3-Nitroindoles Serving as N-Centered Nucleophiles for Aza-1,6-Michael Addition to para-Quinone Methides

An unprecedented N-alkylation of 3-nitroindoles with para-quinone methides was developed for the first time. Using potassium carbonate as the base, a wide range of structurally diverse N-diarylmethylindole derivatives were obtained with moderated to good yields via the protection group migration/aza-1,6-Michael addition sequences. The reaction process was also demonstrated by control experiments. Different from the previous advances where 3-nitrodoles served as electrophiles trapping by various nucleophiles, the reaction herein is featured that 3-nitrodoles is defined with latent N-centered nucleophiles to react with ortho-hydrophenyl p-QMs for construction of various N-diarylmethylindoles.


Introduction
Indole-based motifs are privileged structures for construction of various valuable complex heteroaromatic units, which widely exist in numerous biologically active natural products and pharmaceutically relevant compounds with potential pharmacological activities, such as against cancer, HIV, inflammation, tuberculosis, hypertension, diabetes, and against microbial, viral, and fungal infections [1 -6]. As a result, enormous efforts have been devoted to exploring versatile techniques for the efficient synthesis of structurally diverse indole derivatives, and thus the indole-based chemistry has become a hotspot in organic synthesis [7][8][9][10][11][12]. In conventional indole alkylation reactions, the most common synthetic modifications occurred at the C2 and C3-positions of indoles due to the innate nucleophilic nature (Scheme 1a) [13,14]. In contrast, the N-alkylation of indoles is challenging, and only a few reports have been disclosed to directly fabricate such compounds (Scheme 1b) [15,16]. Among the established N-alkylation of indoles, the studies mainly focused on modification of N-H indole derivatives by taking advantage of the nucleophilicity of the nitrogen atom [17][18][19][20][21][22][23]. However, the weak nucleophilicity of the nitrogen atom in indoles commonly resulted in the C2 or C3-positions alkylated by-products. In order to increase the N-centered nucleophilicity, an alternative method is the introduction of a protecting group at the N1-position of indoles made it latent nucleophiles [24][25][26][27], which are themselves not nucleophilic but can produce a strong nucleophile in situ via deprotection. To the best of our knowledge, it was only in 2019 that the Vilotijevic group reported that N-silyl indoles were employed as latent N-centered nucleophiles in the substitution of allylic fluorides for N-allyl indoles [28]. Therefore, the exploration of N-protected indoles as latent N-centered nucleophiles in N-alkylation reaction is huge challenges.
In recent years, there have an increasing number of reports on 3-nitroindoles as electrophiles in the reaction with various nucleophiles for the construction of diverse indolines via dearomative process [29][30][31][32][33]. Among these reactions, 3-nitroindoles are characterized by their readiness to be attacked by nucleophiles at the C2-position and sequentially trapped by electrophiles with the C3-position for the synthesis of indoline-containing polycyclic compounds (Scheme 2a). On the other hand, we have noticed that in the field of para-quinone methides (p-QMs) chemistry [34][35][36][37], ortho-hydrophenyl p-QMs have been used as donors to trigger some cycloaddition reactions with electron-deficient 2π-components, providing an access to chromans with structural diversity [38][39][40][41][42][43][44]. Along this line, as well as our continuing efforts on the dearomatization of nitroheteroarenes [45][46][47][48], we conceived that the dearomative [4 + 2] cycloaddition of electron-deficient 3-nitroindoles and ortho-hydrophenyl p-QMs might occur via the tandem oxy-Michael addition/1,6-addition under alkaline conditions (Scheme 2b) [49]. To our surprise, the reaction between 3-nitroindoles and ortho-hydrophenyl p-QMs did undergo smoothly but providing unanticipated N-alkylation products via protection group migration/aza-1,6-Michael addition pathway instead of the dearomative [4 + 2] cyclo-adducts (Scheme 2c). In this manuscript, the N-protected 3-nitroindoles served as latent N-centered nucleophiles to couple with ortho-hydrophenyl p-QMs and the protecting group was transferred from the N-center of indoles to the O-center of ortho-hydrophenyl p-QMs, leading to the N-diarylmethylindoles with good yields. Obviously, different from the previous advances where 3-nitroindoles serving as electrophiles were attacked by various nucleophiles, the reaction herein is featured that 3-nitrodoles is defined with latent N-centered nucleophiles to react with ortho-hydrophenyl p-QMs. Herein, we wish to reported the initial finds toward this protection group migration/aza-1,6-Michael addition sequences. In recent years, there have an increasing number of reports on 3-nitroindoles as electrophiles in the reaction with various nucleophiles for the construction of diverse indolines via dearomative process [29][30][31][32][33]. Among these reactions, 3-nitroindoles are characterized by their readiness to be attacked by nucleophiles at the C2-position and sequentially trapped by electrophiles with the C3-position for the synthesis of indoline-containing polycyclic compounds (Scheme 2a). On the other hand, we have noticed that in the field of para-quinone methides (p-QMs) chemistry [34][35][36][37], ortho-hydrophenyl p-QMs have been used as donors to trigger some cycloaddition reactions with electron-deficient 2π-components, providing an access to chromans with structural diversity [38][39][40][41][42][43][44]. Along this line, as well as our continuing efforts on the dearomatization of nitroheteroarenes [45][46][47][48], we conceived that the dearomative [4 + 2] cycloaddition of electron-deficient 3-nitroindoles and ortho-hydrophenyl p-QMs might occur via the tandem oxy-Michael addition/1,6-addition under alkaline conditions (Scheme 2b) [49]. To our surprise, the reaction between 3-nitroindoles and ortho-hydrophenyl p-QMs did undergo smoothly but providing unanticipated N-alkylation products via protection group migration/aza-1,6-Michael addition pathway instead of the dearomative [4 + 2] cyclo-adducts (Scheme 2c). In this manuscript, the N-protected 3-nitroindoles served as latent N-centered nucleophiles to couple with ortho-hydrophenyl p-QMs and the protecting group was transferred from the N-center of indoles to the O-center of ortho-hydrophenyl p-QMs, leading to the N-diarylmethylindoles with good yields. Obviously, different from the previous advances where 3-nitroindoles serving as electrophiles were attacked by various nucleophiles, the reaction herein is featured that 3-nitrodoles is defined with latent N-centered nucleophiles to react with ortho-hydrophenyl p-QMs. Herein, we wish to reported the initial finds toward this protection group migration/aza-1,6-Michael addition sequences.

Optimization Studies
We started our research with the selection of N-Ts 3-nitroindole 1a and ortho-hydroxyphenyl-substituted para-quinone methide 2a as the model substrates for optimizing the reaction conditions (Table 1). Using 1,4-diazabicyclo[2.2.2]octane (DABCO) as the base, the desired N-alkylated product 3a was obtained in 44% yield in toluene at 50 • C for 7 days (entry 1). However, when DABCO was replaced with stronger organic base 1,8diazabicyclo [5.4.0]undec-7-ene (DBU), a reduced yield was observed (entry 2). We then tested different inorganic bases such as Na 2 CO 3 and K 2 CO 3 (entries 3 and 4), and it was found that K 2 CO 3 was the best candidate, giving the product 3a with a yield of 60% (entry 4). Afterward, various solvents including CH 2 Cl 2 , THF, EtOAc, CH 3 CN and MeOH were examined, and it was found that CH 3 CN was the best choice to give the product 3a in 67% yield (entry 8 vs. entries 5-7 and 9). By cooling the reaction temperature to room temperature (rt), the yield of 3a could be increased to 71% (entry 10). A slightly lower yield was obtained when the amount of K 2 CO 3 was reduced to 1.0 equivalent (entry 11). Though a series of detailed investigations, the reaction conditions were eventually optimized as follows: 1.0 mmol of 1a and 1.0 mmol of 2a, 2.0 equiv. of K 2 CO 3 as base in CH 3 CN as solvent at room temperature. [a] Unless otherwise noted, the reaction was carried out with 1a (0.05 mmol), 2a (0.05 mmol), and base (2.0 equiv.) in 0.5 mL of solvent at indicated temperature for specified time.

Substrate Scope Studies
With the optimal reaction conditions in hand, we next surveyed the scope and generality for the N-alkylation of 3-nitroindoles with para-quinone methides. As shown in Scheme 3, by installing a fluorine atom into the aromatic ring at the C5-, C6-or C7position of N-Ts-3-nitroindoles, these reactions proceeded well to provide the corresponding products 3b-d in moderate yields. Moreover, 3-nitroindoles bearing different electronwithdrawing group, such as Cl-and Br-, regardless of their position on the aromatic ring, could react smoothly with 2a to deliver products 3e-i in satisfactory results. Nevertheless, the 3-nitroindole bearing a methyl group on the aromatic ring was also viable under the standard conditions, as demonstrated by the formation of product 3j in 49% yield. Changing the N1-proceting group of 3-nitroindole from -Ts to -Bs, had little effect on the reactivity, which could react smoothly with ortho-hydroxyphenyl-substituted para-quinone methide 2a, providing the corresponding product 3k in 69% yield. In addition, the developed catalytic system was also compatible with the N-Ac and N-alkoxycarbonylated protected 3-nitroindoles, generating the desired products 3l and 3m in acceptable yields via tandem protection group migration/aza-1,6-Michael addition sequences. On the other hand, various ortho-hydroxy p-QMs with either electron-withdrawing or -donating groups in the phenyl ring irrespective of their position were well tolerated to provide the expected products 3n-t in moderate to good yields.

Scale-Up Experiment
To demonstrate the synthetic potential of this unprecedented N-alkylation of 3-nitroindoles and para-quinone methides, a scale-up experiment was performed between 1a and 2a, which is 27 times larger than the scale of the model reaction in Scheme 3. As shown in Scheme 4, the gram-scale reaction proceeded well under the standard Scheme 3. Substrate scope of ortho-hydroxy p-QMs and 3-nitroindoles. Reaction conditions: the reactions were carried out with 1 (0.1 mmol), 2 (0.1 mmol) and K 2 CO 3 (2.0 equiv) in 1.0 mL of CH 3 CN at room temperature. The yield refers to the isolated yield.

Scale-Up Experiment
To demonstrate the synthetic potential of this unprecedented N-alkylation of 3-nitroindoles and para-quinone methides, a scale-up experiment was performed between 1a and 2a, which is 27 times larger than the scale of the model reaction in Scheme 3. As shown in Scheme 4, the gram-scale reaction proceeded well under the standard conditions and afforded the desired product 3a in 64% yield, suggesting that the developed protocol has good scalability in organic synthesis.
Molecules 2023, 28, x FOR PEER REVIEW 6 of 14 conditions and afforded the desired product 3a in 64% yield, suggesting that the developed protocol has good scalability in organic synthesis.

Control Experiments
In order to clarify the possible reaction mechanism, some control experiments were carried out (Scheme 5). The reaction of 1a and 2a provided the desired N-alkylated product 3a in 69% yield under the standard reaction conditions (Scheme 5a). Changing the nitro group of 1a to methyl resulted in the substrate 4 being formed, which failed to react with 2a (Scheme 5b). When the N-Ts indole-3-carboxylate 5 was reacted with 2a, the reaction gave the corresponding product 6 in 40% yield (Scheme 5c). These experimental results show that the installation of an electron-withdrawing group at the C3-posion of indole is crucial for this aza-1,6-Michael addition. Furthermore, the effect of the N1-protecting group of 3-nitroindole on the reactivity was also investigated (Scheme 5d,e). With the electron-donating group N-Me 3-nitroindole 7 or N-H 3-nitroindole 8 as the substrate, no desired N-alkylated product was detected (Scheme 5d,e). Comparing the results with Scheme 5a, it can be concluded that the N1-electron-withdrawing group of indoles plays an important role in assisting migration of N-electron-withdrawing group of 3-nitroindoles to O-center of ortho-hydrophenyl p-QMs and forming the N-centered nucleophiles. In addition, it was found that the one-pot reaction of N-H 3-nitroindole 8, 2a and TsCl could give product 3a in 53% yield (Scheme 5f), and the reaction of N-H 3-nitroindole 8 and ortho-oTs p-QM 9 could also afford 3a in 63% yield (Scheme 5g). From these two reactions, it can be confirmed that the sulfonylation of ortho-hydroxy p-QMs could enhance the electrophilicity and facilitate subsequent aza-1,6-Michael addition. Moreover, the reaction of N-Ts-3-nitroindole 1a and ortho-OTs p-QM 9 could not happen under the standard reaction conditions (Scheme 5h). However, by adding 1.0 equivalent PhOH into the reaction system, the reaction was able to give 3a in 60% yield, together with the formation of PhOTs (Scheme 5i). Meanwhile, the three-component reaction of 1a, ortho-OMe p-QM 10 and PhOH also proceeded to give product 11 and PhOTs (Scheme 5j). These control experiments show that the N-EWG of 1a is first transferred to O-EWG of 2a to form 9 under alkaline condition, and then the aza-1,6-Michel addition to para-quinone methides takes place to give the N-alkylated products.

Control Experiments
In order to clarify the possible reaction mechanism, some control experiments were carried out (Scheme 5). The reaction of 1a and 2a provided the desired N-alkylated product 3a in 69% yield under the standard reaction conditions (Scheme 5a). Changing the nitro group of 1a to methyl resulted in the substrate 4 being formed, which failed to react with 2a (Scheme 5b). When the N-Ts indole-3-carboxylate 5 was reacted with 2a, the reaction gave the corresponding product 6 in 40% yield (Scheme 5c). These experimental results show that the installation of an electron-withdrawing group at the C3-posion of indole is crucial for this aza-1,6-Michael addition. Furthermore, the effect of the N1-protecting group of 3-nitroindole on the reactivity was also investigated (Scheme 5d,e). With the electrondonating group N-Me 3-nitroindole 7 or N-H 3-nitroindole 8 as the substrate, no desired N-alkylated product was detected (Scheme 5d,e). Comparing the results with Scheme 5a, it can be concluded that the N1-electron-withdrawing group of indoles plays an important role in assisting migration of N-electron-withdrawing group of 3-nitroindoles to O-center of ortho-hydrophenyl p-QMs and forming the N-centered nucleophiles. In addition, it was found that the one-pot reaction of N-H 3-nitroindole 8, 2a and TsCl could give product 3a in 53% yield (Scheme 5f), and the reaction of N-H 3-nitroindole 8 and ortho-oTs p-QM 9 could also afford 3a in 63% yield (Scheme 5g). From these two reactions, it can be confirmed that the sulfonylation of ortho-hydroxy p-QMs could enhance the electrophilicity and facilitate subsequent aza-1,6-Michael addition. Moreover, the reaction of N-Ts-3-nitroindole 1a and ortho-OTs p-QM 9 could not happen under the standard reaction conditions (Scheme 5h). However, by adding 1.0 equivalent PhOH into the reaction system, the reaction was able to give 3a in 60% yield, together with the formation of PhOTs (Scheme 5i). Meanwhile, the three-component reaction of 1a, ortho-OMe p-QM 10 and PhOH also proceeded to give product 11 and PhOTs (Scheme 5j). These control experiments show that the N-EWG of 1a is first transferred to O-EWG of 2a to form 9 under alkaline condition, and then the aza-1,6-Michel addition to para-quinone methides takes place to give the N-alkylated products.

Plausible Reaction Mechanism
Based on our experimental results and the above control experiments, a plausible reaction mechanism was proposed for this base-mediated N-alkylation of 3-nitroindoles with para-quinone methides. As shown in Scheme 6, the initially K2CO3-promoted deprotonation of ortho-hydroxy phenyl p-QMs 2 affords intermediate A.

Plausible Reaction Mechanism
Based on our experimental results and the above control experiments, a plausible reaction mechanism was proposed for this base-mediated N-alkylation of 3-nitroindoles with para-quinone methides. As shown in Scheme 6, the initially K 2 CO 3 -promoted deprotonation of ortho-hydroxy phenyl p-QMs 2 affords intermediate A.

X-ray Crystallographic Structures
All the N-alkylation products obtained from the reaction of 3-nitroindoles with ortho-hydrophenyl p-QMs were unambiguously characterized by nuclear magnetic resonance spectroscopy and high resolution mass spectroscopy. Nevertheless, the structures of products 3l and 3p were confirmed by X-ray crystallographic study of the single crystals, which could be readily prepared from the mixture solvents of dichloromethane/EtOH (V: V = 1/10) at room temperature by slow evaporation of solvents (Figure 1). CCDC-2268774 (3l) and CCDC-2268775 (3p) contain the supplementary crystallographic data for this paper, which can be obtained free of charge from The Cambridge Crystallographic Data Centre.

General Information
Reagents were purchased from commercial sources and were used as received unless mentioned otherwise. Reactions were monitored by thin layer chromatography Scheme 6. Plausible reaction mechanism.

X-ray Crystallographic Structures
All the N-alkylation products obtained from the reaction of 3-nitroindoles with orthohydrophenyl p-QMs were unambiguously characterized by nuclear magnetic resonance spectroscopy and high resolution mass spectroscopy. Nevertheless, the structures of products 3l and 3p were confirmed by X-ray crystallographic study of the single crystals, which could be readily prepared from the mixture solvents of dichloromethane/EtOH (V:V = 1/10) at room temperature by slow evaporation of solvents (Figure 1). CCDC-2268774 (3l) and CCDC-2268775 (3p) contain the supplementary crystallographic data for this paper, which can be obtained free of charge from The Cambridge Crystallographic Data Centre.

X-ray Crystallographic Structures
All the N-alkylation products obtained from the reaction of 3-nitroindoles with ortho-hydrophenyl p-QMs were unambiguously characterized by nuclear magnetic resonance spectroscopy and high resolution mass spectroscopy. Nevertheless, the structures of products 3l and 3p were confirmed by X-ray crystallographic study of the single crystals, which could be readily prepared from the mixture solvents of dichloromethane/EtOH (V: V = 1/10) at room temperature by slow evaporation of solvents (Figure 1). CCDC-2268774 (3l) and CCDC-2268775 (3p) contain the supplementary crystallographic data for this paper, which can be obtained free of charge from The Cambridge Crystallographic Data Centre.

General Information
Reagents were purchased from commercial sources and were used as received unless mentioned otherwise. Reactions were monitored by thin layer chromatography

General Information
Reagents were purchased from commercial sources and were used as received unless mentioned otherwise. Reactions were monitored by thin layer chromatography (TLC). 1 H NMR and 13 C NMR spectra were recorded in CDCl 3 and DMSO-d 6 . 1 H NMR chemical shifts are reported in ppm relative to tetramethylsilane (TMS) with the solvent resonance employed as the internal standard (CDCl 3 at 7.26 ppm, DMSO-d 6 at 2.50 ppm). Data are reported as follows: chemical shift, multiplicity (s = singlet, br s = broad singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling constants (Hz), and integration. 13 C NMR chemical shifts are reported in ppm from tetramethylsilane (TMS) with the solvent resonance as the internal standard (CDCl 3 at 77.20 ppm, DMSO-d 6 at 39.52 ppm). Melting points products were recorded on a Büchi Melting Point B-545. The HRMS were recorded by The HRMS were recorded by Agilent 6545 LC/Q-TOF mass spectrometer.

General Experimental Procedure for the N-Alkylation of 3-Nitroindoles with para-Quinone Methides for the Synthesis of N-Diarylmethylindole Derivatives 3 (Scheme 3)
In a reaction tube equipped with a magnetic stirring bar, the 3-nitroindoles 1 (0.1 mmol, 1 equiv), ortho-hydroxyphenyl-substituted para-quinone methide 2 (0.1 mmol, 1.0 equiv), K 2 CO 3 (0.2 mmol, 2.0 equiv) and acetonitrile (1.0 mL) were added. Then, the mixture was stirred at room temperature. After completion, the mixture was concentrated and purified by flash chromatography on silica gel to give the corresponding products 3.

Conclusions
In conclusion, we have described an unprecedented N-alkylation of 3-nitroindoles and para-quinone methides by using K 2 CO 3 was the base via a protection group migration/aza-1,6-Michael addition sequences. With the developed protocol, a series of structurally diverse N-diarylmethylindole derivatives were obtained in moderate to good yields under mild conditions. According to the control experiments, a reasonable reaction mechanism was proposed. Importantly, the reaction herein is featured that 3-nitrodoles is defined with latent N-centered nucleophiles to react with ortho-hydrophenyl p-QMs, which is different from the previous reports where 3-nitrodoles was served as electrophiles trapped by various nucleophiles.
Supplementary Materials: The following supporting information can be downloaded at: https: //www.mdpi.com/article/10.3390/molecules28145529/s1, X-ray data for products 3l and 3p; copies of 1 H and 13 C NMR spectra.