Triflic Acid Promoted Decarboxylation of Adamantane-oxazolidine-2-one: Access to Chiral Amines and HeterocyclesRadim 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 chirallipophilic and conformationally rigid amines and heterocycles by decarbox-ylation of adamantane-oxazolidine-2-one. Triflic acid or aluminum triflatepromote the addition of diverse nucleophiles to the oxazolidine-2-one moietyaccompanied by the release of carbon dioxide. The resulting amine orheterocycle is then protonated/metalated by the catalyst (promotor).Additionally, the starting racemic material, adamantane-oxazolidine-2-one, wasresolved 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

Adamantane based amines (bulky, lipophilic) are syntheticallyuseful building blocks in the preparation of bioactivecompounds1 (drug development), ligands (transition metalcatalysis), organocatalysts,2 and functional materials aspolymers3 and organic frameworks.4 Typically, these adaman-tane derivatives (diamondoids5 for higher congeners) are usedas add-on structures, exploiting the reactivity of an amino groupto form an amide bond, thereby increasing the lipophilicity ofthe target compounds.Monosubstituted adamantane amines, or achiral amines, are

generally prepared by undirected C−H oxidation of theadamantane core.6 A number of procedures have beendeveloped to achieve these compounds in an effective way.7

The modular approach to chiral 1,2-disubstituted adaman-tane derivatives (avoiding the cage opening8) is currentlystudied 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 acidcatalyzed decarboxylation of the adamantane-oxazolidine-2-oneand subsequent reaction with the nucleophile (Figure 1).Addition of water, Brønstedt acids, heteroatom nucleophiles,arenes, nitriles, and carboxylic acids give rise to a variety ofprimary amines or heterocycles in one single step, which can befurther used as valuable building blocks in the organic synthesis.

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

the decarboxylation reaction leads to aziridines.12 Theseaziridines can be further protected on the nitrogen for furtherfunctionalization,13 or it may undergo an acid catalyzed openingreaction,14 where the substitution pattern governs thecorresponding regioselectivities.15 In the case of the studiedadamantane derivative, the formation of the aziridine unit isrestricted, which enables the addition of nucleophiles on theformal dipole, possessing a partial positive charge on thetertiary carbon and negative charge on the nitrogen. Thismethod minimizes the number of synthetic steps and enablesthe synthesis of new compounds (Figure 3).16

Received: March 27, 2017Published: April 7, 2017

Figure 1. Synthesis of chiral 1-substituted-adamantane-2 amines.

Figure 2. Decarboxylation of oxazolidine-2-ones.

Article

pubs.acs.org/joc

© 2017 American Chemical Society 4891 DOI: 10.1021/acs.joc.7b00711J. Org. Chem. 2017, 82, 4891−4899

■ RESULTS AND DISCUSSIONThe starting material 2 was prepared according to the publishedprotocol17 from adamantane-1-carbamate 1, and its synthesiswas optimized to lower the loading of the dirhodium catalyst(Scheme 1). By changing the solvent from dichloromethane to

1,2-dichloroethane and increasing the reaction temperature to70 °C, the cyclic carbamate 2 was prepared with a comparableyield, but with a significant decrease in catalyst loading.18

Initial decarboxylation studies were done using arenes asnucleophiles to determine the optimal Brønsted acid and stablesolvent. Among a number of screened acids (trifluoroaceticacid, p-toluenesulfonic acid, sulfuric acid, tetrafluoroboric acid):water-free triflic acid provides the highest conversions and waschosen 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 solidsubstrates, do not decompose under strong acidic conditions,and do not react as a substrate with compound 2. In the case ofBrønsted acid sensitive substrates (ferrocene, methoxyben-zene), Al(OTf)3 was found to be an effective oxophilic Lewisacid promoting the decarboxylation of the carbamate moietyand allowing subsequent Friedel−Crafts reaction.19 Each classof nucleophiles requires specific reaction conditions (acid andsolvent) and is described separately (Figure 4).One of the most important class of compounds are

adamantane-1-halogen-2-amines. These derivatives can beused for highly useful coupling20 and substitution reactions.21

For their synthesis, corresponding salts were used as precursorstoward generating water-free halic acids. The 1-iodo, bromo,and chloro derivatives were prepared following the sameprotocol (Scheme 2).Upon mixing with TfOH, the use of KI, KBr, and NaCl

provides the corresponding HX acids, which exchange with thetriflate substituent in the position 1 of the adamantane coreafter the decarboxylation step. A 2:1 ratio of triflic acid to saltwas found to achieve the highest isolated yields. This protocolcannot be used for the introduction of fluorine as a substituent,due to the low nucleophilicity of HF. Preparation of the 1-fluoro derivative 3d was optimized separately mimicking the

Figure 3. Faster approach to known compounds.

Scheme 1. Improved Synthesis of Starting Material 2a

aChanges to original protocol highlighted in red.

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

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Balz−Schiemann reaction.22 The addition of an excess of theHBF4−Et2O complex in CH2Cl2 provides the desiredcompound in 41% yield. The azide derivative 3e was preparedfollowing the same protocol by generating 1.5 equiv of HN3from NaN3 (excess of HN3 leads to undesired formation of bisazide derivative).Introduction of ether, thioether, and phosphine moieties at

the position next to the amino group on the adamantane isdesirable for the development of new bidenatate ligands andorganocatalysts.23 Conversion to the products is observed(Scheme 3) by using triflic acid; however, in the case of the

phenolic derivatives, side reactions occur. Therefore, triflic acidwas replaced with the less acidic p-toluenesulfonic acid, whichdoes not degrade the starting nucleophile. The phosphinederivative oxidizes upon exposure to air and is characterized asphosphine 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

products in good yields using triflic acid (3j, 3k) or Al(OTf)3(3l, 3m, 3k) as the catalyst. Compound 3j was prepared fromthe enantiopure (S)-2 in 87% yield and with measurableunexpected loss of enantiopurity (86% ee).Starting material 2 was N-benzylated to attempt an

intramolecular variant of this reaction to form piperidinederivatives 3o and 3p. In both cases the reaction proceeds veryslowly using Al(OTf)3 as the promotor at 140 °C. Furtherincreasing of the temperature leads to undesired side reactions.The utilization of triflic acid leads to cleavage of the benzylgroup from the nitrogen atom.Retrosynthetically, the addition of a nitrile to the generated

dipole upon decarboxylation leads to the formation of anamidine. Derivative 3q was successfully prepared usingequimolar mixtures of p-chlorobenzonitrile and Al(OTf)3.The amidine 3q was formed in 64% yield (Scheme 5).

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

of acid and a subsequent condensation reaction does notprovide the desired compounds. Starting material 2 is firstacylated and then subjected to the triflic acid promoteddecarboxylation step. The reaction does not proceed usingAl(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-benzoxazoleusing the procedure developed by Hierso et al.25 The couplingreaction proceeded in 69% yield (Scheme 7) demonstrating theapplicability of our method toward the preparation ofderivatives with heterocycles in the position next to theamine group on the adamantane framework.

Generally, the decarboxylation/nucleophile addition methodis practical for electron-rich systems, which are stable in acidicconditions. The method is not applicable for carbamatesderived from adamantane-2-ol 2′. In this case, the formation of1-amino-2-phenyl-adamantane was not observed (Figure 5).

Among a number of side products, the mass of imine I wasdetected using HRMS, suggesting that the intramolecularrearrangement is kinetically favored over the addition of thenucleophile.Finally, starting material 2 was resolved into single

enantiomers using the Evans methodology (Scheme 8).26

Scheme 2. Synthesis of 1-Halogen-2-amines and 1-Azide-2-amines

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

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

Scheme 5. Synthesis of Heterocycles (Amidine)

Scheme 6. Synthesis of Heterocycles (Oxazolines)

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

Figure 5. Limits of the method.

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Compound 2 was converted to amide 2f, in a 1:1 mixture ofdiastereomers, which are separable by simple flash chromatog-raphy on silica gel. The (R,S)-2f isomer was crystallized todetermine the absolute configuration. In the next step, theobtained diastereomers were hydrolyzed separately to enantio-pure compounds: (R)-(−)-2 and (S)-(+)-2. The enantiopurecompound (S)-(+)-2 was utilized for the preparation ofenantio-enriched compound 3j and to observe the unexpectedcomplete racemization of the compound 3a (Figure 6).

■ CONCLUSIONWe have developed a general and facile approach to a variety of1,2-disubstituted adamantane based amines and heterocycles.An example of the postfunctionalization reaction wasdemonstrated by coupling of the β-substituted tertiary iodo-adamantane with a selected heterocycle. The mechanism of theracemization of 1,2-disubstituted (anti)-Bredt-like compoundswill be part of future studies.

■ EXPERIMENTAL SECTIONCompound 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 dry1,2-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 °Cand was filtered through the pad of silica gel. Silica gel was washedwith a hexane/EtOAc 1:1 mixture to filter out the product from thedirhodium catalyst and salts. The organic solvents were evaporatedunder vacuo, and crude product (2) was washed with hexane toremove the side product (iodobenzene). Colorless solid, crystallineproduct 2 was used for next step or purified by columnchromatography on silica gel in mobile phase (hexane/ethyl acetate2:1). 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 withpublished data.27

Compound 3a. Starting material 2 (97 mg, 0.5 mmol) and KI (166mg, 1.0 mmol) were suspended in 2 mL of 1,3,4-trichlorobenzene, andthen TfOH (300 mg, 2.0 mmol) was added dropwise to the reactionmixture at 25 °C. The reaction mixture was stirred at this temperaturefor 18 h. Afterward, the reaction mixture was quenched andneutralized using a 10% NaOH/water solution. The product wasextracted using EtOAc, and the solvent was evaporated under vacuo.The crude residue was purified by column chromatography on silicagel using EtOAc/Et3N (100:1) as a mobile phase to provide 95 mg ofa 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): ν/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 1,3,4-trichlorobenzene, and then TfOH (300 mg, 2.0 mmol) was addeddropwise to the reaction mixture at 25 °C. The reaction mixture wasstirred at this temperature for 18 h. Afterward, the reaction mixturewas quenched and neutralized using a 10% NaOH/water solution. Theproduct was extracted using EtOAc, and solvent was evaporated undervacuo. The crude residue was purified by column chromatography onsilica gel using EtOAc/Et3N (100:1) as the mobile phase to provide105 mg of a colorless noncrystalline solid 3b; Yield: 105 mg, 92%; Rf0.2 (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): ν/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 forC10H17NBr 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 thereaction mixture at 25 °C. The reaction mixture was stirred at thistemperature for 18 h. Afterward, the reaction mixture was quenchedand neutralized using a 10% NaOH/water solution. The product wasextracted using EtOAc, and solvent was evaporated under vacuo. Thecrude residue was purified by column chromatography on silica gelusing EtOAc/Et3N (100:1) as the mobile phase to provide 89 mg of acolorless 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): ν/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) wasdissolved in 2 mL of CH2Cl2, and then 1 mL of HBF4 /diethyl ether w50% was added dropwise to the reaction mixture at 25 °C. Thereaction 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, andsolvent was evaporated under vacuo. The crude residue was purified bycolumn chromatography on silica gel using EtOAc/EtOH/Et3N(10:1:0.1) as the mobile phase to provide 35 mg of a colorlessnoncrystalline solid 3d; Yield: 35 mg, 41%; Rf 0.2 (silica gel, mobilephase: 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

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

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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 = 188Hz, C); 19F NMR (400 MHz, MeOD): δ/ppm = − 144.6 (s); IR(neat): ν/cm−1 = 3370, 2910, 2856, 1602, 1455, 1344, 1058, 961, 931,893, 663; HRMS (ESI/TOF) m/z: [M + H]+ calcd for C10H17NF170.1345; 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 thenTfOH (300 mg, 176 μL) was added dropwise to the reaction mixtureat 25 °C. The reaction mixture was stirred at this temperature for 18 h.Afterward, the reaction mixture was cooled to 25 °C and neutralizedusing a 10% NaOH/water solution. The product was extracted usingEtOAc, and solvent was evaporated under vacuo. The crude residuewas purified by short pad column chromatography on silica gel usingEtOAc as the mobile phase to provide 56 mg of a colorlessnoncrystalline solid 3e; Yield: 56 mg, 58%; Rf 0.15 (silica gel, mobilephase: 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):ν/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-trichlorobenzeneand then p-toluenesulfonic acid (268 mg, 1.6 mmol) was added to thereaction mixture at 25 °C. The reaction mixture was heated to the 90°C and stirred at this temperature for 18 h. Afterward, the reactionmixture was cooled to 25 °C and neutralized using a 10% NaOH/water solution. The product was extracted using EtOAc, and solventfrom organic fractions was evaporated under vacuo. The crude residuewas purified by column chromatography on silica gel using EtOAc/EtOH/Et3N (100:10:1) as the mobile phase to provide 88 mg of acolorless 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): ν/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 forC17H24NO 258.1858; found 258.1859.Compound 3g. Starting material 2 (97 mg, 0.5 mmol) and napth-2-

ol (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 thereaction mixture at 25 °C. The reaction mixture was heated to the 90°C and stirred at this temperature for 18 h. Afterward, the reactionmixture was cooled to 25 °C and neutralized using a 10% NaOH/water solution. The product was extracted using EtOAc, and solventfrom organic fractions was evaporated under vacuo. The crude residuewas purified by column chromatography on silica gel using EtOAc/EtOH/Et3N (100:10:1) as the mobile phase to provide 96 mg of acolorless 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): ν/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 forC20H24NO 294.1858; found 294.1863.

Compound 3h. Starting material 2 (97 mg, 0.5 mmol) andthiophenol (1.40 g, 10.0 mmol) were dissolved in 2 mL of 1,3,4-trichlorobenzene, and then TfOH (300 mg, 176 μL) was addeddropwise to the reaction mixture at 25 °C. The reaction mixture washeated to 90 °C and stirred at this temperature for 18 h. Afterward, thereaction mixture was cooled to 25 °C and neutralized using a 10%NaOH/water solution. The product was extracted using EtOAc, andsolvent was evaporated under vacuo. The crude residue was purified bycolumn chromatography on silica gel using EtOAc/Et3N (100:1) asthe mobile phase to provide 56 mg of a colorless noncrystalline solid3h; Yield: 108 mg, 79%; Rf 0.15 (silica gel, mobile phase: EtOAc/Et3N100:1); 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 (101MHz, 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): ν/cm−1 = 3370, 2917, 2855, 1583, 1474, 1439, 1260, 1170,1030, 750, 694, 638; HRMS (ESI/TOF) m/z: [M + H]+ calcd forC16H22NS 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 1,3,4-trichlorobenzene, and then TfOH (466 mg, 274 μL, 3.2 mmol) wasadded to the reaction mixture at 25 °C. The reaction mixture washeated to the 120 °C and stirred at this temperature for 18 h.Afterward, the reaction mixture was cooled to 25 °C and neutralizedusing a 10% NaOH/water solution. The product was extracted usingEtOAc, and solvent from organic fractions was evaporated undervacuo. The crude residue was dissolved in 1 mL of EtOAc and wasstirred for 18 h under an air atmosphere to fully oxidize the phosphinegroup to phosphine oxide. The crude product was purified by columnchromatography on silica gel using EtOAc/EtOH/Et3N (100:10:1) asthe mobile phase to provide 50 mg of a colorless noncrystalline solid.Compound 3i contained an impurity; for structure verification anddescription, 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 byX-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):ν/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] (97mg, 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. Thereaction mixture was heated to 60 °C and stirred at this temperaturefor 18 h. Afterward, the reaction mixture was cooled to 25 °C andneutralized using a 10% NaOH/water solution. The product wasextracted using EtOAc, and solvent from organic fractions wasevaporated under vacuo. The crude residue was purified by columnchromatography on silica gel using EtOAc/EtOH/Et3N (100:10:1) asthe mobile phase to provide 103 mg of a colorless noncrystalline solid3j; 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 = 13.4Hz, 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

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(CH2), 39.1 (C), 45.1 (CH2), 61.4 (CH), 125.9 (2CH), 128.1 (CH),130.0 (2CH), 143.8 (C); IR (neat): ν/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 enantio-

enriched product 3j, (rac)-3j and (S)-3j (50 mg, 0.22 mmol) wereseparately 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. Thereaction was quenched by addition of 1 mL of water, and the crudeproduct was extracted using EtOAc. The organic fraction was driedover MgSO4, and the solvent was evaporated under vacuo. The cruderesidue was purified by column chromatography on silica gel usingEtOAc as a mobile phase to obtain 55 mg, 93% of 3j-Ac and (S)-3j-Acrespectively; 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):ν/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 reactionmixture was heated to 90 °C and stirred at this temperature for 18 h.Afterward, the reaction mixture was cooled to 25 °C and neutralizedusing a 10% NaOH/water solution. The product was extracted usingEtOAc, and solvent from organic fractions was evaporated undervacuo. The crude residue was purified by column chromatography onsilica gel using EtOAc/EtOH/Et3N (100:10:1) as the mobile phase toprovide 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);1H 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 (101MHz, 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): ν/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) wasadded to the reaction mixture at 25 °C. The reaction mixture washeated 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, andsolvent from organic fractions was evaporated under vacuo. The cruderesidue was purified by column chromatography on silica gel usingEtOAc/EtOH/Et3N (100:10:1) as the mobile phase to provide 92 mgof a colorless noncrystalline solid (mixture of para and ortho isomer3l/3m in ratio 4:1); Yield: 92 mg, 70%; Rf 0.45 (silica gel, mobilephase: 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): ν/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

(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): ν/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) andferrocene (960 mg, 5.0 mmol) were dissolved in 6 mL of 1,3,4-trichlorobenzene, and then Al(OTf)3 (268 mg, 1.6 mmol) was addedto the reaction mixture at 25 °C. The reaction mixture was heated tothe 90 °C and stirred at this temperature for 18 h. Afterward, thereaction mixture was cooled to 25 °C and neutralized using a 10%NaOH/water solution. The product was extracted using EtOAc, andsolvent from organic fractions was evaporated under vacuo. The cruderesidue was purified by column chromatography on silica gel usingEtOAc/EtOH/Et3N (100:10:1) as the mobile phase to provide 128mg 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): ν/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) wasdissolved in 2 mL of dry tetradydrofuran, and the solution was cooledto 0 °C. BuLi (1.6 M in hexane; 0.8 mL) was added to the reactionmixture and stirred at 0 °C for 1 h. Then benzyl bromide (340 mg, 2.0mmol) was added, and the reaction mixture was heated to 25 °C andstirred at this temperature for 18 h. Afterward, the reaction wasquenched by adding brine, and the product was extracted usingEtOAc. The organic fraction was dried using MgSO4, and solvent fromorganic fractions was evaporated under vacuo. The crude residue waspurified by column chromatography on silica gel using hexane/EtOAc(2:1) as the mobile phase to provide 214 mg of a colorlessnoncrystalline solid 2b; Yield: 214 mg, 88%; Rf 0.6 (silica gel, mobilephase: 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): ν/cm−1

= 2932, 2862, 1741, 1495, 1431, 1331, 1027, 956, 742, 704, 644;HRMS (ESI/TOF) m/z: [M + Na]+ calcd for C18H21NO2Na306.1470; found 306.1469.

Compound 3o. Starting material 2b (225 mg, 0.79 mmol) andAl(OTf)3 (416 mg, 0.88 mmol) were suspended in 8 mL of 1,3,4-trichlorobenzene at 25 °C. The reaction mixture was heated to the 140°C and stirred at this temperature for 18 h. Afterward, the reactionmixture was cooled to 25 °C and neutralized using a 10% NaOH/water solution. The product was extracted using EtOAc, and solventfrom organic fractions was evaporated under vacuo. The crude productwas purified by column chromatography on silica gel using EtOAc/EtOH/Et3N (100:10:1) as the mobile phase to provide 31 mg ofcolorless 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 (101MHz, 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

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(CH), 134.3 (C), 144.4 (C); IR (neat): ν/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 andstirred at 0 °C for 1 h. Then para-methyl-benzyl bromide (368 mg, 2.0mmol) was added, and the reaction mixture was heated to 25 °C andstirred at this temperature for 18 h. Afterward, the reaction wasquenched by adding brine and the product was extracted using EtOAc.The organic fraction was dried using MgSO4, and solvent from theorganic fractions was evaporated under vacuo. The crude residue waspurified by column chromatography on silica gel using hexane/EtOAc(2:1) as the mobile phase to provide 224 mg of colorlessnoncrystalline solid 2c. Yield: 224 mg, 75%; Rf 0.6 (silica gel, mobilephase: 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): ν/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; found320.1624.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 1,3,4-trichlorobenzene at 25 °C. The reaction mixture was heated to the 140°C and stirred at this temperature for 18 h. Afterward, the reactionmixture was cooled to 25 °C and neutralized using a 10% NaOH/water solution. The product was extracted using EtOAc, and solventfrom the organic fractions was evaporated under vacuo. The cruderesidue was purified by column chromatography on silica gel usingEtOAc/EtOH/Et3N (100:10:1) as the mobile phase to provide 30 mgof 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): ν/cm−1 = 3009, 2907, 2849, 1612, 1501, 1449, 1343,1255, 1126, 803, 704, 642; HRMS (ESI/TOF) m/z: [M + H]+ calcdfor C18H24N 254.1909; found 254.1908.Compound 3q. Starting material 2 (96 mg, 0.5 mmol), 4-cyano-

chlorobenzene (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. Thereaction mixture was heated to 90 °C and stirred at this temperaturefor 18 h. Afterward, the reaction mixture was cooled to 25 °C andneutralized using 10% NaOH/water solution. The product wasextracted using EtOAc, and solvent from organic fractions wasevaporated under vacuo. The crude residue was purified by columnchromatography on silica gel using EtOAc/Et3N (100:1) as the mobilephase 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): ν/cm−1 = 3443, 3129, 2919, 2852, 1604, 1452,1332, 1085, 837, 732, 584; HRMS (ESI/TOF) m/z: [M + H]+ calcdfor 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 reactionmixture 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 °Cand stirred at this temperature for 18 h. Afterward, the reaction wasquenched by adding brine, and the product was extracted usingEtOAc. Organic fractions were dried using MgSO4, and solvent fromorganic fractions was evaporated under vacuo. The crude product waspurified 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/EtOAc2:1); 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): ν/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. Thereaction mixture was heated to 60 °C and stirred at this temperaturefor 18 h. Afterward, the reaction mixture was cooled to 25 °C andneutralized using a 10% NaOH/water solution. The product wasextracted using EtOAc, and solvent from the organic fractions wasevaporated under vacuo. The crude product was purified by columnchromatography on silica gel using hexane/EtOAc (3:1) as the mobilephase 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 (101MHz, 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): ν/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) wasdissolved in 5 mL of dry tetradydrofuran, and the solution was cooledto 0 °C. BuLi (1.6 M in hexane; 0.25 mL) was added to the reactionmixture 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 to25 °C and stirred at this temperature for 18 h. Afterward, the reactionwas quenched by adding brine, and the product was extracted usingEtOAc. The organic fraction was dried using MgSO4, and solvent fromorganic fractions was evaporated under vacuo. The crude product waspurified by column chromatography on silica gel using Hexane/EtOAc(2:1) as the mobile phase to provide 105 mg of colorless solid2e.Yield: 105 mg, 83%; Rf 0.8 (silica gel, mobile phase: hexane/EtOAc2:1); 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 = 3Hz, 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): ν/cm−1 = 2911, 2853, 1778, 1684, 1612, 1455, 1327, 1203,1040, 905, 758, 660; HRMS (ESI/TOF) m/z: [M + Na]+ calcd forC18H18NFO3Na 338.11684; found 338.1169.

Compound 3s. Starting material 2e (80 mg, 0.25 mmol) wasdissolved 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 thistemperature for 18 h. Afterward, the reaction mixture was cooled to 25

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°C and neutralized using a 10% NaOH/water solution. The productwas extracted using EtOAc, and solvent from the organic fractions wasevaporated under vacuo. The crude product was purified by columnchromatography on silica gel using hexane/EtOAc (3:1) as the mobilephase 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 = 12Hz, 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): ν/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; found294.1264.Compound R,S-2f. Starting material 2 (193 mg, 1.0 mmol) was

dissolved in 2 mL of dry tetradydrofuran, and the solution was cooledto 0 °C. BuLi (1.6 M in hexane; 0.7 mL) was added to the reactionmixture 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 THFwas added, and the reaction mixture was heated to 25 °C and stirred atthis temperature for 18 h. Afterward, the reaction was quenched byadding brine and the product was extracted using EtOAc. The organicfractions were dried using MgSO4, and solvent from the organicfractions was evaporated under vacuo. The crude product (ratio ofdiastereomers 1:1) was purified by column chromatography on silicagel using hexane/EtOAc (5:1) as the mobile phase to provideseparated diastereomers (R,R-2f) (less polar) and (R,S-2f) (morepolar) 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): ν/cm−1 =2907, 2852, 1762, 1717, 1372, 1324, 1288, 1268, 1198, 1111, 1028,963, 736, 692; HRMS (ESI/TOF) m/z: [M + Na]+ calcd forC20H23NO4Na 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): ν/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 C20H23NO4Na364.1525; 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 wascooled to 0 °C. Then water (4 mL) and LiOH (390 mg) were addedto the solution, and the reaction mixture was stirred at 0 °C for 2 h.Afterward, the reaction was stopped and the product was extractedusing EtOAc. The organic fractions were dried using MgSO4, andsolvent from the organic fractions was evaporated under vacuo. Thecrude product was purified by column chromatography on silica gelusing (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 fromEtOAc); Specific optical rotation: [α]D = + 14.6 (c 1.3, CHCl3).

Compound 3a-Ac. A solution of 3a (96 mg, 0.346 mmol) inpyridine (3.0 mL) was treated with Ac2O (35 μL, 0.37 mmol) andstirred 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 solid3a-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): ν/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 forC12H18NOINa 342.0331; found 342.0325.

Compound 5. Pd(PPh3)4 (5.6 mg, 0.005 mmol) and DPPP (2.8mg, 0.007 mmol) in PhCF3 (0.5 mL) were stirred at 25 °C for 10 minunder 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 roomtemperature and solvent was removed under vacuo. The crude residuewas flash chromatographed on silica gel: 30 → 50% EtOAc/hexane togive 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):ν/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.

■ ASSOCIATED CONTENT

*S Supporting InformationThe Supporting Information is available free of charge on theACS Publications website at DOI: 10.1021/acs.joc.7b00711.

Crystallographic data (CIF, CIF)

NMR spectra, HPLC chromatograms (PDF)

■ AUTHOR INFORMATION

Corresponding Author*E-mail: radim.hrdina@org.chemie.uni-giessen.de.

ORCID

Radim Hrdina: 0000-0001-5060-6666NotesThe authors declare no competing financial interest.

■ 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 forhis generous support, Dr. D. R. Bhandari for MALDImeasurements, Dr. H. Hausmann for NMR measurements,and Dr. Sean Culver for language corrections.

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