Synthesis of 4-Substituted-1,2-Dihydroquinolines by Means of Gold-Catalyzed Intramolecular Hydroarylation Reaction of N-Ethoxycarbonyl-N-Propargylanilines

An alternative Au(I)-catalyzed synthetic route to functionalized 1,2-dihydroquinolines is reported. This novel approach is based on the use of N-ethoxycarbonyl protected-N-propargylanilines as building blocks that rapidly undergo the IMHA reaction affording the 6-endo cyclization product in good to high yields. In the presence of N-ethoxycarbonyl-N-propargyl-meta-substituted anilines, the regiodivergent cyclization at the ortho-/para-position is achieved by the means of catalyst fine tuning.


Introduction
4-Substituted-1,2-dihydroquinolines represent key structural units in a variety of naturally occurring products/pharmaceuticals and are used as building blocks in organic synthesis [1][2][3][4][5]. Many methods for the synthesis of functionalized 1,2-dihydroquinolines are known, [1], but due to their pharmaceutical relevance, the development of practical approaches using mild reaction conditions remains an active research area [6][7][8][9][10][11]. Among them, the transition metal-catalyzed as well as the metal-free mediated intramolecular hydroarylation (IMHA) reactions involving the activation of the N-substituted-Npropargyl anilines carbon-carbon triple bond by using an electrophilic source have been extensively used [12,13]. In particular, the synthetic potential of gold catalysis in the IMHA of N-tosyl-N-propargylanilines was explored and the corresponding 4-substituted-1,2-dihydroquinoline derivatives were efficiently isolated (Scheme 1a) [14][15][16]. Alternatively these latter products can be obtained by the sequential catalyzed IMHA/Pdcatalyzed cross-coupling of 3-bromo-2-propynyl-N-tosylanilines, which afforded the corresponding 4-substituted-1,2-dihydroquinoline derivatives [17,18]. However, the behavior of the substituent attached to N-propargylaniline nitrogen has a significant impact on the reaction outcome. While N-propargylanilines bearing the more easily removable 2nitrobenzenesulfonyl (Ns) nitrogen protecting group underwent the gold-catalyzed IMHA to give the corresponding dihydroquinoline in good yield, subjection of the N-Boc protected derivatives under the same reaction conditions afforded the divergent formation of an oxazolidinone derivative as the exclusive product [16]. Moreover, 1-azaspirotrienone derivatives were produced exclusively instead of the expected dihydroquinolines when N-(4-methoxyphenyl)-N-(3-substituted-2-propyn-1-yl)triflamides were reacted with 2 equiv. of ICl in CH 2 Cl 2 at −78 • C for 0.5 [19]. As part of our ongoing interest on the development of efficient atom-economical routes of heterocycles by means of gold-catalyzed IMHA [20][21][22], we envisaged that the introduction of the more suitable ethyl carbamate Herein, we report the results of our investigations.

Results and Discussion
We started our study by examining the transformation of the N-ethoxycarbonyl-Npropargylaniline 1a into 2a under different reaction conditions. The results of this preliminary screening are summarized in Table 1.
As shown, the IMHA of 1a occurred in almost quantitative yield in the presence of the commercially available JohnPhosAu(MeCN)SbF6 catalyst (4 mol %) in anhydrous DCM at 80 °C (Table 1, entry 3) [15,16]. Herein, we report the results of our investigations.

Results and Discussion
We started our study by examining the transformation of the N-ethoxycarbonyl-N-propargylaniline 1a into 2a under different reaction conditions. The results of this preliminary screening are summarized in Table 1. About the same result was obtained using the catalytic system JPAuCl/AgNTf2 (T 1, entry 6) while slightly poorer results were observed when CHCl3 was used a solvent instead of DCM (Table 1,  As shown, the IMHA of 1a occurred in almost quantitative yield in the presence of the commercially available JohnPhosAu(MeCN)SbF 6 catalyst (4 mol %) in anhydrous DCM at 80 • C (Table 1, entry 3) [15,16].
About the same result was obtained using the catalytic system JPAuCl/AgNTf 2 (Table 1, entry 6) while slightly poorer results were observed when CHCl 3 was used as the solvent instead of DCM (Table 1, entries 4, 5). In this latter solvent, the hydration derivative ethyl 3-oxo-3-phenylpropyl(phenyl)carbamate 3a was isolated to some extent ( Figure 1). About the same result was obtained using the catalytic system JPAuCl/AgNTf2 (Table  1, entry 6) while slightly poorer results were observed when CHCl3 was used as the solvent instead of DCM (Table 1, entries 4, 5). In this latter solvent, the hydration derivative ethyl 3-oxo-3-phenylpropyl(phenyl)carbamate 3a was isolated to some extent ( Figure 1). In contrast with the good efficiency showed by NaAuCl4·2H2O in the sequential alkylation/gold-catalyzed annulation reactions of anilines with propargylic bromide derivatives providing quinoline scaffolds in ethanol [24], this gold salt was ineffective as the catalyst of the IMHA of N-ethoxycarbonyl-N-propargylaniline 1a, affording only the formation of the hydration product 3a in good yield (Table 1, entry 2) [25]. Starting material 1a was recovered in almost quantitative yield when PtCl2 was used as the catalyst in ethanol (Table 1, entry 1) [26].
Then, to briefly explore the influence of the protecting group on the reaction outcome, we used the optimized reaction condition for the cyclization of the N-propargylaniline derivatives 4a and 4b (Scheme 2). In contrast with the good efficiency showed by NaAuCl 4 ·2H 2 O in the sequential alkylation/gold-catalyzed annulation reactions of anilines with propargylic bromide derivatives providing quinoline scaffolds in ethanol [24], this gold salt was ineffective as the catalyst of the IMHA of N-ethoxycarbonyl-N-propargylaniline 1a, affording only the formation of the hydration product 3a in good yield (Table 1, entry 2) [25]. Starting material 1a was recovered in almost quantitative yield when PtCl 2 was used as the catalyst in ethanol ( Table 1, entry 1) [26].
Then, to briefly explore the influence of the protecting group on the reaction outcome, we used the optimized reaction condition for the cyclization of the N-propargylaniline derivatives 4a and 4b (Scheme 2). As shown by the results reported in Scheme 2, the N-trifluoroacetyl-Npropargylaniline derivative failed to undergo the desired gold-catalyzed IMHA to give the corresponding dihydroquinoline 5a in the presence of 4 mol % of JPAu(CH3CN)SbF6 in DCM at 80 °C. Interestingly, under the same reaction conditions, the simple N-(3phenylprop-2-yn-1-yl)aniline 4b underwent a complete gold-catalyzed IMHA, but the 4phenyl-1,2-dihydroquinoline 5b (25% yield) was prone to be partially oxidized under the reaction conditions to give the corresponding 4-phenylquinoline 6b (56% yield). The partial oxidation of 5b to 6b occurs even under a nitrogen atmosphere. Furthermore, we observed the formation of 7b, which was isolated in 7% of yield (see Figure 2) [27]. As shown by the results reported in Scheme 2, the N-trifluoroacetyl-N-propargylaniline derivative failed to undergo the desired gold-catalyzed IMHA to give the corresponding dihydroquinoline 5a in the presence of 4 mol % of JPAu(CH 3 CN)SbF 6 in DCM at 80 • C. Interestingly, under the same reaction conditions, the simple N-(3-phenylprop-2-yn-1-yl)aniline 4b underwent a complete gold-catalyzed IMHA, but the 4-phenyl-1,2-dihydroquinoline 5b (25% yield) was prone to be partially oxidized under the reaction conditions to give the corresponding 4-phenylquinoline 6b (56% yield). The partial oxidation of 5b to 6b occurs even under a nitrogen atmosphere. Furthermore, we observed the formation of 7b, which was isolated in 7% of yield (see Figure 2) [27]. the corresponding dihydroquinoline 5a in the presence of 4 mol % of JPAu(CH3CN)SbF6 in DCM at 80 °C. Interestingly, under the same reaction conditions, the simple N-(3phenylprop-2-yn-1-yl)aniline 4b underwent a complete gold-catalyzed IMHA, but the 4phenyl-1,2-dihydroquinoline 5b (25% yield) was prone to be partially oxidized under the reaction conditions to give the corresponding 4-phenylquinoline 6b (56% yield). The partial oxidation of 5b to 6b occurs even under a nitrogen atmosphere. Furthermore, we observed the formation of 7b, which was isolated in 7% of yield (see Figure 2) [27].  Table 2. The 4-arylsubstituted-1,2-dihydroquinoline derivatives 2 were isolated in high yields both when the electron donating -OMe group or the strong withdrawing -COOMe were introduced into the para-position of the aromatic ring attached to the alkyne (Table 2, entries 2, 3). Conversely, the introduction of substituents onto the aromatic ring attached to the nitrogen moiety had a different pronounced effect according to their electronic features. The formation of the target 4-aryl-1,2dihydroquinoline derivative 2 efficiently occurred by the introduction of an electrondonating group on the phenyl ring para to the nitrogen and in the para position of both aromatic rings of the starting aryl-substituted propargylic aniline derivatives ( Table 2, entries 4-6). Moreover, the IMHA was also allowed in almost quantitative yield in the presence of the -Me group on the phenyl ring para to the nitrogen and of a withdrawing Subsequently, we continued to establish the scope and the generality of gold(I) catalyzed-IMHA reactions of aryl-substituted N-ethoxycarbonyl-N-propargylanilines 1 in terms of ring substitution. The utilization of electron-deficient substrates and the control of the regioselectivity of substituted aromatics remain challenges of gold(I) catalyzed-IMHA reactions of aryl-substituted N-propargylanilines. To that end, a range of readily accessible derivatives 1a-j were prepared and then subjected to the IMHA in CH 2 Cl 2 at 80 • C in the presence of the JohnPhosAu(CH 3 CN)SbF 6 as the catalyst. The outcomes of such studies are shown in Table 2. The 4-arylsubstituted-1,2-dihydroquinoline derivatives 2 were isolated in high yields both when the electron donating -OMe group or the strong withdrawing -COOMe were introduced into the para-position of the aromatic ring attached to the alkyne ( Table 2, entries 2, 3). Conversely, the introduction of substituents onto the aromatic ring attached to the nitrogen moiety had a different pronounced effect according to their electronic features. The formation of the target 4-aryl-1,2-dihydroquinoline derivative 2 efficiently occurred by the introduction of an electron-donating group on the phenyl ring para to the nitrogen and in the para position of both aromatic rings of the starting arylsubstituted propargylic aniline derivatives ( Table 2, entries 4-6). Moreover, the IMHA was also allowed in almost quantitative yield in the presence of the -Me group on the phenyl ring para to the nitrogen and of a withdrawing carbonyl in the para position of the other aryl group (Table 2, entry 7). In absolute agreement with considerations of the positive effect of electronic releasing groups on the aromatic ring attached to the nitrogen on the gold-catalyzed IMHA of substrate 1, substrate 1h bearing two methyl groups on the same benzene nucleus was smoothly converted to the corresponding 1,2-dihydroquilonine 2h in about quantitative yield either by the gold-catalyzed IMHA ( Table 2, entry 8). Substrate 1i, possessing a Cl-substituent on the same aromatic ring, cyclized as expected to afford the corresponding dihydroquinoline derivative 2i in moderate yield (Table 2, entry 9). The formation of the IMHA products occurred only in low yield in the presence of the strong electron-withdrawing CF 3 -substituent probably due to the poorer coordination of the alkyne moiety with the gold catalyst (Table 2, entry 10).
With regard to the regiochemical outcome, the meta-substituted derivatives 1k-n mainly underwent the para-position cyclization to give the corresponding 1,2-dihydroquinolines 2k-n in the presence of JohnPhosAu(CH 3 CN)SbF 6 (catalyst A). Fine tuning factors such as valency state, counterion, and auxiliary ligand in homogeneous gold catalysis is imperative in controlling the product divergence [28]. Indeed, for compounds 1k-l, the para-position cyclization was revealed to be enhanced in the presence of catalyst A bearing NTf 2 as counterion (catalyst A , entries 2 and 6). The electron-rich tri-isopropylphenyl ring on the ligand and the slightly more strongly coordinated NTf 2 − jointly lower the electrophilicity of the gold center. On the other hand, the regiodivergent cyclization to the sterically hindered ortho-position to give the regioisomeric 1,2-dihydroquinolines 2 k-n resulted governed by the electron-deficient ligand features, according to the literature (Table 3) [29]. by the gold-catalyzed IMHA (Table 2, entry 8). Substrate 1i, possessing a Cl-substit on the same aromatic ring, cyclized as expected to afford the correspon dihydroquinoline derivative 2i in moderate yield (Table 2, entry 9). The formation o IMHA products occurred only in low yield in the presence of the strong elec withdrawing CF3-substituent probably due to the poorer coordination of the al moiety with the gold catalyst (Table 2, entry 10).  N-ethoxycarbonyl-N-propargylanilines 1 a Reactions were carried out on 0.35 mmol scale of 1 in 2 mL of CH2Cl2; b The starting alkyne 1 was recovered in 8% yield; c The starting alkyne 1i was recovered in 18% yield; d The starting alkyne 1j was recovered in 60% yield.
With regard to the regiochemical outcome, the meta-substituted derivatives 1 mainly underwent the para-position cyclization to give the corresponding dihydroquinolines 2k-n in the presence of JohnPhosAu(CH3CN)SbF6 (catalyst A). tuning factors such as valency state, counterion, and auxiliary ligand in homogen gold catalysis is imperative in controlling the product divergence [28]. Indeed compounds 1k-l, the para-position cyclization was revealed to be enhanced in presence of catalyst A' bearing NTf2 as counterion (catalyst A', entries 2 and 6). electron-rich tri-isopropylphenyl ring on the ligand and the slightly more stro coordinated NTf2 -jointly lower the electrophilicity of the gold center. On the other h the regiodivergent cyclization to the sterically hindered ortho-position to give regioisomeric 1,2-dihydroquinolines 2′k-n resulted governed by the electron-defi ligand features, according to the literature ( Very likely, the control of ortho/para site-selectivity in these substrates is the result of the different coordination modes of the gold catalyst influenced by sterics and electronics of the auxiliary ligand. The prowess of electron-rich bulk ligands in pushing the π-system toward the para C-H bond through a Au(I)-bicoordinate activation was also explored in the 6-endo-dig gold catalyzed hydroarylation of functionalized N-aryl alkynamides ( Figure 3) [30].  Indeed, according to the literature [13], the gold catalyzed IMHA proceeds through a Friedel-Crafts type mechanism: η 2 -coordination of alkyne moiety affords complex I, which undergoes an electrophilic aromatic substitution to give the Wheland-type intermediate II. This latter, after aromatization and protodeauration would give the product 2. The proposed mechanism is outlined in the Scheme 3. Indeed, according to the literature [13], the gold catalyzed IMHA proceeds through a Friedel-Crafts type mechanism: η 2 -coordination of alkyne moiety affords complex I, which undergoes an electrophilic aromatic substitution to give the Wheland-type intermediate II. This latter, after aromatization and protodeauration would give the product 2. The proposed mechanism is outlined in the Scheme 3. Table 3. Orthovs. para-position annulation in the gold(I)-catalyzed IMHA of the N-ethoxycarbonyl-N-propargylanilines 1k-n a .
a Reactions were carried out on 0.35 mmol of 1k-n in 2 mL in CH2Cl2; b Overall yield refers to the mixture of regioisomers 2 + 2′; c The isomeric ratio was determined by 1 H NMR analyses.
Very likely, the control of ortho/para site-selectivity in these substrates is the result of the different coordination modes of the gold catalyst influenced by sterics and electronics of the auxiliary ligand. The prowess of electron-rich bulk ligands in pushing the π-system toward the para C-H bond through a Au(I)-bicoordinate activation was also explored in  Indeed, according to the literature [13], the gold catalyzed IMHA proceeds through a Friedel-Crafts type mechanism: η 2 -coordination of alkyne moiety affords complex I, which undergoes an electrophilic aromatic substitution to give the Wheland-type intermediate II. This latter, after aromatization and protodeauration would give the product 2. The proposed mechanism is outlined in the Scheme 3.

General Information
All the commercially available reagents, catalysts, bases, and solvents were used as purchased without further purification. Reaction products 2a-e and 2g-h were filtered on a pad of SiO2 using AcOEt, while reaction products 2f, 2i and 2j were purified by chromatography on SiO2 (25-40 μm), eluting with n-hexane/AcOEt mixtures. Reaction products 2k/2′k-2o/2′o were obtained as isomeric mixtures by filtration on a pad of SiO2 using AcOEt to eliminate the catalysts before calculating the isomeric ratio by 1 H NMR. When possible, to obtain suitable NMR spectra of each compound, the isomeric mixtures were further purified by semi-preparative HPLC under normal phase condition using a Scheme 3. Proposed Friedel-Crafts mechanism for the Au(I)-catalyzed cyclization of N-substituted-N-propargylanilines.

General Information
All the commercially available reagents, catalysts, bases, and solvents were used as purchased without further purification. Reaction products 2a-e and 2g-h were filtered on a pad of SiO 2 using AcOEt, while reaction products 2f, 2i and 2j were purified by chromatography on SiO 2 (25-40 µm), eluting with n-hexane/AcOEt mixtures. Reaction products 2k/2 k-2o/2 o were obtained as isomeric mixtures by filtration on a pad of SiO 2 using AcOEt to eliminate the catalysts before calculating the isomeric ratio by 1 H NMR. When possible, to obtain suitable NMR spectra of each compound, the isomeric mixtures were further purified by semi-preparative HPLC under normal phase condition using a Nucleodur 100-5 column (762,007.100) and eluting with n-hexane/AcOEt mixtures. 1 H NMR (400.13 MHz), 13 C NMR (100.6 MHz), and 19 F spectra (376.5 MHz) were recorded with a Bruker Avance 400 spectrometer. Splitting patterns were designed as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), or bs (broad singlet). IR spectra were recorded with a Jasco FT/IR-430 spectrometer. HRMS were recorded with an Orbitrap Exactive Mass spectrometer with ESI source. Melting points were determined with a Büchi B-545 apparatus and are uncorrected.

Preparation of Substrates 1
Substrates were prepared as described in the Supplementary Materials.

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Data Availability Statement: Data is contained within the article or supplementary material.