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

Abstract

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.

1. 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-N-propargyl 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/Pd-catalyzed 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 2-nitrobenzenesulfonyl (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 CH₂Cl₂ 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 protecting group could allow for some of the drawbacks of the previously reported gold-catalyzed IMHA of N-substituted-N-propargylanilines (Scheme 1b) to be overcome. The carbamate motif, indeed, in addition to being widely known as excellent protecting groups for amines in organic synthesis, has received a great deal of attention in drug design and medicinal chemistry for its application in the construction of drugs and prodrugs [23].

Herein, we report the results of our investigations.

2. 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.

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].

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).

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(CH₃CN)SbF₆ 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].

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 CH₂Cl₂ at 80 °C in the presence of the JohnPhosAu(CH₃CN)SbF₆ 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 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 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 CF₃-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(CH₃CN)SbF₆ (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 NTf₂ as counterion (catalyst A′, entries 2 and 6). The electron-rich tri-isopropylphenyl ring on the ligand and the slightly more strongly coordinated NTf₂⁻ 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].

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: η²-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.

3. Materials and Methods

3.1. 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 ¹H 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. ¹H NMR (400.13 MHz), ¹³C NMR (100.6 MHz), and ¹⁹F 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.

3.2. Synthetic Procedures

3.2.1. Preparation of Substrates 1

Substrates were prepared as described in the Supplementary Materials.

3.2.2. Preparation of Derivatives 2: Typical Procedure for the Preparation of the Ethyl 4-Phenylquinoline-1(2H)-Carboxylate 2a

A Carousel Tube Reactor (Radley Discovery Technology) equipped with a magnetic stirring bar was charged with ethyl phenyl(3-phenylprop-2-yn-1-yl)carbamate 1a (97.8 mg, 0.35 mmol, 1 equiv.), CH₂Cl₂ (2 mL), JohnPhosAu(MeCN)SbF₆ (10.8 mg, 0.014 mmol, 0.04 equiv.), and sealed. Then, the reaction mixture was stirred at 80 °C and monitored by TLC until the disappearance of the starting material. After 1 h, the obtained mixture was cooled at room temperature and concentrated under reduced pressure. The residue was filtered on a pad of SiO₂ to afford 97.1 mg of ethyl 4-phenylquinoline-1(2H)-carboxylate 2a (99% yield).

Compound 2a: yield: 99% (97.1 mg); yellow oil; IR (neat): 2912, 1707, 1380 cm⁻¹; ¹H NMR (400.13 MHz) (CDCl₃): δ = 7.69 (d, J = 7.4 Hz, 1H), 7.45–7.36 (m, 5H), 7.31–7.27 (m, 1H), 7.12–7.05 (m, 2H), 6.07 (t, J = 4.5 Hz, 1H), 4.51 (d, J = 4.5 Hz, 2H), 4.33 (q, J = 7.1 Hz, 2H), 1.39 (t, J = 7.1 Hz, 3H); ¹³C NMR (100.6 MHz) (CDCl₃): δ = 154.2 (q), 138.9 (q), 137.3 (q), 129.3 (q), 128.8 (CH), 128.5 (CH), 127.9 (CH), 127.7 (CH), 126.1 (CH), 124.2 (CH), 124.1 (CH), 123.4 (CH), 62.3 (CH₂), 43.1 (CH₂), 14.7 (CH₃); MS (EI ion source): m/z (%) = 279 (18, [M⁺]), 206 (100), 204 (62), 102 (21); HRMS: m/z [M + Na]⁺ calcd. for C₁₈H₁₇NO₂Na: 302.1152; found: 302.1152.

3.3. Characterization Data

3.3.1. Characterization Data of Compound 1a–o

Characterization data of substrate 1 are reported in the Supplementary Materials.

3.3.2. Characterization Data of Compound 2b–j, 2l–o, 2′l–2′o

Compound 2b. Yield: 82% (88.9 mg); yellow oil; IR (neat): 2980, 1699, 1608, 1510, 1051 cm⁻¹; ¹H NMR (400.13 MHz) (CDCl₃): δ = 7.56 (bd, J = 7.7 Hz, 1H), 7.19 (d, J = 8.8 Hz, 2H), 7.18–7.15 (m, 1H), 7.01 (dd, J₁ = 7.8 Hz, J₂ = 1.7 Hz, 1H), 6.95 (dt, J₁ = 7.2 Hz, J₂ = 1.2 Hz, 1H), 6.84 (d, J = 8.8 Hz, 2H), 5.91 (t, J = 4.5 Hz, 1H), 4.37 (d, J = 4.5 Hz, 2H), 4.20 (q, J = 7.1 Hz, 2H), 3.76 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H); ¹³C NMR (100.6 MHz) (CDCl₃): δ = 159.4 (q), 154.2 (q), 138.4 (q), 137.4 (q), 131.3 (q), 130.0 (CH), 129.5 (q), 127.6 (CH), 126.1 (CH), 124.15 (CH), 124.08 (CH), 122.5 (CH), 113.9 (CH), 62.2 (CH₂), 55.4 (CH₃), 43.1 (CH₂), 14.7 (CH₃); MS (EI ion source): m/z (%) = 309 (47, [M⁺]), 280 (93), 236 (100), 221 (21), 192 (20); HRMS: m/z [M + Na]⁺ calcd. for C₁₉H₁₉NO₃Na: 332.1257; found: 332.1261.

Compound 2c. Yield: 99% (111.3 mg); white solid; m.p. = 110–111 °C; IR (neat): 2977, 1698, 1604, 1484 cm⁻¹; ¹H NMR (400.13 MHz) (CDCl₃): δ = 7.98 (d, J = 8.5 Hz, 2H), 7.67–7.65 (m, 1H), 7.45 (d, J = 8.5 Hz, 2H), 7.30–7.25 (m, 1H), 7.06–6.99 (m, 2H), 6.10 (t, J = 4.6 Hz, 1H), 4.49 (d, J = 4.6 Hz, 2H), 4.28 (q, J = 7.1 Hz, 2H), 2.63 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H); ¹³C NMR (100.6 MHz) (CDCl₃): δ = 197.8 (q), 154.2 (q), 143.9 (q), 138.3 (q), 137.4 (q), 136.6 (q), 129.1 (CH), 128.7 (CH), 128.1 (CH), 126.0 (CH), 124.6 (CH), 124.4 (CH), 120.6 (q), 62.4 (CH₂), 43.1 (CH₂), 26.8 (CH₃), 14.7 (CH₃); MS (EI ion source): m/z (%) = 321 (27, [M⁺]), 292 (71), 248 (100), 205 (28); HRMS: m/z [M + H]⁺ calcd. for C₂₀H₂₀NO₃: 322.1438; found: 322.1431.

Compound 2d. Yield: 82% (88.6 mg); pale yellow oil; IR (neat): 2980, 1702, 1491, 1382 cm⁻¹; ¹H NMR (400.13 MHz) (CDCl₃): δ = 7.56–7.53 (m, 1H), 7.40–7.33 (m, 5H), 6.81 (dd, J₁ = 8.9 Hz, J₂ = 2.9 Hz, 1H), 6.60 (d, J = 2.9 Hz, 1H), 6.06 (t, J = 4.5 Hz, 1H), 4.44 (d, J = 4.5 Hz, 2H), 4.26 (q, J = 7.1 Hz, 2H), 3.69 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H); ¹³C NMR (100.6 MHz) (CDCl₃): δ = 156.2 (q), 154.4 (q), 138.9 (q), 138.8 (q), 130.51 (q), 130.47 (q), 128.8 (CH), 128.5 (CH), 127.9 (CH), 125.2 (CH), 113.0 (CH), 111.6 (CH), 62.1 (CH₂), 55.6 (CH₃), 43.2 (CH₂), 14.7 (CH₃); MS (EI ion source): m/z (%) = 309 (21, [M⁺]), 280 (24), 236 (100), 193 (36), 165 (19), 63 (30); HRMS: m/z [M + H]⁺ calcd. for C₁₉H₂₀NO₃: 310.1438; found: 310.1443.

Compound 2e. Yield: 99% (101.4 mg); orange oil; IR (neat): 2981, 1697, 1493, 1378 cm⁻¹; ¹H NMR (400.13 MHz) (CDCl₃): δ = 7.53–7.52 (m, 1H), 7.42–7.34 (m, 5H), 7.07 (dd, J₁ = 8.3 Hz, J₂ = 1.4 Hz, 1H), 6.86 (bd, J = 1.4 Hz, 1H), 6.02 (t, J = 4.5 Hz, 1H), 4.45 (d, J = 4.5 Hz, 2H), 4.28 (q, J = 7.1 Hz, 2H), 2.24 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H); ¹³C NMR (100.6 MHz) (CDCl₃): δ = 154.2 (q), 139.1 (q), 139.0 (q), 134.8 (q), 133.8 (q), 129.1 (q), 128.8 (CH), 128.5 (CH), 128.4 (CH), 127.8 (CH), 126.5 (CH), 124.0 (CH), 123.5 (CH), 62.2 (CH₂), 43.1 (CH₂), 21.1 (CH₃), 14.7 (CH₃); MS (EI ion source): m/z (%) = 293 (39, [M⁺]), 264 (49), 220 (100), 204 (55), 63 (29); HRMS: m/z [M + H]⁺ calcd. for C₁₉H₂₀NO₂: 294.1489; found: 294.1491.

Compound 2f. Yield: 68% (77.2 mg); yellow oil; IR (neat): 2980, 2836, 1702, 1608, 1509, 1463 cm⁻¹; ¹H NMR (400.13 MHz) (CDCl₃): δ = 7.53–7.51 (m, 1H), 7.28 (d, J = 8.8 Hz, 2H), 7.07 (dd, J₁ = 8.3 Hz, J₂ = 1.6 Hz, 1H), 6.93 (d, J = 8.8 Hz, 2H), 6.89 (bd, J = 1.6 Hz, 1H), 5.97 (t, J = 4.5 Hz, 1H), 4.43 (d, J = 4.5 Hz, 2H), 4.27 (q, J = 7.1 Hz, 2H), 3.85 (s, 3H), 2.24 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H); ¹³C NMR (100.6 MHz) (CDCl₃): δ = 159.3 (q), 154.2 (q), 138.5 (q), 134.8 (q), 133.7 (q), 131.4 (q), 129.9 (CH), 129.3 (CH), 128.3 (CH), 126.5 (CH), 123.9 (CH), 122.7 (q), 113.9 (CH), 62.1 (CH₂), 55.4 (CH₃), 43.1 (CH₂), 21.1 (CH₃), 14.7 (CH₃); MS (EI ion source): m/z (%) = 323 (43, [M⁺]), 294 (87), 250 (100), 235 (20), 207 (17); HRMS: m/z [M + H]⁺ calcd. for C₂₀H₂₂NO₃: 324.1594; found: 324.1597.

Compound 2g. Yield: 96% (112.4 mg); orange wax; IR (neat): 2980, 2243, 1705, 1596, 1494 cm⁻¹; ¹H NMR (400.13 MHz) (CDCl₃): δ = 7.99 (d, J = 8.4 Hz, 2H), 7.54–7.52 (m, 1H), 7.45 (d, J = 8.4 Hz, 2H), 7.11–7.07 (m, 1H), 6.79 (bd, J = 1.4 Hz, 1H), 6.08 (t, J = 4.4 Hz, 1H), 4.46 (d, J = 4.4 Hz, 2H), 4.27 (q, J = 7.1 Hz, 2H), 2.64 (s, 3H), 2.23 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H); ¹³C NMR (100.6 MHz) (CDCl₃): δ = 197.9 (q), 154.2 (q), 144.0 (q), 138.3 (q), 136.5 (q), 134.8 (q), 133.9 (q), 129.6 (CH), 129.0 (CH), 128.7 (CH), 128.6 (CH), 128.5 (q), 126.3 (CH), 124.1 (CH), 62.3 (CH₂), 43.1 (CH₂), 26.8 (CH₃), 21.1 (CH₃), 14.7 (CH₃); MS (EI ion source): m/z (%) = 351 (M⁺, 31), 322 (50), 278 (14), 157 (46), 134 (100), 114 (62); HRMS: m/z [M + H]⁺ calcd. for C₂₁H₂₂NO₃: 336.1594; found: 336.1598.

Compound 2h. Yield: 99% (106.3 mg); yellow oil; IR (neat): 2979, 1703, 1608, 1557, 1376, 1271 cm⁻¹; ¹H NMR (400.13 MHz) (CDCl₃): δ = 7.28–7.14 (m, 6H), 6.68 (s, 1H), 6.01 (t, J = 5.2 Hz, 1H), 4.20–4.14 (m, 4H), 2.26 (s, 3H), 1.65 (s, 3H), 1.24 (t, J = 7.1 Hz, 3H); ¹³C NMR (100.6 MHz) (CDCl₃): δ = 153.9 (q), 141.8 (q), 139.9 (q), 139.1 (q), 137.3 (q), 135.3 (q), 129.0 (CH), 128.5 (CH), 127.4 (CH), 127.2 (CH), 125.8 (q), 125.3 (CH), 122.4 (CH), 62.1 (CH₂), 42.6 (CH₂), 23.0 (CH₃), 21.5 (CH₃), 14.7 (CH₃); MS (EI ion source): m/z (%) = 307 (20, [M⁺]), 278 (27), 234 (100), 218 (18); HRMS: m/z [M + H]⁺ calcd. for C₂₀H₂₂NO₂: 308.1645; found: 308.1649.

Compound 2i. Yield: 56% (61.7 mg); pale yellow oil; IR (neat): 2981, 2847, 1702, 1594, 1481 cm⁻¹; ¹H NMR (400.13 MHz) (CDCl₃): δ = 7.59 (bd, J = 8.1 Hz, 1H), 7.43–7.36 (m, 3H), 7.33–7.30 (m, 2H), 7.21 (dd, J₁ = 8.7 Hz, J₂ = 2.5 Hz, 1H), 7.02 (d, J = 2.5 Hz, 1H), 6.06 (t, J = 4.5 Hz, 1H), 4.47 (d, J = 4.5 Hz, 2H), 4.28 (q, J = 7.1 Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H); ¹³C NMR (100.6 MHz) (CDCl₃): δ = 153.9 (q), 138.1 (q), 135.6 (q), 130.7 (q), 129.5 (CH), 128.61 (CH), 128.60 (CH), 128.0 (CH), 127.4 (CH), 125.7 (CH), 125.3 (CH), 124.4 (q), 62.3 (CH₂), 43.0 (CH₂), 14.5 (CH₃). MS (EI ion source): m/z (%) = 313 (30, [M⁺]), 284 (72), 240 (100), 204 (62), 176 (19); HRMS: m/z [M + H]⁺ calcd. for C₁₈H₁₇ClNO₂: 314.0942; found: 314.0952.

Compound 2j. Yield: 10% (13.0 mg); colorless oil; IR (eat): 2919, 2848, 1710, 1609, 1382, 1051 cm⁻¹; ¹H NMR (400.13 MHz) (CDCl₃): δ = 7.77 (bd, J = 8.5 Hz, 1H), 7.49 (dd, J₁ = 8.6 Hz, J₂ = 1.6 Hz, 1H), 7.33 (bd, J = 1.6 Hz, 1H), 7.25 (d, J = 8.8 Hz, 2H), 6.94 (d, J = 8.8 Hz, 2H), 6.04 (t, J = 4.5 Hz, 1H), 4.48 (d, J = 4.5 Hz, 2H), 4.30 (q, J = 7.1 Hz, 2H), 3.86 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H); ¹³C NMR (100.6 MHz) (CDCl₃): δ = 159.7 (q), 153.9 (q), 140.4 (q), 137.8 (q), 130.4 (q), 129.9 (q), 129.7 (CH), 126.1 (q, q, J = 32.5 Hz), 124.5 (CH, q, J = 3.7 Hz), 124.20 (q, q, J = 270.3 Hz), 124.19 (CH), 123.7 (CH), 123.1 (CH, q, J = 3.7 Hz), 114.2 (CH), 62.7 (CH₂), 55.5 (CH₃), 43.2 (CH₂), 14.6 (CH₃); ¹⁹F NMR (376.5 MHz) (CDCl₃): δ = −62.3; MS (EI ion source): m/z (%) = 377 (26, [M⁺]), 348 (77), 304 (100), 289 (14), 261 (18); HRMS: m/z [M + Na]⁺ calcd. for C₂₀H₁₈F₃NO₃Na: 400.1131; found: 400.1119.

Isomeric mixture 2k + 2′k. Overall yield (catalyst A): 99% (107.2.0 mg); 2k/2′k = 67/33; overall yield (catalyst A′): 99% (107.1 mg); 2k/2′k = 94/6; overall yield (catalyst B): 90% (97.1 mg); 2k/2′k = 44/56; overall yield (catalyst C): 67% (72.7 mg); 2k/2′k = 46/54.

2k: orange oil; IR (Neat): 2980, 2243, 1705, 1596, 1494 cm⁻¹; ¹H NMR (400.13 MHz) (CDCl₃): δ = 7.29–7.21 (m, 6H), 6.90 (d, J = 8.7 Hz, 1H), 6.52 (dd, J₁ = 8.7 Hz, J₂ = 2.6 Hz, 1H), 5.80 (t, J = 4.5 Hz, 1H), 4.38 (d, J = 4.6 Hz, 2H), 4.21 (q, J = 7.1 Hz, 2H), 3.74 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H); ¹³C NMR (100.6 MHz) (CDCl₃): δ = 159.1 (q), 154.1 (q), 139.2 (q), 138.7 (q), 138.6 (q), 128.8 (CH), 128.5 (CH), 127.8 (CH), 127.0 (CH), 122.5 (q), 120.4 (CH), 110.2 (CH), 109.7 (CH), 62.3 (CH₂), 55.5 (CH₃), 43.3 (CH₂), 14.7 (CH₃). MS (EI ion source): m/z (%) = 309 (0.2, [M⁺]), 235 (100), 220 (17), 204 (29), 191 (24), 165 (15); HRMS: m/z [M + Na]⁺ calcd. for C₁₉H₁₉NO₃Na: 332.1257; found: 332.1260.

2′k: colorless oil; IR (neat): 2982, 1708, 1610, 1504, 1466 cm⁻¹; ¹H NMR (400.13 MHz) (CDCl₃): δ = 7.36–7.24 (m, 6H), 6.69 (d, J = 8.9 Hz, 1H), 6.08 (t, J = 5.1 Hz, 1H), 4.33 (d, J = 5.1 Hz, 2H), 4.29 (q, J = 7.2 Hz, 2H), 3.43 (s, 3H), 1.35 (t, J = 7.2 Hz, 3H); ¹³C NMR (100.6 MHz) (CDCl₃): δ = 156.2 (q), 153.9 (q), 141.5 (q), 139.8 (q), 137.8 (q), 128.3 (CH), 127.7 (CH), 126.68 (CH), 126.62 (CH), 124.5 (CH), 118.6 (q), 117.0 (CH), 108.4 (CH), 62.2 (CH₂), 55.5 (CH₃), 42.7 (CH₂), 14.7 (CH₃); MS (EI ion source): m/z (%) = 309 (42, [M⁺]), 280 (51), 236 (100), 220 (51), 193 (15); HRMS: m/z [M + Na]⁺ calcd. for C₁₉H₁₉NO₃Na: 332.1257; found: 332.1260.

Isomeric mixture 2l + 2′l. Overall yield (catalyst A): 98% (120.4 mg); 2l/2′l = 61/39; overall yield (catalyst A′): 99% (120.9); 2l/2′l = 75/29; overall yield (catalyst B): 99% (121.9 mg); 2l/2′l = 54/46; overall yield (catalyst C): 86% (105.5 mg); 2l/2′l = 54/46; yellow wax; IR (KBr): 3060, 2922, 1680, 1593, 1480, 1232 cm⁻¹.

Reported NMR spectra refer to an isomeric mixture 2l + 2′l in the ratio 54/46; ¹H NMR signals were assigned to each specific isomer while ¹³C NMR signals were not assigned.

¹H NMR (400.13 MHz) (CDCl₃) (selected signals): δ = 7.89 (d, J = 8.4 Hz, 2H 2l), 7.81 (d, J = 8.4 Hz, 2H 2′l), 7.35 (d, J = 8.4 Hz, 2H 2l), 7.24–7.17 (m, 1H 2l + 4H 2′l), 6.84 (d, J = 8.6 Hz, 1H 2l), 6.59 (d, J = 9.0 Hz, 1H 2′l), 6.52 (dd, J₁ = 8.6 Hz, J₂ = 2.6 Hz, 1H 2l), 6.03 (t, J = 5.0 Hz, 1H 2′l), 5.87 (t, J = 4.6 Hz, 1H 2l), 4.39 (d, J = 4.6 Hz, 2H 2l), 4.25–4.15 (m, 2H 2l + 4H 2′l), 3.74 (s, 3H 2l), 3.32 (s, 3H 2′l), 2.54 (s, 3H 2l), 2.53 (s, 3H 2′l), 1.29–1.23 (m, 3H 2l + 3H 2′l); ¹³C NMR (100.6 MHz) (CDCl₃): δ = 198.1, 197.9, 159.4, 156.0, 154.1, 153.9, 146.7, 144.1, 139.8, 138.7, 138.1, 137.1, 136.6, 135.5, 129.0, 128.8, 128.7, 128.0, 126.93, 126.90, 126.0, 121.9, 121.7, 117.9, 117.1, 110.4, 109.9, 108.2, 62.43, 62.39, 55.6, 55.4, 43.2, 42.7, 26.85, 26.79, 14.8, 14.7; MS (EI ion source): m/z (%) = 351 (51, [M⁺]), 322 (63), 278 (100), 262 (23), 235 (20), 43 (23); HRMS: m/z [M + H]⁺ calcd. for C₂₁H₂₂NO₄: 352.1543; found: 352.1536.

Isomeric mixture 2m + 2′m. Overall yield (catalyst A): 70% (83.0 mg); 2m/2′m = 91/9; overall yield (catalyst A′): 73% (86.5 mg); 2m/2′m = 91/9; overall yield (catalyst B): 83% (98.6 mg); 2m/2′m = 63/37; overall yield (catalyst C): 77% (91.8 mg); 2m/2′m = 51/49.

Compound 2m. Colorless oil; IR (Neat): 2915, 1711, 1577, 1386, 1244 cm⁻¹; ¹H NMR (400.13 MHz) (CDCl₃): δ = 7.27–7.24 (m, 3H), 7.00 (d, J = 8.6 Hz, 1H), 6.91 (d, J = 8.8 Hz, 2H), 6.60 (dd, J₁ = 8.6 Hz, J₂ = 2.6 Hz, 1H), 5.84 (t, J = 4.5 Hz, 1H), 4.43 (d, J = 4.5 Hz, 2H), 4.28 (q, J = 7.1 Hz, 2H), 3.84 (s, 3H), 3.82 (s, 3H), 1.35 (t, J = 7.1 Hz, 3H); ¹³C NMR (100.6 MHz) (CDCl₃): δ = 159.3 (q), 159.0 (q), 154.1 (q), 138.6 (q), 138.2 (q), 131.6 (q), 129.9 (CH), 127.0 (CH), 122.7 (q), 119.6 (CH), 113.9 (CH), 110.2 (CH), 109.6 (CH), 62.2 (CH₂), 55.5 (CH₃), 55.4 (CH₃), 43.2 (CH₂), 14.7 (CH₃); MS (EI ion source): m/z (%) = 339 (1, [M⁺]), 265 (100), 250 (13), 222 (10), 207 (15); HRMS: m/z [M + K]⁺ calcd. for C₂₀H₂₁NO₄K: 378.1102; found: 378.1095.

Compound 2′m. Colorless oil; IR (neat): 2915, 1694, 1609, 1381, 1239, 1042 cm⁻¹; ¹H NMR (400.13 MHz) (CDCl₃): δ = 7.26–7.24 (m, 1H), 7.17 (t, J = 8.2 Hz, 1H), 7.08 (d, J = 8.8 Hz, 2H), 6.75 (d, J = 8.8 Hz, 2H), 6.60 (d, J = 8.9 Hz, 1H), 5.93 (t, J = 5.1 Hz, 1H), 4.20 (d, J = 5.1 Hz, 2H), 4.18 (q, J = 7.1 Hz, 2H), 3.75 (s, 3H), 3.37 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H); ¹³C NMR (100.6 MHz) (CDCl₃): δ = 158.6 (q), 156.3 (q), 153.9 (q), 140.0 (q), 137.2 (q), 134.1 (q), 128.3 (CH), 127.8 (CH), 123.6 (CH), 118.7 (q), 117.0 (CH), 113.1 (CH), 108.4 (CH), 62.3 (CH₂), 55.7 (CH₃), 55.5 (CH₃), 42.7 (CH₂), 14.7 (CH₃); MS (EI ion source): m/z (%) = 339 (66, [M⁺]), 310 (67), 266 (100), 251 (23); HRMS: m/z [M + H]⁺ calcd. for C₂₀H₂₂NO₄: 340.1543; found: 340.1539.

Isomeric mixture 2n + 2′n. Overall yield (catalyst A): 85% (112.9 mg); 2n/2′n = 88/12; overall yield (catalyst A′): 75% (99.7); 2n/2′n = 64/36; overall yield (catalyst B): 99% (131.6 mg); 2n/2′n = 40/60; overall yield (catalyst C): 72% (95.1 mg); 2n/2′n = 19/81.

Compound 2n: pale yellow solid; m.p. = 140–141 °C; IR (neat): 2930, 1751, 1657, 1583, 1298 cm⁻¹; ¹H NMR (400.13 MHz) (CDCl₃): δ = 8.27 (bs, 1H), 8.08 (d, J = 8.4 Hz, 2H), 7.62 (dd, J₁ = 8.2 Hz, J₂ = 1.7 Hz, 1H), 7.41 (d, J = 8.4 Hz, 2H), 7.08 (d, J = 8.2 Hz, 1H), 6.21 (t, J = 4.5 Hz, 1H), 4.53 (d, J = 4.5 Hz, 2H), 4.31 (q, J = 7.1 Hz, 2H), 3.94 (s, 3H), 2.60 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H); ¹³C NMR (100.6 MHz) (CDCl₃): δ = 197.3 (q), 166.7 (q), 153.9 (q), 142.8 (q), 137.7 (q), 137.3 (q), 136.4 (q), 132.6, (q) 129.9 (CH), 129.8 (CH), 128.7 (CH), 126.9 (q), 125.9 (CH), 124.4 (CH), 123.9 (CH), 62.5 (CH₂), 52.2 (CH₃), 43.0 (CH₂), 26.7 (CH₃), 14.5 (CH₃); MS (EI ion source): m/z (%) = 379 (67, [M⁺]), 350 (15), 306 (100), 290 (52), 264 (70), 204 (26); HRMS: m/z [M + Na]⁺ calcd. for C₂₂H₂₁NO₅Na: 402.1312; found: 402.1312.

Compound 2′n: yellow oil; IR (neat): 2919, 1725, 1599, 1268, 1023 cm⁻¹; ¹H NMR (400.13 MHz) (CDCl₃): δ = 7.90 (d, J = 8.5 Hz, 2H), 7.77 (m, 1H), 7.30 (t, J = 7.8 Hz, 1H), 7.23–7.19 (m, 3H), 6.21 (t, J = 5.2 Hz, 1H), 4.33 (d, J = 5.2 Hz, 2H), 4.21 (q, J = 7.1 Hz, 2H), 3.84 (s,3 H), 2.00 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H); ¹³C NMR (100.6 MHz) (CDCl₃): δ = 202.2 (q), 166.7 (q), 153.6 (q), 145.4 (q), 139.8 (q), 139.5 (q), 138.0 (q), 129.9 (q), 129.1 (CH), 127.6 (CH), 127.3 (CH), 127.1 (q), 126.7 (CH), 123.9 (CH), 62.5 (CH₂), 52.1 (CH₃), 42.4 (CH₂), 29.1 (CH₃), 14.5 (CH₃); MS (EI ion source): m/z (%) = 379 (58, [M⁺]), 350 (100), 306 (95), 264 (44), 204 (36), 43 (27); HRMS: m/z [M + Na]⁺ calcd. for C₂₂H₂₁NO₅Na: 402.1312; found: 402.1310.

Isomeric mixture 2o + 2′o. Overall yield (catalyst A): 88% (112.0 mg); 2o/2′o = 88/12; overall yield (catalyst A′): 90% (114.3); 2o/2′o = 65/35; overall yield (catalyst B): 70% (89.0 mg); 2o/2′o = 33/67; overall yield (catalyst C): 82% (104.4 mg); 2o/2′o = 20/80.

Compound 2o. Yellow wax; IR (neat): 2982, 1680, 1607, 1556, 1256 cm⁻¹; ¹H NMR (400.13 MHz) (CDCl₃): δ = 8.27 (bs, 1H), 8.00 (d, J = 8.4 Hz, 2H), 7.63 (dd, J₁ = 8.2 Hz, J₂ = 1.7 Hz, 1H), 7.43 (d, J = 8.4 Hz, 2H), 7.08 (d, J = 8.2 Hz, 1H), 6.22 (t, J = 4.6 Hz, 1H), 4.54 (d, J = 4.6 Hz, 2H), 4.32 (q, J = 7.1 Hz, 2H), 2.64 (s, 3H), 2.60 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H); ¹³C NMR (100.6 MHz) (CDCl₃): δ = 197.8 (q), 197.5 (q), 154.0 (q), 143.1 (q), 137.9 (q), 137.5 (q), 136.9 (q), 136.7 (q), 132.7 (q), 129.1 (CH), 128.9 (CH), 127.2 (CH), 126.1 (CH), 124.6 (CH), 124.0 (CH), 62.7 (CH₂), 43.3 (CH₂), 26.9 (CH₃, 2C), 14.7 (CH₃); MS (EI ion source): m/z (%) = 363 (62, [M⁺]), 333 (12), 290 (83), 248 (70), 43 (100); HRMS: m/z [M + Na]⁺ calcd. for C₂₂H₂₁NO₄Na: 386.1363; found: 386.1359.

Compound 2′o. Yellow wax; IR (neat): 2981, 1682, 1603, 1450, 1376, 1265 cm⁻¹; ¹H NMR (400.13 MHz) (CDCl₃): δ = 7.89 (d, J = 8.6 Hz, 2H), 7.85 (m, 1H) 7.38 (t, J = 7.7 Hz, 1H), 7.31–7.27 (m, 3H), 6.28 (t, J = 5.2 Hz, 1H), 4.40 (d, J = 5.2 Hz, 2H), 4.28 (q, J = 7.1 Hz, 2H), 2.59 (s, 3H), 2.07 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H); ¹³C NMR (100.6 MHz) (CDCl₃): δ = 202.3 (q), 197.6 (q), 153.7 (q), 145.8 (q), 139.9 (q), 139.6 (q), 138.1 (q), 136.1 (q), 128.8 (CH), 127.7 (CH), 127.39 (CH), 127.34 (q), 126.9 (CH), 124.1 (CH), 62.6 (CH₂), 42.5 (CH₂), 29.3 (CH₃), 26.7 (CH₃), 14.6 (CH₃); MS (EI ion source): m/z (%) = 363 (26, [M⁺]), 334 (41), 290 (54), 232 (28), 204 (30), 43 (100); HRMS: m/z [M + Na]⁺ calcd. for C₂₂H₂₁NO₄Na: 386.1363; found: 386.1361.

3.3.3. Characterization Data of Compounds 3a, 5b, 6b, 7b

Characterization data of the listed compounds are reported in the Supplementary Materials.

4. Conclusions

The employment of ethyl carbamate N-protecting group represents a viable alternative to the tosyl N-protecting group, allowing the efficient synthesis of the corresponding 4-substituted-1,2-dihydroquinolines by means of the gold-catalyzed IMHA reaction. The reaction proceeds with internal alkynes bearing electron-rich and electron-deficient substituents in the benzenes affording only the 6-endo cyclization product in fair to high yields. Au(I)- catalyzed regiodivergent intramolecular hydroarylation of the N-ethoxycarbonyl-N-propargyl-meta-substituted anilines at the ortho- and para-position cyclization could be successfully established respectively through fine-tuning electronic and steric effects of the gold complexes ligands.

Supplementary Materials

The following are available online, general information of reagents and methods, synthetic procedures, and characterization data.

Author Contributions

Project administration, G.F.; Supervision, A.G.; Conceptualization, A.G. and A.I.; Methodology, A.G. and A.I.; Investigation, A.F., F.M., A.S. and G.M.; Data curation, A.I.; Writing—original draft preparation, review and editing, A.A.; Writing—review and editing, V.M., A.C., A.G. and A.I. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data is contained within the article or supplementary material.

Acknowledgments

We gratefully acknowledge the PRIN project 2017 “Targeting Hedgehog pathway: virtual screening identification and sustainable synthesis of novel Smo and Gli inhibitors and their pharmacological drug delivery strategies for improved therapeutic effects in tumors.” (20175XBSX4) and La Sapienza, University of Rome, for financial support.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Samples of the compounds are not available from the authors.

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Figures, Schemes and Tables

Scheme 1. Gold(I)-catalyzed IMHA of N-tosyl- (a) vs. N-ethoxy carbonyl-N-propargylanilines (b).

Figure 1. Structure of the hydration derivative 3a.

Scheme 2. JPAu(CH3CN)SbF6 catalyzed IMHA of N-propargylaniline derivatives 4a and 4b a. a Compound 4b was recovered in almost quantitative yield when the reaction was carried out in the absence of the catalyst.

Figure 2. Structure of the 4-phenylquinoline 6b and 4-phenyl-1,2,3,4-tetrahydroquinoline 7b obtained from compound 4b in the condition reported in Scheme 2.

Figure 3. Ligand control of ortho/para site-selectivity.

Scheme 3. Proposed Friedel–Crafts mechanism for the Au(I)-catalyzed cyclization of N-substituted-N-propargylanilines.

Table 1

Screening optimal conditions for the IMHA of the N-ethoxycarbonyl-N-propargylaniline 1a ^a.

Scheme 3. Proposed Friedel–Crafts mechanism for the Au(I)-catalyzed cyclization of N-substituted-N-propargylanilines.

Entry	Catalyst	T (°C)	Solvent	Time (h)	2a (Yield %)
1	PtCl2	80	EtOH	24	- b
2	NaAuCl4	80	EtOH	48	- c
3	JPAu(CH3CN)SbF6	80	DCM d	1	98
4	JPAu(CH3CN)SbF6	100	CHCl3	4.5	70 e
5	JPAu(CH3CN)SbF6	100	CHCl3 d	0.75	86 f
6	JPAuCl/AgNTf2	80	CH2Cl2	3.5	94

^a Reactions were carried out on a 0.35 mmol of 1a in 2 mL of solvent in the presence of 0.014 mmol of the catalyst. ^b 1a was recovered in 30% yield, ethyl 3-oxo-3-phenylpropyl(phenyl)carbamate 3a was isolated in 35% yield; ^c 1a was recovered in 18% yield, 3a was isolated in 75% yield; ^d Commercial anhydrous solvent; ^e 3a was isolated in 21% yield; ^f 3a was isolated in 7% yield.

Table 2

Scope of the gold(I)-catalyzed IMHA of the N-ethoxycarbonyl-N-propargylanilines 1 ^a.

Scheme 3. Proposed Friedel–Crafts mechanism for the Au(I)-catalyzed cyclization of N-substituted-N-propargylanilines.

Entry	R	R2	1	Time (h)	2 (Yield %)
1	H	H	a	1	2a (98)
2	H	OMe	b	18	2b (82)
3	H	COMe	c	2	2c (99)
4	4-OMe	H	d	2	2d (82)
5	4-Me	H	e	1	2e (99)
6	4-Me	OMe	f	5	2f (68) b
7	4-Me	COMe	g	1	2g (99)
8	3,5-(Me)2	H	h	1	2h (99)
9	4-Cl	H	i	24	2i (56) c
10	4-CF3	OMe	j	24	2j (10) d

^a Reactions were carried out on 0.35 mmol scale of 1 in 2 mL of CH₂Cl₂; ^b The starting alkyne 1f 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.

Table 3

Ortho- vs. para-position annulation in the gold(I)-catalyzed IMHA of the N-ethoxycarbonyl-N-propargylanilines 1k–n^a.

Scheme 3. Proposed Friedel–Crafts mechanism for the Au(I)-catalyzed cyclization of N-substituted-N-propargylanilines.

Entry	R1	R2	Catalyst	Overall Yield (%) b	2/2′	(Ratio) c
1	OMe	H	A	99	2k/2′k	(67/33)
2			A′	99		(94/6)
3			B	90		(44/56)
4			C	67		(46/54)
5	OMe	COMe	A	99	2l/2′l	(61/39)
6			A′	99		(75/25)
7			B	99		(54/46)
8			C	86		(54/46)
9	OMe	OMe	A	70	2m/2′m	(91/9)
10			A′	73		(91/9)
11			B	83		(63/37)
12			C	77		(51/49)
13	COMe	COOMe	A	85	2n/2′n	(88/12)
14			A′	75		(64/36)
15			B	99		(40/60)
16			C	72		(19/81)
17	COMe	COMe	A	88	2o/2′o	(88/12)
18			A′	90		(65/35)
19			B	70		(33/67)
20			C	82		(20/80)

^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 ¹H NMR analyses.