Triflic Acid Promoted Decarboxylation of Adamantane-oxazolidine-2-one

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Triflic Acid Promoted Decarboxylation of Adamantane-oxazolidine2-one: Access to Chiral Amines and Heterocycles Radim Hrdina,*,† Marta Larrosa,† and Christian Logemann‡ †

Institute of Organic Chemistry, Justus-Liebig University, Heinrich-Buff-Ring 17, 35392 Giessen, Germany Institute of Inorganic and Analytical Chemistry, Justus-Liebig University, Heinrich-Buff-Ring 17, 35392 Giessen, Germany

‡

S Supporting Information *

ABSTRACT: We have developed a one-step procedure to a variety of chiral lipophilic and conformationally rigid amines and heterocycles by decarboxylation of adamantane-oxazolidine-2-one. Triflic acid or aluminum triflate promote the addition of diverse nucleophiles to the oxazolidine-2-one moiety accompanied by the release of carbon dioxide. The resulting amine or heterocycle is then protonated/metalated by the catalyst (promotor). Additionally, the starting racemic material, adamantane-oxazolidine-2-one, was resolved into single enantiomers using a chiral auxiliary to access enantioenriched products and to study the racemization pathway of chiral 1,2-disubstituted adamantane derivatives.

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INTRODUCTION Adamantane based amines (bulky, lipophilic) are synthetically useful building blocks in the preparation of bioactive compounds1 (drug development), ligands (transition metal catalysis), organocatalysts,2 and functional materials as polymers3 and organic frameworks.4 Typically, these adamantane derivatives (diamondoids5 for higher congeners) are used as add-on structures, exploiting the reactivity of an amino group to form an amide bond, thereby increasing the lipophilicity of the target compounds. Monosubstituted adamantane amines, or achiral amines, are generally prepared by undirected C−H oxidation of the adamantane core.6 A number of procedures have been developed to achieve these compounds in an effective way.7 The modular approach to chiral 1,2-disubstituted adamantane derivatives (avoiding the cage opening8) is currently studied in our group employing nitrene insertion methodology9 and C−H activation strategy.10 Herein we describe a one-step procedure to chiral amines (the chirality is embed in the adamantane core) by acid catalyzed decarboxylation of the adamantane-oxazolidine-2-one and subsequent reaction with the nucleophile (Figure 1). Addition of water, Brønstedt acids, heteroatom nucleophiles, arenes, nitriles, and carboxylic acids give rise to a variety of primary amines or heterocycles in one single step, which can be further used as valuable building blocks in the organic synthesis.

The reactivity of adamantane oxazolidine-2-ones differs from the reactivity of oxazolidin-2-ones with flexible alkyl substituents (Figure 2).11 In the case of flexible oxazolidin-2-ones

Figure 2. Decarboxylation of oxazolidine-2-ones.

the decarboxylation reaction leads to aziridines.12 These aziridines can be further protected on the nitrogen for further functionalization,13 or it may undergo an acid catalyzed opening reaction,14 where the substitution pattern governs the corresponding regioselectivities.15 In the case of the studied adamantane derivative, the formation of the aziridine unit is restricted, which enables the addition of nucleophiles on the formal dipole, possessing a partial positive charge on the tertiary carbon and negative charge on the nitrogen. This method minimizes the number of synthetic steps and enables the synthesis of new compounds (Figure 3).16 Received: March 27, 2017 Published: April 7, 2017

Figure 1. Synthesis of chiral 1-substituted-adamantane-2 amines. © 2017 American Chemical Society

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DOI: 10.1021/acs.joc.7b00711 J. Org. Chem. 2017, 82, 4891−4899

Article

The Journal of Organic Chemistry

Initial decarboxylation studies were done using arenes as nucleophiles to determine the optimal Brønsted acid and stable solvent. Among a number of screened acids (trifluoroacetic acid, p-toluenesulfonic acid, sulfuric acid, tetrafluoroboric acid): water-free triflic acid provides the highest conversions and was chosen for further studies. In regards to the tested solvents (hexane, hexafluorohexane, chlorobenzene, α,α,α-trifluorotoluene, 1,2-dichloroethane, tetrachloroethylene), only 1,3,4trichlorobenzene and dichloromethane solubilize the solid substrates, do not decompose under strong acidic conditions, and do not react as a substrate with compound 2. In the case of Brønsted acid sensitive substrates (ferrocene, methoxybenzene), Al(OTf)3 was found to be an effective oxophilic Lewis acid promoting the decarboxylation of the carbamate moiety and allowing subsequent Friedel−Crafts reaction.19 Each class of nucleophiles requires specific reaction conditions (acid and solvent) and is described separately (Figure 4). One of the most important class of compounds are adamantane-1-halogen-2-amines. These derivatives can be used for highly useful coupling20 and substitution reactions.21 For their synthesis, corresponding salts were used as precursors toward generating water-free halic acids. The 1-iodo, bromo, and chloro derivatives were prepared following the same protocol (Scheme 2). Upon mixing with TfOH, the use of KI, KBr, and NaCl provides the corresponding HX acids, which exchange with the triflate substituent in the position 1 of the adamantane core after the decarboxylation step. A 2:1 ratio of triflic acid to salt was found to achieve the highest isolated yields. This protocol cannot be used for the introduction of fluorine as a substituent, due to the low nucleophilicity of HF. Preparation of the 1fluoro derivative 3d was optimized separately mimicking the

Figure 3. Faster approach to known compounds.

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RESULTS AND DISCUSSION The starting material 2 was prepared according to the published protocol17 from adamantane-1-carbamate 1, and its synthesis was optimized to lower the loading of the dirhodium catalyst (Scheme 1). By changing the solvent from dichloromethane to Scheme 1. Improved Synthesis of Starting Material 2a

a

Changes to original protocol highlighted in red.

1,2-dichloroethane and increasing the reaction temperature to 70 °C, the cyclic carbamate 2 was prepared with a comparable yield, but with a significant decrease in catalyst loading.18

Figure 4. Scope of the method (isolated yields of derivatives 3 upon neutralization and purification step). 4892

DOI: 10.1021/acs.joc.7b00711 J. Org. Chem. 2017, 82, 4891−4899

Article

The Journal of Organic Chemistry Scheme 2. Synthesis of 1-Halogen-2-amines and 1-Azide-2amines

Scheme 5. Synthesis of Heterocycles (Amidine)

Of particular importance is the application of this method toward the formation of oxazolines,24 given their utility as ligands in transition metal catalysis (Scheme 6). Direct addition

Balz−Schiemann reaction.22 The addition of an excess of the HBF 4−Et 2O complex in CH 2Cl2 provides the desired compound in 41% yield. The azide derivative 3e was prepared following the same protocol by generating 1.5 equiv of HN3 from NaN3 (excess of HN3 leads to undesired formation of bis azide derivative). Introduction of ether, thioether, and phosphine moieties at the position next to the amino group on the adamantane is desirable for the development of new bidenatate ligands and organocatalysts.23 Conversion to the products is observed (Scheme 3) by using triflic acid; however, in the case of the

Scheme 6. Synthesis of Heterocycles (Oxazolines)

of acid and a subsequent condensation reaction does not provide the desired compounds. Starting material 2 is first acylated and then subjected to the triflic acid promoted decarboxylation step. The reaction does not proceed using Al(OTf)3 as the catalyst or promotor. Compound 3a was acetylated to 3a-Ac, which was tested in the palladium catalyzed coupling reaction with 1,3-benzoxazole using the procedure developed by Hierso et al.25 The coupling reaction proceeded in 69% yield (Scheme 7) demonstrating the applicability of our method toward the preparation of derivatives with heterocycles in the position next to the amine group on the adamantane framework.

Scheme 3. Synthesis of 1-(O,S,P)-Aryl-2-amines

phenolic derivatives, side reactions occur. Therefore, triflic acid was replaced with the less acidic p-toluenesulfonic acid, which does not degrade the starting nucleophile. The phosphine derivative oxidizes upon exposure to air and is characterized as phosphine oxide 3i. C−C bond formation in position 1 of the adamantane skeleton was performed through decarboxylative Friedel− Crafts reaction (Scheme 4). Electron-rich substrates provide

Scheme 7. Postfunctionalization/Coupling of 1,3Benzoxazole 4 and 1-Iodo-2-acetamido Adamantane 3a-Ac

Scheme 4. Synthesis of 1-Aryl-2-amines

Generally, the decarboxylation/nucleophile addition method is practical for electron-rich systems, which are stable in acidic conditions. The method is not applicable for carbamates derived from adamantane-2-ol 2′. In this case, the formation of 1-amino-2-phenyl-adamantane was not observed (Figure 5).

products in good yields using triflic acid (3j, 3k) or Al(OTf)3 (3l, 3m, 3k) as the catalyst. Compound 3j was prepared from the enantiopure (S)-2 in 87% yield and with measurable unexpected loss of enantiopurity (86% ee). Starting material 2 was N-benzylated to attempt an intramolecular variant of this reaction to form piperidine derivatives 3o and 3p. In both cases the reaction proceeds very slowly using Al(OTf)3 as the promotor at 140 °C. Further increasing of the temperature leads to undesired side reactions. The utilization of triflic acid leads to cleavage of the benzyl group from the nitrogen atom. Retrosynthetically, the addition of a nitrile to the generated dipole upon decarboxylation leads to the formation of an amidine. Derivative 3q was successfully prepared using equimolar mixtures of p-chlorobenzonitrile and Al(OTf)3. The amidine 3q was formed in 64% yield (Scheme 5).

Figure 5. Limits of the method.

Among a number of side products, the mass of imine I was detected using HRMS, suggesting that the intramolecular rearrangement is kinetically favored over the addition of the nucleophile. Finally, starting material 2 was resolved into single enantiomers using the Evans methodology (Scheme 8).26 4893

DOI: 10.1021/acs.joc.7b00711 J. Org. Chem. 2017, 82, 4891−4899

Article

The Journal of Organic Chemistry

Compound 3a. Starting material 2 (97 mg, 0.5 mmol) and KI (166 mg, 1.0 mmol) were suspended in 2 mL of 1,3,4-trichlorobenzene, and then TfOH (300 mg, 2.0 mmol) was added dropwise to the reaction mixture at 25 °C. The reaction mixture was stirred at this temperature for 18 h. Afterward, the reaction mixture was quenched and neutralized using a 10% NaOH/water solution. The product was extracted using EtOAc, and the solvent was evaporated under vacuo. The crude residue was purified by column chromatography on silica gel using EtOAc/Et3N (100:1) as a mobile phase to provide 95 mg of a colorless noncrystalline solid 3a. Yield: 95 mg, 83%; Rf 0.2 (silica gel, mobile phase: EtOAc); 1H NMR (400 MHz, CDCl3): δ/ppm = 1.57 (d, J = 12.3 Hz, 1H), 1.68−1.93 (m, 8H), 1.97−2.12 (m, 2H), 2.27− 2.40 (m, 1H), 2.70 (d, J = 12.3 Hz, 1H), 2.77−2.90 (m, 2H), 3.29 (d, J = 2.1 Hz, 1H); 13C NMR (101 MHz, CDCl3): δ/ppm = 29.2 (CH2), 32.6 (CH), 33.1 (CH), 36.2 (CH2), 36.8 (CH), 37.5 (CH2), 45.1 (CH2), 52.8 (CH2), 63.8 (CH), 64.9 (C); IR (neat): ν̃/cm−1 = 3370, 2904, 2851, 1606, 1448, 1340, 1284, 1167, 1105, 1016, 972, 938, 908, 842, 810, 785, 753, 679, 647, 538; HRMS (ESI/TOF) m/z: [M + H]+ calcd for C10H17NI 278.0406; found 278.0402. Compound 3b. Starting material 2 (97 mg, 0.5 mmol) and KBr (119 mg, 1.0 mmol) were suspended in 2 mL of 1,3,4trichlorobenzene, and then TfOH (300 mg, 2.0 mmol) was added dropwise to the reaction mixture at 25 °C. The reaction mixture was stirred at this temperature for 18 h. Afterward, the reaction mixture was quenched and neutralized using a 10% NaOH/water solution. The product was extracted using EtOAc, and solvent was evaporated under vacuo. The crude residue was purified by column chromatography on silica gel using EtOAc/Et3N (100:1) as the mobile phase to provide 105 mg of a colorless noncrystalline solid 3b; Yield: 105 mg, 92%; Rf 0.2 (silica gel, mobile phase: EtOAc); 1H NMR (400 MHz, CD2Cl2): δ/ppm = 1.58 (d, J = 13.6 Hz, 1H), 1.68−1.93 (m, 4H), 1.97−2.06 (m, 3H), 2.16 (d, J = 12.8 Hz, 1H), 2.25 (m, 1H), 2.40 (d, J = 13.2 Hz, 1H), 2.49−2.51 (m, 1H), 2.61 (d, J = 12.9 Hz, 1H), 3.44 (s, 1H), 4.07 (bs, 2H). 13C NMR (101 MHz, CD2Cl2): δ/ppm = 29.0 (CH2), 32.6 (CH), 32.7 (CH), 36.1 (CH2), 36.5 (CH), 36.9 (CH2), 42.6 (CH2), 49.8 (CH2), 62.9 (CH), 71.3 (C); IR (neat): ν̃/cm−1 = 3370, 2915, 2858, 1602, 1539, 1456, 1344, 1255, 1228, 1170, 1023, 983, 939, 910, 823, 796, 761, 689, 631; HRMS (ESI/TOF) m/z: [M + H]+ calcd for C10H17NBr 230.0544; found 230.0543. Compound 3c. Starting material 2 (97 mg, 0.5 mmol) and NaCl (57 mg, 1.0 mmol) were suspended in 2 mL of 1,3,4-trichlorobenzene, and then TfOH (300 mg, 2.0 mmol) was added dropwise to the reaction mixture at 25 °C. The reaction mixture was stirred at this temperature for 18 h. Afterward, the reaction mixture was quenched and neutralized using a 10% NaOH/water solution. The product was extracted using EtOAc, and solvent was evaporated under vacuo. The crude residue was purified by column chromatography on silica gel using EtOAc/Et3N (100:1) as the mobile phase to provide 89 mg of a colorless noncrystalline solid 3c; Yield: 89 mg, 78%; Rf 0.2 (silica gel, mobile phase: EtOAc); 1H NMR (400 MHz, MeOD): δ/ppm = 1.56 (d, J = 13.4 Hz, 1H), 1.74−1.77 (m, 2H), 1.82−2.02 (m, 4H), 2.05− 2.25 (m, 4H), 2.30 (d, J = 12.2 Hz, 1H), 2.49 (d, J = 12.6 Hz, 1H), 3.12 (s, 1H), 3.37 (bs, 2H); 13C NMR (101 MHz, MeOD): δ/ppm = 29.7 (CH2), 32.6 (CH), 32.9 (CH), 36.9 (CH2), 37.5 (CH), 37.8 (CH2), 41.5 (CH2), 49.0 (CH2), 62.6 (CH), 74.2 (C); IR (neat): ν̃/ cm−1 = 3370, 2908, 2858, 1602, 1454, 1342, 1259, 1228, 1171, 1107, 1025, 947, 914, 831, 814, 797, 765, 698, 634; HRMS (ESI/TOF) m/z: [M + H]+ calcd for C10H17NCl 186.1049; found 186.1046. Compound 3d. Starting material 2 (97 mg, 0.5 mmol) was dissolved in 2 mL of CH2Cl2, and then 1 mL of HBF4 /diethyl ether w 50% was added dropwise to the reaction mixture at 25 °C. The reaction mixture was heated to 40 °C and stirred for 18 h. Afterward, the reaction mixture was cooled to 25 °C and neutralized using a 10% NaOH/water solution. The product was extracted using EtOAc, and solvent was evaporated under vacuo. The crude residue was purified by column chromatography on silica gel using EtOAc/EtOH/Et3N (10:1:0.1) as the mobile phase to provide 35 mg of a colorless noncrystalline solid 3d; Yield: 35 mg, 41%; Rf 0.2 (silica gel, mobile phase: EtOAc); 1H NMR (400 MHz, MeOD): δ/ppm = 1.49−1.60 (m, 1H), 1.66−2.07 (m, 8H), 2.09−2.36 (m, 4H), 3.13 (s, 1H); 13C

Scheme 8. Resolution of the Racemic Starting Material 2

Compound 2 was converted to amide 2f, in a 1:1 mixture of diastereomers, which are separable by simple flash chromatography on silica gel. The (R,S)-2f isomer was crystallized to determine the absolute configuration. In the next step, the obtained diastereomers were hydrolyzed separately to enantiopure compounds: (R)-(−)-2 and (S)-(+)-2. The enantiopure compound (S)-(+)-2 was utilized for the preparation of enantio-enriched compound 3j and to observe the unexpected complete racemization of the compound 3a (Figure 6).

Figure 6. Racemization of 3a via C−C bond cleavage or ylide formation in acidic milieu.

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CONCLUSION We have developed a general and facile approach to a variety of 1,2-disubstituted adamantane based amines and heterocycles. An example of the postfunctionalization reaction was demonstrated by coupling of the β-substituted tertiary iodoadamantane with a selected heterocycle. The mechanism of the racemization of 1,2-disubstituted (anti)-Bredt-like compounds will be part of future studies.

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EXPERIMENTAL SECTION

Compound 2. Adamantyl-1-carbamate 1 (1.0 g, 5.12 mmol), iodobenzene 1,1-diacetate (2.20 g, 6.83 mmol), Rh2(OAc)4 (22 mg, 0.051 mol), and MgO (500 mg, 12.5 mmol) were suspended in dry 1,2-dichloroethane (30 mL) and the reaction mixture was heated to 70 °C under argon. The reaction was stirred for 18 h at this temperature. Afterward, the reaction mixture was allowed to cool down to 25 °C and was filtered through the pad of silica gel. Silica gel was washed with a hexane/EtOAc 1:1 mixture to filter out the product from the dirhodium catalyst and salts. The organic solvents were evaporated under vacuo, and crude product (2) was washed with hexane to remove the side product (iodobenzene). Colorless solid, crystalline product 2 was used for next step or purified by column chromatography on silica gel in mobile phase (hexane/ethyl acetate 2:1). Yield: 790 mg, 80%; 1H NMR (400 MHz, CDCl3): δ/ppm = 1.60−1.88 (m, 8H), 2.01−2.04 (m, 1H), 2.09−2.18 (m, 3H), 2.28− 2.29 (m, 2H), 3.66 (s, 1H), 5.07 (br s, 1H); in accordance with published data.27 4894

DOI: 10.1021/acs.joc.7b00711 J. Org. Chem. 2017, 82, 4891−4899

Article

The Journal of Organic Chemistry NMR (101 MHz, MeOD): δ/ppm = 30.0 (d, J = 1 Hz, CH2), 32.1 (d, J = 10 Hz, CH), 32.9 (d, J = 10 Hz, CH), 36.5 (d, J = 17 Hz, CH2), 37.2 (d, J = 2 Hz, CH2), 37.5 (d, J = 2 Hz, CH2), 37.8 (d, J = 5 Hz, CH), 43.6 (d, J = 7 Hz, CH2), 60.0 (d, J = 6 Hz, CH), 94.2 (d, J = 188 Hz, C); 19F NMR (400 MHz, MeOD): δ/ppm = − 144.6 (s); IR (neat): ν̃/cm−1 = 3370, 2910, 2856, 1602, 1455, 1344, 1058, 961, 931, 893, 663; HRMS (ESI/TOF) m/z: [M + H]+ calcd for C10H17NF 170.1345; found 170.1344. Compound 3e. Starting material 2 (97 mg, 0.5 mmol) and NaN3 (35 mg, 0.53 mmol) were dissolved in 2 mL of CH2Cl2, and then TfOH (300 mg, 176 μL) was added dropwise to the reaction mixture at 25 °C. The reaction mixture was stirred at this temperature for 18 h. Afterward, the reaction mixture was cooled to 25 °C and neutralized using a 10% NaOH/water solution. The product was extracted using EtOAc, and solvent was evaporated under vacuo. The crude residue was purified by short pad column chromatography on silica gel using EtOAc as the mobile phase to provide 56 mg of a colorless noncrystalline solid 3e; Yield: 56 mg, 58%; Rf 0.15 (silica gel, mobile phase: EtOAc); 1H NMR (400 MHz, CDCl3): δ/ppm = 1.38−1.51 (m, 1H), 1.54−1.73 (m, 4H), 1.74−1.82 (m, 2H), 1.84−1.97 (m, 3H), 2.03−2.13 (m, 3H), 2.89 (s, 1H); 13C NMR (101 MHz, CDCl3): δ/ ppm = 29.5 (CH), 29.5 (CH2), 30.0 (CH), 34.4 (CH2), 35.9 (CH), 36.5 (CH2), 36.8 (CH2), 41.4 (CH2), 58.6 (CH), 63.0 (C); IR (neat): ν̃/cm−1 = 3370, 2909, 2854, 2087, 1452, 1253, 1109, 1047, 818, 733, 692; HRMS (ESI/TOF) m/z: [M + H]+ calcd for C10H17N4 193.1453; found 193.1457. Compound 3f. Starting material 2 (97 mg, 0.5 mmol) and p-cresol (1.20 g, 10.0 mmol) were dissolved in 2 mL of 1,3,4-trichlorobenzene and then p-toluenesulfonic acid (268 mg, 1.6 mmol) was added to the reaction mixture at 25 °C. The reaction mixture was heated to the 90 °C and stirred at this temperature for 18 h. Afterward, the reaction mixture was cooled to 25 °C and neutralized using a 10% NaOH/ water solution. The product was extracted using EtOAc, and solvent from organic fractions was evaporated under vacuo. The crude residue was purified by column chromatography on silica gel using EtOAc/ EtOH/Et3N (100:10:1) as the mobile phase to provide 88 mg of a colorless noncrystalline solid 3f; Yield: 88 mg, 66%; Rf 0.2 (silica gel, mobile phase: EtOAc/EtOH/Et3N 100:10:1); 1H NMR (400 MHz, CDCl3): δ/ppm = 1.37−1.62 (m, 4H), 1.64−2.00 (m, 8H), 2.00−2.13 (m, 2H), 2.17 (d, J = 12.0 Hz, 1H), 2.30 (s, 3H), 3.16 (s, 1H), 6.83− 6.90 (m, 2H), 7.04−7.05 (m, 2H); 13C NMR (101 MHz, CDCl3): δ/ ppm = 20.9 (CH3), 29.8 (CH2), 30.5 (CH), 31.1 (CH), 35.8 (CH2), 36.2 (CH), 36.6 (CH2), 36.8 (CH2), 41.8 (CH2), 59.0 (CH), 79.7 (C), 124.5 (2CH), 129.5 (2CH), 133.3 (C), 151.5 (C); IR (neat): ν̃/ cm−1 = 3390, 2900, 2853, 1608, 1580, 1505, 1219, 1054, 960, 842, 820, 752, 725, 705, 665; HRMS (ESI/TOF) m/z: [M + H]+ calcd for C17H24NO 258.1858; found 258.1859. Compound 3g. Starting material 2 (97 mg, 0.5 mmol) and napth-2ol (1.44 g, 10 mmol) were dissolved in 2 mL of 1,3,4-trichlorobenzene, and then p-toluenesulfonic acid (268 mg, 1.6 mmol) was added to the reaction mixture at 25 °C. The reaction mixture was heated to the 90 °C and stirred at this temperature for 18 h. Afterward, the reaction mixture was cooled to 25 °C and neutralized using a 10% NaOH/ water solution. The product was extracted using EtOAc, and solvent from organic fractions was evaporated under vacuo. The crude residue was purified by column chromatography on silica gel using EtOAc/ EtOH/Et3N (100:10:1) as the mobile phase to provide 96 mg of a colorless noncrystalline solid 3g; Yield: 96 mg, 63%; Rf 0.20 (silica gel, mobile phase: EtOAc/EtOH/Et3N 100:10:1); 1H NMR (400 MHz, CDCl3): δ/ppm = 1.44−1.46 (m, 2H), 1.53−1.65 (m, 2H), 1.67−1.82 (m, 3H), 1.87−2.16 (m, 8H), 2.24−2.33 (m, 1H), 3.28 (s, 1H), 7.18 (dd, J = 8.8, 2.3 Hz, 1H), 7.48−7.33 (m, 3H), 7.74 (dd, J = 8.4, 2.5 Hz, 2H), 7.80 (d, J = 8.2 Hz, 1H); 13C NMR (101 MHz, CDCl3): δ/ppm = 29.8 (CH2), 30.5 (CH), 31.1 (CH), 36.0 (CH2), 36.3 (CH), 36.6 (CH2), 36.8 (CH2), 41.9 (CH2), 59.1 (CH), 80.6 (C), 120.8 (CH), 124.8 (CH), 125.3 (CH), 126.2 (CH), 127.3 (CH), 127.7 (CH), 128.7 (CH), 130.7 (C), 134.2 (C), 151.9 (C); IR (neat): ν̃/cm−1 = 3054, 2905, 2852, 1627, 1594, 1505, 1465, 1244, 1212, 1165, 1050, 967, 886, 750, 621; HRMS (ESI/TOF) m/z: [M + H]+ calcd for C20H24NO 294.1858; found 294.1863.

Compound 3h. Starting material 2 (97 mg, 0.5 mmol) and thiophenol (1.40 g, 10.0 mmol) were dissolved in 2 mL of 1,3,4trichlorobenzene, and then TfOH (300 mg, 176 μL) was added dropwise to the reaction mixture at 25 °C. The reaction mixture was heated to 90 °C and stirred at this temperature for 18 h. Afterward, the reaction mixture was cooled to 25 °C and neutralized using a 10% NaOH/water solution. The product was extracted using EtOAc, and solvent was evaporated under vacuo. The crude residue was purified by column chromatography on silica gel using EtOAc/Et3N (100:1) as the mobile phase to provide 56 mg of a colorless noncrystalline solid 3h; Yield: 108 mg, 79%; Rf 0.15 (silica gel, mobile phase: EtOAc/Et3N 100:1); 1H NMR (400 MHz, CDCl3): δ/ppm = 1.55−2.07 (m, 15H), 2.87 (s, 1H), 7.36−7.41 (m, 3H), 7.49−7.51 (m, 2H); 13C NMR (101 MHz, CDCl3/ MeOD): δ/ppm = 28.9 (CH), 29.2 (CH2), 29.4 (CH), 33.7 (CH), 36.0 (CH2), 36.2 (CH2), 36.6 (CH2), 43.7 (CH2), 52.0 (C), 56.9 (CH), 128.6 (C), 128.7 (2CH), 129.1 (CH), 137.3 (2CH); IR (neat): ν̃/cm−1 = 3370, 2917, 2855, 1583, 1474, 1439, 1260, 1170, 1030, 750, 694, 638; HRMS (ESI/TOF) m/z: [M + H]+ calcd for C16H22NS 260.1473; found 260.1468. Compound 3i. Starting material 2 (97 mg, 1.0 mmol) and PPh2 (400 mg, 2.16 mmol) were dissolved in 2 mL of 1,3,4trichlorobenzene, and then TfOH (466 mg, 274 μL, 3.2 mmol) was added to the reaction mixture at 25 °C. The reaction mixture was heated to the 120 °C and stirred at this temperature for 18 h. Afterward, the reaction mixture was cooled to 25 °C and neutralized using a 10% NaOH/water solution. The product was extracted using EtOAc, and solvent from organic fractions was evaporated under vacuo. The crude residue was dissolved in 1 mL of EtOAc and was stirred for 18 h under an air atmosphere to fully oxidize the phosphine group to phosphine oxide. The crude product was purified by column chromatography on silica gel using EtOAc/EtOH/Et3N (100:10:1) as the mobile phase to provide 50 mg of a colorless noncrystalline solid. Compound 3i contained an impurity; for structure verification and description, the amine group was protected by an acetyl. Yield: 50 mg, 14%; Rf 0.15 (silica gel, mobile phase: EtOAc/EtOH/Et3N 100:10:1); HRMS (ESI/TOF) m/z: [M + H]+ calcd for C22H27NOP 352.1830; found 352.1826. Compound 3i-Ac. For characterization and structure verification by X-ray diffraction, compound 3i was acetylated to crystalline 3i-Ac; Mp: 177.0−177.5 °C (crystallized from EtOAc); 1H NMR (400 MHz, CDCl3): δ/ppm = 1.51−1.54 (m, 2H), 1.66−1.89 (m, 11 H), 1.99− 2.06 (m, 2H), 2.24−2.26 (m, 1H), 2.47−2.51 (m, 1H), 3.80−3.84 (m, 1H), 7.16 (br s, 1H, NH), 7.47−7.58 (m, 6H), 7.86−7.91 (m, 2H), 7.97−8.00 (m, 2H); 13C NMR (101 MHz, CDCl3): δ/ppm = 23.6 (CH3), 26.8 (d, J = 9 Hz, CH), 27.1 (d, J = 10 Hz, CH), 30.5 (CH2), 30.5 (CH2), 31.4 (d, J = 8 Hz, CH), 35.7 (d, J = 1 Hz, CH2), 36.5 (d, J = 1 Hz, CH2), 37.9 (d, J = 1 Hz, CH2), 39.4 (d, J = 69 Hz, C), 55.1 (d, J = 3 Hz, CH), 128.5 (d, J = 11 Hz, 2CH), 128.8 (d, J = 11 Hz, 2CH), 129.1 (d, J = 24 Hz, C), 130.1 (d, J = 22 Hz, C), 131.7 (d, J = 8 Hz, 2CH), 131.9 (d, J = 3 Hz, CH), 132.3 (d, J = 3 Hz, CH), 132.4 (d, J = 8 Hz, 2CH); 31P NMR (162 MHz, CDCl3): δ/ppm = 35.2; IR (neat): ν̃/cm−1 = 3318, 2907, 2853, 1656, 1529, 1436, 1370, 1263, 1166, 1109, 921, 844, 754, 717, 696, 545. HRMS (ESI/TOF) m/z: [M + Na]+ calcd for C24H28NO2PNa 416.1755; found 416.1763. Compound 3j. Starting material (rac)-2 or [(S)-2 enantiopure] (97 mg, 0.5 mmol) was dissolved in 2 mL of benzene, and then TfOH (300 mg, 2.0 mmol) was added to the reaction mixture at 25 °C. The reaction mixture was heated to 60 °C and stirred at this temperature for 18 h. Afterward, the reaction mixture was cooled to 25 °C and neutralized using a 10% NaOH/water solution. The product was extracted using EtOAc, and solvent from organic fractions was evaporated under vacuo. The crude residue was purified by column chromatography on silica gel using EtOAc/EtOH/Et3N (100:10:1) as the mobile phase to provide 103 mg of a colorless noncrystalline solid 3j; Yield: 103 mg, 87%; Rf 0.5 (silica gel, mobile phase: EtOAc/EtOH/ Et3N 100:10:1); 1H NMR (400 MHz, MeOD): δ/ppm = 1.68−2.00 (m, 5H), 2.01−2.18 (m, 4H), 2.24−2.28 (m, 3H), 2.49 (d, J = 13.4 Hz, 1H), 3.29−3.37 (m, 2H), 3.83 (s, 1H), 7.31−7.34 (m, 1H), 7.43− 7.49 (m, 4H); 13C NMR (101 MHz, CD2Cl2): δ/ppm = 27.9 (CH), 28.7 (CH), 29.5 (CH2), 31.6 (CH), 33.7 (CH2), 36.6 (CH2), 37.1 4895

DOI: 10.1021/acs.joc.7b00711 J. Org. Chem. 2017, 82, 4891−4899

Article

The Journal of Organic Chemistry

(m, 2H), 1.56−1.76 (m, 4H), 1.84−1.98 (m, 5H), 2.04−2.16 (m, 1H), 2.29 (d, J = 12.4 Hz, 1H), 2.82 (d, J = 12.6 Hz, 1H), 4.01 (s, 1H), 6.80−6.97 (m, 2H), 7.12−7.23 (m, 2H); 13C NMR (101 MHz, CDCl3): δ/ppm = 28.7 (CH), 29.1 (CH), 30.4 (CH2), 34.8 (CH), 35.6 (CH2), 37.8 (CH2), 38.1 (CH2), 40.4 (CH2), 42.6 (C), 54.5 (CH), 55.2 (CH3), 111.7 (CH), 120.7 (CH), 127.4 (CH), 128.5 (CH), 135.3 (C), 158.6 C); IR (neat): ν̃/cm−1 = 2903, 2851, 1487, 1452, 1257, 1230, 1174, 1125, 1019, 792, 755, 700, 621; HRMS (ESI/ TOF) m/z: [M + H]+ calcd for C17H23NO 258.1858; found 258.1856. Compound 3n. Starting material 2 (97 mg, 0.5 mmol) and ferrocene (960 mg, 5.0 mmol) were dissolved in 6 mL of 1,3,4trichlorobenzene, and then Al(OTf)3 (268 mg, 1.6 mmol) was added to the reaction mixture at 25 °C. The reaction mixture was heated to the 90 °C and stirred at this temperature for 18 h. Afterward, the reaction mixture was cooled to 25 °C and neutralized using a 10% NaOH/water solution. The product was extracted using EtOAc, and solvent from organic fractions was evaporated under vacuo. The crude residue was purified by column chromatography on silica gel using EtOAc/EtOH/Et3N (100:10:1) as the mobile phase to provide 128 mg of an orange noncrystalline solid 3n; Yield: 128 mg, 74%; Rf 0.4 (silica gel, mobile phase: EtOAc/EtOH/Et3N 100:10:1); 1H NMR (400 MHz, CDCl3): δ/ppm = 1.49 (d, J = 12.2 Hz, 1H), 2.21−1.57 (m, 12H), 2.56 (s, 1H), 3.83−4.43 (m, 9H); 13C NMR (101 MHz, CDCl3): δ/ppm = 28.3 (CH), 28.7 (CH), 30.5 (CH2), 34.7 (CH2), 34.8 (CH), 36.8 (C), 37.8 (CH2), 37.9 (CH2), 43.1 (CH2), 61.3 (CH), 64.4 (CH), 66.0 (CH), 66.7 (CH), 67.4 (CH), 68.3 (5CH), 98.8 (C); IR (neat): ν̃/cm−1 = 3094, 2901, 2850, 1610, 1449, 1347, 1105, 999, 907, 813, 727, 692, 666; HRMS (ESI/TOF) m/z: [M + H]+ calcd for C20H26NFe 336.1415; found 336.1415. Compound 2b. Starting material 2 (193 mg, 1.0 mmol) was dissolved in 2 mL of dry tetradydrofuran, and the solution was cooled to 0 °C. BuLi (1.6 M in hexane; 0.8 mL) was added to the reaction mixture and stirred at 0 °C for 1 h. Then benzyl bromide (340 mg, 2.0 mmol) was added, and the reaction mixture was heated to 25 °C and stirred at this temperature for 18 h. Afterward, the reaction was quenched by adding brine, and the product was extracted using EtOAc. The organic fraction was dried using MgSO4, and solvent from organic fractions was evaporated under vacuo. The crude residue was purified by column chromatography on silica gel using hexane/EtOAc (2:1) as the mobile phase to provide 214 mg of a colorless noncrystalline solid 2b; Yield: 214 mg, 88%; Rf 0.6 (silica gel, mobile phase: hexane/EtOAc 2:1); 1H NMR (400 MHz, CDCl3): δ/ppm = 1.44−1.46 (m, 2H), 1.58−1.61 (m, 3H), 1.67−1.86 (m, 2H), 1.92 (dd, J = 12.5, 3.8 Hz, 1H), 2.04−2.08 (m, 3H), 2.17−2.22 (m, 2H), 3.30 (m, 1H), 4.34 (d, J = 14.9 Hz, 1H), 4.48 (d, J = 14.9 Hz, 1H), 7.25− 7.35 (m, 5H); 13C NMR (101 MHz, CDCl3): δ/ppm = 29.2 (CH), 29.5 (CH2), 30.4 (CH), 31.1 (CH), 36.2 (CH2), 36.4 (CH2), 37.9 (CH2), 40.0 (CH2), 47.3 (CH2), 66.5 (CH), 77.9 (C), 127.8 (CH), 128.6 (2CH), 128.7 (2CH), 136.7 (C), 160.3 (C); IR (neat): ν̃/cm−1 = 2932, 2862, 1741, 1495, 1431, 1331, 1027, 956, 742, 704, 644; HRMS (ESI/TOF) m/z: [M + Na]+ calcd for C18H21NO2Na 306.1470; found 306.1469. Compound 3o. Starting material 2b (225 mg, 0.79 mmol) and Al(OTf)3 (416 mg, 0.88 mmol) were suspended in 8 mL of 1,3,4trichlorobenzene at 25 °C. The reaction mixture was heated to the 140 °C and stirred at this temperature for 18 h. Afterward, the reaction mixture was cooled to 25 °C and neutralized using a 10% NaOH/ water solution. The product was extracted using EtOAc, and solvent from organic fractions was evaporated under vacuo. The crude product was purified by column chromatography on silica gel using EtOAc/ EtOH/Et3N (100:10:1) as the mobile phase to provide 31 mg of colorless crystalline solid 3o.28 Yield: 31 mg, 16%; Rf 0.2 (silica gel, mobile phase: EtOAc/EtOH/Et3N 100:10:1); 1H NMR (400 MHz, CDCl3): δ/ppm = 1.53−1.68 (m, 3H), 1.73−1.97 (m, 6H), 1.97−2.16 (m, 3H), 2.38−2.40 (m, 1H), 2.94 (s, 1H), 4.13 (d, J = 16.2 Hz, 1H), 4.25 (d, J = 16.2 Hz, 1H), 7.00 (d, J = 7.4 Hz, 1H), 7.12−7.13 (m, 1H), 7.16−7.19 (m, 1H), 7.28 (d, J = 7.7 Hz, 1H); 13C NMR (101 MHz, CDCl3): δ/ppm = 28.6 (CH), 29.1 (CH), 30.8 (CH2), 34.0 (CH), 35.8 (C), 37.4 (CH2), 37.8 (CH2), 40.9 (CH2), 41.4 (CH2), 49.5 (CH2), 62.5 (CH), 125.1 (CH), 125.8 (CH), 126.2 (CH), 126.6

(CH2), 39.1 (C), 45.1 (CH2), 61.4 (CH), 125.9 (2CH), 128.1 (CH), 130.0 (2CH), 143.8 (C); IR (neat): ν̃/cm−1 = 3439, 3093, 2926, 2859, 1604, 1502, 1287, 1227, 1170, 1027, 755, 699, 633; HRMS (ESI/ TOF) m/z: [M + H]+ calcd for C16H22N 228.1752; found 228.1753. Compound 3j-Ac. To determine the enantiopurity of the enantioenriched product 3j, (rac)-3j and (S)-3j (50 mg, 0.22 mmol) were separately acetylated using Ac2O (102 mg, 1 mmol) and triethylamine (101 mg, 1 mmol) in CH2Cl2 (1 mL) at 25 °C in 3 h to 3j-Ac. The reaction was quenched by addition of 1 mL of water, and the crude product was extracted using EtOAc. The organic fraction was dried over MgSO4, and the solvent was evaporated under vacuo. The crude residue was purified by column chromatography on silica gel using EtOAc as a mobile phase to obtain 55 mg, 93% of 3j-Ac and (S)-3j-Ac respectively; Yield: 55 mg, 93%; Rf 0.8 (silica gel, mobile phase: EtOAc); 1H NMR (400 MHz, CDCl3): δ/ppm = 1.59 (d, J = 12.9, 1H), 1.65 (s, 3H), 1.66−1.89 (m, 5H), 1.92−2.19 (m, 7H), 4.39 (dd, J = 8.0, 2.7 Hz, 1H), 5.31 (d, J = 7.4 Hz, 1H), 7.10−7.14 (m, 1H), 7.22−7.31 (m, 4H); 13C NMR (101 MHz, CDCl3): δ/ppm = 23.5 (CH3), 28.0 (CH), 28.6 (CH), 31.1 (CH2), 32.7 (CH), 35.6 (CH2), 36.8 (CH2), 36.9 (CH2), 39.5 (C), 46.4 (CH2), 56.2 (CH), 125.3 (2CH), 126.3 (CH), 128.5 (2CH), 147.0 (C), 169.3 (C); IR (neat): ν̃/cm−1 = 3273, 2906, 2852, 1770, 1628, 1546, 1372, 1290, 1123, 1023, 959, 752, 694, 605, 523; HRMS (ESI/TOF) m/z: [M + Na]+ calcd for C18H23NONa 292.1677; found 292.1680. Compound 3k. Starting material 2 (97 mg, 0.5 mmol) was dissolved in 2 mL of 1,2-difluorobenzene, and then TfOH (300 mg, 2.0 mmol) was added to the reaction mixture at 25 °C. The reaction mixture was heated to 90 °C and stirred at this temperature for 18 h. Afterward, the reaction mixture was cooled to 25 °C and neutralized using a 10% NaOH/water solution. The product was extracted using EtOAc, and solvent from organic fractions was evaporated under vacuo. The crude residue was purified by column chromatography on silica gel using EtOAc/EtOH/Et3N (100:10:1) as the mobile phase to provide 111 mg of a colorless noncrystalline solid 3k; Yield: 111 mg, 86%; Rf 0.4 (silica gel, mobile phase: EtOAc/EtOH/Et3N 100:10:1); 1 H NMR (400 MHz, CDCl3): δ/ppm = 1.55 (d, J = 12.6 Hz, 1H), 1.61−1.82 (m, 5H), 1.83−2.04 (m, 7H), 2.05−2.14 (m, 1H), 2.32 (d, J = 10.3 Hz, 1H), 3.17 (s, 1H), 6.97−7.20 (m, 3H); 13C NMR (101 MHz, CDCl3): δ/ppm = 28.3 (CH), 28.8 (CH), 30.0 (CH2), 33.9 (CH2), 35.0 (CH), 37.0 (CH2), 37.9 (CH2), 40.9 (C), 45.0 (CH2), 59.2 (CH), 115.0 (d, J = 18 Hz, CH), 117.0 (d, J = 16 Hz, CH), 121.5 (dd, J = 6 Hz, 4 Hz, CH), 145.6−146.8 (m, C), 148.3 (dd, J = 190 Hz, 12 Hz, CF), 150.7 (dd, J = 190 Hz, 12 Hz, CF); 19F NMR (377 MHz, CDCl3): δ/ppm = − 138.0 (d, J = 24 Hz, F), − 142.1 (d, J = 24 Hz, F); IR (neat): ν̃/cm−1 = 3380, 2905, 2851, 1604, 1519, 1419, 1277, 1219, 1119, 810, 798, 780, 761, 699, 628; HRMS (ESI/TOF) m/z: [M + H]+ calcd for C16H20NF2 264.1564; found 264.1568. Compound 3l. Starting material 2 (97 mg, 0.5 mmol) was dissolved in 2 mL of methoxybenzene, and Al(OTf)3 (261 mg, 0.55 mmol) was added to the reaction mixture at 25 °C. The reaction mixture was heated to the 90 °C and stirred at this temperature for 18 h. Afterward, the reaction mixture was cooled to 25 °C and neutralized using 10% NaOH/water solution. The product was extracted using EtOAc, and solvent from organic fractions was evaporated under vacuo. The crude residue was purified by column chromatography on silica gel using EtOAc/EtOH/Et3N (100:10:1) as the mobile phase to provide 92 mg of a colorless noncrystalline solid (mixture of para and ortho isomer 3l/3m in ratio 4:1); Yield: 92 mg, 70%; Rf 0.45 (silica gel, mobile phase: EtOAc/EtOH/Et3N 100:10:1); 1H NMR (400 MHz, CDCl3): δ/ppm = 1.54 (d, J = 12.3 Hz, 1H), 1.62−1.81 (m, 4H), 1.87−2.17 (m, 7H), 2.33 (d, J = 12.4 Hz, 1H), 3.18 (s, 1H), 3.79 (s, 3H), 6.88 (d, J = 8.9 Hz, 2H), 7.26 (d, J = 8.9 Hz, 2H); 13C NMR (101 MHz, CDCl3): δ/ppm = 28.5 (CH), 29.0 (CH), 30.2 (CH2), 33.9 (CH2), 34.9 (CH), 37.3 (CH2), 38.1 (CH2), 40.5 (C), 45.2 (CH2), 55.3 (CH3), 59.3 (CH), 113.8 (2CH), 126.6 (2CH), 140.4 (C), 157.7 (C); IR (neat): ν̃/cm−1 = 2895, 2845, 1609, 1510, 1468, 1446, 1258, 1243, 1182, 1035, 1023, 875, 832, 801, 702, 557; HRMS (ESI/TOF) m/z: [M + H]+ calcd for C17H23NO 258.1858; found 258.1856. Compound 3m. Rf 0.40 (silica gel, mobile phase: EtOAc/EtOH/ Et3N 100:10:1); 1H NMR (400 MHz, CDCl3): δ/ppm = 1.46−1.53 4896

DOI: 10.1021/acs.joc.7b00711 J. Org. Chem. 2017, 82, 4891−4899

Article

The Journal of Organic Chemistry (CH), 134.3 (C), 144.4 (C); IR (neat): ν̃/cm−1 = 3014, 2903, 2848, 1488, 1448, 1251, 1158, 1100, 1029, 751, 724, 699, 638; HRMS (ESI/ TOF) m/z: [M + H]+ calcd for C17H22N 240.1752; found 240.1749. Compound 2c. Starting material 2 (193 mg, 1 mmol) was dissolved in 2 mL of dry tetradydrofuran, and the solution was cooled to 0 °C. BuLi (1.6 M in hexane; 0.8 mL) was added to the reaction mixture and stirred at 0 °C for 1 h. Then para-methyl-benzyl bromide (368 mg, 2.0 mmol) was added, and the reaction mixture was heated to 25 °C and stirred at this temperature for 18 h. Afterward, the reaction was quenched by adding brine and the product was extracted using EtOAc. The organic fraction was dried using MgSO4, and solvent from the organic fractions was evaporated under vacuo. The crude residue was purified by column chromatography on silica gel using hexane/EtOAc (2:1) as the mobile phase to provide 224 mg of colorless noncrystalline solid 2c. Yield: 224 mg, 75%; Rf 0.6 (silica gel, mobile phase: hexane/EtOAc 2:1); 1H NMR (400 MHz, CDCl3): δ/ppm = 1.48 (s, 2H), 1.53−1.66 (m, 3H), 1.67−1.85 (m, 2H), 1.85−1.97 (m, 1H), 2.02−2.05 (m, 3H), 2.20 (d, J = 15.1 Hz, 2H), 2.33 (s, 3H), 3.28 (d, J = 2.5 Hz, 1H), 4.26 (d, J = 14.9 Hz, 1H), 4.47 (d, J = 14.9 Hz, 1H), 7.12 (d, J = 7.9 Hz, 2H), 7.20 (d, J = 8.0 Hz, 2H); 13C NMR (101 MHz, CDCl3): δ/ppm = 21.3 (CH3), 29.2 (CH), 29.6 (CH2), 30.4 (CH), 31.1 (CH), 36.2 (CH2), 36.4 (CH2), 37.9 (CH2), 40.0 (CH2), 47.0 (CH2), 66.2 (CH), 77.8 (C), 128.6 (2CH), 129.4 (2CH), 133.6 (C), 137.5 (C), 160.3 (C); IR (neat): ν̃/cm−1 = 2925, 2854, 1736, 1450, 1397, 1334, 1306, 1027, 956, 770, 716, 688; HRMS (ESI/ TOF) m/z: [M + Na]+ calcd for C19H23NO2Na 320.1626; found 320.1624. Compound 3p. Starting material 2c (235 mg, 0.79 mmol) and Al(OTf)3 (416 mg, 0.88 mmol) were suspended in 8 mL of 1,3,4trichlorobenzene at 25 °C. The reaction mixture was heated to the 140 °C and stirred at this temperature for 18 h. Afterward, the reaction mixture was cooled to 25 °C and neutralized using a 10% NaOH/ water solution. The product was extracted using EtOAc, and solvent from the organic fractions was evaporated under vacuo. The crude residue was purified by column chromatography on silica gel using EtOAc/EtOH/Et3N (100:10:1) as the mobile phase to provide 30 mg of a colorless crystalline solid 3p. Yield: 30 mg, 15%; Rf 0.3 (silica gel, mobile phase: EtOAc/EtOH/Et3N 100:10:1); 1H NMR (400 MHz, CDCl3): δ/ppm = 1.53−1.66 (m, 3H), 1.78−1.99 (m, 8H), 2.01−2.14 (m, 2H), 2.30−2.32 (m, 3H), 2.37 (d, J = 12.5 Hz, 1H), 2.87 (s, 1H), 4.05 (d, J = 16.0 Hz, 1H), 4.19 (d, J = 16.0 Hz, 1H), 6.85−6.96 (m, 2H), 7.09 (s, 1H); 13C NMR (101 MHz, CDCl3): δ/ppm = 21.4 (CH3), 28.7 (CH), 29.2 (CH), 31.0 (CH2), 34.3 (CH), 35.8 (C), 37.5 (CH2), 37.9 (CH2), 41.0 (CH2), 41.5 (CH2), 49.6 (CH2), 62.6 (CH), 125.6 (CH), 126.1 (CH), 126.6 (CH), 132.0 (C), 135.7 (C), 144.6 (C); IR (neat): ν̃/cm−1 = 3009, 2907, 2849, 1612, 1501, 1449, 1343, 1255, 1126, 803, 704, 642; HRMS (ESI/TOF) m/z: [M + H]+ calcd for C18H24N 254.1909; found 254.1908. Compound 3q. Starting material 2 (96 mg, 0.5 mmol), 4-cyanochlorobenzene (137 mg, 1 mmol), and Al(OTf)3 (474 mg, 1.0 mmol) were suspended in 2 mL of 1,3,4-trichlorobenzene at 25 °C. The reaction mixture was heated to 90 °C and stirred at this temperature for 18 h. Afterward, the reaction mixture was cooled to 25 °C and neutralized using 10% NaOH/water solution. The product was extracted using EtOAc, and solvent from organic fractions was evaporated under vacuo. The crude residue was purified by column chromatography on silica gel using EtOAc/Et3N (100:1) as the mobile phase to provide 94 mg of a colorless crystalline solid 3q. Yield: 94 mg, 64%; Rf 0.15 (silica gel, mobile phase: EtOAc/Et3N 100:1); 1H NMR (400 MHz, CDCl3): δ/ppm = 1.49−1.77 (m, 7H), 1.77−1.85 (m, 1H), 1.91−1.95 (m, 3H), 2.16−2.21 (m, 2H), 2.48 (s, 1H), 3.43 (s, 1H), 7.36 (d, J = 6.9 Hz, 2H), 7.72 (d, J = 6.9 Hz, 2H); 13C NMR (101 MHz, CDCl3): δ/ppm = 28.0 (CH), 30.4 (CH), 30.8 (CH2), 31.5 (CH), 36.9 (CH2), 37.5 (CH2), 38.2 (CH2), 42.0 (CH2), 63.6 (C), 72.7 (CH), 128.1 (2CH), 128.8 (2CH), 129.9 (C), 136.8 (C), 164.0 (C); IR (neat): ν̃/cm−1 = 3443, 3129, 2919, 2852, 1604, 1452, 1332, 1085, 837, 732, 584; HRMS (ESI/TOF) m/z: [M + H]+ calcd for C17H20N2Cl 287.1315; found 287.1316. Compound 2d. Starting material 2 (154 mg, 0.8 mmol) was dissolved in 10 mL of dry tetradydrofuran, and the solution was cooled

to 0 °C. BuLi (1.6 M in hexane; 0.5 mL) was added to the reaction mixture and stirred at 0 °C for 1 h. Then benzoyl chloride (140 mg, 1.0 mmol) was added, and the reaction mixture was heated to 25 °C and stirred at this temperature for 18 h. Afterward, the reaction was quenched by adding brine, and the product was extracted using EtOAc. Organic fractions were dried using MgSO4, and solvent from organic fractions was evaporated under vacuo. The crude product was purified by column chromatography on silica gel using Hexane/EtOAc (2:1) as the mobile phase to provide 200 mg of colorless solid 2d. Yield: 200 mg, 84%; Rf 0.8 (silica gel, mobile phase: hexane/EtOAc 2:1); 1H NMR (400 MHz, CDCl3): δ/ppm = 1.65−1.72 (m, 4H), 1.86−1.89 (m, 2H), 1.98−2.13 (m, 2H), 2.14−2.27 (m, 3H), 2.36 (s, 1H), 2.90−3.07 (m, 1H), 4.08 (d, J = 2.2 Hz, 1H), 7.43−7.46 (m, 2H), 7.51−7.61 (m, 1H), 7.74−7.77 (m, 2H); 13C NMR (101 MHz, CDCl3): δ/ppm = 29.3 (CH), 29.5 (CH2), 29.8 (CH), 30.8 (CH), 35.9 (CH2), 36.2 (CH2), 39.0 (CH2), 39.9 (CH2), 66.4 (CH), 79.3 (C), 128.2 (2CH), 129.6 (2CH), 133.0 (CH), 133.7 (C), 154.9 (C), 171.2 (C); IR (neat): ν̃/cm−1 = 2914, 2855, 1781, 1687, 1450, 1311, 1203, 1149, 1041, 760, 690, 673; HRMS (ESI/TOF) m/z: [M + Na]+ calcd for C18H19NO3Na 320.12626; found 320.1260. Compound 3r. Starting material 2d (154 mg, 0.57 mmol) was dissolved in 4 mL of 1,3,4-trichlorobenzene, and then TfOH (680 mg, 400 μL) was added dropwise to the reaction mixture at 25 °C. The reaction mixture was heated to 60 °C and stirred at this temperature for 18 h. Afterward, the reaction mixture was cooled to 25 °C and neutralized using a 10% NaOH/water solution. The product was extracted using EtOAc, and solvent from the organic fractions was evaporated under vacuo. The crude product was purified by column chromatography on silica gel using hexane/EtOAc (3:1) as the mobile phase to provide 60 mg of colorless solid 3r. Yield: 60 mg, 42%; Rf 0.5 (silica gel, mobile phase: hexane/EtOAc 3:1); 1H NMR (400 MHz, CDCl3): δ/ppm = 1.57−1.77 (m, 5H), 1.79−1.92 (m, 3H), 1.98−2.08 (m, 1H), 2.11−2.22 (m, 1H), 2.24−2.38 (m, 2H), 2.59−2.72 (m, 1H), 3.66 (s, 1H), 7.32−7.53 (m, 3H), 7.90−8.05 (m, 2H); 13C NMR (101 MHz, CDCl3): δ/ppm = 29.2 (CH), 30.7 (CH2), 31.7 (CH), 32.7 (CH), 36.6 (CH2), 36.8 (CH2), 37.7 (CH2), 41.1 (CH2), 74.8 (CH), 83.8 (C), 128.1 (2CH), 128.4 (2CH), 129.3 (C), 131.4 (CH), 165.6 (C); IR (neat): ν̃/cm−1 = 2929, 2853, 1615, 1575, 1491, 1447, 1333, 1263, 1101, 1060, 1035, 1013, 952, 885, 784, 696; HRMS (ESI/TOF) m/z: [M + H]+ calcd for C17H19NONa 276.13643; found 276.1362. Compound 2e. Starting material 2 (77 mg, 0.4 mmol) was dissolved in 5 mL of dry tetradydrofuran, and the solution was cooled to 0 °C. BuLi (1.6 M in hexane; 0.25 mL) was added to the reaction mixture and stirred at 0 °C for 1 h. Then ortho-fluoro-benzoyl chloride (79 mg, 0.5 mmol) was added, and the reaction mixture was heated to 25 °C and stirred at this temperature for 18 h. Afterward, the reaction was quenched by adding brine, and the product was extracted using EtOAc. The organic fraction was dried using MgSO4, and solvent from organic fractions was evaporated under vacuo. The crude product was purified by column chromatography on silica gel using Hexane/EtOAc (2:1) as the mobile phase to provide 105 mg of colorless solid 2e.Yield: 105 mg, 83%; Rf 0.8 (silica gel, mobile phase: hexane/EtOAc 2:1); 1H NMR (400 MHz, CDCl3): δ/ppm = 1.66−1.72 (m, 4H), 1.82−1.91 (m, 2H), 1.95 (d, J = 11.9 Hz, 1H), 2.02−2.12 (m, 1H), 2.13−2.26 (m, 3H), 2.29−2.41 (m, 1H), 3.15 (s, 1H), 4.03 (s, 1H), 7.07−7.14 (m, 1H), 7.20−7.26 (m, 1H), 7.46−7.55 (m, 1H), 7.61− 7.63 (m, 1H); 13C NMR (101 MHz, CDCl3): δ/ppm = 29.2 (CH), 29.4 (CH2), 29.9 (CH), 30.8 (CH), 35.9 (CH2), 36.3 (CH2), 38.5 (d, J = 2 Hz, CH2), 39.6 (CH2), 66.8 (CH), 79.5 (C), 115.8 (d, J = 22 Hz, CH), 123.2 (d, J = 14 Hz, C), 124.5 (d, J = 3 Hz, CH), 130.6 (d, J = 3 Hz, CH), 133.8 (d, J = 9 Hz, CH), 154.1 (C), 160.2 (d, J = 253 Hz, C), 166.6 (C); 19F NMR (377 MHz, CDCl3): δ/ppm = − 112.5; IR (neat): ν̃/cm−1 = 2911, 2853, 1778, 1684, 1612, 1455, 1327, 1203, 1040, 905, 758, 660; HRMS (ESI/TOF) m/z: [M + Na]+ calcd for C18H18NFO3Na 338.11684; found 338.1169. Compound 3s. Starting material 2e (80 mg, 0.25 mmol) was dissolved in 2 mL of 1,3,4-trichlorobenzene at 25 °C, and then TfOH (340 mg, 200 μL) was added dropwise to the reaction mixture at 25 °C. The reaction mixture was heated to 60 °C and stirred at this temperature for 18 h. Afterward, the reaction mixture was cooled to 25 4897

DOI: 10.1021/acs.joc.7b00711 J. Org. Chem. 2017, 82, 4891−4899

Article

The Journal of Organic Chemistry °C and neutralized using a 10% NaOH/water solution. The product was extracted using EtOAc, and solvent from the organic fractions was evaporated under vacuo. The crude product was purified by column chromatography on silica gel using hexane/EtOAc (3:1) as the mobile phase to provide 30 mg of colorless crystalline solid 3s. Yield: 30 mg, 44%; Rf 0.4 (silica gel, mobile phase: hexane/EtOAc 3:1); 1H NMR (400 MHz, CDCl3): δ/ppm = 1.56−1.78 (m, 5H), 1.79−1.97 (m, 3H), 1.99−2.09 (m, 1H), 2.15 (d, J = 11.5, 1H), 2.32 (d, J = 10.1 Hz, 2H), 2.61−2.78 (m, 1H), 3.69 (s, 1H), 6.76−7.21 (m, 2H), 7.35−7.59 (m, 1H), 7.85−7.89 (m,1H); 13C NMR (101 MHz, CDCl3): δ/ppm = 29.3 (CH), 30.8 (CH2), 31.8 (CH), 32.7 (CH), 36.6 (CH2), 36.8 (CH2), 37.7 (CH2), 41.0 (CH2), 75.1 (CH), 83.8 (C), 116.7 (d, J = 12 Hz, CH), 117.8 (d, J = 10 Hz, C), 124.0 (d, J = 4 Hz, CH), 131.0 (d, J = 2 Hz, CH), 132.8 (d, J = 9 Hz, CH), 161.4 (d, J = 258 Hz, C), 162.2 (d, J = 5 Hz, C); 19FNMR (377 MHz, CDCl3): δ/ppm = − 109.8; IR (neat): ν̃/cm−1 = 2908, 2843, 1625, 1604, 1494, 1454, 1336, 1260, 1222, 1105, 1034, 1012, 951, 885, 873, 778, 748, 696; HRMS (ESI/ TOF) m/z: [M + Na]+ calcd for C17H18NFONa 294.12701; found 294.1264. Compound R,S-2f. Starting material 2 (193 mg, 1.0 mmol) was dissolved in 2 mL of dry tetradydrofuran, and the solution was cooled to 0 °C. BuLi (1.6 M in hexane; 0.7 mL) was added to the reaction mixture and stirred at 0 °C for 1 h. Then pentafluorophenylester of (R)-O-Me-mandelic acid (1.5 mmol) dissolved in 1 mL of dry THF was added, and the reaction mixture was heated to 25 °C and stirred at this temperature for 18 h. Afterward, the reaction was quenched by adding brine and the product was extracted using EtOAc. The organic fractions were dried using MgSO4, and solvent from the organic fractions was evaporated under vacuo. The crude product (ratio of diastereomers 1:1) was purified by column chromatography on silica gel using hexane/EtOAc (5:1) as the mobile phase to provide separated diastereomers (R,R-2f) (less polar) and (R,S-2f) (more polar) in equal quantities. Yield: 143 mg, 42%; Mp: 191.5−192.5 °C (crystallized from hexane/CH2Cl2); Rf 0.15 (more polar diastereomer) (silica gel, mobile phase: hexane/EtOAc 5:1); 1H NMR (400 MHz, CDCl3): δ/ppm = 0.92 (d, J = 13.4 Hz, 1H), 1.07−1.09 (m, 1H), 1.36−1.52 (m, 2H), 1.54−1.68 (m, 3H), 1.71−1.77 (m, 3H), 1.87− 2.08 (m, 2H), 2.14−2.36 (m, 1H), 3.01 (s, 1H), 3.42 (s, 3H), 3.87 (s, 1H), 6.06 (s, 1H), 7.26−7.38 (m, 3H), 7.42−7.59 (m, 2H); 13C NMR (101 MHz, CDCl3): δ/ppm = 28.9 (CH), 29.3 (CH2), 30.0 (CH), 30.5 (CH), 35.6 (CH2), 36.2 (CH2), 38.2 (CH2), 39.5 (CH2), 57.4 (CH3), 66.4 (CH), 80.0 (C), 81.8 (CH), 128.1 (CH), 128.8 (CH), 129.1 (CH), 137.0 (C), 154.6 (C), 173.1 (C); IR (neat): ν̃/cm−1 = 2907, 2852, 1762, 1717, 1372, 1324, 1288, 1268, 1198, 1111, 1028, 963, 736, 692; HRMS (ESI/TOF) m/z: [M + Na]+ calcd for C20H23NO4Na 364.15248; found 364.1529. Compound R,R-2f. Yield: 140 mg, 41%; Mp: 121.5−122.0 °C (crystallized from hexane/CH2Cl2); Rf 0.2 (less polar diastereomer) (silica gel, mobile phase: Hexane/EtOAc 5:1); 1H NMR (400 MHz, CDCl3): δ/ppm = 1.58−1.79 (m, 5H), 1.80−1.84 (m, 1H), 1.88−2.07 (m, 3H), 2.07−2.15 (m, 1H), 2.19 (s, 1H), 2.25−2.33 (m, 1H), 3.24 (s, 1H), 3.37 (s, 3H), 3.84 (s, 1H), 5.80 (s, 1H), 7.32−7.41 (m, 3H), 7.49−7.57 (m, 2H); 13C NMR (101 MHz, CDCl3): δ/ppm = 29.1 (CH), 29.8 (CH2), 30.5 (CH), 31.0 (CH), 35.7 (CH2), 36.3 (CH2), 38.5 (CH2), 39.6 (CH2), 57.5 (CH3), 67.3 (CH), 80.0 (C), 81.5 (CH), 128.5 (2CH), 128.90 (CH), 128.93 (2CH), 135.4 (C), 154.3 (C), 172.4 (C); IR (neat): ν̃/cm−1 = 2929, 2860, 1778, 1698, 1517, 1455, 1356, 1263, 1200, 1089, 1026, 977, 916, 760, 739, 700, 655; HRMS (ESI/TOF) m/z: [M + Na]+ calcd for C20H23NO4Na 364.1525; found 364.1529. Compound (S)-(+)-2. Starting material (R,S)-2f (341 mg, 1.0 mmol) was dissolved in 4 mL of tetradydrofuran, and the solution was cooled to 0 °C. Then water (4 mL) and LiOH (390 mg) were added to the solution, and the reaction mixture was stirred at 0 °C for 2 h. Afterward, the reaction was stopped and the product was extracted using EtOAc. The organic fractions were dried using MgSO4, and solvent from the organic fractions was evaporated under vacuo. The crude product was purified by column chromatography on silica gel using (hexane/EtOAc 2:1) as the mobile phase to provide 185 mg,

96% of crystalline solid (S)-2. Mp: 169.5−170.5 °C (crystallized from EtOAc); Specific optical rotation: [α]D = + 14.6 (c 1.3, CHCl3). Compound 3a-Ac. A solution of 3a (96 mg, 0.346 mmol) in pyridine (3.0 mL) was treated with Ac2O (35 μL, 0.37 mmol) and stirred at 25 °C for 18 h. The reaction mixture was diluted with EtOAc (30 mL) and washed with 10% citric acid (10 mL) and brine (10 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. The crude residue was flash chromatographed on silica gel: 30 → 50% EtOAc/hexane to give 82 mg of 3 as a colorless noncrystalline solid 3a-Ac. Yield: 82 mg, 74%; Rf = 0.2 (hexane/EtOAc 5:1); 1H NMR (400 MHz, CDCl3): δ/ppm = 1.62−1.69 (m, 1H), 1.76−1.97 (m, 7H), 2.08 (s, 3H), 2.21−2.24 (m, 1H), 2.44−2.58 (m, 2H), 2.69−2.80 (m, 2H), 4.35−4.40 (m, 1H), 6.12 (br s, 1H); 13C NMR (101 MHz, CDCl3): δ/ppm = 23.6 (CH), 29.9 (CH2), 32.1 (CH3), 32.3 (CH), 35.2 (CH), 35.6 (CH2), 36.1 (CH2), 46.9 (CH2), 52.6 (CH2), 52.9 (C), 60.9 (CH), 169.3 (C); IR (neat): ν̃/cm−1 = 3352, 2908, 2853, 1649, 1542, 1473, 1450, 1372, 1281, 1175, 1126, 1103, 1021, 947, 936, 814, 681, 592; HRMS (ESI/TOF) m/z: [M + Na]+ calcd for C12H18NOINa 342.0331; found 342.0325. Compound 5. Pd(PPh3)4 (5.6 mg, 0.005 mmol) and DPPP (2.8 mg, 0.007 mmol) in PhCF3 (0.5 mL) were stirred at 25 °C for 10 min under Ar. Then 3a-Ac (46 mg, 0.144 mmol) in PhCF3 (1 mL), benzoxazol (11 mg, 0.092 mmol), and Cs2CO3 (62 mg, 0.190 mmol) were added. The resulting suspension was stirred at 110 °C for 3 d. Afterward, the reaction mixture was allowed to reach room temperature and solvent was removed under vacuo. The crude residue was flash chromatographed on silica gel: 30 → 50% EtOAc/hexane to give 20 mg of 4 as a colorless noncrystalline solid 5. Yield: 20 mg, 69%; Rf = 0.15 (hexane/EtOAc 5:1); 1H NMR (400 MHz, CDCl3): δ/ ppm = 1.69−1.75 (m, 1H), 1.75−1.86 (m, 5H), 1.98−2.07 (m, 2H), 2.08−2.21 (m, 4H), 2.44−2.53 (m, 2H), 4.47−4.51 (m, 1H), 5.90− 5.92 (m, 1H), 7.28−7.35 (m, 2H), 7.49−7.54 (m, 1H), 7.68−7.72 (m, 1H); 13C NMR (101 MHz, CDCl3): δ/ppm = 26.9 (CH), 27.2 (CH), 30.7 (CH2), 32.1 (CH), 34.4 (CH2), 36.3 (CH2), 36.4 (CH2), 39.4 (C), 40.4 (CH2), 55.0 (CH), 110.8 (CH), 119.3 (CH), 124.4 (CH), 125.1 (CH), 139.7.3 (C), 150.5 (C), 169.4 (C), 169.9 (C); IR (neat): ν̃/cm−1 = 3307, 2910, 2854, 1648, 1536, 1455, 1372, 1272, 1240, 1179, 1121, 1043, 909, 795, 726; HRMS (ESI/TOF) m/z: [M + Na]+ calcd for C19H22N2O2Na 333.1579; found 333.1573.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b00711. Crystallographic data (CIF, CIF) NMR spectra, HPLC chromatograms (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Radim Hrdina: 0000-0001-5060-6666 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the LOEWE “SynChemBio” project, funded by the State of Hesse and by the DFG (HR 97/ 1-1). The authors would like to thank Prof. P. R. Schreiner for his generous support, Dr. D. R. Bhandari for MALDI measurements, Dr. H. Hausmann for NMR measurements, and Dr. Sean Culver for language corrections. 4898

DOI: 10.1021/acs.joc.7b00711 J. Org. Chem. 2017, 82, 4891−4899

Article

The Journal of Organic Chemistry

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REFERENCES

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DOI: 10.1021/acs.joc.7b00711 J. Org. Chem. 2017, 82, 4891−4899