3-EWG-indoles as molecular platforms for catalytic asymmetric dearomatization and their therapeutic/biological annotations are in progress in our lab.