Synthesis and Catalytic Activity of Organocatalysts Based on Enaminone and Benzenediamine Hydrogen Bond Donors

Abstract

A total of 24 novel organocatalysts based on (S)-quininamine as a chiral tertiary amine and on enaminone or 1,2-benzenediamine as hydrogen bond donors were synthesized. The enaminone-type catalysts were prepared by the transamination of N,N-dimethyl enaminones with (S)-quininamine (9 examples) and the 1,2-benzenediamine-type catalysts were prepared in 3 steps from (S)-quininamine and ortho-fluoronitrobenzene derivatives (15 examples). Their organocatalytic activity was evaluated in the Michael addition of acetylacetone to trans-β-nitrostyrene. Enantioselectivities of up to 72% ee were observed.

1. Introduction

At the turn of the millennium, the field of asymmetric organocatalysis experienced an exponential growth, leading to a plethora of mechanistic investigations and synthetic applications. Easy-to-use reaction conditions, environmentally friendly reagents devoid of potentially toxic metal ions, and readily available tunable organocatalysts operating via different substrate activation modes brought organocatalysis to the forefront of asymmetric synthesis. Nowadays, organocatalysis is considered to be the third pillar of asymmetric catalysis [1,2,3,4,5] along with metal catalysis and biocatalysis; it is increasingly used in the pharmaceutical and biotechnological industries [6,7].

Bifunctional H-bond donor organocatalysts are the workhorses of noncovalent organocatalysis, allowing the simultaneous activation and coordination of both nucleophilic and electrophilic reactants. A typical and most commonly used H-bond donor bifunctional organocatalyst is a derivative of a chiral 1,2-diamine scaffold such as quinuclidine or cyclohexane-1,2-diamine, which contain a tertiary amine functionality and a hydrogen-bonding donor moiety in the form of thiourea or (thio)squaramide (Figure 1a) [1,8,9,10,11]. Structurally and functionally analogous efficient organocatalysts based on chiral 1,3-diamine scaffolds are rare [12,13,14]; highly efficient bifunctional organocatalysts based on camphor-1,3-diamine have recently been developed in our group (Figure 1a) [15,16]. Although single hydrogen bond donors such as (thio)amides, sulfonamides, and phosphoramides (Figure 1b) are not commonly used in bifunctional organocatalysis, a few catalysts of this type exhibit high enantioselectivity in the atroposelective addition of thiophenols to naphthoquinones [17] as well as in the Michael addition of 1,3-dicarbonyls to trans-β-nitrostyrene [18,19]. On the other hand, double hydrogen bond donors (HBDs) such as thiourea and (thio)squaramide are the most common and superior. The use of several other, and less common, double HBDs such as diaminomethylenemalononitrile (DMM) [20,21] and (heterocyclic)guanidines [22], have also been reported in the literature (Figure 1c). As the number of HBDs used in organocatalysis is relatively small, the introduction of novel HBDs could expand the pool of available H-bond donor bifunctional organocatalysts and thus broaden the substrate scope.

Lee et al. developed aniline-containing cinchona alkaloid catalysts for the asymmetric isomerization of β,γ-unsaturated cyclohexenones by cooperative iminium-base catalysis [23]. On the other hand, in the context of H-bond donor bifunctional organocatalysts, HBDs based on 1,2-benzenediamine and enaminone derivatives have not been reported in the literature, although structurally different enaminone reagents [24,25] and benzenediamine precursors (i.e., nitrohalobenzene derivatives) are either readily prepared or commercially available. In an extension of our ongoing studies on enaminones and asymmetric bifunctional organocatalysts, we recently focused our attention to the use of enaminones and 1,2-benzenediamines as possible HBDs in designing novel bifunctional organocatalysts. In this article, we report the synthesis of 24 novel chiral H-bond donor bifunctional organocatalysts based on a chiral (S)-quininamine scaffold and enaminone (A) or 1,2-benzenediamine (B) scaffolds as HBDs (Figure 1d) and their evaluation in a Michael addition model of acetylacetone to trans-β-nitrostyrene.

2. Results and Discussion

2.1. Synthesis of HBDs

Enaminones 2a–g were prepared in 29–99% yields from hippuric acid (1a) or heterocyclic C-nucleophiles 1b–g and N,N-dimethylformamide dimethylacetal (DMFDMA) or bis(dimethylamino)-tert-butoxymethane (Bredereck’s reagent) following the literature procedures from Supplementary Materials. Enaminones 2a–g were then further reacted in the transamination reaction with (S)-(6-methoxyquinolin-4-yl)[(1S,2S,4S,5R)-5-vinylquinuclidin-2-yl]methanamine hydrochloride or (S)-quininamine hydrochloride (3) [26] to afford the desired transamination products 4a–g in 10–93% yields (Scheme 1). The malonate analogs 4h and 4i could not be obtained by the same transamination reaction. They were prepared by a treatment of commercial diethyl ethoxymethylenemalonate (2h) and 2-(ethoxymethylene)malononitrile (2i) with free amine 3 in 22% and 24% yields, respectively (Scheme 1).

The commercial availability of ortho-fluoronitrobenzene derivatives rendered the synthesis of a library of electronically tunable bifunctional organocatalysts containing benzenediamine HBDs. Thus, chiral ortho-nitroanilines 6a–j were prepared by a treatment of (S)-quininamine hydrochloride (3) with ortho-fluoronitrobenzenes 5a–j. A subsequent reduction of the nitro group with stannous chloride gave diamine derivatives 7a–j. The acylation of diamines 7a–c with benzoyl chloride, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI)-activated 3,5-bis(trifluoromethyl)benzoic acid, and benzenesulfonyl chloride in the presence of a base furnished aminoamides 8a–c and aminosulfonamide 9 in 35–82% yields. A reaction of the primary amino group of 7 with enaminone 2b in the presence of acid or with 2-(ethoxymethylene)malononitrile (2i) gave the enaminone-benzenediamine derivatives 10a–k (Scheme 2, Figure 2). Attempts to introduce the 3,5-bis(trifluoromethyl)phenyl group and the 3,5-bis(trifluoromethyl)benzyl group by the alkylation of the primary amino group were unsuccessful.

2.2. Structure Determination

The structures of novel compounds 4 and 8–10 were determined by spectroscopic methods (¹H- and ¹³C-NMR, IR, and HRMS). The intermediates 6 and 7 were used in the next step as they were and without further purification. The intermediates 6c,e–i and 7c–i were characterized by ¹H- and ¹³C-NMR and HRMS, the intermediate 6d was characterized by ¹H- and ¹³C-NMR, the intermediates 6a, 7a, and 7j were characterized by ¹H-NMR, and the intermediates 6b, 7b, and 6j were used in a further transformation without characterization. The structures of compounds 4b and 4f were determined by a single crystal X-ray analysis (Figure 3). The amino and carbonyl groups in compound 4b were cis-oriented (with a (Z)-configuration around the exocyclic C=C double bond); in compound 4f, they were trans-oriented (with a (Z)-configuration around the exocyclic C=C double bond). These configurations were in agreement with the configuration of analogous compounds previously reported in the literature [27,28]. The conformation of the two compounds significantly differed with respect to the enaminone and (S)-quininamine fragments, as shown by the selected torsion angles Θ(C1-C2-N-C3) (168.70 for 4b and −111.30 for 4f) and Θ(C1-C2-C4-C5) (115.40 for 4b and 164.79 for 4f) (Figure 3).

In a solution, enaminones are known to be configurationally labile and adopt a preferred configuration based on the sum of the inter- and intramolecular interactions. They can exist in a solution as mixtures of isomers due to the E/Z isomerism around the enaminone C=C double bond and rotational isomerism around the C–N and C–C bonds. Both types of isomerism are associated with enaminones with a typical order of magnitude of free energy of isomerization of ΔG°₂₉₆ ~5 kJ/mol [29]. A cis-orientation between the amino and the carbonyl group is usually favored in CDCl₃ due to intramolecular –NH····O=C– hydrogen bonding whereas in DMSO-d₆, a trans-orientation between the amino and the carbonyl group is often predominant [24,29,30,31]. For compounds 4a–f, a preferred configuration was adopted in the solution, as shown by the proton spectra in DMSO-d₆, with up to 11% of the minor isomer. The HMBC correlation technique, which is commonly used to determine the configuration of α,β-unsaturated carbonyl compounds on the basis of the difference in the magnitude of the heteronuclear ¹³C-¹H long-range coupling constants of the (Z) and the (E) isomers [32,33,34,35], also failed due to signal overlap, broad peaks, and missing cross-peaks. Consequently, the only way the configuration around the enaminone C=C bond in compounds 4a–f in the CDCl₃ and DMSO-d₆ solution could be determined was on the basis of δ chemical shifts for the enamine NH and CH protons. As shown in Figure S6 in the Supplementary Materials, the chemical shifts of the NH protons in compounds 4a, 4c, and 4d of δ ~6.6 ppm were in line with the trans-orientation between the NH and the C=O group. On the other hand, the much larger chemical shifts of the signals for the NH protons in compounds 4b, 4e, and 4f of δ ~10 ppm were in agreement with intramolecular –NH····O=C– hydrogen bonding and, hence, so was the cis-orientation between the NH and the C=O group [24,25,30,31].

2.3. Organocatalytic Activity of Enaminone- and 1,2-Benzenediamine-Type Catalysts

The organocatalytic activity of the enaminone-type catalysts 4a–i and the 1,2-benzenediamine-type catalysts 8a–c, 9, and 10a–k was tested in a Michael addition of acetylacetone to trans-β-nitrostyrene [15] in dichloromethane at 25 °C for 16 h using 10 mol% and 40 mol% of the catalyst, respectively. The results are summarized in Table S1 of the Supplementary Materials for enaminone-type catalysts 4a–i, in Table S2 for the N-acylated 8a–c and N-sulfonylated 9 1,2-benzenediamine catalysts, and in Table S3 for N-(2,2,-dicyanovinyl)-1,2-benzenediamine-type catalysts 10a–j and their close analog 10k. Catalysts 4 and 8–10 were characterized by low conversions (up to 47%, Table S1, catalyst 4d) and low enantioselectivities (up to 72% ee, Table S3, catalyst 10a). No clear trend between the single or the double HBDs and the corresponding conversions and enantioselectivities could be established for enaminone catalysts 4a–i (Table S1). In 1,2-benzenediamine series 8a–c and 9, there was also no clear correlation between the structures and the observed conversions and enantioselectivities (Tables S2 and S3). Furthermore, although distinguished by the same chiral quinuclidine scaffold, a switch of the sense of enantioselectivity was observed within the same groups of catalysts 4 and 8–9 (Tables S1 and S2 from Supplementary Materials). On the other hand, the N-(2,2,-dicyanovinyl)-1,2-benzenediamine catalysts 10a–j were characterized by consistent (S) selectivity and, with four out of ten representatives, also comparable enantioselectivities (42–72% ee, catalysts 10a–c,f; Table S3). This observation clearly pointed out 1,2-benzenediamine-based general structure 10 with an N-(2,2,-dicyanovinyl) substituent as a promising structural factor for further studies.

3. Materials and Methods

Solvents for extractions and chromatography were of technical grade and were distilled prior to use. Extracts were dried over technical grade anhydrous Na₂SO₄. Melting points were determined on a Kofler micro hot stage (Laica Galen III, Leica, Germany). The NMR spectra were obtained on a Bruker Avance DPX 300 at 300 MHz for 1H nucleus and Bruker UltraShield 500 plus (Bruker, Billerica, MA, USA) at 500 MHz for ¹H and 126 MHz for ¹³C nucleus, using DMSO-d₆ and CDCl₃ with TMS as the internal standard, as solvents. Mass spectra were recorded on an Agilent 6224 Accurate Mass TOF LC/MS (Agilent Technologies, Santa Clara, CA, USA), IR spectra on a Perkin-Elmer Spectrum BX FTIR spectrophotometer (PerkinElmer, Waltham, MA, USA). CD spectra were recorded on a J-1500 Circular Dichroism Spectrophotometer (JASCO corporation, Tokyo, Japan). Column chromatography (CC) was performed on silica gel (Silica gel 60, particle size: 0.035–0.070 mm (Sigma-Aldrich, St. Louis, MO, USA)). HPLC analyses were performed on an Agilent 1260 Infinity LC (Agilent Technologies, Santa Clara, CA, USA) using CHIRALPAK AD-H (0.46 cm ø × 25 cm), as chiral column (CHIRAL TECHNOLOGIES, INC., West Chester, PE, USA). All the commercially available chemicals used were purchased from Sigma-Aldrich (St. Louis, MO, USA).

3.1. Synthesis of Enaminones 2a–i 

3.1.1. Methyl (Z)-2-Benzamido-3-(dimethylamino)acrylate (2a) [36]

Prepared according to modified procedure from the literature. N-Benzoylglycine (1a) (5.58 mmol, 1.00 g) was dissolved in anhydrous toluene (16 mL), DMFDMA (22.3 mmol, 2.97 mL) was added, and the reaction mixture was heated to 90 °C for 30 min. Volatile components were evaporated in vacuo and the residue was crystalized from a mixture of ethanol and water. Yield: 918 mg (3.69 mmol, 66%) of white solid, ¹H-NMR (500 MHz, DMSO-d₆): δ 2.96 (s, 6H), 3.53 (s, 3H), 7.36 (s, 1H), 7.45–7.49 (m, 2H), 7.52–7.56 (m, 1H), 7.85–7.93 (m, 2H), 9.01 (s, 1H). Spectral data are consistent with the literature data [36].

3.1.2. (Z)-4-[(Dimethylamino)methylene]-5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one (2b) [27]

Prepared according to modified procedure from the literature. 5-Methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one (1b) (2.87 mmol, 500 mg) was dissolved in anhydrous toluene (8 mL), DMFDMA (11.48 mmol, 1.525 mL) was added, and the reaction mixture was heated at 90 °C for 30 min. Volatile components were evaporated in vacuo and the residue was purified by CC (EtOAc:petroleum ether = 2:1). Yield: 651 mg (2.83 mmol, 99%) of pale ocher solid. ¹H-NMR (500 MHz, CDCl₃): δ 2.18 (s, 3H), 3.30 (s, 3H), 3.88 (s, 3H), 6.99 (s, 1H), 7.06–7.15 (m, 1H), 7.32–7.38 (m, 2H), 7.92–8.00 (m, 2H). Spectral data are consistent with the literature data [27].

3.1.3. (Z)-5-[(Dimethylamino)methylene]imidazolidine-2,4-dione (2c) [37]

Prepared according to modified procedure from the literature. Imidazolidine-2,4-dione (1c) (17.8 mmol, 1.785 g) was dissolved in acetonitrile (5 mL), Bredereck’s reagent (21.4 mmol, 4.2 mL) was added, and the reaction mixture was heated under reflux for 5 h. Isolation by vacuum filtration of precipitated product. Yield: 1.32 g (8.51 mmol, 48%) of white solid. ¹H-NMR (500 MHz, DMSO-d₆): δ 2.95 (s, 6H), 6.41 (s, 1H), 9.29 (s, 1H), 10.29 (s, 1H). Spectral data are consistent with the literature data [37].

3.1.4. (Z)-5-[(Dimethylamino)methylene]-3-methylimidazolidine-2,4-dione (2d) [37]

Prepared according to modified procedure from the literature. Imidazolidine-2,4-dione (1d) (23.3 mmol, 2.33 g) was dissolved in acetonitrile (5 mL), DMFDMA (65.2 mmol, 8.7 mL) was added, and the reaction mixture was refluxed for 5 h. Isolation by vacuum filtration of precipitated product. Yield: 2.16 g (12.7 mmol, 62%) of white solid. ¹H-NMR (500 MHz, DMSO-d₆): δ 2.84 (s, 3H), 2.98 (s, 6H), 6.56 (s, 1H), 9.52 (s, 1H). Spectral data are consistent with the literature data [37].

3.1.5. (Z)-5-[(Dimethylamino)methylene]-3-phenyl-2-thioxoimidazolidin-4-one (2e) [38]

Prepared according to modified procedure from the literature. 3-Phenyl-2-thioxoimidazolidin-4-one (1e) (2.87 mmol, 552 mg) was dissolved in anhydrous toluene (4 mL), DMFDMA (5.74 mmol, 0.56 mL) was added, and the reaction mixture was refluxed for 0.5 h. Isolation by vacuum filtration of precipitated product. Yield: 243 mg (0.98 mmol, 34%) of pale pink solid. ¹H-NMR (500 MHz, CDCl₃): δ 3.18 (s, 6H), 6.84 (s, 1H), 7.35–7.39 (m, 2H), 7.40–7.44 (m, 1H), 7.46–7.53 (m, 2H), 9.02 (br s, 1H). Spectral data are consistent with the literature data [38].

3.1.6. (Z)-5-[(Dimethylamino)methylene]-3-phenyl-2-thioxothiazolidin-4-one (2f) [28]

Prepared according to modified procedure from the literature. 3-Phenyl-2-thioxothiazolidin-4-one (1f) (4.78 mmol, 1.00 g) was dissolved in anhydrous toluene (13 mL), DMFDMA (9.56 mmol, 1.3 mL) was added, and the reaction mixture was heated to 90 °C for 30 min. Isolation by CC (EtOAc). Yield: 370 mg (1.40 mmol, 29%) of yellowish solid. ¹H-NMR (500 MHz, CDCl₃): δ 3.16 (s, 6H), 7.23–7.32 (m, 2H), 7.43–7.47 (m, 1H), 7.49–7.54 (m, 2H), 7.59 (s, 1H). Spectral data are consistent with the literature data [28].

3.1.7. 5-[(Dimethylamino)methylene]-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (2g) [39]

Prepared according to modified procedure from the literature. 1,3-Dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (1g) (6.40 mmol, 1 g) was dissolved in chloroform (6 mL) and cooled to 0 °C, then DMFDMA was added, and the reaction mixture was stirred for 2 h at 25 °C. Isolation by dilution with dichloromethane (10 mL) and washing with NaCl_(sat.); the organic phase was dried over anhydrous Na₂SO₄, filtered, and volatile components evaporated in vacuo. Yield: 1.00 g (4.73 mmol, 74%) of yellow solid. ¹H-NMR (500 MHz, DMSO-d₆): δ 3.12 (s, 6H), 3.23 (s, 3H), 3.44 (s, 3H), 8.14 (s, 1H). Spectral data are consistent with the literature data [39].

3.1.8. 2-(Ethoxymethylene)malononitrile (2i) [40]

Prepared according to modified procedure from the literature. Malononitrile (1i) (15.0 mmol, 1.00 g) was dissolved in acetic anhydride (4 mL), triethyl orthoformate (22.7 mmol, 3.78 mL) was added, and the reaction mixture was heated under reflux for 6 h. Volatile components were evaporated in vacuo and the residue was crystalized from a mixture of ethanol and water. Yield: 1.561 g (12.8 mmol, 85%) of colorless solid. ¹H-NMR (500 MHz, CDCl₃): δ 1.48 (t, J = 7.1, 3H), 4.41 (q, J = 7.1, 2H), 7.58 (s, 1H). Spectral data are consistent with the literature data [40].

3.2. Synthesis of Compounds 4a –i 

General procedure 1 (GP1): To a solution of enaminone 2 in AcOH, (S)-quininamine trihydrochloride (3) (1 equivalent) was added and the reaction mixture was stirred at 25 °C for 24 h. Acetic acid was evaporated in vacuo and the residue was purified by CC. Fractions containing the product 4 were combined and volatile components evaporated in vacuo.

General procedure 2 (GP2): To a solution of enaminone or ethoxymethylene compound 2 in EtOH, (S)-quininamine trihydrochloride (3) (1 equivalent) was added and the reaction mixture was stirred at 25 °C for 24 h. Ethanol was evaporated in vacuo and the residue was purified by CC. Fractions containing the product 4 were combined and volatile components evaporated in vacuo.

3.2.1. Methyl 2-Benzamido-3-({(S)-(6-methoxyquinolin-4-yl)[(1S,2S,4S,5R)-5-vinylquinuclidin-2-yl]methyl}amino)acrylate (4a)

Following GP1. Prepared from 3 (1 mmol, 433 mg), and methyl 2-benzamido-3-(dimethylamino)acrylate (2a) (1 mmol, 248 mg), AcOH (2 mL), 25 °C, 24 h, CC (EtOAc). Yield: 490 mg (0.93 mmol, 93%) of white solid, ratio of isomers: 1:8, mp = 92.9–94.9 °C. [α]_D^r.t. = −119 (0.067, MeOH). EI-HRMS: m/z = 264.1360 (M + 2H)⁺²; C₃₁H₃₆N₄O₄ requires: m/z = 264.1363 (M + 2H)⁺²; ν_max 3245, 2944, 1693, 1644, 1617, 1579, 1507, 1476, 1433, 1359, 1227, 1186, 1140, 1025, 915, 853, 830, 760, 707, 641, 613 cm⁻¹. ¹H-NMR (500 MHz, DMSO-d₆): δ major isomer 0.65–0.79 (m, 1H), 1.11–1.26 (m, 1H), 1.44–1.64 (m, 3H), 2.16–2.25 (m, 1H), 2.52–2.54 (m, 1H), 2.57–2.68 (m, 2H), 3.10 (dd, J = 13.7, 10.0 Hz, 1H), 3.17–3.30 (m, 1H), 3.45 (s, 3H), 3.98 (s, 3H), 4.85–4.99 (m, 2H), 5.15–5.40 (m, 1H), 5.72–5.89 (m, 1H), 6.73 (dd, J = 5.3, 13.8 Hz, 1H), 7.32 (br s, 1H), 7.43–7.52 (m, 3H), 7.53–7.58 (m, 1H), 7.63 (dd, J = 7.4, 4.5 Hz, 1H), 7.74–7.83 (m, 1H), 7.90–8.02 (m, 3H), 8.77 (d, J = 4.6 Hz, 1H), 8.93 (s, 1H); minor isomer 2.25–2.30 (m, 1H), 2.68–2.78 (m, 2H), 3.23 (dd, J = 9.9, 13.6 Hz, 1H), 3.55 (s, 3H), 3.94 (s, 3H), 7.38 (dd, J = 7.0, 8.4 Hz, 1H), 8.56 (br d, J = 12.5 Hz, 1H). ¹³C-NMR (126 MHz, DMSO-d₆): δ 25.46, 27.04, 27.31, 40.31, 50.40, 50.40, 55.19, 55.67, 55.76, 78.95, 96.95, 102.60, 114.19, 121.61, 127.33, 127.71, 128.09, 128.15, 131.16, 131.38, 134.56, 142.01, 142.07, 143.75, 144.20, 147.68, 157.52, 165.39, 165.92.

3.2.2. (Z)-4-[({(S)-(6-methoxyquinolin-4-yl)[(1S,2S,4S,5R)-5-vinylquinuclidin-2-yl]methyl}amino)methylene]-5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one (4b)

Following GP2. Prepared from 3 (0.50 mmol, 215 mg), and (E)-4-[(dimethylamino)methylene]-5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one (2b) (0.50 mmol, 115 mg), EtOH (1 mL), 25 °C, 24 h; CC (EtOAc). Yield: 203 mg (0.40 mmol, 80%) of pale orange solid, mp = 157.7–158.0 °C. [α]_D^r.t. = −564 (0.185, MeOH). EI-HRMS: m/z = 254.6388 (M + 2H)⁺²; C₃₁H₃₅N₅O₂ requires: m/z = 254.6390 (M + 2H)⁺²; ν_max 3377, 2934, 2604, 1663, 1618, 1598, 1545, 1499, 1458, 1383, 1347, 1250, 1161, 1117, 1092, 1025, 923, 853, 759, 715, 694, 670, 42 cm⁻¹. ¹H-NMR (500 MHz, DMSO-d₆): δ 1.03–1.11 (m, 1H), 1.66–1.79 (m, 1H), 1.88–2.05 (m, 3H), 2.16 (s, 3H), 2.76–2.84 (m, 1H), 3.24–3.36 (m, 2H), 4.11 (s, 3H), 4.24 (br s, 1H), 4.80 (q, J = 9.6 Hz, 1H), 5.18 (d, J = 10.5 Hz, 1H), 5.25 (d, J = 17.2 Hz, 1H), 5.89–6.07 (m, 2H), 7.08 (t, J = 7.4 Hz, 1H), 7.34 (t, J = 7.8 Hz, 2H), 7.62 (d, J = 9.2 Hz, 1H), 7.92 (d, J = 8.2 Hz, 2H), 7.95 (d, J = 5.0 Hz, 1H), 8.03 (s, 1H), 8.12 (d, J = 9.2 Hz, 1H), 8.62 (br s, 1H), 8.99 (d, J = 4.8 Hz, 1H), 9.56 (s, 1H), 9.97 (br s, 1H). ¹³C-NMR (126 MHz, DMSO-d₆): δ 12.54, 21.18, 25.38, 27.09, 33.89, 40.46, 54.99, 56.19, 58.61, 79.38, 99.61, 102.43, 114.60, 117.42, 120.89, 121.84, 123.35, 127.58, 128.64, 131.60, 139.32, 142.16, 144.32, 147.86, 148.22, 152.27, 157.94, 164.91, 172.01.

3.2.3. (Z)-5-[({(S)-(6-methoxyquinolin-4-yl)[(1S,2S,4S,5R)-5-vinylquinuclidin-2-yl]methyl}amino)methylene]imidazolidine-2,4-dione (4c)

Following GP1. Prepared from 3 (1.2 mmol, 517 mg), and (Z)-5-[(dimethylamino)methylene]imidazolidine-2,4-dione (2c) (1.2 mmol, 186 mg), AcOH (2.5 mL), 25 °C, 24 h, CC (EtOAc:MeOH = 4:1). Yield: 234 mg (0.54 mmol, 45%) of white solid, mp = 232–234 °C. [α]_D^r.t. = −153 (0.027, MeOH). EI-HRMS: m/z = 434.2181 (M + H)⁺; C₂₄H₂₈N₅O₃ requires: m/z = 434.2187 (M + H)⁺; ν_max 3292, 2970, 2945, 2882, 1697, 1655, 1619, 1559, 1509, 1473, 1225, 1090, 1025, 918, 855, 717, 674 cm⁻¹. ¹H-NMR (500 MHz, DMSO-d₆): δ 0.63 (s, 1H), 1.08–1.30 (m, 1H), 1.40–1.60 (m, 4H), 2.23 (s, 1H), 2.57–2.77 (m, 2H), 3.09–3.17 (m, 2H), 3.98 (s, 3H), 4.88–5.04 (m, 2H), 5.12 (br s, 1H), 5.82 (ddd, J = 17.5, 10.3, 7.6, 1H), 6.55 (br s, 1H), 7.42 (dd, J = 9.2, 2.7, 1H), 7.49 (dd, J = 13.3, 6.4, 1H), 7.68 (d, J = 4.6, 1H), 7.74 (s, 1H), 7.95 (d, J = 9.2, 1H), 8.73 (d, J = 4.6, 1H), 9.59 (s, 1H), 10.09 (s, 1H). ¹³C-NMR (126 MHz, DMSO-d₆): δ 22.53, 25.57, 27.21, 27.46, 40.40, 45.51, 55.26, 55.96, 55.97, 102.46, 104.17, 114.25, 121.66, 131.39, 131.48, 132.04, 141.13, 142.17, 144.14, 147.72, 152.70, 157.52, 164.22, 174.05.

3.2.4. (Z)-5-[({(S)-(6-methoxyquinolin-4-yl)[(1S,2S,4S,5R)-5-vinylquinuclidin-2-yl]methyl}amino)methylene]-1-methylimidazolidine-2,4-dione (4d)

Following GP2. Prepared from 3 (1.2 mmol, 517 mg), and (Z)-5-[(dimethylamino)methylene]-3-methylimidazolidine-2,4-dione (2d) (1.2 mmol, 203 mg), EtOH (2.5 mL), 25 °C, 24 h, CC (EtOAc:MeOH = 4:1). Yield: 56 mg (0.125 mmol, 10%) of colorless solid, mp = 120–133.3 °C. [α]_D^r.t. = −170 (0.11, MeOH). EI-HRMS: m/z = 224.6209 (M + 2H)⁺²; C₂₅H₃₁N₅O₃ requires: m/z = 224.6208 (M + 2H)⁺²; ν_max 3367, 3011, 2784, 2452, 1730, 1620, 1509, 1466, 1435, 1392, 1229, 1122, 1022, 833 cm⁻¹. ¹H-NMR (500 MHz, CDCl₃): δ 0.97 (dd, J = 14.2, 6.6 Hz, 1H), 1.49 (br s, 1H), 1.67–1.87 (m, 3H), 2.45 (br s, 1H), 2.91 (s, 3H), 2.92–3.13 (m, 2H), 3.26–3.55 (m, 2H), 3.67 (br s, 1H), 3.85–4.01 (m, 4H), 4.95–5.17 (m, 1H), 5.05 (dd, J = 13.9, 9.8 Hz, 2H), 5.61–5.83 (m, 1H), 6.53 (br s, 1H), 7.34–7.58 (m, 4H), 8.05 (d, J = 9.3 Hz, 1H), 8.76 (d, J = 4.8 Hz, 1H). ¹³C-NMR (126 MHz, CDCl₃): δ 23.91, 24.29, 26.98, 38.17, 41.05, 54.66, 55.96, 76.91, 77.16, 77.36, 77.42, 101.35, 105.95, 116.26, 121.97, 123.78, 132.29, 136.85, 139.13, 144.93, 147.77, 154.03, 158.58, 164.08, 179.10.

3.2.5. (Z)-5-[({(S)-(6-methoxyquinolin-4-yl)[(1S,2S,4S,5R)-5-vinylquinuclidin-2-yl]methyl}amino)methylene]-3-phenyl-2-thioxoimidazolidin-4-one (4e)

Following GP1. Prepared from 3 (0.98 mmol, 424 mg), and (Z)-5-[(dimethylamino)methylene]-3-phenyl-2-thioxoimidazolidin-4-one (2e) (0.98 mmol, 243 mg), AcOH (5 mL), 60 °C, 24 h. Isolation by filtration. Yield: 430 mg (0.82 mmol, 84%) of red solid, mp = 191–193 (m°C. [α]_D^r.t. = –792 (0.02, MeOH). EI-HRMS: m/z = 263.6170 (M + 2H)⁺²; C₃₀H₃₃N₅O₂S requires: m/z = 263.6172 (M + 2H)⁺²; ν_max 3330, 3090, 2921, 2359, 2042, 1964, 1707, 1648, 1593, 1543, 1478, 1387, 1366, 1329, 1302, 1262, 1211, 1175, 1097, 1031, 1004, 983, 933, 917, 868, 823, 773, 750, 706, 678, 646 cm⁻¹. ¹H-NMR (500 MHz, DMSO-d₆): δ 0.98–1.07 (m, 1H), 1.73–1.83 (m, 1H), 1.91–2.01 (m, 3H), 2.76–2.85 (m, 1H), 3.23–3.39 (m, 2H), 3.90–4.01 (m, 1H), 4.06 (s, 3H), 4.43 (br s, 1H), 5.16 (d, J=10.4, 1H), 5.25 (d, J = 17.2, 1H), 5.73 (br s, 1H), 5.91–6.02 (m, 1H), 7.18–7.23 (m, 2H), 7.35 (br s, 1H), 7.37–7.41 (m, 1H), 7.45 (dd, J = 8.3, 6.7, 2H), 7.63 (dd, J = 9.3, 2.5, 1H), 7.90 (s, 1H), 7.95 (d, J = 4.9, 1H), 8.13 (d, J = 9.3, 1H), 8.83 (br s, 1H), 9.00 (d, J = 4.9, 1H), 9.74–9.79 (m, 1H), 11.54 (s, 1H). ¹³C-NMR (126 MHz, DMSO-d₆): δ 23.43, 23.71, 25.51, 35.85, 41.68, 47.71, 52.01, 56.36, 58.89, 87.42, 89.78, 102.48, 116.65, 120.85, 123.40, 127.85, 128.62, 128.75, 130.24, 133.38, 133.98, 138.30, 146.65, 158.76, 159.10, 169.62, 172.76, 182.99.

3.2.6. (Z)-5-[({(S)-(6-methoxyquinolin-4-yl)((1S,2S,4S,5R)-5-vinylquinuclidin-2-yl]methyl}amino)methylene]-3-phenyl-2-thioxothiazolidin-4-one (4f)

Following GP1. Prepared from 3 (1.2 mmol, 517 mg), and (Z)-5-[(dimethylamino)methylene]-3-phenyl-2-thioxoimidazolidin-4-one (2f) (1.2 mmol, 320 mg), AcOH (3 mL), 25 °C, 24 h. Isolation by filtration followed by CC (EtOAc). Yield: 464 mg (0.85 mmol, 71%) of yellow solid, mp = 153.1–155.6 °C. [α]_D^r.t. = −475.3 (0.235, MeOH). EI-HRMS: m/z = 272.0976 (M + 2H)⁺²; C₃₀H₃₂N₄O₂S₂ requires: m/z = 272.0978 (M + 2H)⁺²; ν_max 3274, 3067, 2940, 2865, 1674, 1608, 1508, 1475, 1455, 1431, 1354, 1228, 1157, 1109, 1030, 984, 917, 854, 834, 744, 690, 641 cm⁻¹. ¹H-NMR (500 MHz, DMSO-d₆): δ 0.57–0.83 (m, 1H), 1.26–1.41 (m, 1H), 1.48–1.71 (m, 3H), 2.21–2.34 (m, 1H), 2.61–2.83 (m, 2H), 3.11–3.25 (m, 1H), 3.34–3.43 (m, 1H), 3.45–3.60 (m, 1H), 3.99 (s, 3H), 4.88–5.08 (m, 2H), 5.50 (br s, 1H), 5.88 (ddd, J = 17.6, 10.3, 7.5, 1H), 7.02–7.13 (m, 1H), 7.29–7.37 (m, 2H), 7.49 (dd, J = 9.2, 2.6, 1H), 7.72 (d, J = 4.6, 2H), 7.86–7.96 (m, 3H), 8.01 (d, J = 9.2, 1H), 8.82 (d, J = 4.6, 1H), 10.17 (br s, 1H). ¹³C-NMR (126 MHz, DMSO-d₆): δ 25.72, 27.28, 27.28, 40.31, 55.12, 55.42, 56.05, 58.79, 89.06, 102.54, 114.27, 120.06, 121.60, 127.49, 131.47, 131.54, 135.84, 136.41, 141.93, 142.12, 143.64, 144.20, 144.46, 147.73, 147.82, 157.81, 166.46, 191.03.

3.2.7. 5-[({(S)-(6-methoxyquinolin-4-yl)((1S,2S,4S,5R)-5-vinylquinuclidin-2-yl]methyl}amino)methylene]-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (4g)

Prepared from 3 (1 mmol, 433 mg), and 5-[(dimethylamino)methylene]-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (2g) (1 mmol, 215 mg), K₂CO₃ (3 mmol, 415 mg), MeOH (2 mL), 25 °C, 24 h. Isolation by filtration followed by CC (EtOAc). Yield: 197 mg (0.40 mmol, 40%) of yellowish solid, mp = 113.3–115.8 °C. [α]_D^r.t. = −88.5 (0.135, MeOH). EI-HRMS: m/z = 245.6258 (M + 2H)⁺²; C₂₇H₃₃N₅O₄ requires: m/z = 245.6261 (M + 2H)⁺²; ν_max 3551, 3216, 2947, 2890, 1714, 1650, 1591, 1508, 1478, 1334, 1261, 1230, 1097, 1054, 1028, 915, 855, 834, 779, 757 cm⁻¹. ¹H-NMR (500 MHz, DMSO-d₆): δ 0.68 (br s, 1H), 1.40–1.28 (m, 1H), 1.62–1.46 (m, 3H), 2.27 (d, J = 8.1 Hz, 1H), 2.79–2.62 (m, 2H), 3.06 (s, 3H), 3.12 (s, 3H), 3.18 (dd, J = 13.6, 9.9 Hz, 1H), 3.46–3.37 (m, 1H), 3.50 (q, J = 9.4 Hz, 1H), 3.97 (s, 3H), 4.94 (dt, J = 10.5, 1.3 Hz, 1H), 5.02 (dt, J = 17.2, 1.5 Hz, 1H), 5.94–5.81 (br s, 1H), 5.64 (s, 1H), 7.48 (dd, J = 9.2, 2.6 Hz, 1H), 7.71 (d, J = 4.6 Hz, 1H), 7.83 (br s, 1H), 8.01 (d, J = 9.2 Hz, 1H), 8.10 (bd, J = 14.7 Hz, 1H), 8.81 (d, J = 4.5 Hz, 1H), 10.84 (br s, 1H). ¹³C-NMR (126 MHz, DMSO-d₆): δ 25.50, 26.79, 27.18, 27.29, 27.36, 40.23, 55.20, 55.94, 58.82, 79.25, 90.16, 102.24, 114.41, 120.66, 121.90, 127.90, 131.65, 142.06, 144.32, 147.89, 151.51, 157.86, 157.97, 162.05, 163.90.

3.2.8. Diethyl 2-[({(S)-(6-methoxyquinolin-4-yl)((1S,2S,4S,5R)-5-vinylquinuclidin-2-yl]methyl}amino)methylene]malonate (4h)

Following GP2. Prepared from 3 (1.2 mmol, 517 mg), and diethyl 2-(ethoxymethylene)malonate (2h) (1.2 mmol, 258 mg), EtOH (2 mL), 25 °C, 24 h, CC (EtOAc). Yield: 131 mg (0.26 mmol, 22%) of colorless semisolid. [α]_D^r.t. = –255 (0.067, MeOH). EI-HRMS: m/z = 247.6358 (M + 2H)⁺²; C₂₈H₃₇N₃O₅ requires: m/z = 247.6361 (M + 2H)⁺²; ν_max 3266, 2936, 2867, 1683, 1646, 1620, 1597, 1507, 1475, 1430, 1344, 1222, 1170, 1074, 1030, 913, 855, 801, 718 cm⁻¹. ¹H-NMR (500 MHz, DMSO-d₆): δ 0.64–0.77 (m, 1H), 1.03 (t, J = 7.1 Hz, 3H), 1.20 (t, J = 7.1 Hz, 3H), 1.30 (br s, 1H), 1.46–1.64 (m, 3H), 2.27 (br s, 1H), 2.62–2.81 (m, 2H), 3.20 (br t, J = 11.7 Hz, 1H), 3.25–3.55 (br s, 2H, overlapped by the signal for H₂O), 3.86–3.93 (m, 2H), 3.95 (s, 3H), 4.09 (q, J = 7.1 Hz, 2H), 4.93 (d, J = 10.4 Hz, 1H), 5.01 (d, J = 17.0 Hz, 1H), 5.46 (br s, 1H), 5.85 (quintet, J = 8.8 Hz, 1H), 7.48 (dd, J = 9.2, 2.6 Hz, 1H), 7.63 (d, J = 4.6 Hz, 1H), 7.68–7.86 (m, 2H), 8.00 (d, J = 9.2 Hz, 1H), 8.79 (d, J = 4.5 Hz, 1H), 9.72 (d, J = 13.7 Hz, 1H). ¹³C-NMR (126 MHz, DMSO-d₆): δ 14.19, 14.23, 25.46, 27.09, 27.29, 40.25, 55.17, 55.82, 58.81, 59.04, 89.19, 102.31, 114.41, 121.05, 121.82, 127.91, 131.63, 142.03, 142.50, 144.35, 147.88, 157.71, 157.82, 165.36, 167.42.

3.2.9. 2-[({(S)-(6-methoxyquinolin-4-yl)((1S,2S,4S,5R)-5-vinylquinuclidin-2-yl]methyl}amino)methylene]malononitrile (4i)

Following GP2. Prepared from 3 (0.761 mmol, 328 mg), 2-(ethoxymethylene)malononitrile (2i) (0.761 mmol, 77.4 mg), EtOH (2 mL), 25 °C, 24 h, CC (EtOAc). Yield: 79 mg (0.20 mmol, 26%) of colorless semisolid. [α]_D^r.t. = −264 (0.13, MeOH). EI-HRMS: m/z = 200.6102 (M + 2H)⁺²; C₂₄H₂₇N₅O requires: m/z = 200.6102 (M + 2H)⁺²; ν_max 3286, 3233, 2931, 2861, 2203, 1644,1619, 1592, 1552, 1506, 1474, 1432, 1338, 1281, 1258, 1241, 1226, 1170, 1135, 1088, 1030, 988, 900, 846, 818, 781, 758, 714, 687, 665, 636 cm⁻¹. ¹H-NMR (500 MHz, DMSO-d₆): δ 0.59–0.51 (m, 1H), 1.39–1.30 (m, 1H), 1.53–1.46 (m, 2H), 1.58–1.53 (m, 1H), 2.29–2.22 (m, 1H), 2.74–2.64 (m, 2H), 3.18 (dd, J = 13.7, 10.0 Hz, 1H), 3.32–3.24 (m, 1H), 3.54–3.45 (m, 1H), 3.99 (s, 3H), 4.98 (dt, J = 10.3, 1.4 Hz, 1H), 5.03 (dt, J = 17.1, 1.6 Hz, 1H), 5.30 (br d, J = 10.9 Hz, 1H), 5.88 (ddd, J = 17.5, 10.4, 7.5 Hz, 1H), 7.47 (dd, J = 9.2, 2.6 Hz, 1H), 7.66 (d, J = 2.7 Hz, 1H), 7.71 (d, J = 4.6 Hz, 1H), 7.99 (d, J = 9.2 Hz, 1H), 8.19 (br s, 1H), 8.79 (d, J = 4.6 Hz, 1H), 9.58 (br s, 1H). ¹³C-NMR (126 MHz, DMSO-d₆): δ 21.10, 25.65, 27.20, 27.28, 46.52, 55.18, 55.98, 57.70, 58.50, 102.06, 114.38, 114.88, 117.20, 120.36, 121.57, 127.47, 131.60, 142.07, 142.17, 144.15, 147.80, 157.93, 160.86.

3.3. Synthesis of Compounds 6a –j 

General procedure 3 (GP3): To a solution of ortho-fluoronitrobenzene derivative 5 and Na₂CO₃ in DMF, (S)-quininamine trihydrochloride (3) was added. The reaction mixture was stirred at 25 °C for 168 h. The reaction mixture was evaporated in vacuo and the residue was purified by column chromatography (CC). Fractions containing the product 6 were combined and volatile components evaporated in vacuo.

3.3.1. N-{[(S)-(6-methoxyquinolin-4-yl)[(1S,2S,4S,5R)-5-vinylquinuclidin-2-yl)methyl]}-2-nitroaniline (6a) [23]

Following GP3. Prepared from 3 (2.3 mmol, 1 g), 3-fluoro-2-nitrobenzene (5a) (2.30 mmol, 239 mL), K₂CO₃ (6.15 mmol, 0.85 g), and DMF (5 mL). Isolation by CC (petroleum ether:EtOAc = 2:1). Yield: 759 mg (1.71 mmol, 74%) of yellowish semisolid. ¹H-NMR (500 MHz, CDCl₃): δ 1.13–1.22 (m, 1H), 1.35–1.47 (m, 1H), 1.58–1.68 (m, 2H), 1.69–1.76 (m, 1H), 2.26–2.36 (m, 1H), 2.74–2.89 (m, 2H), 3.00 (br s, 1H), 3.36 (dd, 1H), 3.96 (br s, 3H), 4.91 (d, 1H), 4.97 (d, 1H), 5.64–5.74 (m, 1H), 6.35 (br s, 1H), 6.52 (ddd, J = 8.4, 7.0, 1.3 Hz, 1H), 7.05 (br t, 1H), 7.43 (br s, 1H), 7.56 (d, J = 4.5 Hz, 1H), 7.73 (br s, 1H), 8.08 (s, 1H), 8.15–8.10 (m, 2H), 8.75 (d, J = 4.5 Hz, 1H), 9.32 (s, 1H). Spectral data are in agreement with the literature data [23]. The product was used in next step as it is, without further purification.

3.3.2. N-{[(S)-(6-methoxyquinolin-4-yl)[(1S,2S,4S,5R)-5-vinylquinuclidin-2-yl]methyl}-2-nitro-4-(trifluoromethyl)aniline (6b) [23]

Following GP3. Prepared from 3 (1.15 mmol, 0.5 g), 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (5b) (1.15 mmol, 298 mL), K₂CO₃ (6.15 mmol, 0.85 g), and DMF (5 mL). Isolation by CC (petroleum ether:EtOAc = 2:1). Yield: 562 mg (1.10 mmol, 96%) of yellowish semisolid. The product was used in next step as it is, without further purification.

3.3.3. 4-({(S)-(6-methoxyquinolin-4-yl)[(1S,2S,4S,5R)-5-vinylquinuclidin-2-yl]methyl}amino)-3-nitrobenzonitrile (6c)

Following GP3. Prepared from 3 (2.31 mmol, 1 g), 4-fluoro-3-nitrobenzonitrile (5c) (2.30 mmol, 384 mg), K₂CO₃ (6.15 mmol, 0.85 g), and DMF (5 mL). Isolation by CC (EtOAc). Yield: 1.06 g (2.26 mmol, 98%) of yellowish semisolid. EI-HRMS: m/z = 235.6126 (M + 2H)⁺²; C₂₇H₂₉N₅O₃ requires: m/z = 235.6130 (M + 2H)⁺². ¹H-NMR (500 MHz, CDCl₃): δ 1.08–1.20 (m, 1H), 1.35–1.53 (m, 1H), 1.56–1.68 (m, 2H), 1.74 (br s, 1H), 2.25–2.38 (m, 1H), 3.20–2.73 (m, 4H), 3.25–3.42 (m, 1H), 3.97 (br s, 3H), 4.81–5.17 (m, 3H), 5.58–5.75 (m, 1H), 6.68–6.32 (m, 1H), 6.76 (dd, J = 8.6, 1.6 Hz, 1H), 7.47 (br s, 1H), 7.51 (d, J = 4.5 Hz, 1H), 7.62 (br s, 1H), 8.09 (br s, 1H), 8.17 (d, J = 8.7 Hz, 1H), 8.76 (s, 1H), 9.36 (br s, 1H). ¹³C-NMR (126 MHz, DMSO): δ 14.14, 27.36, 27.96, 39.53, 40.75, 53.67, 55.60, 55.84, 57.49, 63.03, 100.41, 114.64, 117.08, 117.71, 118.50, 119.20, 121.95, 123.08, 127.75, 132.51, 134.77, 141.17, 143.25, 143.95, 144.81, 147.95, 158.51. The product was used in next step as it is, without further purification.

3.3.4. 3-({(S)-(6-methoxyquinolin-4-yl)[(1S,2S,4S,5R)-5-vinylquinuclidin-2-yl]methyl}amino)-4-nitrobenzonitrile (6d)

Following GP3. Prepared from 3 (1.15 mmol, 0.5 g), 3-fluoro-4-nitrobenzonitrile (5d) (1.15 mmol, 191 mg), K₂CO₃ (6.15 mmol, 0.85 g), and DMF (5 mL). Isolation by CC (EtOAc). Yield: 498 mg (1.06 mmol, 92%) of yellowish semisolid. ¹H-NMR (500 MHz, CDCl₃): δ 1.08–1.18 (m, 1H), 1.41 (br s, 1H), 1.57–1.68 (m, 2H), 1.73 (br s, 1H), 2.04 (s, 1H), 2.27–2.36 (m, 1H), 2.73–2.87 (m, 2H), 2.97 (br s, 1H), 3.33 (dd, J = 13.9, 10.1 Hz, 1H), 3.95 (s, 3H), 4.84–5.00 (m, 2H), 4.99–5.24 (m, 1H), 5.66 (ddd, J = 17.4, 10.4, 7.4 Hz, 1H), 6.57 (br s, 1H), 6.74 (dd, J = 8.7, 1.7 Hz, 1H), 7.29–7.49 (m, 1H), 7.54 (d, J = 4.6 Hz, 1H), 7.58–7.69 (m, 1H), 8.10 (br s, 1H), 8.15 (d, J = 8.7 Hz, 1H), 8.76 (s, 1H), 9.29 (br s, 1H). ¹³C-NMR (126 MHz, CDCl₃): δ 21.39, 25.43, 27.41, 27.93, 39.47, 40.83, 53.69, 55.75, 57.64, 62.94, 77.36, 100.51, 114.89, 117.14, 117.95, 118.66, 119.14, 122.18, 127.87, 132.26, 134.94, 141.05, 143.28, 144.34, 147.71, 158.60, 174.87. The product was used in next step as it is, without further purification.

3.3.5. 4-Bromo-N-{(S)-(6-methoxyquinolin-4-yl)[(1S,2S,4S,5R)-5-vinylquinuclidin-2-yl]methyl}-2-nitroaniline (6e)

Following GP3. Prepared from 3 (1.15 mmol, 0.5 g), 4-bromo-1-fluoro-2-nitrobenzene (5e) (1.15 mmol, 253 mg), K₂CO₃ (6.15 mmol, 0.85 g), and DMF (5 mL). Isolation by CC (petroleum ether:EtOAc = 2:1). Yield: 550 mg (1.05 mmol, 91%) of yellowish semisolid. EI-HRMS: m/z = 262.0705 (M + 2H)⁺²; C₂₆H₂₉BrN₄O₃ requires: m/z = 262.0706 (M + 2H)⁺². ¹H-NMR (500 MHz, CDCl₃): δ 1.11–1.22 (m, 1H), 1.35–1.51 (br m, 1H), 1.64 (br t, J = 7.1 Hz, 2H), 1.73 (s, 1H), 2.25–2.38 (br m, 1H), 2.73–2.88 (m, 2H), 2.97 (br s, 1H), 3.13 (br s, 1H), 3.37 (br dd, J = 10.5, 13.6 Hz, 1H), 3.67–4.19 (br m, 3H), 4.93 (br d, J = 10.3 Hz, 1H), 4.98 (br d, J = 17.1 Hz, 1H), 5.09 (br s, 1H), 5.70 (ddd, J = 17.1, 10.3, 7.3 Hz, 1H), 6.30 (br s, 1H), 7.19–7.30 (br m, 1H), 7.46 (br s, 1H), 7.51 (d, J = 4.4 Hz, 1H), 7.62 (br s, 1H), 8.10 (br s, 1H), 8.42 (br s, 1H), 8.75 (br d, J = 4.6 Hz, 1H), 9.58 (br s, 1H). ¹³C-NMR (126 MHz, CDCl₃): δ 25.62, 27.56, 28.24, 39.70, 40.93, 53.89, 55.71, 56.00, 63.13, 100.78, 114.84, 115.64, 119.15, 121.72, 122.48, 124.63, 124.94, 127.60, 131.92, 132.16, 132.78, 141.31, 144.46, 145.51, 148.15, 158.32. The product was used in next step as it is, without further purification.

3.3.6. 5-Bromo-N-{(S)-(6-methoxyquinolin-4-yl)[(1S,2S,4S,5R)-5-vinylquinuclidin-2-yl]methyl}-2-nitroaniline (6f)

Following GP3. Prepared from 3 (1.15 mmol, 0.5 g), 4-bromo-2-fluoro-1-nitrobenzene (5f) (1.15 mmol, 253 mg), K₂CO₃ (6.15 mmol, 0.85 g), and DMF (5 mL). Isolation by CC (petroleum ether:EtOAc = 2:1). Yield: 450 mg (0.860 mmol, 75%) of yellowish semisolid. EI-HRMS: m/z = 262.0706 (M + 2H)⁺²; C₂₆H₂₉BrN₄O₃ requires: m/z = 262.0706 (M + 2H)⁺². ¹H-NMR (500 MHz, CDCl₃): δ 1.11 (br q, J = 6.1 Hz, 1H), 1.44 (br t, J = 11.9 Hz, 1H), 1.66 (br t, J = 6.7 Hz, 2H), 1.75 (br s, 1H), 2.28–2.37 (br m, 1H), 2.75–2.90 (m, 2H), 2.91–3.08 (m, 1H), 3.36 (dd, J = 10.1, 14.0 Hz, 1H), 3.81–4.10 (br m, 3H), 4.95 (br d, J = 10.4 Hz, 1H), 4.77–5.24 (br m, 1H), 4.99 (br d, J = 17.1 Hz, 1H), 5.69 (ddd, J = 7.5, 10.4, 14.4 Hz, 1H), 6.51–6.74 (br m, 1H), 6.66 (dd, J = 9.0, 1.9 Hz, 1H), 7.46 (br m, 2H), 7.58 (d, J = 4.6 Hz, 1H), 7.66 (br m, 1H), 7.96 (d, J = 9.1 Hz, 1H), 8.12 (br s, 1H), 8.78 (d, J = 4.6 Hz, 1H), 9.22 (br s, 1H). ¹³C-NMR (126 MHz, CDCl₃): δ 20.99, 27.45, 28.00, 39.48, 40.79, 45.03, 55.75, 63.02, 73.73, 100.59, 104.80, 104.98, 112.05, 112.07, 114.86, 117.64, 119.27, 122.34, 128.17, 131.08, 131.87, 132.06, 141.08, 144.22, 147.57, 158.33. The product was used in next step as it is, without further purification.

3.3.7. N-{(S)-(6-methoxyquinolin-4-yl)[(1S,2S,4S,5R)-5-vinylquinuclidin-2-yl]methyl}-4-methyl-2-nitroaniline (6g)

Following GP3. Prepared from 3 (1.15 mmol, 0.5 g), 1-fluoro-4-methyl-2-nitrobenzene (5g) (1.15 mmol, 178 mg), K₂CO₃ (6.15 mmol, 0.85 g), and DMF (5 mL). Isolation by CC (petroleum ether: EtOAc = 2:1). Yield: 251 mg (0.55 mmol, 48%) of yellowish semisolid. EI-HRMS: m/z = 230.1229 (M + 2H)⁺²; C₂₇H₃₂N₄O₃ requires: m/z = 230.1232 (M + 2H)⁺². ¹H-NMR (500 MHz, CDCl₃): δ 1.10–1.19 (m, 1H), 1.32–1.45 (m, 1H), 1.57–1.67 (br m, 2H), 1.71 (br s, 1H), 2.13 (s, 3H), 2.22–2.35 (m, 1H), 2.88–2.74 (m, 2H), 2.98 (br s, 1H), 3.06–3.29 (br s, 1H), 3.42–3.30 (m, 1H), 3.94 (br s, 3H), 5.19–4.74 (m, 3H), 5.76–5.61 (m, 1H), 6.25 (br s, 1H), 6.88 (d, J = 8.5 Hz, 1H), 7.41 (br s, 1H), 7.54 (d, J = 4.6 Hz, 1H), 7.80–7.62 (m, 1H), 7.92 (br s, 1H), 8.07 (br s, 1H), 8.73 (d, J = 4.5 Hz, 1H), 9.17 (br s, 1H). ¹³C-NMR (126 MHz, CDCl₃): δ 19.97, 24.04, 26.40, 27.69, 28.35, 39.82, 40.95, 54.19, 55.73, 56.09, 63.16, 77.37, 101.21, 114.70, 115.02, 121.80, 125.51, 126.36, 127.79, 132.39, 132.81, 137.29, 141.52, 142.20, 145.01, 147.85, 158.02. The product was used in next step as it is, without further purification.

3.3.8. N-{(S)-(6-methoxyquinolin-4-yl)[(1S,2S,4S,5R)-5-vinylquinuclidin-2-yl]methyl}-5-methyl-2-nitroaniline (6h)

Following GP3. Prepared from 3 (1.15 mmol, 0.5 g), 2-fluoro-4-methyl-1-nitrobenzene (5h) (1.15 mmol, 178 mg), K₂CO₃ (6.15 mmol, 0.85 g), and DMF (5 mL). Isolation by CC (petroleum ether:EtOAc = 2:1). Yield: 430 mg (0.938 mmol, 82%) of yellowish semisolid. EI-HRMS: m/z = 230.1225 (M + 2H)⁺²; C₂₇H₃₂N₄O₃ requires: m/z = 230.1232 (M + 2H)⁺². ¹H-NMR (500 MHz, CDCl₃): δ 1.08–1.17 (m, 1H), 1.34–1.44 (m, 1H), 1.581.65 (m, 2H), 1.66–1.75 (m, 1H), 1.93 (s, 3H), 2.25–2.35 (m, 1H), 2.72–2.86 (m, 2H), 2.98 (d, J = 15.5 Hz, 1H), 3.34 (dd, J = 10.0, 14.0 Hz, 1H), 3.13–3.42 (m, 1H), 3.93 (s, 3H), 5.12–4.64–5.12 (m, 3H), 5.68 (ddd, J = 17.4, 10.4, 7.5 Hz, 1H), 6.20 (br s, 1H), 6.33 (dd, J = 8.7, 1.6 Hz, 1H), 7.41 (br s, 1H), 7.56 (d, J = 4.5 Hz, 1H), 7.73 (br s, 1H), 7.99 (d, J = 8.7 Hz, 1H), 8.07 (d, J = 10.1 Hz, 1H), 8.74 (d, J = 4.5 Hz, 1H), 9.27 (br s, 1H). ¹³C-NMR (126 MHz, CDCl₃): δ 21.40, 22.07, 26.27, 27.63, 28.23, 39.71, 40.88, 55.74, 55.98, 63.21, 77.36, 101.02, 114.68, 114.85, 117.50, 121.95, 126.91, 127.76, 131.14, 132.20, 141.41, 144.02, 144.81, 147.20, 147.74, 158.04, 174.42. The product was used in next step as it is, without further purification.

3.3.9. 5-Methoxy-N-{(S)-(6-methoxyquinolin-4-yl)[(1S,2S,4S,5R)-5-vinylquinuclidin-2-yl]methyl}-2-nitroaniline (6i)

Following GP3. Prepared from 3 (1.15 mmol, 0.5 g), 2-fluoro-4-methoxy-1-nitrobenzene (5i) (1.15 mmol, 197 mg), K₂CO₃ (6.15 mmol, 0.85 g), and DMF (5 mL). Isolation by CC (petroleum ether:EtOAc = 2:1). Yield: 476 mg (1.00 mmol, 87%) of yellowish semisolid. EI-HRMS: m/z = 238.1204 (M + 2H)⁺²; C₂₇H₃₂N₄O₄ requires: m/z = 238.1206 (M + 2H)⁺². ¹H-NMR (500 MHz, CDCl₃): δ 0.79–0.89 (m, 1H), 1.08–1.16 (m, 1H), 1.21–1.34 (m, 1H), 1.37–1.47 (m, 1H), 1.55–1.67 (m, 2H), 1.68–1.76 (m, 1H), 2.26–2.35 (m, 1H), 2.74–2.88 (m, 2H), 3.02 (br s, 3H), 3.34 (dd, J = 14.0, 10.0 Hz, 1H), 3.82–4.08 (m, 3H), 4.87–5.00 (m, 2H), 5.00–5.23 (m, 1H), 5.60 (br s, 1H), 5.69 (ddd, J = 17.4, 10.8, 7.6 Hz, 1H), 6.06 (dd, J = 9.5, 2.5 Hz, 1H), 7.44 (br s, 1H), 7.57 (d, J = 4.5 Hz, 1H), 7.70 (br s, 1H), 8.04 (d, J = 9.5 Hz, 1H), 8.07 (br s, 1H), 8.75 (d, J = 4.5 Hz, 1H), 9.49 (br s, 1H). ¹³C-NMR (126 MHz, CDCl₃): δ 21.32, 27.58, 28.22, 39.63, 40.90, 53.79, 55.14, 55.76, 55.91, 62.60, 77.36, 96.65, 100.77, 105.56, 114.74, 119.71, 121.89, 127.22, 129.15, 132.35, 141.34, 144.38, 146.20, 148.25, 158.22, 165.30, 174.66. The product was used in next step as it is, without further purification.

3.3.10. N-{(S)-(6-methoxyquinolin-4-yl)[(1S,2S,4S,5R)-5-vinylquinuclidin-2-yl]methyl}-2-nitropyridin-3-amine (6j) [23]

Following GP3. Prepared from 3 (2.3 mmol, 1 g), 3-fluoro-2-nitropyridine (5j) (2.30 mmol, 328 mg), K₂CO₃ (6.15 mmol, 0.85 g), and DMF (5 mL). Isolation by extraction followed by CC (petroleum ether:EtOAc = 2:1). Yield: 874 mg (1.96 mmol, 85%) of brownish semisolid. The product was used in next step as it is, without further purification.

3.4. Synthesis of Compounds 7a –j 

General procedure 4 (GP4): To a solution of nitroaniline 6 in EtOH, SnCl₂·2H₂O (4 equivalents) was added and the mixture was stirred at 25 °C for 24 h. Then, the reaction mixture was diluted with 2 M NaOH_(aq) until pH 12. Dichloromethane was added and the mixture was stirred vigorously for 30 min. The aqueous phase and the organic phase were separated. The organic phase was dried over anhydrous Na₂SO₄, filtered, and volatile components evaporated in vacuo. The product was used in next step as it is, without further purification.

3.4.1. N¹-{(S)-(6-methoxyquinolin-4-yl)[(1S,2S,4S,5R)-5-vinylquinuclidin-2-yl]methyl}benzene-1,2-diamine (7a) [23]

Following GP4. Prepared from 6a (1.71 mmol, 759 mg) and SnCl₂·2H₂O (6.84 mmol, 1.54 g) in EtOH (10 mL). Yield: 330 mg (0.67 mmol, 76%) of brownish semisolid. ¹H-NMR (500 MHz, CDCl₃): δ 1.10–1.19 (m, 1H), 1.23–1.36 (m, 1H), 1.52–1.71 (m, 3H), 2.28 (br s, 1H), 2.68–2.80 (m, 2H), 2.98–3.15 (m, 2H), 3.28 (dd, J = 13.9, 10.0, 1H), 3.38–3.63 (br s, 2H), 3.99 (s, 3H), 4.84 (br s, 1H), 4.90–5.00 (m, 2H), 5.41 (br s, 1H), 5.70 (ddd, J = 17.5, 10.3, 7.6, 1H), 6.17 (br s, 1H), 6.41–6.48 (m, 1H), 6.56 (td, J = 7.5, 1.3, 1H), 6.67 (dd, J = 7.6, 1.5, 1H), 7.42 (dd, J = 9.3, 2.7, 1H), 7.69 (d, J = 4.4, 1H), 8.02 (s, 1H), 8.07 (d, J = 9.3, 1H), 8.71 (d, J = 4.6, 1H). Spectral data are in agreement with the literature data [23]. The product was used in next step as it is, without further purification.

3.4.2. N¹-{(S)-(6-methoxyquinolin-4-yl)[(1S,2S,4S,5R)-5-vinylquinuclidin-2-yl]methyl}-4-(trifluoromethyl)benzene-1,2-diamine (7b) [23]

Following GP4. Prepared from 6b (0.79 mmol, 404 mg) and SnCl₂·2H₂O (3.16 mmol, 711 mg) in EtOH (10 mL). Yield: 352 mg (0.73 mmol, 92%) of yellowish solid. The product was used in next step as it is, without further purification.

3.4.3. 3-Amino-4-({(S)-(6-methoxyquinolin-4-yl)[(1S,2S,4S,5R)-5-vinylquinuclidin-2-yl]methyl}amino)benzonitrile (7c)

Following GP4. Prepared from 6c (1.89 mmol, 889 mg) and SnCl₂·2H₂O (7.56 mmol, 1.70 g) in EtOH (10 mL). Yield: 795 mg (1.81 mmol, 96%) of yellowish solid. EI-HRMS: m/z = 220.6255 (M + 2H)⁺²; C₂₇H₃₁N₅O requires: m/z = 220.6259 (M + 2H)⁺². ¹H-NMR (500 MHz, CDCl₃) δ 1.09 (dd, J = 14.3, 6.3, 1H), 1.39 (dt, J = 10.6, 7.1, 1H), 1.72 (d, J = 11.7, 3H), 2.27 (t, J = 8.1, 1H), 2.55–2.73 (m, 2H), 2.86 (d, J = 14.4, 1H), 3.10 (d, J = 13.6, 1H), 3.39 (s, 1H), 4.02 (s, 3H), 5.02 (dd, J = 32.1, 13.7, 2H), 5.08–5.20 (m, 1H), 5.43 (br s, 2H), 6.25 (s, 1H), 6.34 (s, 1H), 7.02–7.10 (m, 1H), 7.11–7.17 (m, 1H), 7.42–7.60 (m, 4H), 8.13 (d, J = 9.2, 1H), 8.79 (d, J = 4.6, 1H). ¹³C-NMR (126 MHz, CDCl₃) δ 18.56, 24.48, 26.87, 27.29, 38.70, 40.79, 52.90, 55.23, 55.89, 61.61, 100.74, 111.61, 114.88, 115.96, 118.67, 119.81, 121.17, 126.39, 127.23, 128.04, 132.21, 133.10, 139.54, 143.57, 144.47, 148.49, 158.58, 158.69. The product was used in next step as it is, without further purification.

3.4.4. 4-Amino-3-({(S)-(6-methoxyquinolin-4-yl)[(1S,2S,4S,5R)-5-vinylquinuclidin-2-yl]methyl}amino)benzonitrile (7d)

Following GP4. Prepared from 6d (0.84 mmol, 394 mg) and SnCl₂·2H₂O (3.36 mmol, 757 mg) in EtOH (10 mL). Yield: 231 mg (0.53 mmol, 63%) of colorless solid. EI-HRMS: m/z = 220.6259 (M + 2H)⁺²; C₂₇H₃₁N₅O requires: m/z = 220.6259 (M + 2H)⁺². ¹H-NMR (500 MHz, CDCl₃): δ 1.09–1.17 (m, 1H), 1.26–1.35 (m, 1H), 1.53–1.69 (m, 3H), 2.23–2.32 (m, 1H), 2.66–2.77 (m, 2H), 2.92–3.04 (m, 1H), 3.13 (br s, 1H), 3.20–3.28 (m, 1H), 3.95 (s, 3H), 4.24 (br s, 2H), 4.81 (br s, 1H), 4.86–4.96 (m, 2H), 5.44 (s, 1H), 5.64 (ddd, J = 14.3, 10.4, 7.4 Hz, 1H), 6.41 (br s, 1H), 6.56 (dd, J = 7.8, 2.6 Hz, 1H), 6.83 (dd, J = 8.0, 1.8 Hz, 1H), 7.38–7.46 (m, 1H), 7.60 (d, J = 4.6 Hz, 1H), 7.78 (br s, 1H), 8.07 (d, J = 9.2 Hz, 1H), 8.71 (d, J = 4.5 Hz, 1H). ¹³C-NMR (126 MHz, CDCl₃): δ 14.20, 21.07, 25.34, 27.32, 27.86, 39.51, 40.82, 53.88, 55.76, 62.17, 77.36, 100.89, 101.30, 114.35, 114.75, 115.39, 121.47, 124.76, 128.29, 132.23, 135.07, 140.76, 140.81, 141.07, 144.71, 147.87, 158.02. The product was used in next step as it is, without further purification.

3.4.5. 4-Bromo-N¹-{(S)-(6-methoxyquinolin-4-yl)[(1S,2S,4S,5R)-5-vinylquinuclidin-2-yl]methyl}benzene-1,2-diamine (7e)

Following GP4. Prepared from 6e (1.05 mmol, 550 mg) and SnCl₂·2H₂O (4.20 mmol, 950 mg) in EtOH (10 mL). Yield: 372 mg (0.75 mmol, 71%) of yellowish solid. EI-HRMS: m/z = 247.0841 (M + 2H)⁺²; C₂₆H₃₁BrN₄O requires: m/z = 247.0835 (M + 2H)⁺². ¹H-NMR (500 MHz, CDCl₂): δ 1.03–1.15 (m, 1H), 1.22–1.31 (m, 1H), 1.45–1.66 (m, 3H), 2.17–2.29 (m, 1H), 2.61–2.74 (m, 2H), 2.91–2.99 (m, 2H), 3.21 (dd, J = 13.9, 10.0, 1H), 3.73 (br s, 2H), 3.94 (s, 3H), 4.61–4.82 (m, 1H), 4.83–4.97 (m, 2H), 5.32 (s, 1H), 5.54–5.70 (m, 1H), 5.99 (s, 1H), 6.46 (dd, J = 8.5, 2.2, 1H), 6.72 (d, J = 2.3, 1H), 7.34–7.46 (m, 1H), 7.63 (d, 1H), 7.79 (br s, 1H), 8.05 (d, J = 9.2, 1H), 8.67 (d, J = 4.5, 1H). ¹³C-NMR (126 MHz, CDCl₃): δ 27.35, 28.06, 31.34, 36.40, 39.63, 40.73, 55.55, 55.91, 62.34, 101.46, 110.85, 113.79, 114.44, 117.91, 119.87, 121.13, 121.92, 128.37, 132.07, 134.97, 137.00, 141.34, 145.85, 147.98, 157.66, 162.47. The product was used in next step as it is, without further purification.

3.4.6. 5-Bromo-N¹-{(S)-(6-methoxyquinolin-4-yl)[(1S,2S,4S,5R)-5-vinylquinuclidin-2-yl]methyl}benzene-1,2-diamine (7f)

Following GP4. Prepared from 6f (0.88 mmol, 460 mg) and SnCl₂·2H₂O (3.52 mmol, 794 mg) in EtOH (10 mL). Isolation by extraction. Yield: 330 mg (0.67 mmol, 76%) of yellowish solid. EI-HRMS: m/z = 247.0836 (M + 2H)⁺²; C₂₆H₃₁BrN₄O requires: m/z = 247.0835 (M + 2H)⁺². ¹H-NMR (500 MHz, CDCl₃): δ 1.03–1.12 (m, 1H), 1.27–1.34 (m, 1H), 1.52–1.69 (m, 3H), 2.23–2.30 (m, 1H), 2.66–2.77 (m, 2H), 2.92–3.01 (m, 1H), 3.10 (br s, 1H), 3.26 (dd, J = 13.9, 10.0 Hz, 1H), 3.46–3.63 (m, 2H), 3.99 (s, 3H), 4.75 (s, 1H), 4.86–4.98 (m, 2H), 5.48 (s, 1H), 5.68 (ddd, J = 17.6, 10.3, 7.6 Hz, 1H), 6.36 (s, 1H), 6.49 (d, J = 8.1 Hz, 1H), 6.64 (dd, J = 8.2, 2.1 Hz, 1H), 7.43 (dd, J = 9.2, 2.6 Hz, 1H), 7.64 (dd, J = 5.2, 3.0 Hz, 1H), 7.74–7.90 (m, 1H), 8.07 (d, J = 9.2 Hz, 1H), 8.73 (d, J = 4.5 Hz, 1H). ¹³C-NMR (126 MHz, CDCl₃): δ 25.52, 27.46, 28.14, 31.44, 36.49, 39.77, 40.83, 55.75, 56.07, 77.30, 101.14, 111.91, 114.57, 115.68, 116.68, 120.39, 121.37, 128.48, 132.21, 134.30, 137.81, 141.43, 144.75, 147.99, 157.88, 162.55. The product was used in next step as it is, without further purification.

3.4.7. N¹-{(S)-(6-methoxyquinolin-4-yl)[(1S,2S,4S,5R)-5-vinylquinuclidin-2-yl]methyl}-4-methylbenzene-1,2-diamine (7g)

Following GP4. Prepared from 6g (0.47 mmol, 216 mg) and SnCl₂·2H₂O (1.88 mmol, 425 mg) in EtOH (5 mL). Yield: 155 mg (0.361 mmol, 77%) of brownish solid. EI-HRMS: m/z = 215.1365 (M + 2H)⁺²; C₂₇H₃₄N₄O requires: m/z = 215.1361 (M + 2H)⁺². ¹H-NMR (500 MHz, CDCl₃): δ 1.10–1.19 (m, 1H), 1.24–1.35 (m, 1H), 1.54–1.63 (m, 2H), 1.6–1.70 (m, 1H), 2.10 (s, 3H), 2.23–2.31 (m, 1H), 2.68–2.80 (m, 2H), 2.97–3.17 (m, 3H), 3.28 (dd, J = 13.9, 10.0, 1H), 3.98 (s, 3H), 4.83 (br s, 1H), 4.90–4.99 (m, 2H), 5.70 (ddd, J = 17.1, 10.3, 7.5, 1H), 6.10 (br s, 1H), 6.22–6.28 (m, 1H), 6.50 (d, J = 1.9, 1H), 7.42 (dd, J = 9.2, 2.7, 1H), 7.69 (s, 1H), 7.82 (br s, 1H), 8.06 (d, J = 9.2, 1H), 8.71 (d, J = 4.5, 1H). ¹³C-NMR (126 MHz, CDCl₃) δ 20.63, 25.53, 27.66, 28.36, 39.98, 40.98, 55.69, 56.23, 62.37, 77.37, 101.74, 113.12, 114.59, 116.79, 120.18, 120.55, 121.26, 128.72, 132.24, 133.88, 135.56, 141.69, 141.71, 144.80, 146.66, 148.31, 157.69. The product was used in next step as it is, without further purification.

3.4.8. N¹-{(S)-(6-methoxyquinolin-4-yl)[(1S,2S,4S,5R)-5-vinylquinuclidin-2-yl]methyl}-5-methylbenzene-1,2-diamine (7h)

Following GP4. Prepared from 6h (0.64 mmol, 295 mg) and SnCl₂·2H₂O (2.56 mmol, 580 mg) in EtOH (5 mL). Yield: 176 mg (0.41 mmol, 64%) of brownish solid. EI-HRMS: m/z = 215.1361 (M + 2H)⁺²; C₂₇H₃₄N₄O requires: m/z = 215.1361 (M + 2H)⁺². ¹H-NMR (500 MHz, CDCl₃): δ 1.13 (dd, J = 14.1, 7.1, 1H), 1.25 (s, 1H), 1.32 (t, J = 12.0, 1H), 1.55–1.70 (m, 3H), 1.89 (s, 1H), 2.17 (d, J = 1.0, 1H), 2.23–2.33 (m, 1H), 2.69–2.82 (m, 2H), 2.99–3.08 (m, 1H), 3.14 (br s, 1H), 3.30 (dd, J = 13.9, 10.1, 1H), 3.62–3.73 (m, 1H), 3.99 (s, 3H), 4.83 (br s, 1H), 4.90–5.00 (m, 2H), 5.70 (ddd, J = 17.5, 10.4, 7.6, 1H), 6.06 (s, 1H), 6.37 (d, J = 7.7, 1H), 6.56 (d, J = 7.7, 1H), 7.42 (d, J = 9.1, 1H), 7.69 (s, 1H), 7.87 (br s, 1H), 8.07 (d, J = 9.3, 1H), 8.73 (d, J = 4.5, 1H), two protons are missing. ¹³C-NMR (126 MHz, CDCl₃): δ 21.09, 25.58, 25.59, 27.66, 28.24, 29.85, 31.10, 39.88, 40.98, 55.77, 56.14, 76.77, 113.94, 114.71, 116.10, 119.24, 121.43, 128.65, 129.44, 132.23, 132.27, 132.59, 136.64, 141.49, 141.53, 148.28, 157.82. The product was used in next step as it is, without further purification.

3.4.9. 5-Methoxy-N¹-{(S)-(6-methoxyquinolin-4-yl)[(1S,2S,4S,5R)-5-vinylquinuclidin-2-yl]methyl}benzene-1,2-diamine (7i)

Following GP4. Prepared from 6i (0.88 mmol, 390 mg) and SnCl₂·2H₂O (3.52 mmol, 794 mg) in EtOH (10 mL). Yield: 367 mg (0.77 mmol, 88%) of white solid. EI-HRMS: m/z = 223.1331 (M + 2H)⁺²; C₂₇H₃₄N₄O₂ requires: m/z = 223.1335 (M + 2H)⁺². ¹H-NMR (500 MHz, CDCl₃): δ 1.11–1.17 (m, 1H), 1.29–1.37 (m, 1H), 1.56–1.63 (m, 2H), 1.65–1.69 (m, 1H), 2.25–2.32 (m, 1H), 2.70–2.80 (m, 2H), 2.83–3.07 (m, 3H), 3.13 (br s, 1H), 3.24–3.35 (m, 4H), 3.98 (s, 3H), 4.81 (br s, 1H), 4.89–4.99 (m, 2H), 5.62 (s, 1H), 5.71 (ddd, J = 17.5, 10.3, 7.6 Hz, 1H), 5.81 (br s, 1H), 6.08 (dd, J = 8.3, 2.7 Hz, 1H), 6.58 (d, J = 8.3 Hz, 1H), 7.41 (dd, J = 9.2, 2.7 Hz, 1H), 7.68 (d, J = 4.6 Hz, 1H), 7.85 (br s, 1H), 8.07 (d, J = 9.2 Hz, 1H), 8.73 (d, J = 4.5 Hz, 1H). ¹³C-NMR (126 MHz, CDCl₃): δ 25.57, 27.62, 28.32, 39.91, 40.95, 55.09, 55.72, 56.18, 62.47, 77.36, 99.91, 101.54, 102.57, 114.61, 117.10, 120.59, 121.33, 127.90, 128.56, 132.32, 138.48, 141.60, 144.80, 146.43, 148.28, 154.39, 157.76. The product was used in next step as it is, without further purification.

3.4.10. N³-{(S)-(6-methoxyquinolin-4-yl)[(1S,2S,4S,5R)-5-vinylquinuclidin-2-yl]methyl}pyridine-2,3-diamine (7j) [23]

Following GP4. Prepared from 6j (1.95 mmol, 872 mg) and SnCl₂·2H₂O (7.8 mmol, 1.76 g) in EtOH (10 mL). Yield: 760 mg (1.83 mmol, 94%) of brown solid. ¹H-NMR (500 MHz, CDCl₃) δ 1.08–1.19 (m, 1H), 1.29–1.37 (m, 2H), 1.58–1.77 (m, 3H), 2.29 (s, 1H), 2.71–2.81 (m, 2H), 2.97–3.17 (m, 1H), 3.28 (dd, J = 13.9, 10.0, 1H), 4.00 (s, 3H), 4.79 (brs, 1H), 4.90–5.00 (m, 2H), 5.64–5.76 (m, 1H), 6.23–6.35 (m, 2H), 7.41–7.50 (m, 2H), 7.59–7.68 (m, 1H), 8.02 (d, J = 2.9, 1H), 8.09 (d, J = 9.2, 1H), 8.73 (dd, J = 4.5, 1.1, 1H), three protons are missing. Spectral data are in agreement with the literature data [23]. The product was used in next step as it is, without further purification.

3.5. Amidation of Benzenediamines 7 

General procedure 5 (GP5): To a solution of diamine 7 in anhydrous CH₂Cl₂, Et₃N (1 equivalent) was added. Aroyl chloride (1 equivalent) or benzenesulphonyl chloride (1.1 equivalent) was slowly added and the mixture was stirred at 25 °C for 24 h. The reaction mixture was evaporated in vacuo and the residue was purified by CC. Fractions containing the products 8 or 9 were combined and volatile components evaporated in vacuo. Alternatively, DMAP (1 equivalent) and EDC·HCl (1 equivalent) were added to a stirred solution of carboxylic acid in anhydrous CH₂Cl₂ at 0 °C (ice-bath). The reaction mixture was stirred at 0 °C for 1 h and then the ice-bath was removed and the reaction mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with CH₂Cl₂ (10 mL) and washed with distilled water (2 × 5 mL). The organic phase was dried over anhydrous Na₂SO₄, filtered, volatile components were evaporated in vacuo, and the residue was purified by CC. Fractions containing the product were combined and volatile components evaporated in vacuo.

3.5.1. N-[2-({(S)-(6-methoxyquinolin-4-yl)[(1S,2S,4S,5R)-5-vinylquinuclidin-2-yl]methyl}amino)phenyl]benzamide (8a)

Following GP5. Prepared from 7a (0.24 mmol, 100 mg), benzoyl chloride (0.24 mmol, 28 µL), and Et₃N (0.24 mmol, 33 µL) in CH₂Cl₂ (5 mL), 25 °C, 24 h, CC (EtOAc). Yield: 82 mg (0.16 mmol, 66%) of colorless semisolid. [α]_D^r.t. = −62.3 (0.13, MeOH). EI-HRMS: m/z = 260.1413 (M + 2H)⁺²; C₃₃H₃₆N₄O₂ requires: m/z = 260.1414 (M + 2H)⁺²; ν_max 3286, 2937, 2864, 1655, 1620, 1604, 1508, 1473, 1454, 1259, 1241, 1227, 1136, 1029, 915, 857, 746, 710 cm⁻¹. ¹H-NMR (500 MHz, CDCl₃): δ 1.07–1.13 (m, 1H), 1.31–1.38 (m, 1H), 1.53–1.62 (m, 2H), 1.64–1.69 (m, 1H), 1.84 (br s, 2H), 2.23–2.30 (m, 1H), 2.62–2.75 (m, 2H), 2.97–3.11 (m, 1H), 3.12–3.20 (m, 1H), 3.95 (s, 3H), 4.79 (br s, 1H), 4.89–4.98 (m, 2H), 5.68 (ddd, J = 17.6, 10.3, 7.6 Hz, 1H), 5.84 (br s, 1H), 6.28 (d, J = 7.8 Hz, 1H), 6.76 (t, J = 7.6 Hz, 1H), 6.79–6.84 (m, 1H), 7.42 (dd, J = 9.2, 2.6 Hz, 1H), 7.52 (t, J = 7.5 Hz, 2H), 7.58 (t, J = 7.2 Hz, 1H), 7.60–7.67 (m, 2H), 7.71 (br s, 1H), 7.88–7.97 (m, 2H), 8.07 (d, J = 9.2 Hz, 1H), 8.71 (d, J = 4.5 Hz, 1H). ¹³C-NMR (126 MHz, CDCl₃): δ 25.70, 27.56, 28.18, 39.89, 40.89, 55.72, 56.04, 62.63, 77.37, 101.59, 114.76, 119.39, 120.36, 121.45, 125.48, 125.61, 126.99, 127.38, 128.39, 128.87, 131.82, 132.30, 135.40, 141.47, 141.51, 144.83, 146.06, 148.21, 157.90, 166.66.

3.5.2. N-[5-Cyano-2-({(S)-(6-methoxyquinolin-4-yl)[(1S,2S,4S,5R)-5-vinylquinuclidin-2-yl]methyl}amino)phenyl]benzamide (8b)

Following GP5. Prepared from 7c (0.23 mmol, 100 mg), benzoyl chloride (0.23 mmol, 27 µL), and Et₃N (0.23 mmol, 32 µL) in CH₂Cl₂ (2 mL), 0 °C, 24 h, CC (EtOAc). Yield: 60 mg (0.11 mmol, 48%) of brown semisolid. [α]_D^r.t. = −55.1 (0.058, MeOH). EI-HRMS: m/z = 272.6383 (M + 2H)⁺²; C₃₄H₃₅N₅O₂ requires: m/z = 272.6390 (M + 2H)⁺²; ν_max 3275, 2936, 2215, 1655, 1607, 1508, 1474, 1432, 1345, 1289, 1261, 1229, 1145, 1080, 1028, 917, 857, 815, 753, 711, 666, 622 cm⁻¹. ¹H-NMR (500 MHz, CDCl₃): δ 1.13–1.21 (m, 1H), 1.34–1.41 (m, 1H), 1.57–1.66 (m, 2H), 1.67–1.72 (m, 1H), 2.12–2.31 (m, 2H), 2.61–2.75 (m, 2H), 3.03 (br s, 2H), 3.14 (dd, J = 13.8, 10.1 Hz, 1H), 3.97 (s, 3H), 4.82–4.98 (m, 3H), 5.63 (ddd, J = 17.5, 10.3, 7.5 Hz, 1H), 6.13 (br s, 1H), 6.76 (s, 1H), 7.01 (dd, J = 8.5, 1.9 Hz, 1H), 7.45 (dd, J = 9.3, 2.6 Hz, 1H), 7.52 (t, J = 7.6 Hz, 2H), 7.55–7.62 (m, 3H), 7.66 (br s, 1H), 7.95 (d, J = 7.4 Hz, 2H), 8.09 (d, J = 9.2 Hz, 1H), 8.72 (d, J = 4.5 Hz, 1H). ¹³C-NMR (126 MHz, CDCl₃): δ 25.47, 27.27, 27.79, 39.52, 40.68, 55.60, 55.74, 62.94, 76.77, 99.86, 101.19, 112.78, 114.92, 119.66, 119.96, 121.58, 123.86, 127.40, 127.94, 128.83, 130.22, 132.03, 132.17, 132.34, 134.28, 140.87, 141.09, 144.69, 145.89, 148.04, 158.12, 166.92.

3.5.3. N-[2-({(S)-(6-methoxyquinolin-4-yl)[(1S,2S,4S,5R)-5-vinylquinuclidin-2-yl]methyl}amino)-5-trifluoromethyl]phenyl}-3,5-bis(trifluoromethyl)benzamide (8c)

A solution of EDCI·HCl (138 mg, 0.72 mmol) in CH₂Cl₂ (3 mL) was slowly added to a stirred mixture of compound 7b (0.6 mmol, 248 mg), 3,5-bis(trifluoromethyl)benzoic acid (0.6 mmol, 155 mg), DMAP (0.06 mmol, 7.3 mg), and CH₂Cl₂ (3 mL) at 0 °C (an ice bath). The ice bath was then removed and stirring was continued at 25 °C for 24 h. The reaction mixture was diluted with CH₂Cl₂ (25 mL) and the combined organic phase was washed with distilled water (5 mL), dried over anhydrous Na₂SO₄, filtered and the filtrate was evaporated in vacuo. The residue was purified by CC (EtOAc). Fractions containing the products were combined and the volatile components were evaporated in vacuo to give 8c. Yield: 353 mg (0.49 mmol, 82%) of colorless solid, mp = 107–109 °C. [α]_D^r.t. = –119 (0.083, MeOH). EI-HRMS: m/z = 362.1222 (M + 2H)⁺²; C₃₆H₃₃F₉N₄O₂ requires: m/z = 362.1224 (M + 2H)⁺²; ν_max 3241, 2931, 2870, 1652, 1618, 1509, 1453, 1327, 1276, 1170, 1127, 1032, 907, 817, 765, 701, 680, 629 cm⁻¹. ¹H-NMR (500 MHz, CDCl₃): δ 0.82–0.89 (m, 1H), 1.08–1.15 (m, 1H), 1.22–1.31 (m, 1H), 1.32–1.38 (m, 1H), 1.53–1.64 (m, 2H), 1.68 (br s, J = 3.2, 1H), 2.22–2.30 (m, 1H), 2.60–2.69 (m, 2H), 2.8– 3.17 (m, 2H), 3.96 (s, 3H), 4.72–4.98 (m, 3H), 5.62 (ddd, J = 17.4, 10.4, 7.3, 1H), 6.22 (br s, 1H), 6.29 (s, 1H), 7.06 (dd, J = 8.6, 2.1, 1H), 7.43 (dd, J = 9.3, 2.6, 1H), 7.53 (d, J = 4.5, 1H), 7.63 (br s, 1H), 8.05 (d, J = 9.2 Hz, 1H), 8.09 (s, 1H), 8.41 (s, 2H), 8.57 (s, 1H), 8.66 (d, J = 4.5, 1H). ¹³C-NMR (126 MHz, CDCl₃): δ 25.58, 27.29, 28.03, 39.49, 40.92, 51.08, 55.71, 62.71, 77.37, 101.33, 113.20, 114.98, 119.84, 121.61, 121.93, 123.09, 124.10, 125.51, 126.27, 127.86, 128.15, 128.91, 131.06, 132.08, 132.33, 132.62, 132.89, 136.86, 140.98, 144.71, 145.06, 148.03, 158.22, 164.31.

3.5.4. N-[2-({(S)-(6-methoxyquinolin-4-yl)[(1S,2S,4S,5R)-5-vinylquinuclidin-2-yl]methyl}amino)phenyl]benzenesulfonamide (9)

Following GP5. Prepared from 7a (0.24 mmol, 100 mg), benzenesulfonyl chloride (0.24 mmol, 30 mL), and Et₃N (0.24 mmol, 33 µL) in CH₂Cl₂ (5 mL), 25 °C, 24 h, CC (EtOAc). Yield: 47 mg (0.085 mmol, 35%) of colorless solid, mp = 85.1–86.4 °C. [α]_D^r.t. = –152 (0.027, MeOH). EI-HRMS: m/z = 278.1249 (M + 2H)⁺²; C₃₂H₃₆N₄O₃S requires: m/z = 278.1249 (M + 2H)⁺²; ν_max 3068, 2942, 2865, 1621, 1602, 1507, 1473, 1446, 1431, 1325, 1258, 1240, 1228, 1157, 1092, 1029, 987, 918, 857, 830, 748, 688, 666 cm⁻¹. ¹H-NMR (500 MHz, CDCl₃): δ 0.98–1.05 (m, 1H), 1.28–1.36 (m, 1H), 1.5–1.64 (m, 2H), 1.65–1.69 (m, 1H), 2.28–2.36 (m, 1H), 2.70–2.84 (m, 2H), 2.90–3.02 (m, 2H), 3.34 (dd, J = 13.9, 10.0 Hz, 1H), 3.96 (s, 3H), 4.70 (br s, 1H), 4.93–5.03 (m, 2H), 5.29 (br s, 1H), 5.45 (d, J = 15.6 Hz, 1H), 5.71 (ddd, J = 17.5, 10.4, 7.4 Hz, 1H), 6.06 (s, 1H), 6.51–6.57 (m, 1H), 6.68–6.74 (m, 1H), 6.99 (s, 1H), 7.22 (d, J = 4.6 Hz, 1H), 7.41 (dd, J = 9.3, 2.6 Hz, 1H), 7.49 (t, J = 7.9 Hz, 2H), 7.54–7.66 (m, 2H), 7.82–7.88 (m, 2H), 8.06 (d, J = 9.2 Hz, 1H), 8.65 (d, J = 4.5 Hz, 1H). ¹³C-NMR (126 MHz, CDCl₃): δ 25.54, 27.53, 28.06, 39.59, 40.84, 55.72, 88.82, 62.17, 77.36, 101.39, 114.83, 114.89, 118.75, 119.93, 121.48, 123.85, 127.06, 127.52, 127.83, 128.43, 129.06, 129.07, 132.22, 132.75, 140.67, 141.29, 142.73, 144.61, 145.89, 148.03, 148.09, 157.96.

3.6. Synthesis of Benzenediamines 10 

General procedure 6 (GP6): To a solution of diamine 7 in anhydrous CH₂Cl₂, 2-(ethoxymethylene)malononitrile (2i) was added. The reaction mixture was stirred at 25 °C for 24 h, volatile components were evaporated in vacuo, and the residue was purified by CC. Fractions containing the product 10 were combined and volatile components evaporated in vacuo.

3.6.1. 2-({[2-({(S)-(6-methoxyquinolin-4-yl)[(1S,2S,4S,5R)-5-vinylquinuclidin-2-yl]methyl}amino)phenyl]amino}methylene)malononitrile (10a)

Following GP6. Prepared from 7a (0.63 mmol, 263 mg) and 2i (0.761 mmol, 77.4 mg) in CH₂Cl₂ (1 mL), 25 °C, 24 h, CC (EtOAc). Yield: 178 mg (0.36 mmol, 57%) of colorless solid, mp = 121–122 °C. [α]_D^r.t. = −87.8 (0.067, MeOH). EI-HRMS: m/z = 246.1312 (M + 2H)⁺²; C₃₀H₃₂N₆O requires: m/z = 246.1313 (M + 2H)⁺²; ν_max 3365, 2929, 2214, 1993, 1620, 1598, 1506, 1454, 1431, 1314, 1257, 1225, 1136, 1081, 1028, 987, 911, 855, 824, 728, 683, 645 cm⁻¹. ¹H-NMR (500 MHz, CDCl₃): δ 1.02–1.12 (m, 1H), 1.37–1.46 (m, 1H), 1.62–1.75 (m, 3H), 2.27–2.38 (m, 1H), 2.69–2.79 (m, 1H), 2.74 (br d, J = 12.2 Hz, 1H), 2.83 (br quintet, J = 8.0 Hz, 1H), 3.05–3.17 (m, 1H), 3.17–3.29 (m, 2H), 4.00 (s, 3H), 4.88–5.03 (m, 3H), 5.39 (br s, 1H), 5.70 (ddd, J = 19.3, 10.0, 7.2 Hz, 1H), 6.25 (br s, 1H), 6.72 (t, J = 7.8 Hz, 1H), 6.85 (t, J = 7.7 Hz, 1H), 6.90 (dd, J = 7.8, 1.4 Hz, 1H), 7.46 (dd, J = 9.2, 2.6 Hz, 1H), 7.52 (d, J = 4.6 Hz, 1H), 7.59 (s, 1H), 7.62 (s, 1H), 8.11 (d, J = 9.3 Hz, 1H), 8.76 (d, J = 4.5 Hz, 1H). ¹³C-NMR (126 MHz, CDCl₃): δ 27.24, 27.66, 39.05, 40.76, 55.16, 55.31, 55.83, 64.57, 77.36, 101.31, 114.24, 115.35, 115.47, 119.81, 120.33, 121.40, 121.67, 121.71, 128.25, 128.40, 132.63, 132.93, 138.70, 139.39, 140.52, 144.71, 144.75, 148.23, 157.39, 158.29.

3.6.2. 2-[({[2-({(S)-(6-methoxyquinolin-4-yl)[(1S,2S,4S,5R)-5-vinylquinuclidin-2-yl]methyl}amino)-5-trifluoromethyl]phenyl}amino)methylene]malononitrile (10b)

Following GP6. Prepared from 7b (0.49 mmol, 236 mg) and 2i (0.50 mmol, 60.9 mg) in CH₂Cl₂ (2 mL), 25°C, 24 h, CC (EtOAc). Yield: 100 mg (0.18 mmol, 36%) of colorless solid, mp = 107–109 °C. [α]_D^r.t. = –141.5 (0.092, MeOH). EI-HRMS: m/z = 280.1248 (M + 2H)⁺²; C₃₁H₃₁F₃N₆O requires: m/z = 280.1250 (M + 2H)⁺²; ν_max 3348, 2930, 2869, 2218, 1614, 1507, 1433, 1326, 1265, 1109, 1029, 919, 813, 716, 616 cm⁻¹. ¹H-NMR (500 MHz, CDCl₃): δ 1.04–1.12 (m, 1H), 1.36–1.45 (m, 1H), 1.61–1.75 (m, 3H), 2.17–2.24 (m, 1H), 2.53–2.69 (m, 2H), 2.81 (d, J = 12.8 Hz, 1H), 3.06 (d, J = 12.8 Hz, 1H), 3.37 (br s, 1H), 4.02 (s, 3H), 4.93 (d, J = 16.8 Hz, 1H), 5.00 (d, J = 10.4, 1.2 Hz, 1H), 5.04–5.18 (m, 1H), 5.67 (ddd, J = 17.5, 10.4, 7.5 Hz, 1H), 6.16 (d, J = 6.2 Hz, 1H), 6.31 (d, J = 8.6 Hz, 1H), 7.04 (d, J = 2.1 Hz, 1H), 7.14 (dd, J = 8.3, 2.1 Hz, 1H), 7.48 (dd, J = 9.3, 2.5 Hz, 1H), 7.54–7.59 (m, 2H), 7.61 (s, 1H), 7.98 (br s, 1H), 8.12 (d, J = 9.2 Hz, 1H), 8.80 (d, J = 4.6 Hz, 1H). ¹³C-NMR (126 MHz, CDCl₃): δ 24.67, 26.94, 27.48, 38.89, 40.73, 53.21, 55.44, 55.82, 61.50, 77.36, 100.83, 111.61, 114.92, 115.07, 115.64, 119.77, 120.01, 121.17, 122.90, 125.06, 125.96, 126.84, 128.13, 133.01, 139.69, 142.65, 144.53, 144.58, 148.52, 158.49, 158.55.

3.6.3. 2-({[5-Cyano-2-({(S)-(6-methoxyquinolin-4-yl)[(1S,2S,4S,5R)-5-vinylquinuclidin-2-yl]methyl}amino)phenyl]amino}methylene)malononitrile (10c)

Following GP6. Prepared from 7c (0.63 mmol, 279 mg) and 2i (0.77 mmol, 78 mg) in CH₂Cl₂ (1 mL), 25 °C, 24 h, CC (EtOAc). Yield: 280 mg (0.54 mmol, 86%) of colorless solid, mp = 138–140 °C. [α]_D^r.t. = –142.7 (0.075, MeOH). EI-HRMS: m/z = 258.6286 (M + 2H)⁺²; C₃₁H₃₁N₇O requires: m/z = 258.6290 (M + 2H)⁺²; ν_max 3565, 2922, 2862, 2215, 2196, 2163, 2023, 1952, 1729, 1605, 1589, 1555, 1506, 1455, 1431, 1311, 1256, 1226, 1129, 1083, 1026, 985, 947, 915, 854, 809, 717, 683, 610 cm⁻¹. ¹H-NMR (500 MHz, CDCl₃): δ 1.05–1.14 (m, 1H), 1.35–1.45 (m, 1H), 1.56–1.79 (m, 4H), 2.21–2.30 (m, 1H), 2.58–2.72 (m, 2H), 2.80–2.90 (m, 1H), 3.05–3.15 (m, 1H), 3.32–3.47 (m, 1H), 4.02 (s, 3H), 4.94–5.08 (m, 2H), 5.12 (br s, 1H), 5.68 (ddd, J = 17.4, 10.4, 7.3 Hz, 1H), 6.24 (br s, 1H), 6.34 (br s, 1H), 7.05–7.10 (m, 1H), 7.11–7.16 (m, 1H), 7.37–7.52 (br m, 1H), 7.49 (d, J = 9.4 Hz, 1H), 7.53–7.59 (m, 2H), 8.13 (d, J = 9.2 Hz, 1H), 8.79 (d, J = 4.6 Hz, 1H). ¹³C-NMR (126 MHz, CDCl₃): δ 24.41, 26.87, 27.29, 38.69, 40.79, 52.96, 55.23, 55.89, 56.26, 61.61, 77.36, 99.99, 100.73, 111.62, 114.88, 114.99, 115.96, 118.67, 119.92, 121.17, 126.42, 127.23, 128.04, 132.21, 133.11, 139.54, 143.57, 144.47, 148.50, 158.58, 158.70.

3.6.4. 2-({[4-Cyano-2-({(S)-(6-methoxyquinolin-4-yl)[(1S,2S,4S,5R)-5-vinylquinuclidin-2-yl]methyl}amino)phenyl]amino}methylene)malononitrile (10d)

Following GP6. Prepared from 7d (0.31 mmol, 136 mg) and 2i (0.50 mmol, 60.9 mg) in CH₂Cl₂ (2 mL), 25 °C, 24 h, CC (EtOAc). Yield: 75 mg (0.145 mmol, 47%) of white solid, mp = 117–120 °C. [α]_D^r.t. = –218 (0.11, MeOH). EI-HRMS: m/z = 258.6289 (M + 2H)⁺²; C₃₁H₃₁N₇O requires: m/z = 258.6290 (M + 2H)⁺²; ν_max 3330, 2928, 2864, 2220, 2194, 2171, 1980, 1621, 1587, 1547, 1509, 1462, 1432, 1359, 1312, 1257, 1090, 1029, 921, 834, 787, 721, 621 cm⁻¹. ¹H-NMR (500 MHz, CDCl₃): δ 1.01–1.12 (m, 1H), 1.37–1.47 (m, 1H), 1.64–1.78 (m, 3H), 2.22–2.32 (m, 1H), 2.56–2.68 (m, 1H), 2.68–2.79 (m, 1H), 2.86–2.96 (m, 1H), 3.05–3.17 (m, 1H), 3.29 –3.44 (m, 1H), 4.02 (s, 3H), 4.91–5.10 (m, 3H), 5.68 (ddd, J = 17.3, 10.4, 7.2 Hz, 1H), 5.89 (br s, 1H), 6.53 (br s, 1H), 6.84–7.00 (m, 3H), 7.49 (dd, J = 9.4, 2.5 Hz, 1H), 7.51 (d, J = 4.5 Hz, 1H), 7.57 (br s, 1H), 7.63 (s, 1H), 8.13 (d, J = 9.3 Hz, 1H), 8.80 (d, J = 4.5 Hz, 1H). ¹³C-NMR (126 MHz, CDCl₃): δ 24.85, 26.97, 27.21, 38.65, 40.81, 55.10, 55.99, 56.62, 61.31, 77.37, 100.70, 111.07, 114.93, 115.19, 115.70, 116.22, 118.41, 121.65, 121.92, 122.89, 128.11, 132.15, 132.50, 133.00, 139.75, 139.80, 143.56, 144.69, 148.25, 157.61, 158.83.

3.6.5. 2-({[5-Bromo-2-({(S)-(6-methoxyquinolin-4-yl)[(1S,2S,4S,5R)-5-vinylquinuclidin-2-yl]methyl}amino)phenyl]amino}methylene)malononitrile (10e)

Following GP9. Prepared from 7e (0.5 mmol, 246 mg) and 2i (0.50 mmol, 60.9 mg) in CH₂Cl₂ (2 mL), 25 °C, 24 h, CC (EtOAc). Yield: 256 mg (0.45 mmol, 90%) of colorless solid, mp = 121–123 °C. [α]_D^r.t. = –67.7 (0.12, MeOH). EI-HRMS: m/z = 285.0863 (M + 2H)⁺²; C₃₀H₃₁BrN₆O requires: m/z = 258.0866 (M + 2H)⁺²; ν_max 3305, 2933, 2864, 2833, 2191, 1727, 1620, 1588, 1546, 1505, 1452, 1311, 1240, 1138, 1083, 1028, 916, 854, 827, 716, 649 cm⁻¹. ¹H-NMR (500 MHz, CDCl₃): δ 1.10–1.25 (m, 1H), 1.39–1.54 (m, 1H), 1.72–1.90 (m, 3H), 2.36–2.52 (m, 1H), 2.76–2.91 (m, 1H), 2.91–3.08 (m, 1H), 3.21–3.42 (m, 2H), 3.48–3.66 (m, 1H), 4.01 (s, 3H), 4.98–5.11 (m, 2H), 5.17 (s, 1H), 5.69 (ddd, J = 17.3, 10.4, 7.0 Hz, 1H), 5.89 (s, 1H), 6.22 (s, 1H), 6.93–7.01 (m, 2H), 7.41–7.46 (m, 1H), 7.47–7.53 (m, 2H), 7.55–7.60 (m, 1H), 8.06 (d, J = 9.2 Hz, 1H), 8.74 (d, J = 4.5 Hz, 1H), 9.66 (s, 1H). ¹³C-NMR (126 MHz, CDCl₃): δ 24.20, 26.17, 37.80, 40.87, 53.04, 54.29, 54.51, 61.30, 77.36, 100.70, 110.27, 114.91, 115.08, 115.75, 116.38, 119.66, 120.00, 121.58, 125.83, 128.27, 129.43, 131.04, 132.17, 132.53, 138.69, 143.70, 144.29, 148.08, 158.67, 178.38.

3.6.6. 2-({[4-Bromo-2-({(S)-(6-methoxyquinolin-4-yl)[(1S,2S,4S,5R)-5-vinylquinuclidin-2-yl]methyl}amino)phenyl]amino}methylene)malononitrile (10f)

Following GP9. Prepared from 7f (0.5 mmol, 246 mg) and 2i (0.5 mmol, 60.9 mg), CH₂Cl₂ (2 mL), 25 °C, 24 h, CC (EtOAc). Yield: 214 mg (0.38 mmol, 75%) of yellowish solid, mp = 116.1–118.9 °C. [α]_D^r.t. = –118 (0.083, MeOH). EI-HRMS: m/z = 285.0862 (M + 2H)⁺²; C₃₀H₃₁BrN₆O requires: m/z = 285.0866 (M + 2H)⁺²; ν_max 3344, 2949, 2877, 2359, 2219, 2163, 2034, 1960, 1622, 1593, 1508, 1474, 1421, 1322, 1258, 1175, 1030, 922, 827, 788, 717, 685 cm⁻¹. ¹H-NMR (500 MHz, CDCl₃): δ 0.93–1.02 (m, 1H), 1.31–1.42 (m, 1H), 1.58–1.74 (m, 3H), 2.15–2.23 (m, 1H), 2.47–2.64 (m, 2H), 2.69–2.80 (m, 1H), 3.03–3.13 (m, 1H), 3.28–3.43 (m, 1H), 4.04 (s, 3H), 4.89–5.08 (m, 3H), 5.67 (ddd, J = 17.4, 10.4, 7.2 Hz, 1H), 5.88 (d, J = 6.9 Hz, 1H), 6.51 (s, 1H), 6.62 (d, J = 8.3 Hz, 1H), 6.68 (dd, J = 8.3, 2.0 Hz, 1H), 7.45 (dd, J = 9.2, 2.5 Hz, 1H), 7.51 (s, 1H), 7.55–7.59 (m, 2H), 8.09 (d, J = 9.2 Hz, 1H), 8.36 (br s, 1H), 8.79 (d, J = 4.6 Hz, 1H). ¹³C-NMR (126 MHz, CDCl₃): δ 24.78, 26.94, 27.39, 38.63, 40.67, 54.78, 55.13, 55.86, 61.17, 77.36, 99.97, 115.14, 115.17, 115.32, 115.50, 120.15, 120.50, 121.87, 121.93, 123.89, 126.37, 128.14, 132.75, 140.03, 141.03, 144.47, 144.64, 148.34, 158.24, 158.64.

3.6.7. 2-({[2-({(S)-(6-methoxyquinolin-4-yl)[(1S,2S,4S,5R)-5-vinylquinuclidin-2-yl]methyl}amino)-4-methylphenyl]amino}methylene)malononitrile (10g)

Following GP9. Prepared from 7g (0.31 mmol, 130 mg) and 2i (0.33 mmol, 40.0 mg) in CH₂Cl₂ (2 mL), 25 °C, 24 h, CC (EtOAc). Yield: 77 mg (0.149 mmol, 48%) of brownish solid, mp = 102.9–107.2 °C. [α]_D^r.t. = –143 (0.1, MeOH). EI-HRMS: m/z = 253.1392 (M + 2H)⁺²; C₃₁H₃₄N₆O requires: m/z = 253.1392 (M + 2H)⁺²; ν_max 3305, 2942, 2873, 2844, 2358, 2217, 2193, 2087, 2036, 1962, 1613, 1548, 1510, 1474, 1433, 1329, 1260, 1240, 1139, 1030, 921, 856, 717, 668, 621 cm⁻¹. ¹H-NMR (500 MHz, CDCl₃): δ 1.15 (dd, J = 13.6, 7.0, 1H), 1.41 (s, 1H), 1.61–1.70 (m, 2H), 1.73 (s, 1H), 2.33 (s, 1H), 2.71–2.90 (m, 3H), 2.99 (s, 1H), 3.36 (dd, J = 14.0, 10.1, 1H), 3.79–4.11 (m, 3H), 4.90–5.07 (m, 2H), 5.62–5.78 (m, 1H), 6.69 (s, 1H), 7.36–7.70 (m, 3H), 8.08 (s, 2H), 8.50–8.58 (m, 1H), 8.75 (d, J = 4.6, 1H). ¹³C-NMR (126 MHz, CDCl₃): δ 21.20, 27.56, 28.21, 39.64, 40.97, 55.82, 58.63, 89.46, 111.85, 114.95, 115.94, 116.89, 117.49, 140.41, 141.21, 144.32, 152.73, 153.20, 175.10.

3.6.8. 2-({[2-({(S)-(6-methoxyquinolin-4-yl)[(1S,2S,4S,5R)-5-vinylquinuclidin-2-yl]methyl}amino)-5-methylphenyl]amino}methylene)malononitrile (10h)

Following GP9. Prepared from 7h (0.33 mmol, 140 mg) and 2i (0.50 mmol, 60.9 mg) in CH₂Cl₂ (2 mL), 25 °C, 24 h, CC (EtOAc). Yield: 105 mg (0.20 mmol, 62%) of brownish solid, mp = 110–112 °C. [α]_D^r.t. = –230 (0.125, MeOH). EI-HRMS: m/z = 253.1388 (M + 2H)⁺²; C₃₁H₃₄N₆O requires: m/z = 253.1392 (M + 2H)⁺²; ν_max 3363, 2943, 2358, 2215, 2035, 1970, 1622, 1590, 1508, 1473, 1432, 1314, 1259, 1228, 1139, 1030, 989, 919, 854, 717, 683 cm⁻¹. ¹H-NMR (500 MHz, CDCl₃): δ 0.96–1.04 (m, 1H), 1.19–1.33 (m, 1H), 1.38–1.48 (m, 1H), 1.61–1.68 (m, 2H), 1.69–1.72 (m, 1H), 1.97 (s, 3H), 2.29–2.36 (m, 1H), 2.69–2.77 (m, 1H), 2.79–2.87 (m, 1H), 3.01–3.09 (m, 1H), 3.16–3.30 (m, 2H), 4.00 (s, 3H), 4.88 (br s, 1H), 4.96–5.02 (m, 2H), 5.23 (br s, 1H), 5.71 (ddd, J = 17.4, 10.1, 7.2 Hz, 1H), 6.10 (br s, 1H), 6.55 (dd, J = 8.1, 1.8 Hz, 1H), 6.79 (d, J = 7.9 Hz, 1H), 7.46 (dd, J = 9.2, 2.6 Hz, 1H), 7.49 (d, J = 4.5 Hz, 1H), 7.56 (s, 1H), 7.65 (br s, 1H), 8.11 (d, J = 9.2 Hz, 1H), 8.78 (d, J = 4.6 Hz, 1H). ¹³C-NMR (126 MHz, CDCl₃): δ 21.42, 25.69, 27.31, 27.79, 39.19, 40.74, 54.73, 55.45, 55.84, 60.83, 77.37, 101.18, 114.23, 115.20, 115.52, 117.16, 120.43, 120.82, 121.40, 121.51, 126.19, 128.40, 132.58, 138.29, 139.31, 140.77, 143.09, 144.80, 148.17, 157.28, 158.24.

3.6.9. 2-({[4-Methoxy-2-({(S)-(6-methoxyquinolin-4-yl)[(1S,2S,4S,5R)-5-vinylquinuclidin-2-yl]methyl}amino)phenyl]amino}methylene)malononitrile (10i)

Following GP9. Prepared from 7i (0.675 mmol, 300 mg) and 2i (0.742 mmol, 90.2 mg) in CH₂Cl₂ (3 mL), 25 °C, 24 h, CC (EtOAc). Yield: 251 mg (0.48 mmol, 71%) of yellowish solid, decompose >250 °C. [α]_D^r.t. = –177 (0.092, MeOH). EI-HRMS: m/z = 261.1361 (M + 2H)⁺²; C₃₁H₃₄N₆O₂ requires: m/z = 261.1366 (M + 2H)⁺²; ν_max 3369, 2942, 2872, 2358, 2200, 2012, 1980, 1621, 1592, 1548, 1509, 1455, 1433, 1319, 1261, 1215, 1173, 1138, 1033, 991, 918, 856, 825, 719 cm⁻¹. ¹H-NMR (500 MHz, CDCl₃): δ 1.02–1.09 (m, 1H), 1.39–1.48 (m, 1H), 1.60–1.70 (m, 2H), 1.70–1.75 (m, 1H), 2.33 (s, 1H), 2.70–2.86 (m, 2H), 3.01–3.12 (m, 1H), 3.17–3.29 (m, 2H), 3.33 (s, 3H), 4.00 (s, 3H), 4.91 (s, 1H), 4.96–5.03 (m, 2H), 5.49 (s, 1H), 5.71 (ddd, J= 17.3, 10.0, 7.2, 1H), 5.78 (s, 1H), 6.20 (dt, J = 8.7, 2.2, 1H), 6.81 (dd, J = 8.6, 1.7, 1H), 7.26 (s, 1H), 7.45 (dd, J = 9.3, 2.6, 1H), 7.51 (s, 1H), 7.54 (d, J = 4.5, 1H), 7.66 (s, 1H), 8.11 (d, J=9.2, 1H), 8.78 (d, J = 4.6, 1H). ¹³C-NMR (126 MHz, CDCl₃): δ 14.28, 22.81, 25.59, 27.30, 27.87, 31.74, 39.23, 40.79, 54.44, 55.12, 55.50, 55.84, 100.96, 104.52, 115.20, 115.44, 120.90, 121.44, 123.73, 128.33, 128.61, 132.21, 132.29, 132.70, 133.07, 140.79, 141.50, 144.80, 148.30, 158.21, 159.88.

3.6.10. 2-({[3-({(S)-(6-methoxyquinolin-4-yl)[(1S,2S,4S,5R)-5-vinylquinuclidin-2-yl]methyl}amino)pyridin-2-yl]amino}methylene)malononitrile (10j)

Following GP9. Prepared from 7j (0.65 mmol, 270 mg) and 2i (0.77 mmol, 78 mg) in CH₂Cl₂ (1 mL), 25 °C, 24 h, CC (EtOAc). Yield: 88 mg (0.18 mmol, 27%) of yellowish solid, decompose 243 °C. [α]_D^r.t. = –30.4 (0.092, MeOH). EI-HRMS: m/z = 246.6286 (M + 2H)⁺²; C₂₉H₃₁N₇O requires: m/z = 246.6290 (M + 2H)⁺²; ν_max 3326, 3213, 2944, 2223, 2035, 1621, 1579, 1508, 1475, 1432, 1361, 1231, 1027, 916, 831 cm⁻¹. ¹H-NMR (500 MHz, CDCl₃): δ 1.12–1.19 (m, 1H), 1.27–1.37 (m, 1H), 1.57–1.65 (m, 2H), 1.65–1.72 (m, 1H), 2.24–2.33 (m, 1H), 2.99–3.09 (m, 1H), 3.13 (br s, 1H), 3.30 (dd, J = 13.8, 10.0, 1H), 3.99 (s, 3H), 4.86 (br s, 1H), 4.90–5.00 (m, 2H), 5.70 (ddd, J = 17.6, 10.3, 7.5, 1H), 6.19 (br s, 1H), 6.44 (td, J = 7.7, 1.5, 1H), 6.57 (td, J = 7.5, 1.3, 1H), 6.66 (dd, J = 7.5, 1.5, 1H), 7.40–7.48 (m, 1H), 7.68–7.74 (m, 1H), 7.83 (br s, 1H), 8.08 (d, J = 9.2, 1H), 8.72 (d, J = 4.4, 1H). ¹³C-NMR (126 MHz, CDCl₃): δ 25.45, 27.60, 28.23, 39.84, 40.94, 55.69, 56.09, 77.37, 101.66, 112.81, 114.67, 115.88, 119.08, 120.05, 121.28, 128.57, 128.63, 128.67, 132.17, 132.24, 135.32, 136.35, 141.50, 144.74, 146.39, 148.26, 157.75.

3.6.11. (E)-4-({[2-({(S)-(6-methoxyquinolin-4-yl)[(1S,2S,4S,5R)-5-vinylquinuclidin-2-yl]methyl}amino)phenyl]amino}methylene)-5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one (10k)

Prepared from 7a (0.24 mmol, 100 mg), 2b (0.24 mmol, 55 mg), and AcOH (5 µL) in EtOH (1 mL), 25 °C, 24 h. The precipitate was collected by filtration and washed with cold EtOH (1 mL) to give 10k. Yield: 126 mg (0.21 mmol, 88%) of yellow solid, mp = 167.1–169.2 °C. [α]_D^r.t. = –517 (0.027, MeOH). EI-HRMS: m/z = 300.1596 (M + 2H)⁺²; C₃₇H₄₀N₆O₂ requires: m/z = 300.1601 (M + 2H)⁺²; ν_max 3312, 3075, 2912, 2863, 1672, 1621, 1596, 1552, 1510, 1496, 1474, 1455, 1416, 1363, 1335, 1320, 1296, 1259, 1204, 1174, 1157, 1109, 1083, 1037, 1004, 952, 906, 878, 864, 822, 788, 734, 712, 686, 670, 636, 621 cm⁻¹. ¹H-NMR (500 MHz, CDCl₃): δ 1.05–1.16 (m, 1H), 1.28–1.40 (m, 1H), 1.53–1.66 (m, 2H), 1.67–1.75 (m, 1H), 2.24–2.36 (m, 4H), 2.66–2.81 (m, 1H), 2.91–3.06 (m, 2H), 3.23 (dd, J = 13.9, 10.0 Hz, 2H), 3.99 (s, 3H), 4.65–5.07 (m, 3H), 5.74 (ddd, J = 17.4, 10.4, 7.3 Hz, 1H), 5.96 (s, 1H), 6.39 (s, 1H), 6.74 (td, J = 7.6, 1.3 Hz, 1H), 6.83 (t, J = 7.7 Hz, 1H), 7.10–7.21 (m, 2H), 7.36–7.47 (m, 3H), 7.69 (s, 1H), 7.87 (s, 2H), 7.99–8.16 (m, 3H), 8.72 (d, J = 4.5 Hz, 1H), one proton is missing. ¹³C-NMR (126 MHz, CDCl₃): δ 12.87, 25.63, 27.62, 28.33, 39.91, 40.89, 55.66, 55.94, 77.36, 101.63, 103.51, 114.54, 114.60, 117.71, 118.70, 119.19, 121.47, 124.27, 126.94, 128.05, 128.43, 128.87, 132.21, 139.06, 139.29, 141.67, 144.46, 144.95, 147.96, 148.23, 157.88, 166.01, three carbons are missing.

3.7. Evaluation of Organocatalysts on a Model Reaction

To a solution of trans-β-nitrostyrene (0.10 mmol) and an organocatalyst (10 mol% or 40 mol%; 4, 8, 9, or 10) in anhydrous CH₂Cl₂ (1 mL), acetylacetone (0.15 mmol) was added. The reaction mixture was stirred at 25 °C for 24 h. The volatile components were evaporated in vacuo and the residue was purified by FC (EtOAc–petroleum ether). Fractions containing the product were combined and the volatile components were evaporated in vacuo. The residue was analyzed by ¹H-NMR and HPLC to determine the conversion and ee.

3.8. X-ray Crystallography

Single-crystal X-ray diffraction data was collected on Agilent Technologies SuperNova Dual diffractometer with an Atlas detector using monochromated Mo-K_α radiation (λ = 0.71073 Å) at 150 K. The data was processed using CrysAlis PRO [41]. Using Olex2.1.2. [42], the structures were solved by direct methods implemented in SHELXS [43] or SHELXT [44] and refined by a full-matrix least-squares procedure based on F² with SHELXT-2014/7 [45]. All nonhydrogen atoms were refined anisotropically. Hydrogen atoms were placed in geometrically calculated positions and were refined using a riding model. The drawings and the analysis of bond lengths, angles and intermolecular interactions were carried out using Mercury [46] and Platon [47]. Structural and other crystallographic details on data collection and refinement for compounds 4b and 4f have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication number CCDC Deposition Numbers 2192843 and 2193411, respectively. These data can be obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; fax: [phone]; e-mail: [email protected]).

4. Conclusions

Novel derivatives of (S)-quininamine (3) were synthesized as potential organocatalysts containing enaminone and 1,2-benzenediamine structural elements as hydrogen bond donors. Starting from (S)-quininamine trihydrochloride (3), the single and the double BHD enaminone-type catalysts 4a–i were prepared by the transamination of (dimethylamino)enaminones 2 (9 examples). The 1,2-benzenediamine-type catalysts 8–10 were prepared in three steps from (S)-quininamine hydrochloride (3) and ortho-fluoronitrobenzene derivatives 5a–j to give the substitution products 6a–j, followed by a reduction of the nitro group and the derivatization of the formed primary amines 7a–j (15 examples). The organocatalytic activity of compounds 4 and 8–10 was evaluated in the Michael addition of acetylacetone to trans-β-nitrostyrene. Generally, the organocatalytic activity of all tested compounds of 4 and 8–10 was low in terms of the conversion and enantioselectivity. Due to an inconsistent enantiospecificity observed in the reactions with enaminone-type catalyst 4 and N-acyl-1,2-benzenediamine-type catalysts 8a–c and 9, these compounds were not suitable organocatalysts in the Michael addition of acetylacetone to trans-β-nitrostyrene. On the other hand, N-(2,2-dicyanovinyl)-1,2-benzenediamine-type catalysts 10a–j were consistently (S)-enantioselective, with four out of ten representatives exhibiting comparable enantioselectivities (42–72% ee). This result indicated the potential of a general structure of 10 with the 2,2-dicyanovinyl substituent as a promising structural element for further studies.

Author Contributions

Conceptualization, L.C., U.G., J.S. and B.Š.; methodology, L.C. and U.G.; software, L.C., U.G., J.S. and B.Š.; validation, L.C., U.G., J.S., F.P. and B.Š.; formal analysis, U.G., H.B. and L.C.; investigation, L.C. and U.G.; resources, L.C., U.G. and J.S.; data curation, L.C., U.G., J.S., H.B. and B.Š.; writing—original draft preparation, L.C., U.G., J.S. and B.Š.; writing—review and editing, L.C., U.G., J.S., F.P. and B.Š.; visualization, L.C., U.G., B.Š. and J.S.; supervision, U.G.; project administration, U.G. and J.S.; funding acquisition, U.G. and J.S. All authors have read and agreed to the published version of the manuscript.

Data Availability Statement

Not applicable.

Acknowledgments

We thank the EN-FIST Centre of Excellence, Dunajska 156, 1000 Ljubljana, Slovenia, for the use of their BX FTIR spectrophotometer and Agilent 1260 Infinity LC for the HPLC analyses.

Conflicts of Interest

The authors declare no conflict of interest.

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures and Schemes

Figure 1. (a) Typical examples of the most frequently applied 1,2-diamine-derived bifunctional H-bond donor organocatalysts and an efficient 1,3-diamine analog; (b) selected single HBDs incorporated into chiral bifunctional organocatalysts; (c) selected double HBDs incorporated into chiral bifunctional organocatalysts; (d) enaminone A and 1,2-benzenediamine B HBD types to be incorporated into bifunctional organocatalysts.

Scheme 1. A two-step synthesis of enaminone-type organocatalysts 4a–i.

Scheme 2. Three-step synthesis of (S)-quininamine (3)-derived 1,2-benzenediamine-type organocatalysts 8a–c, 9, and 10a–k.

Figure 2. H-bond donor bifunctional 1,2-benzenediamine-type organocatalysts 8–10 as prepared.

Figure 3. Molecular structures of enaminones 4b (left) and 4f (right). Thermal ellipsoids are shown at a 50% probability.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/catal12101132/s1, Synthesis and characterization data; HPLC data; Copies of ¹H- and ¹³C-NMR spectra; Copies of HRMS reports; CD spectra; Structure determination by X-ray diffraction analysis; Determination of the E/Z-configuration of enaminones 4a–f.

References

1. Torres, R.R. Stereoselective Organocatalysis: Bond Formation Methodologies and Activation Modes; 1st ed. JohnWiley & Sons: Hoboken, NJ, USA, 2013.

2. List, B. Asymmetric Organocatalysis 1. Lewis Base and Acid Catalysis. Science of Synthesis; Georg Thieme Verlag KG: Stuttgart, Germany, 2012.

3. Dalko, P.I. Comprehensive Enantioselective Organocatalysis: Catalysts, Reactions, and Applications; Wiley-VCH: Weinheim, Germany, 2013.

4. Pellissier, H. Asymmetric organocatalysis. Tetrahedron; 2007; 63, pp. 9267-9331. [DOI: https://dx.doi.org/10.1016/j.tet.2007.06.024]

5. The Nobel Prize in Chemistry 2021 Awarded to List B. and MacMillan D.W.C. “For the Development of Asymmetric Organocatalysis”. Available online: https://www.nobelprize.org/prizes/chemistry/2021/advanced-information/ (accessed on 20 August 2022).

6. de Figueiredo, R.M.; Christmann, M. Organocatalytic Synthesis of Drugs and Bioactive Natural Products. Eur. J. Org. Chem.; 2007; 2007, pp. 2575-2600. [DOI: https://dx.doi.org/10.1002/ejoc.200700032]

7. Sun, B.-F. Total synthesis of natural and pharmaceutical products powered by organocatalytic reactions. Tetrahedron Lett.; 2015; 56, pp. 2133-2140. [DOI: https://dx.doi.org/10.1016/j.tetlet.2015.03.046]

8. Okino, T.; Hoashi, Y.; Takemoto, Y. Enantioselective Michael Reaction of Malonates to Nitroolefins Catalyzed by Bifunctional Organocatalysts. J. Am. Chem. Soc.; 2003; 125, pp. 12672-12673. [DOI: https://dx.doi.org/10.1021/ja036972z] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/14558791]

9. Malerich, J.P.; Hagihara, K.; Rawal, V.H. Chiral Squaramide Derivatives are Excellent Hydrogen Bond Donor Catalysts. J. Am. Chem. Soc.; 2008; 130, pp. 14416-14417. [DOI: https://dx.doi.org/10.1021/ja805693p] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/18847268]

10. Rombola, M.; Sumaria, C.S.; Montgomery, T.D.; Rawal, V.H. Development of Chiral, Bifunctional Thiosquaramides: Enantioselective Michael Additions of Barbituric Acids to Nitroalkenes. J. Am. Chem. Soc.; 2017; 139, pp. 5297-5300. [DOI: https://dx.doi.org/10.1021/jacs.7b01115]

11. Alemán, J.; Parra, A.; Jiang, H.; Jørgensen, K.A. Squaramides: Bridging from Molecular Recognition to Bifunctional Organocatalysis. Chem. Eur. J.; 2011; 17, pp. 6890-6899. [DOI: https://dx.doi.org/10.1002/chem.201003694]

12. Wang, W.-H.; Abe, T.; Wang, X.-B.; Kodama, K.; Hirose, T.; Zhang, G.-Y. Self-assembled proline-amino thioureas as efficient organocatalysts for the asymmetric Michael addition of aldehydes to nitroolefins. Tetrahedron Asymmetry; 2010; 21, pp. 2925-2933. [DOI: https://dx.doi.org/10.1016/j.tetasy.2010.11.025]

13. Yao, W.; Chen, M.; Liu, X.; Jiang, R.; Zhang, S.; Chen, W. Ferrocene as a scaffold for effective bifunctional amine–thiourea organocatalysts. Catal. Sci. Technol.; 2014; 4, pp. 1726-1729. [DOI: https://dx.doi.org/10.1039/C4CY00199K]

14. Sohtome, Y.; Shin, B.; Horitsugi, N.; Takagi, R.; Noguchi, K.; Nagasawa, K. Entropy-Controlled Catalytic Asymmetric 1,4-Type Friedel–Crafts Reaction of Phenols Using Conformationally Flexible Guanidine/Bisthiourea Organocatalyst. Angew. Chem. Int. Ed.; 2010; 49, pp. 7299-7303. [DOI: https://dx.doi.org/10.1002/anie.201003172]

15. Ričko, S.; Svete, J.; Štefane, B.; Perdih, A.; Golobič, A.; Meden, A.; Grošelj, U. 1,3-Diamine-Derived Bifunctional Organocatalyst Prepared from Camphor. Adv. Synth. Catal.; 2016; 358, pp. 3786-3796. [DOI: https://dx.doi.org/10.1002/adsc.201600498]

16. Ričko, S.; Meden, A.; Ivančič, A.; Perdih, S.; Štefane, B.; Svete, J.; Grošelj, U. Organocatalyzed Deracemization of Δ²-Pyrrolin-4-ones. Adv. Synth. Catal.; 2017; 359, pp. 2288-2296. [DOI: https://dx.doi.org/10.1002/adsc.201700539]

17. Maddox, S.M.; Dawson, G.A.; Rochester, N.C.; Ayonon, A.B.; Moore, C.E.; Rheingold, A.L.; Gustafson, J.L. Enantioselective Synthesis of Biaryl Atropisomers via the Addition of Thiophenols into Aryl-Naphthoquinones. ACS Catal.; 2018; 8, pp. 5443-5447. [DOI: https://dx.doi.org/10.1021/acscatal.8b00906] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/30455999]

18. Kwiatkowski, J.; Lu, Y. Highly Enantioselective Michael Addition of 2-Fluoro-1,3-diketones to Nitroalkenes. Eur. J. Org. Chem.; 2015; 2015, pp. 320-324. [DOI: https://dx.doi.org/10.1002/ejoc.201403361]

19. Ding, M.; Zhou, F.; Liu, Y.-L.; Wang, C.-H.; Zhao, X.-L.; Zhou, J. Cinchona alkaloid-based phosphoramide catalyzed highly enantioselective Michael addition of unprotected 3-substituted oxindoles to nitroolefins. Chem. Sci.; 2011; 2, pp. 2035-2039. [DOI: https://dx.doi.org/10.1039/c1sc00390a]

20. Hirashima, S.-I.; Arai, R.; Nakashima, K.; Kawai, N.; Kondo, J.; Koseki, Y.; Miura, T. Asymmetric Hydrophosphonylation of Aldehydes using a Cinchona–Diaminomethylenemalononitrile Organocatalyst. Adv. Synth. Catal.; 2015; 357, pp. 3863-3867. [DOI: https://dx.doi.org/10.1002/adsc.201500816]

21. Arai, R.; Hirashima, S.-i.; Kondo, J.; Nakashima, K.; Koseki, V.; Miura, T. Cinchona–Diaminomethylenemalononitrile Organocatalyst for the Highly Enantioselective Hydrophosphonylation of Ketones and Enones. Org. Lett.; 2018; 20, pp. 5569-5572. [DOI: https://dx.doi.org/10.1021/acs.orglett.8b02241]

22. Kobayashi, Y.; Taniguchi, Y.; Hayama, N.; Inokuma, T.; Takemoto, Y. A Powerful Hydrogen-Bond-Donating Organocatalyst for the Enantioselective Intramolecular Oxa-Michael Reaction of α,β-Unsaturated Amides and Esters. Angew. Chem. Int. Ed.; 2013; 52, pp. 11114-11118. [DOI: https://dx.doi.org/10.1002/anie.201305492]

23. Lee, J.H.; Deng, L. Asymmetric Approach toward Chiral Cyclohex-2-enones from Anisoles via an Enantioselective Isomerization by a New Chiral Diamine Catalyst. J. Am. Chem. Soc.; 2012; 134, pp. 18209-18212. [DOI: https://dx.doi.org/10.1021/ja308623n]

24. Stanovnik, B.; Svete, J. Synthesis of Heterocycles from Alkyl 3-(Dimethylamino)propenoates and Related Enaminones. Chem. Rev.; 2004; 104, pp. 2433-2480. [DOI: https://dx.doi.org/10.1021/cr020093y]

25. Stanovnik, B.; Svete, J. Alkyl 2-Substituted 3-(Dimethylamino)propenoates and Related Compounds—Versatile Reagents in Heterocyclic Chemistry. Synlett; 2000; 2000, pp. 1077-1091. [DOI: https://dx.doi.org/10.1002/chin.200041276]

26. Cassani, C.; Martín-Rapún, R.; Arceo, E.; Bravo, F.; Melchiorre, P. Synthesis of 9-amino(9-deoxy)epi cinchona alkaloids, general chiral organocatalysts for the stereoselective functionalization of carbonyl compounds. Nat. Protoc.; 2013; 8, pp. 325-344. [DOI: https://dx.doi.org/10.1038/nprot.2012.155] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/23329005]

27. Zhou, S.; Ren, J.; Liu, M.; Ren, L.; Liu, Y.; Gong, P. Design, synthesis and pharmacological evaluation of 6,7-disubstituted-4-phenoxyquinoline derivatives as potential antitumor agents. Bioorg. Chem.; 2014; 57, pp. 30-42. [DOI: https://dx.doi.org/10.1016/j.bioorg.2014.07.011] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/25173590]

28. Jakse, R.; Groselj, U.; Sorsak, G.; Svete, J.; Stanovnik, B. Synthesis of Thioaplysinopsin Analogs derived from 5-Dimethylaminomethylidene-2-thioxo-1,3-thiazol-4-ones. Heterocycles; 2007; 73, pp. 743-750. [DOI: https://dx.doi.org/10.3987/COM-07-S(U)55]

29. Grošelj, U.; Bevk, D.; Jakše, R.; Meden, A.; Pirc, S.; Rečnik, S.; Stanovnik, B.; Svete, J. Synthesis and properties of N-substituted (1R,5S)-4-aminomethylidene-1,8,8-trimethyl-2-oxabicyclo3.2.1octan-2-ones. Tetrahedron Asymmetry; 2004; 15, pp. 2367-2383. [DOI: https://dx.doi.org/10.1016/j.tetasy.2004.06.008]

30. Šenica, L.; Grošelj, U.; Kasunič, M.; Kočar, D.; Stanovnik, B.; Svete, J. Synthesis of Enaminone-Based Vinylogous Peptides. Eur. J. Org. Chem.; 2014; 2014, pp. 3067-3071. [DOI: https://dx.doi.org/10.1002/ejoc.201402033]

31. Tomažin, U.; Grošelj, U.; Počkaj, M.; Požgan, F.; Štefane, B.; Svete, J. Combinatorial Synthesis of Acacen-Type Ligands and Their Coordination Compounds. ACS Comb. Sci.; 2017; 19, pp. 386-396. [DOI: https://dx.doi.org/10.1021/acscombsci.7b00027]

32. Titman, J.J.; Foote, J.; Jarvis, J.; Keeler, J.; Neuhaus, D. Structure and conformation of a phenyloxazolone derivative used in studies of antibodies, determined using ¹H NMR and measurement of long-range (¹³C, ¹H) coupling constants. J. Chem. Soc. Chem. Commun.; 1991; 6, pp. 419-421. [DOI: https://dx.doi.org/10.1039/c39910000419]

33. Ando, T.; Koseki, N.; Toia, R.F.; Casida, J.E. Three-bond ¹³C–¹H coupling constants for chrysanthemic acid and phenothrin metabolites: Detection by two-dimensional long-range ¹³C–¹H J-resolution spectroscopy. Magn. Reson. Chem.; 1993; 31, pp. 90-93. [DOI: https://dx.doi.org/10.1002/mrc.1260310118]

34. Fischer, P.; Schweizer, E.; Langner, J.; Schmidt, U. ¹³C, ¹H long-range coupling constants in configuration assignment of some trisubstituted alkenes. Magn. Reson. Chem.; 1994; 32, pp. 567-568. [DOI: https://dx.doi.org/10.1002/mrc.1260320918]

35. Golič Grdadolnik, S.; Stanovnik, B. NMR Studies of Substituted 2,3-Diaminopropenoates. Magn. Reson. Chem.; 1997; 35, pp. 482-486. [DOI: https://dx.doi.org/10.1002/(SICI)1097-458X(199707)35:7<482::AID-OMR117>3.0.CO;2-9]

36. Stanovnik, B.; Svete, J.; Tišler, M.; Žorž, L.; Hvala, A.; Simonič, I. Transformation of Amines and N-Heteroarylformamidines into Esters of Substituted β-Amino-α,β-dehydro-α-amino Acids. Heterocycles; 1988; 27, pp. 903-909. [DOI: https://dx.doi.org/10.3987/COM-87-4418]

37. Selič, L.; Jakše, R.; Lampič, K.; Golič, L.; Golič-Grdadolnik, S.; Stanovnik, B. A Simple Stereoselective Synthesis of Aplysinopsin Analogs. Helv. Chim. Acta; 2000; 83, pp. 2802-2811. [DOI: https://dx.doi.org/10.1002/1522-2675(20001004)83:10<2802::AID-HLCA2802>3.0.CO;2-9]

38. Jakše, R.; Rečnik, S.; Svete, J.; Golobič, A.; Golič, L.; Stanovnik, B. A simple synthesis of aplysinopsin analogues by dimethylamine substitution in N,N-(dimethylamino)methylidene derivatives of five-membered heterocycles. Tetrahedron; 2001; 57, pp. 8395-8403. [DOI: https://dx.doi.org/10.1016/S0040-4020(01)00838-9]

39. Dekany, G.; Bornaghi, L.; Papageorgiou, J.; Taylor, S. A novel amino protecting group: DTPM. Tetrahedron Lett.; 2001; 42, pp. 3129-3132. [DOI: https://dx.doi.org/10.1016/S0040-4039(01)00366-5]

40. Jones, R.G. Reactions of Orthoesters with Active Methylene Compounds. J. Am. Chem. Soc.; 1952; 74, pp. 4889-4891. [DOI: https://dx.doi.org/10.1021/ja01139a046]

41. CrysAlis PRO; Agilent Technologies UK Ltd.: Yarnton, UK, 2011.

42. Dolomanov, O.V.; Bourhis, L.J.; Gildea, R.J.; Howard, J.A.K.; Puschmann, H. OLEX2: A complete structure solution, refinement and analysis program. J. Appl. Cristallogr.; 2009; 42, pp. 339-341. [DOI: https://dx.doi.org/10.1107/S0021889808042726]

43. Sheldrick, G.M. A short history of SHELX. Acta Crystallogr. A; 2008; 64, pp. 112-122. [DOI: https://dx.doi.org/10.1107/S0108767307043930]

44. Sheldrick, G.M. SHELXT-Integrated space-group and crystal-structure determination. Acta Crystallogr. Sect. Found. Adv.; 2015; 71, pp. 3-8. [DOI: https://dx.doi.org/10.1107/S2053273314026370]

45. Sheldrick, G.M. Crystal structure refinement with SHELXL. Acta Crystallogr. Sect. C Struct. Chem.; 2015; 71, pp. 3-8. [DOI: https://dx.doi.org/10.1107/S2053229614024218]

46. Macrae, C.F.; Edgington, P.R.; McCabe, P.; Pidcock, E.; Shields, G.P.; Taylor, R.; Towler, M.; van de Streek, J. Synthesis, Crystal Structure and Infrared Characterization of Bis(4-dimethylamino-pyridinium) Tetrachlorocuprate. J. Appl. Crystallogr.; 2006; 39, pp. 453-457. [DOI: https://dx.doi.org/10.1107/S002188980600731X]

47. Spek, A.L. Single-crystal structure validation with the program PLATON. J. Appl. Crystallogr.; 2003; 36, pp. 7-13. [DOI: https://dx.doi.org/10.1107/S0021889802022112]