Triflic Acid Promoted Decarboxylation of Adamantane-Oxazolidine- 2-One

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Triflic Acid Promoted Decarboxylation of Adamantane-oxazolidine- 2-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 enantio- enriched products and to study the racemization pathway of chiral 1,2-disubstituted adamantane derivatives.

■ INTRODUCTION The reactivity of adamantane oxazolidine-2-ones differs from fl Adamantane based amines (bulky, lipophilic) are synthetically the reactivity of oxazolidin-2-ones with exible alkyl sub- stituents (Figure 2).11 In the case of flexible oxazolidin-2-ones 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 9 studied in our group employing nitrene insertion methodology Figure 2. Decarboxylation of oxazolidine-2-ones. 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 the decarboxylation reaction leads to aziridines.12 These and subsequent reaction with the nucleophile (Figure 1). aziridines can be further protected on the nitrogen for further Addition of water, Brønstedt acids, heteroatom nucleophiles, functionalization,13 or it may undergo an acid catalyzed opening arenes, nitriles, and carboxylic acids give rise to a variety of reaction,14 where the substitution pattern governs the primary amines or heterocycles in one single step, which can be corresponding regioselectivities.15 In the case of the studied further used as valuable building blocks in the organic synthesis. 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

Figure 1. Synthesis of chiral 1-substituted-adamantane-2 amines. Received: March 27, 2017 Published: April 7, 2017

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-trifluoroto- luene, 1,2-dichloroethane, tetrachloroethylene), only 1,3,4- trichlorobenzene 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 Figure 3. Faster approach to known compounds. Brønsted acid sensitive substrates (ferrocene, methoxyben- ff zene), Al(OTf)3 was found to be an e ective oxophilic Lewis ■ RESULTS AND DISCUSSION acid promoting the decarboxylation of the carbamate moiety and allowing subsequent Friedel−Crafts reaction.19 Each class The starting material 2 was prepared according to the published fi protocol17 from adamantane-1-carbamate 1, and its synthesis of nucleophiles requires speci c reaction conditions (acid and was optimized to lower the loading of the dirhodium catalyst solvent) and is described separately (Figure 4). (Scheme 1). By changing the solvent from dichloromethane to One of the most important class of compounds are adamantane-1-halogen-2-amines. These derivatives can be a 20 21 Scheme 1. Improved Synthesis of Starting Material 2 used for highly useful coupling and substitution reactions. 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 aChanges to original protocol highlighted in red. after the decarboxylation step. A 2:1 ratio of triflic acid to salt was found to achieve the highest isolated yields. This protocol 1,2-dichloroethane and increasing the reaction temperature to cannot be used for the introduction of fluorine as a substituent, 70 °C, the cyclic carbamate 2 was prepared with a comparable due to the low nucleophilicity of HF. Preparation of the 1- yield, but with a significant decrease in catalyst loading.18 fluoro derivative 3d was optimized separately mimicking the

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 The Journal of Organic Chemistry Article

Scheme 2. Synthesis of 1-Halogen-2-amines and 1-Azide-2- Scheme 5. Synthesis of Heterocycles (Amidine) amines

Of particular importance is the application of this method 24 Balz−Schiemann reaction.22 The addition of an excess of the toward the formation of oxazolines, given their utility as − HBF4 Et2O complex in CH2Cl2 provides the desired ligands in transition metal catalysis (Scheme 6). Direct addition compound in 41% yield. The azide derivative 3e was prepared following the same protocol by generating 1.5 equiv of HN3 Scheme 6. Synthesis of Heterocycles (Oxazolines) 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 of acid and a subsequent condensation reaction does not Scheme 3. Synthesis of 1-(O,S,P)-Aryl-2-amines 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 phenolic derivatives, side reactions occur. Therefore, triflic acid applicability of our method toward the preparation of was replaced with the less acidic p-toluenesulfonic acid, which derivatives with heterocycles in the position next to the does not degrade the starting nucleophile. The phosphine amine group on the adamantane framework. derivative oxidizes upon exposure to air and is characterized as phosphine oxide 3i. Scheme 7. Postfunctionalization/Coupling of 1,3- C−C bond formation in position 1 of the adamantane Benzoxazole 4 and 1-Iodo-2-acetamido Adamantane 3a-Ac skeleton was performed through decarboxylative Friedel− Crafts reaction (Scheme 4). Electron-rich substrates provide

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 ﬂ 1-amino-2-phenyl-adamantane was not observed (Figure 5). products in good yields using tri ic 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 Figure 5. Limits of the method. 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. Among a number of side products, the mass of imine I was Retrosynthetically, the addition of a nitrile to the generated detected using HRMS, suggesting that the intramolecular dipole upon decarboxylation leads to the formation of an rearrangement is kinetically favored over the addition of the amidine. Derivative 3q was successfully prepared using nucleophile. equimolar mixtures of p-chlorobenzonitrile and Al(OTf)3. Finally, starting material 2 was resolved into single The amidine 3q was formed in 64% yield (Scheme 5). enantiomers using the Evans methodology (Scheme 8).26

4893 DOI: 10.1021/acs.joc.7b00711 J. Org. Chem. 2017, 82, 4891−4899 The Journal of Organic Chemistry Article

Scheme 8. Resolution of the Racemic Starting Material 2 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, 1 δ mobile phase: EtOAc); H NMR (400 MHz, CDCl3): /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 13 δ = 2.1 Hz, 1H); C NMR (101 MHz, CDCl3): /ppm = 29.2 (CH2), 32.6 (CH), 33.1 (CH), 36.2 (CH2), 36.8 (CH), 37.5 (CH2), 45.1 ν̃ −1 Compound 2 was converted to amide 2f, in a 1:1 mixture of (CH2), 52.8 (CH2), 63.8 (CH), 64.9 (C); IR (neat): /cm = 3370, fl 2904, 2851, 1606, 1448, 1340, 1284, 1167, 1105, 1016, 972, 938, 908, diastereomers, which are separable by simple ash chromatog- 842, 810, 785, 753, 679, 647, 538; HRMS (ESI/TOF) m/z:[M+H]+ raphy on silica gel. The (R,S)-2f isomer was crystallized to fi calcd for C10H17NI 278.0406; found 278.0402. determine the absolute con guration. In the next step, the Compound 3b. Starting material 2 (97 mg, 0.5 mmol) and KBr obtained diastereomers were hydrolyzed separately to enantio- (119 mg, 1.0 mmol) were suspended in 2 mL of 1,3,4- pure compounds: (R)-(−)-2 and (S)-(+)-2. The enantiopure trichlorobenzene, and then TfOH (300 mg, 2.0 mmol) was added compound (S)-(+)-2 was utilized for the preparation of dropwise to the reaction mixture at 25 °C. The reaction mixture was enantio-enriched compound 3j and to observe the unexpected stirred at this temperature for 18 h. Afterward, the reaction mixture complete racemization of the compound 3a (Figure 6). 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 1 0.2 (silica gel, mobile phase: EtOAc); H 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 13 δ (bs, 2H). C NMR (101 MHz, CD2Cl2): /ppm = 29.0 (CH2), 32.6 (CH), 32.7 (CH), 36.1 (CH2), 36.5 (CH), 36.9 (CH2), 42.6 (CH2), ν̃ −1 49.8 (CH2), 62.9 (CH), 71.3 (C); IR (neat): /cm = 3370, 2915, 2858, 1602, 1539, 1456, 1344, 1255, 1228, 1170, 1023, 983, 939, 910, Figure 6. Racemization of 3a via C−C bond cleavage or ylide 823, 796, 761, 689, 631; HRMS (ESI/TOF) m/z:[M+H]+ calcd for formation in acidic milieu. 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 ■ CONCLUSION reaction mixture at 25 °C. The reaction mixture was stirred at this We have developed a general and facile approach to a variety of temperature for 18 h. Afterward, the reaction mixture was quenched 1,2-disubstituted adamantane based amines and heterocycles. and neutralized using a 10% NaOH/water solution. The product was extracted using EtOAc, and solvent was evaporated under vacuo. The An example of the postfunctionalization reaction was fi demonstrated by coupling of the β-substituted tertiary iodo- crude residue was puri ed by column chromatography on silica gel adamantane with a selected heterocycle. The mechanism of the 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, racemization of 1,2-disubstituted (anti)-Bredt-like compounds mobile phase: EtOAc); 1H NMR (400 MHz, MeOD): δ/ppm = 1.56 will be part of future studies. (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), ■ EXPERIMENTAL SECTION 3.12 (s, 1H), 3.37 (bs, 2H); 13C NMR (101 MHz, MeOD): δ/ppm = Compound 2. Adamantyl-1-carbamate 1 (1.0 g, 5.12 mmol), 29.7 (CH2), 32.6 (CH), 32.9 (CH), 36.9 (CH2), 37.5 (CH), 37.8 ν̃ iodobenzene 1,1-diacetate (2.20 g, 6.83 mmol), Rh (OAc) (22 mg, (CH2), 41.5 (CH2), 49.0 (CH2), 62.6 (CH), 74.2 (C); IR (neat): / 2 4 − 0.051 mol), and MgO (500 mg, 12.5 mmol) were suspended in dry cm 1 = 3370, 2908, 2858, 1602, 1454, 1342, 1259, 1228, 1171, 1107, 1,2-dichloroethane (30 mL) and the reaction mixture was heated to 70 1025, 947, 914, 831, 814, 797, 765, 698, 634; HRMS (ESI/TOF) m/z: + °C under argon. The reaction was stirred for 18 h at this temperature. [M + H] calcd for C10H17NCl 186.1049; found 186.1046. Afterward, the reaction mixture was allowed to cool down to 25 °C Compound 3d. Starting material 2 (97 mg, 0.5 mmol) was and was filtered through the pad of silica gel. Silica gel was washed dissolved in 2 mL of CH2Cl2, and then 1 mL of HBF4 /diethyl ether w with a hexane/EtOAc 1:1 mixture to filter out the product from the 50% was added dropwise to the reaction mixture at 25 °C. The dirhodium catalyst and salts. The organic solvents were evaporated reaction mixture was heated to 40 °C and stirred for 18 h. Afterward, under vacuo, and crude product (2) was washed with hexane to the reaction mixture was cooled to 25 °C and neutralized using a 10% remove the side product (iodobenzene). Colorless solid, crystalline NaOH/water solution. The product was extracted using EtOAc, and product 2 was used for next step or purified by column solvent was evaporated under vacuo. The crude residue was purified by chromatography on silica gel in mobile phase (hexane/ethyl acetate column chromatography on silica gel using EtOAc/EtOH/Et3N 1 δ 2:1). Yield: 790 mg, 80%; H NMR (400 MHz, CDCl3): /ppm = (10:1:0.1) as the mobile phase to provide 35 mg of a colorless − − − − 1.60 1.88 (m, 8H), 2.01 2.04 (m, 1H), 2.09 2.18 (m, 3H), 2.28 noncrystalline solid 3d; Yield: 35 mg, 41%; Rf 0.2 (silica gel, mobile 2.29 (m, 2H), 3.66 (s, 1H), 5.07 (br s, 1H); in accordance with phase: EtOAc); 1H NMR (400 MHz, MeOD): δ/ppm = 1.49−1.60 published data.27 (m, 1H), 1.66−2.07 (m, 8H), 2.09−2.36 (m, 4H), 3.13 (s, 1H); 13C

4894 DOI: 10.1021/acs.joc.7b00711 J. Org. Chem. 2017, 82, 4891−4899 The Journal of Organic Chemistry Article δ NMR (101 MHz, MeOD): /ppm = 30.0 (d, J = 1 Hz, CH2), 32.1 (d, Compound 3h. Starting material 2 (97 mg, 0.5 mmol) and J = 10 Hz, CH), 32.9 (d, J = 10 Hz, CH), 36.5 (d, J = 17 Hz, CH2), thiophenol (1.40 g, 10.0 mmol) were dissolved in 2 mL of 1,3,4- μ 37.2 (d, J = 2 Hz, CH2), 37.5 (d, J = 2 Hz, CH2), 37.8 (d, J = 5 Hz, trichlorobenzene, and then TfOH (300 mg, 176 L) was added ° CH), 43.6 (d, J = 7 Hz, CH2), 60.0 (d, J = 6 Hz, CH), 94.2 (d, J = 188 dropwise to the reaction mixture at 25 C. The reaction mixture was Hz, C); 19F NMR (400 MHz, MeOD): δ/ppm = − 144.6 (s); IR heated to 90 °C and stirred at this temperature for 18 h. Afterward, the (neat): ν̃/cm−1 = 3370, 2910, 2856, 1602, 1455, 1344, 1058, 961, 931, reaction mixture was cooled to 25 °C and neutralized using a 10% + 893, 663; HRMS (ESI/TOF) m/z:[M+H] calcd for C10H17NF NaOH/water solution. The product was extracted using EtOAc, and 170.1345; found 170.1344. solvent was evaporated under vacuo. The crude residue was purified by Compound 3e. Starting material 2 (97 mg, 0.5 mmol) and NaN3 column chromatography on silica gel using EtOAc/Et3N (100:1) as (35 mg, 0.53 mmol) were dissolved in 2 mL of CH2Cl2, and then the mobile phase to provide 56 mg of a colorless noncrystalline solid μ TfOH (300 mg, 176 L) was added dropwise to the reaction mixture 3h; Yield: 108 mg, 79%; Rf 0.15 (silica gel, mobile phase: EtOAc/Et3N ° 1 δ − at 25 C. The reaction mixture was stirred at this temperature for 18 h. 100:1); H NMR (400 MHz, CDCl3): /ppm = 1.55 2.07 (m, 15H), Afterward, the reaction mixture was cooled to 25 °C and neutralized 2.87 (s, 1H), 7.36−7.41 (m, 3H), 7.49−7.51 (m, 2H); 13C NMR (101 δ using a 10% NaOH/water solution. The product was extracted using MHz, CDCl3/ MeOD): /ppm = 28.9 (CH), 29.2 (CH2), 29.4 (CH), EtOAc, and solvent was evaporated under vacuo. The crude residue 33.7 (CH), 36.0 (CH2), 36.2 (CH2), 36.6 (CH2), 43.7 (CH2), 52.0 was purified by short pad column chromatography on silica gel using (C), 56.9 (CH), 128.6 (C), 128.7 (2CH), 129.1 (CH), 137.3 (2CH); EtOAc as the mobile phase to provide 56 mg of a colorless IR (neat): ν̃/cm−1 = 3370, 2917, 2855, 1583, 1474, 1439, 1260, 1170, + noncrystalline solid 3e; Yield: 56 mg, 58%; Rf 0.15 (silica gel, mobile 1030, 750, 694, 638; HRMS (ESI/TOF) m/z:[M+H] calcd for 1 δ − phase: EtOAc); H NMR (400 MHz, CDCl3): /ppm = 1.38 1.51 C16H22NS 260.1473; found 260.1468. − − − (m, 1H), 1.54 1.73 (m, 4H), 1.74 1.82 (m, 2H), 1.84 1.97 (m, 3H), Compound 3i. Starting material 2 (97 mg, 1.0 mmol) and PPh2 − 13 δ 2.03 2.13 (m, 3H), 2.89 (s, 1H); C NMR (101 MHz, CDCl3): / (400 mg, 2.16 mmol) were dissolved in 2 mL of 1,3,4- μ ppm = 29.5 (CH), 29.5 (CH2), 30.0 (CH), 34.4 (CH2), 35.9 (CH), trichlorobenzene, and then TfOH (466 mg, 274 L, 3.2 mmol) was ° 36.5 (CH2), 36.8 (CH2), 41.4 (CH2), 58.6 (CH), 63.0 (C); IR (neat): added to the reaction mixture at 25 C. The reaction mixture was ν̃/cm−1 = 3370, 2909, 2854, 2087, 1452, 1253, 1109, 1047, 818, 733, heated to the 120 °C and stirred at this temperature for 18 h. + ° 692; HRMS (ESI/TOF) m/z:[M+H] calcd for C10H17N4 193.1453; Afterward, the reaction mixture was cooled to 25 C and neutralized found 193.1457. using a 10% NaOH/water solution. The product was extracted using Compound 3f. Starting material 2 (97 mg, 0.5 mmol) and p-cresol EtOAc, and solvent from organic fractions was evaporated under (1.20 g, 10.0 mmol) were dissolved in 2 mL of 1,3,4-trichlorobenzene vacuo. The crude residue was dissolved in 1 mL of EtOAc and was and then p-toluenesulfonic acid (268 mg, 1.6 mmol) was added to the stirred for 18 h under an air atmosphere to fully oxidize the phosphine reaction mixture at 25 °C. The reaction mixture was heated to the 90 group to phosphine oxide. The crude product was purified by column ° C and stirred at this temperature for 18 h. Afterward, the reaction chromatography on silica gel using EtOAc/EtOH/Et3N (100:10:1) as mixture was cooled to 25 °C and neutralized using a 10% NaOH/ the mobile phase to provide 50 mg of a colorless noncrystalline solid. water solution. The product was extracted using EtOAc, and solvent Compound 3i contained an impurity; for structure verification and from organic fractions was evaporated under vacuo. The crude residue description, the amine group was protected by an acetyl. Yield: 50 mg, fi was puri ed by column chromatography on silica gel using EtOAc/ 14%; Rf 0.15 (silica gel, mobile phase: EtOAc/EtOH/Et3N 100:10:1); + EtOH/Et3N (100:10:1) as the mobile phase to provide 88 mg of a HRMS (ESI/TOF) m/z:[M+H] calcd for C22H27NOP 352.1830; colorless noncrystalline solid 3f; Yield: 88 mg, 66%; Rf 0.2 (silica gel, found 352.1826. 1 fi mobile phase: EtOAc/EtOH/Et3N 100:10:1); H NMR (400 MHz, Compound 3i-Ac. For characterization and structure veri cation by δ − − − ff CDCl3): /ppm = 1.37 1.62 (m, 4H), 1.64 2.00 (m, 8H), 2.00 2.13 X-ray di raction, compound 3i was acetylated to crystalline 3i-Ac; Mp: (m, 2H), 2.17 (d, J = 12.0 Hz, 1H), 2.30 (s, 3H), 3.16 (s, 1H), 6.83− 177.0−177.5 °C (crystallized from EtOAc); 1H NMR (400 MHz, − 13 δ δ − − − 6.90 (m, 2H), 7.04 7.05 (m, 2H); C NMR (101 MHz, CDCl3): / CDCl3): /ppm = 1.51 1.54 (m, 2H), 1.66 1.89 (m, 11 H), 1.99 − − − ppm = 20.9 (CH3), 29.8 (CH2), 30.5 (CH), 31.1 (CH), 35.8 (CH2), 2.06 (m, 2H), 2.24 2.26 (m, 1H), 2.47 2.51 (m, 1H), 3.80 3.84 (m, − − 36.2 (CH), 36.6 (CH2), 36.8 (CH2), 41.8 (CH2), 59.0 (CH), 79.7 1H), 7.16 (br s, 1H, NH), 7.47 7.58 (m, 6H), 7.86 7.91 (m, 2H), ν̃ − 13 δ (C), 124.5 (2CH), 129.5 (2CH), 133.3 (C), 151.5 (C); IR (neat): / 7.97 8.00 (m, 2H); C NMR (101 MHz, CDCl3): /ppm = 23.6 −1 cm = 3390, 2900, 2853, 1608, 1580, 1505, 1219, 1054, 960, 842, 820, (CH3), 26.8 (d, J = 9 Hz, CH), 27.1 (d, J = 10 Hz, CH), 30.5 (CH2), + 752, 725, 705, 665; HRMS (ESI/TOF) m/z:[M+H] calcd for 30.5 (CH2), 31.4 (d, J = 8 Hz, CH), 35.7 (d, J = 1 Hz, CH2), 36.5 (d, J C17H24NO 258.1858; found 258.1859. = 1 Hz, CH2), 37.9 (d, J = 1 Hz, CH2), 39.4 (d, J = 69 Hz, C), 55.1 (d, Compound 3g. Starting material 2 (97 mg, 0.5 mmol) and napth-2- J = 3 Hz, CH), 128.5 (d, J = 11 Hz, 2CH), 128.8 (d, J = 11 Hz, 2CH), ol (1.44 g, 10 mmol) were dissolved in 2 mL of 1,3,4-trichlorobenzene, 129.1 (d, J = 24 Hz, C), 130.1 (d, J = 22 Hz, C), 131.7 (d, J = 8 Hz, and then p-toluenesulfonic acid (268 mg, 1.6 mmol) was added to the 2CH), 131.9 (d, J = 3 Hz, CH), 132.3 (d, J = 3 Hz, CH), 132.4 (d, J = ° 31 δ reaction mixture at 25 C. The reaction mixture was heated to the 90 8 Hz, 2CH); P NMR (162 MHz, CDCl3): /ppm = 35.2; IR (neat): °C and stirred at this temperature for 18 h. Afterward, the reaction ν̃/cm−1 = 3318, 2907, 2853, 1656, 1529, 1436, 1370, 1263, 1166, mixture was cooled to 25 °C and neutralized using a 10% NaOH/ 1109, 921, 844, 754, 717, 696, 545. HRMS (ESI/TOF) m/z:[M+ + water solution. The product was extracted using EtOAc, and solvent Na] calcd for C24H28NO2PNa 416.1755; found 416.1763. from organic fractions was evaporated under vacuo. The crude residue Compound 3j. Starting material (rac)-2 or [(S)-2 enantiopure] (97 was purified by column chromatography on silica gel using EtOAc/ mg, 0.5 mmol) was dissolved in 2 mL of benzene, and then TfOH ° EtOH/Et3N (100:10:1) as the mobile phase to provide 96 mg of a (300 mg, 2.0 mmol) was added to the reaction mixture at 25 C. The ° colorless noncrystalline solid 3g; Yield: 96 mg, 63%; Rf 0.20 (silica gel, reaction mixture was heated to 60 C and stirred at this temperature 1 ° mobile phase: EtOAc/EtOH/Et3N 100:10:1); H NMR (400 MHz, for 18 h. Afterward, the reaction mixture was cooled to 25 C and δ − − − CDCl3): /ppm = 1.44 1.46 (m, 2H), 1.53 1.65 (m, 2H), 1.67 1.82 neutralized using a 10% NaOH/water solution. The product was (m, 3H), 1.87−2.16 (m, 8H), 2.24−2.33 (m, 1H), 3.28 (s, 1H), 7.18 extracted using EtOAc, and solvent from organic fractions was (dd, J = 8.8, 2.3 Hz, 1H), 7.48−7.33 (m, 3H), 7.74 (dd, J = 8.4, 2.5 Hz, evaporated under vacuo. The crude residue was purified by column 13 δ 2H), 7.80 (d, J = 8.2 Hz, 1H); C NMR (101 MHz, CDCl3): /ppm chromatography on silica gel using EtOAc/EtOH/Et3N (100:10:1) as = 29.8 (CH2), 30.5 (CH), 31.1 (CH), 36.0 (CH2), 36.3 (CH), 36.6 the mobile phase to provide 103 mg of a colorless noncrystalline solid (CH2), 36.8 (CH2), 41.9 (CH2), 59.1 (CH), 80.6 (C), 120.8 (CH), 3j; Yield: 103 mg, 87%; Rf 0.5 (silica gel, mobile phase: EtOAc/EtOH/ 1 δ − 124.8 (CH), 125.3 (CH), 126.2 (CH), 127.3 (CH), 127.7 (CH), Et3N 100:10:1); H NMR (400 MHz, MeOD): /ppm = 1.68 2.00 128.7 (CH), 130.7 (C), 134.2 (C), 151.9 (C); IR (neat): ν̃/cm−1 = (m, 5H), 2.01−2.18 (m, 4H), 2.24−2.28 (m, 3H), 2.49 (d, J = 13.4 3054, 2905, 2852, 1627, 1594, 1505, 1465, 1244, 1212, 1165, 1050, Hz, 1H), 3.29−3.37 (m, 2H), 3.83 (s, 1H), 7.31−7.34 (m, 1H), 7.43− + 13 δ 967, 886, 750, 621; HRMS (ESI/TOF) m/z:[M+H] calcd for 7.49 (m, 4H); C NMR (101 MHz, CD2Cl2): /ppm = 27.9 (CH), C20H24NO 294.1858; found 294.1863. 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 The Journal of Organic Chemistry Article − − − (CH2), 39.1 (C), 45.1 (CH2), 61.4 (CH), 125.9 (2CH), 128.1 (CH), (m, 2H), 1.56 1.76 (m, 4H), 1.84 1.98 (m, 5H), 2.04 2.16 (m, 1H), 130.0 (2CH), 143.8 (C); IR (neat): ν̃/cm−1 = 3439, 3093, 2926, 2859, 2.29 (d, J = 12.4 Hz, 1H), 2.82 (d, J = 12.6 Hz, 1H), 4.01 (s, 1H), 1604, 1502, 1287, 1227, 1170, 1027, 755, 699, 633; HRMS (ESI/ 6.80−6.97 (m, 2H), 7.12−7.23 (m, 2H); 13C NMR (101 MHz, + δ TOF) m/z:[M+H] calcd for C16H22N 228.1752; found 228.1753. CDCl3): /ppm = 28.7 (CH), 29.1 (CH), 30.4 (CH2), 34.8 (CH), Compound 3j-Ac. To determine the enantiopurity of the enantio- 35.6 (CH2), 37.8 (CH2), 38.1 (CH2), 40.4 (CH2), 42.6 (C), 54.5 enriched product 3j,(rac)-3j and (S)-3j (50 mg, 0.22 mmol) were (CH), 55.2 (CH3), 111.7 (CH), 120.7 (CH), 127.4 (CH), 128.5 ν̃ −1 separately acetylated using Ac2O (102 mg, 1 mmol) and triethylamine (CH), 135.3 (C), 158.6 C); IR (neat): /cm = 2903, 2851, 1487, ° (101 mg, 1 mmol) in CH2Cl2 (1 mL) at 25 Cin3hto3j-Ac. The 1452, 1257, 1230, 1174, 1125, 1019, 792, 755, 700, 621; HRMS (ESI/ + reaction was quenched by addition of 1 mL of water, and the crude TOF) m/z:[M+H] calcd for C17H23NO 258.1858; found 258.1856. product was extracted using EtOAc. The organic fraction was dried Compound 3n. Starting material 2 (97 mg, 0.5 mmol) and over MgSO4, and the solvent was evaporated under vacuo. The crude ferrocene (960 mg, 5.0 mmol) were dissolved in 6 mL of 1,3,4- fi residue was puri ed by column chromatography on silica gel using trichlorobenzene, and then Al(OTf)3 (268 mg, 1.6 mmol) was added EtOAc as a mobile phase to obtain 55 mg, 93% of 3j-Ac and (S)-3j-Ac to the reaction mixture at 25 °C. The reaction mixture was heated to ° respectively; Yield: 55 mg, 93%; Rf 0.8 (silica gel, mobile phase: the 90 C and stirred at this temperature for 18 h. Afterward, the 1 δ ° EtOAc); H NMR (400 MHz, CDCl3): /ppm = 1.59 (d, J = 12.9, reaction mixture was cooled to 25 C and neutralized using a 10% 1H), 1.65 (s, 3H), 1.66−1.89 (m, 5H), 1.92−2.19 (m, 7H), 4.39 (dd, J NaOH/water solution. The product was extracted using EtOAc, and = 8.0, 2.7 Hz, 1H), 5.31 (d, J = 7.4 Hz, 1H), 7.10−7.14 (m, 1H), solvent from organic fractions was evaporated under vacuo. The crude − 13 δ fi 7.22 7.31 (m, 4H); C NMR (101 MHz, CDCl3): /ppm = 23.5 residue was puri ed by column chromatography on silica gel using (CH3), 28.0 (CH), 28.6 (CH), 31.1 (CH2), 32.7 (CH), 35.6 (CH2), EtOAc/EtOH/Et3N (100:10:1) as the mobile phase to provide 128 36.8 (CH2), 36.9 (CH2), 39.5 (C), 46.4 (CH2), 56.2 (CH), 125.3 mg of an orange noncrystalline solid 3n; Yield: 128 mg, 74%; Rf 0.4 1 (2CH), 126.3 (CH), 128.5 (2CH), 147.0 (C), 169.3 (C); IR (neat): (silica gel, mobile phase: EtOAc/EtOH/Et3N 100:10:1); H NMR ν̃ −1 δ − /cm = 3273, 2906, 2852, 1770, 1628, 1546, 1372, 1290, 1123, (400 MHz, CDCl3): /ppm = 1.49 (d, J = 12.2 Hz, 1H), 2.21 1.57 1023, 959, 752, 694, 605, 523; HRMS (ESI/TOF) m/z: [M + Na]+ (m, 12H), 2.56 (s, 1H), 3.83−4.43 (m, 9H); 13C NMR (101 MHz, δ calcd for C18H23NONa 292.1677; found 292.1680. CDCl3): /ppm = 28.3 (CH), 28.7 (CH), 30.5 (CH2), 34.7 (CH2), Compound 3k. Starting material 2 (97 mg, 0.5 mmol) was 34.8 (CH), 36.8 (C), 37.8 (CH2), 37.9 (CH2), 43.1 (CH2), 61.3 dissolved in 2 mL of 1,2-difluorobenzene, and then TfOH (300 mg, (CH), 64.4 (CH), 66.0 (CH), 66.7 (CH), 67.4 (CH), 68.3 (5CH), 2.0 mmol) was added to the reaction mixture at 25 °C. The reaction 98.8 (C); IR (neat): ν̃/cm−1 = 3094, 2901, 2850, 1610, 1449, 1347, mixture was heated to 90 °C and stirred at this temperature for 18 h. 1105, 999, 907, 813, 727, 692, 666; HRMS (ESI/TOF) m/z:[M+ ° + Afterward, the reaction mixture was cooled to 25 C and neutralized H] calcd for C20H26NFe 336.1415; found 336.1415. using a 10% NaOH/water solution. The product was extracted using Compound 2b. Starting material 2 (193 mg, 1.0 mmol) was EtOAc, and solvent from organic fractions was evaporated under dissolved in 2 mL of dry tetradydrofuran, and the solution was cooled vacuo. The crude residue was purified by column chromatography on to 0 °C. BuLi (1.6 M in hexane; 0.8 mL) was added to the reaction silica gel using EtOAc/EtOH/Et3N (100:10:1) as the mobile phase to mixture and stirred at 0 °C for 1 h. Then benzyl bromide (340 mg, 2.0 provide 111 mg of a colorless noncrystalline solid 3k; Yield: 111 mg, mmol) was added, and the reaction mixture was heated to 25 °C and 86%; Rf 0.4 (silica gel, mobile phase: EtOAc/EtOH/Et3N 100:10:1); stirred at this temperature for 18 h. Afterward, the reaction was 1 δ H NMR (400 MHz, CDCl3): /ppm = 1.55 (d, J = 12.6 Hz, 1H), quenched by adding brine, and the product was extracted using 1.61−1.82 (m, 5H), 1.83−2.04 (m, 7H), 2.05−2.14 (m, 1H), 2.32 (d, J EtOAc. The organic fraction was dried using MgSO4, and solvent from = 10.3 Hz, 1H), 3.17 (s, 1H), 6.97−7.20 (m, 3H); 13C NMR (101 organic fractions was evaporated under vacuo. The crude residue was δ fi MHz, CDCl3): /ppm = 28.3 (CH), 28.8 (CH), 30.0 (CH2), 33.9 puri ed by column chromatography on silica gel using hexane/EtOAc (CH2), 35.0 (CH), 37.0 (CH2), 37.9 (CH2), 40.9 (C), 45.0 (CH2), (2:1) as the mobile phase to provide 214 mg of a colorless 59.2 (CH), 115.0 (d, J = 18 Hz, CH), 117.0 (d, J = 16 Hz, CH), 121.5 noncrystalline solid 2b; Yield: 214 mg, 88%; Rf 0.6 (silica gel, mobile − 1 δ (dd, J = 6 Hz, 4 Hz, CH), 145.6 146.8 (m, C), 148.3 (dd, J = 190 Hz, phase: hexane/EtOAc 2:1); H NMR (400 MHz, CDCl3): /ppm = 12 Hz, CF), 150.7 (dd, J = 190 Hz, 12 Hz, CF); 19F NMR (377 MHz, 1.44−1.46 (m, 2H), 1.58−1.61 (m, 3H), 1.67−1.86 (m, 2H), 1.92 (dd, δ − − − − CDCl3): /ppm = 138.0 (d, J = 24 Hz, F), 142.1 (d, J = 24 Hz, J = 12.5, 3.8 Hz, 1H), 2.04 2.08 (m, 3H), 2.17 2.22 (m, 2H), 3.30 F); IR (neat): ν̃/cm−1 = 3380, 2905, 2851, 1604, 1519, 1419, 1277, (m, 1H), 4.34 (d, J = 14.9 Hz, 1H), 4.48 (d, J = 14.9 Hz, 1H), 7.25− 13 δ 1219, 1119, 810, 798, 780, 761, 699, 628; HRMS (ESI/TOF) m/z:[M 7.35 (m, 5H); C NMR (101 MHz, CDCl3): /ppm = 29.2 (CH), + +H] calcd for C16H20NF2 264.1564; found 264.1568. 29.5 (CH2), 30.4 (CH), 31.1 (CH), 36.2 (CH2), 36.4 (CH2), 37.9 Compound 3l. Starting material 2 (97 mg, 0.5 mmol) was dissolved (CH2), 40.0 (CH2), 47.3 (CH2), 66.5 (CH), 77.9 (C), 127.8 (CH), ν̃ −1 in 2 mL of methoxybenzene, and Al(OTf)3 (261 mg, 0.55 mmol) was 128.6 (2CH), 128.7 (2CH), 136.7 (C), 160.3 (C); IR (neat): /cm added to the reaction mixture at 25 °C. The reaction mixture was = 2932, 2862, 1741, 1495, 1431, 1331, 1027, 956, 742, 704, 644; ° + heated to the 90 C and stirred at this temperature for 18 h. Afterward, HRMS (ESI/TOF) m/z: [M + Na] calcd for C18H21NO2Na the reaction mixture was cooled to 25 °C and neutralized using 10% 306.1470; found 306.1469. NaOH/water solution. The product was extracted using EtOAc, and Compound 3o. Starting material 2b (225 mg, 0.79 mmol) and solvent from organic fractions was evaporated under vacuo. The crude Al(OTf)3 (416 mg, 0.88 mmol) were suspended in 8 mL of 1,3,4- residue was purified by column chromatography on silica gel using trichlorobenzene at 25 °C. The reaction mixture was heated to the 140 ° EtOAc/EtOH/Et3N (100:10:1) as the mobile phase to provide 92 mg C and stirred at this temperature for 18 h. Afterward, the reaction of a colorless noncrystalline solid (mixture of para and ortho isomer mixture was cooled to 25 °C and neutralized using a 10% NaOH/ 3l/3m in ratio 4:1); Yield: 92 mg, 70%; Rf 0.45 (silica gel, mobile water solution. The product was extracted using EtOAc, and solvent 1 phase: EtOAc/EtOH/Et3N 100:10:1); H NMR (400 MHz, CDCl3): from organic fractions was evaporated under vacuo. The crude product δ/ppm = 1.54 (d, J = 12.3 Hz, 1H), 1.62−1.81 (m, 4H), 1.87−2.17 was purified by column chromatography on silica gel using EtOAc/ (m, 7H), 2.33 (d, J = 12.4 Hz, 1H), 3.18 (s, 1H), 3.79 (s, 3H), 6.88 (d, EtOH/Et3N (100:10:1) as the mobile phase to provide 31 mg of 13 28 J = 8.9 Hz, 2H), 7.26 (d, J = 8.9 Hz, 2H); C NMR (101 MHz, colorless crystalline solid 3o. Yield: 31 mg, 16%; Rf 0.2 (silica gel, δ 1 CDCl3): /ppm = 28.5 (CH), 29.0 (CH), 30.2 (CH2), 33.9 (CH2), mobile phase: EtOAc/EtOH/Et3N 100:10:1); H NMR (400 MHz, δ − − − 34.9 (CH), 37.3 (CH2), 38.1 (CH2), 40.5 (C), 45.2 (CH2), 55.3 CDCl3): /ppm = 1.53 1.68 (m, 3H), 1.73 1.97 (m, 6H), 1.97 2.16 − (CH3), 59.3 (CH), 113.8 (2CH), 126.6 (2CH), 140.4 (C), 157.7 (C); (m, 3H), 2.38 2.40 (m, 1H), 2.94 (s, 1H), 4.13 (d, J = 16.2 Hz, 1H), IR (neat): ν̃/cm−1 = 2895, 2845, 1609, 1510, 1468, 1446, 1258, 1243, 4.25 (d, J = 16.2 Hz, 1H), 7.00 (d, J = 7.4 Hz, 1H), 7.12−7.13 (m, 1182, 1035, 1023, 875, 832, 801, 702, 557; HRMS (ESI/TOF) m/z: 1H), 7.16−7.19 (m, 1H), 7.28 (d, J = 7.7 Hz, 1H); 13C NMR (101 + δ [M + H] calcd for C17H23NO 258.1858; found 258.1856. MHz, CDCl3): /ppm = 28.6 (CH), 29.1 (CH), 30.8 (CH2), 34.0 Compound 3m. Rf 0.40 (silica gel, mobile phase: EtOAc/EtOH/ (CH), 35.8 (C), 37.4 (CH2), 37.8 (CH2), 40.9 (CH2), 41.4 (CH2), 1 δ − Et3N 100:10:1); H NMR (400 MHz, CDCl3): /ppm = 1.46 1.53 49.5 (CH2), 62.5 (CH), 125.1 (CH), 125.8 (CH), 126.2 (CH), 126.6

4896 DOI: 10.1021/acs.joc.7b00711 J. Org. Chem. 2017, 82, 4891−4899 The Journal of Organic Chemistry Article

(CH), 134.3 (C), 144.4 (C); IR (neat): ν̃/cm−1 = 3014, 2903, 2848, to 0 °C. BuLi (1.6 M in hexane; 0.5 mL) was added to the reaction 1488, 1448, 1251, 1158, 1100, 1029, 751, 724, 699, 638; HRMS (ESI/ mixture and stirred at 0 °C for 1 h. Then benzoyl chloride (140 mg, + ° TOF) m/z:[M+H] calcd for C17H22N 240.1752; found 240.1749. 1.0 mmol) was added, and the reaction mixture was heated to 25 C Compound 2c. Starting material 2 (193 mg, 1 mmol) was dissolved and stirred at this temperature for 18 h. Afterward, the reaction was in 2 mL of dry tetradydrofuran, and the solution was cooled to 0 °C. quenched by adding brine, and the product was extracted using BuLi (1.6 M in hexane; 0.8 mL) was added to the reaction mixture and EtOAc. Organic fractions were dried using MgSO4, and solvent from stirred at 0 °C for 1 h. Then para-methyl-benzyl bromide (368 mg, 2.0 organic fractions was evaporated under vacuo. The crude product was mmol) was added, and the reaction mixture was heated to 25 °C and purified by column chromatography on silica gel using Hexane/EtOAc stirred at this temperature for 18 h. Afterward, the reaction was (2:1) as the mobile phase to provide 200 mg of colorless solid 2d. quenched by adding brine and the product was extracted using EtOAc. Yield: 200 mg, 84%; Rf 0.8 (silica gel, mobile phase: hexane/EtOAc 1 δ − The organic fraction was dried using MgSO4, and solvent from the 2:1); H NMR (400 MHz, CDCl3): /ppm = 1.65 1.72 (m, 4H), organic fractions was evaporated under vacuo. The crude residue was 1.86−1.89 (m, 2H), 1.98−2.13 (m, 2H), 2.14−2.27 (m, 3H), 2.36 (s, purified by column chromatography on silica gel using hexane/EtOAc 1H), 2.90−3.07 (m, 1H), 4.08 (d, J = 2.2 Hz, 1H), 7.43−7.46 (m, (2:1) as the mobile phase to provide 224 mg of colorless 2H), 7.51−7.61 (m, 1H), 7.74−7.77 (m, 2H); 13C NMR (101 MHz, δ noncrystalline solid 2c. Yield: 224 mg, 75%; Rf 0.6 (silica gel, mobile CDCl3): /ppm = 29.3 (CH), 29.5 (CH2), 29.8 (CH), 30.8 (CH), 1 δ phase: hexane/EtOAc 2:1); H NMR (400 MHz, CDCl3): /ppm = 35.9 (CH2), 36.2 (CH2), 39.0 (CH2), 39.9 (CH2), 66.4 (CH), 79.3 1.48 (s, 2H), 1.53−1.66 (m, 3H), 1.67−1.85 (m, 2H), 1.85−1.97 (m, (C), 128.2 (2CH), 129.6 (2CH), 133.0 (CH), 133.7 (C), 154.9 (C), 1H), 2.02−2.05 (m, 3H), 2.20 (d, J = 15.1 Hz, 2H), 2.33 (s, 3H), 3.28 171.2 (C); IR (neat): ν̃/cm−1 = 2914, 2855, 1781, 1687, 1450, 1311, (d, J = 2.5 Hz, 1H), 4.26 (d, J = 14.9 Hz, 1H), 4.47 (d, J = 14.9 Hz, 1203, 1149, 1041, 760, 690, 673; HRMS (ESI/TOF) m/z: [M + Na]+ 13 1H), 7.12 (d, J = 7.9 Hz, 2H), 7.20 (d, J = 8.0 Hz, 2H); C NMR calcd for C18H19NO3Na 320.12626; found 320.1260. δ (101 MHz, CDCl3): /ppm = 21.3 (CH3), 29.2 (CH), 29.6 (CH2), Compound 3r. Starting material 2d (154 mg, 0.57 mmol) was 30.4 (CH), 31.1 (CH), 36.2 (CH2), 36.4 (CH2), 37.9 (CH2), 40.0 dissolved in 4 mL of 1,3,4-trichlorobenzene, and then TfOH (680 mg, μ ° (CH2), 47.0 (CH2), 66.2 (CH), 77.8 (C), 128.6 (2CH), 129.4 (2CH), 400 L) was added dropwise to the reaction mixture at 25 C. The 133.6 (C), 137.5 (C), 160.3 (C); IR (neat): ν̃/cm−1 = 2925, 2854, reaction mixture was heated to 60 °C and stirred at this temperature 1736, 1450, 1397, 1334, 1306, 1027, 956, 770, 716, 688; HRMS (ESI/ for 18 h. Afterward, the reaction mixture was cooled to 25 °C and + TOF) m/z: [M + Na] calcd for C19H23NO2Na 320.1626; found neutralized using a 10% NaOH/water solution. The product was 320.1624. extracted using EtOAc, and solvent from the organic fractions was Compound 3p. Starting material 2c (235 mg, 0.79 mmol) and evaporated under vacuo. The crude product was purified by column Al(OTf)3 (416 mg, 0.88 mmol) were suspended in 8 mL of 1,3,4- chromatography on silica gel using hexane/EtOAc (3:1) as the mobile ° trichlorobenzene at 25 C. The reaction mixture was heated to the 140 phase to provide 60 mg of colorless solid 3r. Yield: 60 mg, 42%; Rf 0.5 °C and stirred at this temperature for 18 h. Afterward, the reaction (silica gel, mobile phase: hexane/EtOAc 3:1); 1H NMR (400 MHz, ° δ − − − mixture was cooled to 25 C and neutralized using a 10% NaOH/ CDCl3): /ppm = 1.57 1.77 (m, 5H), 1.79 1.92 (m, 3H), 1.98 2.08 water solution. The product was extracted using EtOAc, and solvent (m, 1H), 2.11−2.22 (m, 1H), 2.24−2.38 (m, 2H), 2.59−2.72 (m, 1H), from the organic fractions was evaporated under vacuo. The crude 3.66 (s, 1H), 7.32−7.53 (m, 3H), 7.90−8.05 (m, 2H); 13C NMR (101 fi δ residue was puri ed by column chromatography on silica gel using MHz, CDCl3): /ppm = 29.2 (CH), 30.7 (CH2), 31.7 (CH), 32.7 EtOAc/EtOH/Et3N (100:10:1) as the mobile phase to provide 30 mg (CH), 36.6 (CH2), 36.8 (CH2), 37.7 (CH2), 41.1 (CH2), 74.8 (CH), of a colorless crystalline solid 3p. Yield: 30 mg, 15%; Rf 0.3 (silica gel, 83.8 (C), 128.1 (2CH), 128.4 (2CH), 129.3 (C), 131.4 (CH), 165.6 1 ν̃ −1 mobile phase: EtOAc/EtOH/Et3N 100:10:1); H NMR (400 MHz, (C); IR (neat): /cm = 2929, 2853, 1615, 1575, 1491, 1447, 1333, δ − − − CDCl3): /ppm = 1.53 1.66 (m, 3H), 1.78 1.99 (m, 8H), 2.01 2.14 1263, 1101, 1060, 1035, 1013, 952, 885, 784, 696; HRMS (ESI/TOF) − + (m, 2H), 2.30 2.32 (m, 3H), 2.37 (d, J = 12.5 Hz, 1H), 2.87 (s, 1H), m/z:[M+H] calcd for C17H19NONa 276.13643; found 276.1362. 4.05 (d, J = 16.0 Hz, 1H), 4.19 (d, J = 16.0 Hz, 1H), 6.85−6.96 (m, Compound 2e. Starting material 2 (77 mg, 0.4 mmol) was 13 δ 2H), 7.09 (s, 1H); C NMR (101 MHz, CDCl3): /ppm = 21.4 dissolved in 5 mL of dry tetradydrofuran, and the solution was cooled ° (CH3), 28.7 (CH), 29.2 (CH), 31.0 (CH2), 34.3 (CH), 35.8 (C), 37.5 to 0 C. BuLi (1.6 M in hexane; 0.25 mL) was added to the reaction ° fl (CH2), 37.9 (CH2), 41.0 (CH2), 41.5 (CH2), 49.6 (CH2), 62.6 (CH), mixture and stirred at 0 C for 1 h. Then ortho- uoro-benzoyl chloride 125.6 (CH), 126.1 (CH), 126.6 (CH), 132.0 (C), 135.7 (C), 144.6 (79 mg, 0.5 mmol) was added, and the reaction mixture was heated to (C); IR (neat): ν̃/cm−1 = 3009, 2907, 2849, 1612, 1501, 1449, 1343, 25 °C and stirred at this temperature for 18 h. Afterward, the reaction 1255, 1126, 803, 704, 642; HRMS (ESI/TOF) m/z:[M+H]+ calcd was quenched by adding brine, and the product was extracted using for C18H24N 254.1909; found 254.1908. EtOAc. The organic fraction was dried using MgSO4, and solvent from Compound 3q. Starting material 2 (96 mg, 0.5 mmol), 4-cyano- organic fractions was evaporated under vacuo. The crude product was fi chlorobenzene (137 mg, 1 mmol), and Al(OTf)3 (474 mg, 1.0 mmol) puri ed by column chromatography on silica gel using Hexane/EtOAc were suspended in 2 mL of 1,3,4-trichlorobenzene at 25 °C. The (2:1) as the mobile phase to provide 105 mg of colorless solid ° reaction mixture was heated to 90 C and stirred at this temperature 2e.Yield: 105 mg, 83%; Rf 0.8 (silica gel, mobile phase: hexane/EtOAc ° 1 δ − for 18 h. Afterward, the reaction mixture was cooled to 25 C and 2:1); H NMR (400 MHz, CDCl3): /ppm = 1.66 1.72 (m, 4H), neutralized using 10% NaOH/water solution. The product was 1.82−1.91 (m, 2H), 1.95 (d, J = 11.9 Hz, 1H), 2.02−2.12 (m, 1H), extracted using EtOAc, and solvent from organic fractions was 2.13−2.26 (m, 3H), 2.29−2.41 (m, 1H), 3.15 (s, 1H), 4.03 (s, 1H), evaporated under vacuo. The crude residue was purified by column 7.07−7.14 (m, 1H), 7.20−7.26 (m, 1H), 7.46−7.55 (m, 1H), 7.61− 13 δ chromatography on silica gel using EtOAc/Et3N (100:1) as the mobile 7.63 (m, 1H); C NMR (101 MHz, CDCl3): /ppm = 29.2 (CH), phase to provide 94 mg of a colorless crystalline solid 3q. Yield: 94 mg, 29.4 (CH2), 29.9 (CH), 30.8 (CH), 35.9 (CH2), 36.3 (CH2), 38.5 (d, 1 64%; Rf 0.15 (silica gel, mobile phase: EtOAc/Et3N 100:1); H NMR J = 2 Hz, CH2), 39.6 (CH2), 66.8 (CH), 79.5 (C), 115.8 (d, J = 22 Hz, δ − − (400 MHz, CDCl3): /ppm = 1.49 1.77 (m, 7H), 1.77 1.85 (m, CH), 123.2 (d, J = 14 Hz, C), 124.5 (d, J = 3 Hz, CH), 130.6 (d, J =3 1H), 1.91−1.95 (m, 3H), 2.16−2.21 (m, 2H), 2.48 (s, 1H), 3.43 (s, Hz, CH), 133.8 (d, J = 9 Hz, CH), 154.1 (C), 160.2 (d, J = 253 Hz, 13 19 δ − 1H), 7.36 (d, J = 6.9 Hz, 2H), 7.72 (d, J = 6.9 Hz, 2H); C NMR C), 166.6 (C); F NMR (377 MHz, CDCl3): /ppm = 112.5; IR δ ν̃ −1 (101 MHz, CDCl3): /ppm = 28.0 (CH), 30.4 (CH), 30.8 (CH2), (neat): /cm = 2911, 2853, 1778, 1684, 1612, 1455, 1327, 1203, + 31.5 (CH), 36.9 (CH2), 37.5 (CH2), 38.2 (CH2), 42.0 (CH2), 63.6 1040, 905, 758, 660; HRMS (ESI/TOF) m/z: [M + Na] calcd for (C), 72.7 (CH), 128.1 (2CH), 128.8 (2CH), 129.9 (C), 136.8 (C), C18H18NFO3Na 338.11684; found 338.1169. 164.0 (C); IR (neat): ν̃/cm−1 = 3443, 3129, 2919, 2852, 1604, 1452, Compound 3s. Starting material 2e (80 mg, 0.25 mmol) was 1332, 1085, 837, 732, 584; HRMS (ESI/TOF) m/z:[M+H]+ calcd dissolved in 2 mL of 1,3,4-trichlorobenzene at 25 °C, and then TfOH μ for C17H20N2Cl 287.1315; found 287.1316. (340 mg, 200 L) was added dropwise to the reaction mixture at 25 Compound 2d. Starting material 2 (154 mg, 0.8 mmol) was °C. The reaction mixture was heated to 60 °C and stirred at this dissolved in 10 mL of dry tetradydrofuran, and the solution was cooled 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 The Journal of Organic Chemistry Article

°C and neutralized using a 10% NaOH/water solution. The product 96% of crystalline solid (S)-2. Mp: 169.5−170.5 °C (crystallized from fi α was extracted using EtOAc, and solvent from the organic fractions was EtOAc); Speci c optical rotation: [ ]D = + 14.6 (c 1.3, CHCl3). evaporated under vacuo. The crude product was purified by column Compound 3a-Ac. A solution of 3a (96 mg, 0.346 mmol) in μ chromatography on silica gel using hexane/EtOAc (3:1) as the mobile pyridine (3.0 mL) was treated with Ac2O (35 L, 0.37 mmol) and phase to provide 30 mg of colorless crystalline solid 3s. Yield: 30 mg, stirred at 25 °C for 18 h. The reaction mixture was diluted with EtOAc 1 44%; Rf 0.4 (silica gel, mobile phase: hexane/EtOAc 3:1); H NMR (30 mL) and washed with 10% citric acid (10 mL) and brine (10 mL). δ − − fi (400 MHz, CDCl3): /ppm = 1.56 1.78 (m, 5H), 1.79 1.97 (m, The organic layer was dried over Na2SO4, ltered, and concentrated. 3H), 1.99−2.09 (m, 1H), 2.15 (d, J = 11.5, 1H), 2.32 (d, J = 10.1 Hz, The crude residue was flash chromatographed on silica gel: 30 → 50% 2H), 2.61−2.78 (m, 1H), 3.69 (s, 1H), 6.76−7.21 (m, 2H), 7.35−7.59 EtOAc/hexane to give 82 mg of 3 as a colorless noncrystalline solid 13 1 (m, 1H), 7.85−7.89 (m,1H); C NMR (101 MHz, CDCl ): δ/ppm = 3a-Ac. Yield: 82 mg, 74%; Rf = 0.2 (hexane/EtOAc 5:1); H NMR 3 δ − − 29.3 (CH), 30.8 (CH2), 31.8 (CH), 32.7 (CH), 36.6 (CH ), 36.8 (400 MHz, CDCl3): /ppm = 1.62 1.69 (m, 1H), 1.76 1.97 (m, 2 − − − (CH2), 37.7 (CH2), 41.0 (CH2), 75.1 (CH), 83.8 (C), 116.7 (d, J =12 7H), 2.08 (s, 3H), 2.21 2.24 (m, 1H), 2.44 2.58 (m, 2H), 2.69 2.80 Hz, CH), 117.8 (d, J = 10 Hz, C), 124.0 (d, J = 4 Hz, CH), 131.0 (d, J (m, 2H), 4.35−4.40 (m, 1H), 6.12 (br s, 1H); 13C NMR (101 MHz, δ = 2 Hz, CH), 132.8 (d, J = 9 Hz, CH), 161.4 (d, J = 258 Hz, C), 162.2 CDCl3): /ppm = 23.6 (CH), 29.9 (CH2), 32.1 (CH3), 32.3 (CH), 19 δ − 35.2 (CH), 35.6 (CH2), 36.1 (CH2), 46.9 (CH2), 52.6 (CH2), 52.9 (d, J = 5 Hz, C); FNMR (377 MHz, CDCl3): /ppm = 109.8; IR − (neat): ν̃/cm−1 = 2908, 2843, 1625, 1604, 1494, 1454, 1336, 1260, (C), 60.9 (CH), 169.3 (C); IR (neat): ν̃/cm 1 = 3352, 2908, 2853, 1222, 1105, 1034, 1012, 951, 885, 873, 778, 748, 696; HRMS (ESI/ 1649, 1542, 1473, 1450, 1372, 1281, 1175, 1126, 1103, 1021, 947, 936, + + TOF) m/z: [M + Na] calcd for C17H18NFONa 294.12701; found 814, 681, 592; HRMS (ESI/TOF) m/z: [M + Na] calcd for 294.1264. C12H18NOINa 342.0331; found 342.0325. Compound R,S-2f. Starting material 2 (193 mg, 1.0 mmol) was Compound 5. Pd(PPh3)4 (5.6 mg, 0.005 mmol) and DPPP (2.8 ° dissolved in 2 mL of dry tetradydrofuran, and the solution was cooled mg, 0.007 mmol) in PhCF3 (0.5 mL) were stirred at 25 C for 10 min to 0 °C. BuLi (1.6 M in hexane; 0.7 mL) was added to the reaction under Ar. Then 3a-Ac (46 mg, 0.144 mmol) in PhCF3 (1 mL), mixture and stirred at 0 °C for 1 h. Then pentafluorophenylester of benzoxazol (11 mg, 0.092 mmol), and Cs2CO3 (62 mg, 0.190 mmol) ° (R)-O-Me-mandelic acid (1.5 mmol) dissolved in 1 mL of dry THF were added. The resulting suspension was stirred at 110 C for 3 d. was added, and the reaction mixture was heated to 25 °C and stirred at Afterward, the reaction mixture was allowed to reach room this temperature for 18 h. Afterward, the reaction was quenched by temperature and solvent was removed under vacuo. The crude residue fl → adding brine and the product was extracted using EtOAc. The organic was ash chromatographed on silica gel: 30 50% EtOAc/hexane to fractions were dried using MgSO , and solvent from the organic give 20 mg of 4 as a colorless noncrystalline solid 5. Yield: 20 mg, 4 1 δ fractions was evaporated under vacuo. The crude product (ratio of 69%; Rf = 0.15 (hexane/EtOAc 5:1); H NMR (400 MHz, CDCl3): / − − − diastereomers 1:1) was purified by column chromatography on silica ppm = 1.69 1.75 (m, 1H), 1.75 1.86 (m, 5H), 1.98 2.07 (m, 2H), − − − − gel using hexane/EtOAc (5:1) as the mobile phase to provide 2.08 2.21 (m, 4H), 2.44 2.53 (m, 2H), 4.47 4.51 (m, 1H), 5.90 − − − separated diastereomers (R,R-2f) (less polar) and (R,S-2f) (more 5.92 (m, 1H), 7.28 7.35 (m, 2H), 7.49 7.54 (m, 1H), 7.68 7.72 (m, 13 δ polar) in equal quantities. Yield: 143 mg, 42%; Mp: 191.5−192.5 °C 1H); C NMR (101 MHz, CDCl3): /ppm = 26.9 (CH), 27.2 (CH), 30.7 (CH ), 32.1 (CH), 34.4 (CH ), 36.3 (CH ), 36.4 (CH ), 39.4 (crystallized from hexane/CH2Cl2); Rf 0.15 (more polar diastereomer) 2 2 2 2 (silica gel, mobile phase: hexane/EtOAc 5:1); 1H NMR (400 MHz, (C), 40.4 (CH2), 55.0 (CH), 110.8 (CH), 119.3 (CH), 124.4 (CH), δ − 125.1 (CH), 139.7.3 (C), 150.5 (C), 169.4 (C), 169.9 (C); IR (neat): CDCl3): /ppm = 0.92 (d, J = 13.4 Hz, 1H), 1.07 1.09 (m, 1H), − − − − − ν̃/cm 1 = 3307, 2910, 2854, 1648, 1536, 1455, 1372, 1272, 1240, 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, 1179, 1121, 1043, 909, 795, 726; HRMS (ESI/TOF) m/z: [M + Na] 1H), 6.06 (s, 1H), 7.26−7.38 (m, 3H), 7.42−7.59 (m, 2H); 13C NMR calcd for C19H22N2O2Na 333.1579; found 333.1573. δ (101 MHz, CDCl3): /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 ■ ASSOCIATED CONTENT (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 = S Supporting Information 2907, 2852, 1762, 1717, 1372, 1324, 1288, 1268, 1198, 1111, 1028, The Supporting Information is available free of charge on the 963, 736, 692; HRMS (ESI/TOF) m/z: [M + Na]+ calcd for ACS Publications website at DOI: 10.1021/acs.joc.7b00711. C20H23NO4Na 364.15248; found 364.1529. Compound R,R-2f. Yield: 140 mg, 41%; Mp: 121.5−122.0 °C Crystallographic data (CIF, CIF) (crystallized from hexane/CH2Cl2); Rf 0.2 (less polar diastereomer) NMR spectra, HPLC chromatograms (PDF) (silica gel, mobile phase: Hexane/EtOAc 5:1); 1H NMR (400 MHz, δ − − − CDCl3): /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 ■ AUTHOR INFORMATION (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, CDCl ): δ/ppm = 29.1 Corresponding Author 3 * (CH), 29.8 (CH2), 30.5 (CH), 31.0 (CH), 35.7 (CH2), 36.3 (CH2), E-mail: [email protected]. 38.5 (CH2), 39.6 (CH2), 57.5 (CH3), 67.3 (CH), 80.0 (C), 81.5 ORCID (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, Radim Hrdina: 0000-0001-5060-6666 1455, 1356, 1263, 1200, 1089, 1026, 977, 916, 760, 739, 700, 655; Notes + HRMS (ESI/TOF) m/z:[M+Na] calcd for C20H23NO4Na The authors declare no competing financial interest. 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 ■ ACKNOWLEDGMENTS ° cooled to 0 C. Then water (4 mL) and LiOH (390 mg) were added This work was supported by the LOEWE “SynChemBio” 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 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 using EtOAc. The organic fractions were dried using MgSO4, and solvent from the organic fractions was evaporated under vacuo. The his generous support, Dr. D. R. Bhandari for MALDI crude product was purified by column chromatography on silica gel measurements, Dr. H. Hausmann for NMR measurements, using (hexane/EtOAc 2:1) as the mobile phase to provide 185 mg, and Dr. Sean Culver for language corrections.

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