Supporting Information Diversity-Oriented Synthesis

Supporting Information

Diversity-Oriented Synthesis of a Library of Star-Shaped 2H-Imidazolines

Xuepu Yu,# Nikolaus Guttenberger,# Elisabeth Fuchs, Martin Peters, Hansjörg Weber, and Rolf Breinbauer* Institute of Organic Chemistry, Graz University of Technology, A-8010 Graz, Austria

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General Experimental Aspects, Materials and Methods NMR spectra were recorded on a Bruker Avance III 300 MHz FT NMR spectrometer (300.36 MHz (1H), 75.53 MHz (13C)), or on a Varian Unity Inova 500 MHz NB high resolution FT NMR spectrometer (499.76 MHz (1H), 125.67 MHz (13C), 470.35 MHz (19F)) at 27°C. Chemical shifts δ [ppm] are referenced to residual protonated solvent signals as internal standard [D6]DMSO: δ = 2.50 ppm (1H), 39.52 ppm (13C) and CDCl3: δ = 7.26 ppm (1H), 77.16 ppm (13C).[1] Signal multiplicities are abbreviated as s (singlet), d (doublet), dd (doublet of doublet), t (triplet), dt (doublet of triplet), q (quadruplet), dq (doublet of quadruplet), sept (septet), m (multiplet) with the prefix b in case of broad signals. Superscript abbreviations are used as follows: Aryl/Heteroaryl: -Ar, the abbreviation Cq is used for quaternary carbon atoms. Analytical thin layer chromatography (TLC) was performed on Merck silica gel 60F254 and spots were visualized by UV-light (λ = 254 and/or 366 nm), or by treatment with the following reagents followed by warming with a heat gun: -

Cerium ammonium molybdate solution (CAM) (CAM: 2.0 g Ce(IV)(SO)4, 50 g (NH4)2MoO4, 50 mL concentrated H2SO4 in 400 mL water)

-

Ninhydrin solution (250.0 mg ninhydrin, 5 mL pyridine and 95 mL MeOH)

-

Potassium permanganate solution (3.0 g potassium permanganate, 20.0 g K2CO3, 300 mL of a 5% aqueous NaOH solution)

Flash column chromatography was performed using silica gel 60 Å (35-70 µm particle size) from ACROS Organics at an air pressure of ~1.5 bar. A 20 to 100-fold excess of silica gel was used with respect to the amount of dry raw material (exact values are given in experimental procedures). The stationary phase was filled in an appropriate sized column resulting in a pad of 15-25 cm silica gel. The column was equilibrated with the solvent or solvent mixture, and the sample was loaded onto the pad by diluting the crude product with 2

the eluent. If the crude product was not good soluble in the eluent, the sample was dissolved in a proper solvent (MeOH or EtOAc), and the double amount of silica gel (or Celite® 545, particle size 0.02-0.1 mm) was added, followed by removing the solvent using a rotary evaporator and drying in vacuo. The mobile phase was forced through the column by means of a rubber bulb pump. For semi-preparative HPLC a Thermo Scientific Dionex Ulti Mate 3000 Instrument was used. Semi-preparative HPLC was carried out utilizing a MachereyNagel VP 125/21 Nucleodur 100-5 C18 ec column. Demineralized water was additionally purified by filtering through a 0.2 µm cellulose nitrate membrane filter. High pressure hydrogenation experiments were performed using the H-CubeTM continuous hydrogenation unit (HC-2.SS) from Thales Nanotechnology Inc. running with a Knauer Smartline pump 100 and equipped with a 10 mL ceramic pump head. As hydrogenation catalyst 10% Pd/C catalyst cartridges were used (Thales Nanotechnology inc., THS01111, 10% Pd/C CatCartTM). GC-MS analyses were carried out on an Agilent Technologies 7890A GC system equipped with a 5975C mass selective detector (inert MSD with Triple Axis Detector system, EI, 70 eV). In both systems samples were injected by employing autosampler 7683B in a split mode 1/175 (inlet temperature: 250°C; injection volume: 2.0 μL) and separated on an Agilent Technologies J&W GC HP-5MS capillary column ((5%-phenyl)-methylpolysiloxane; 30 m × 0.25 mm × 0.25 μm) at a constant helium flow rate (He 5.0 (Air Liquide), 1.085 mL/min, average velocity 41.6 cm/sec). General gradient temperature method was used XY_50_S.m (M1): (initial temperature: 50°C for 1 min, linear increase 40°C/min to 300°C, hold for 5 min, 1 min post-run at 300°C, detecting range: 50.0 to 550.0 amu, solvent delay of 2.80 min). When reactions were monitored by GC-MS, the samples were prepared using a microscale workup. This means, an 3

aliquot was taken from the reaction mixture, quenched with ~1 mL sat. NaHCO3 solution and ~1 mL DCM or EtOAc. After proper mixing and phase separation, the organic layer was collected, dried over MgSO4 and filtered through cotton in a Pasteur-pipette. Reaction mixtures containing transition metals were additionally filtered through a short pad of silica gel (~1 cm) over cotton in a Pasteur-pipette (eluted with EtOAc or MeOH). High Resolution Mass Spectrometry (HRMS) was performed on an Agilent Technologies 7890A (G3440A) GC system equipped with an Agilent Technologies J&W GC-column DB-5MS (length: 30 m; inner-diameter: 0.250 mm; film: 0.25 µm) at a constant helium flow. The GC was coupled to a Waters GCT Premier Micromass. For Direct Inlet (DI-EI) the Waters GCT Premier Micromass unit was used. Melting points were determined on a “Mel-Temp” melting-point apparatus (Electrothermal) and are given uncorrected. All used chemicals and reagents were purchased from the companies Aldrich, Sigma Aldrich, Fluka, Merck, ABCR, Alfa Aesar, Fisher Scientific and ACROS Organics. All compounds were used without further purification unless otherwise noted. The solvents listed below were used as absolute solvents in the reactions carried out. Acetonitrile: Acetonitrile was purchased from ACROS Organics in 99.9% purity without any stabilizer and stored over 3 Å molecular sieves in a brown 1 L Schlenk bottle under argon atmosphere. Chloroform: Chloroform was purchased from ACROS Organics as extra dry solvent (99.9%, Extra Dry, over 4 Å molecular sieves, AcroSeal®). Dichloromethane: Dichloromethane was first distilled over phosphorus pentoxide and then over calciumhydride under argon atmosphere and stored over 4 Å molecular sieves in a brown 1 L Schlenk bottle under argon atmosphere.

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N,N-Dimethylformamide: N,N-Dimethylformamide was purchased from ACROS Organics as extra dry solvent (99.8%, over 3 Å molecular sieves, AcroSeal®) and directly used in the reactions. Dimethylsulfoxide: Dimethylsulfoxide was purchased from ACROS Organics and stored over 4 Å molecular sieves in a brown 1 L Schlenk bottle. Ethanol: Ethanol was purchased from Merck (99%, 1% ethyl methyl ketone as poisoning agent), distilled over sodium and diethyl phthalate and stored over 3 Å molecular sieves in an amber 1 L Schlenk bottle under argon atmosphere. Alternatively, it was purchased from Sigma-Aldrich as anhydrous solvent (99.8%) and stored over 3 Å molecular sieves in an amber 1 L Schlenk bottle under argon atmosphere. Ethylacetate: Ethylacetate was purchased from ACROS Organics as extra dry solvent (99.9%, AcroSeal®, over molecular sieves) and directly used in the reactions. Methanol: Methanol was distilled over magnesium turnings and iodine under argon atmosphere and stored over 3 Å molecular sieves in an amber 1 L Schlenk bottle under argon atmosphere. Alternatively, it was purchased from Sigma-Aldrich as anhydrous solvent (99.8%) and stored over 3 Å molecular sieves in an amber 1 L Schlenk bottle under argon atmosphere. Pyridine: Pyridine was purchased from Acros Organics as extra dry solvent (99.5%, over 4 Å molecular sieves, AcroSeal®). Tetrahydrofuran: Tetrahydrofuran was dried at reflux temperature under argon atmosphere over sodium until benzophenone indicated dryness by a deep violet color and distilled. The dried THF was stored over 4 Å molecular sieves in a brown 1 L Schlenk bottle under argon atmosphere. 5

Triethylamine: Triethylamine was first distilled over KOH and then distilled over calcium hydride under argon atmosphere and stored over 4 Å molecular sieves in a 1 L Schlenk bottle under argon atmosphere. For reactions, which could be performed in air, for work-ups and purification steps the following solvents listed below were used: cyclohexane, chloroform, dichloromethane, ethyl acetate and methanol were purchased from Fisher Scientific as analytical grade (99.99%) solvents and used directly without any purification. If needed, solvents were additionally distilled using a rotary evaporator to remove trace impurities or stabilizers. Diethylether and tetrahydrofuran were distilled and stored over KOH pellets in a brown 1 L bottle. Acetic acid was purchased from Sigma-Aldrich (glacial, 99.8%) or ACROS Organics (96%). Acetonitrile was purchased from Alfa Aesar (99.9%). Ethanol was purchased from Merck (1% ethyl methyl ketone as stabilizer). n-Hexane was received dry and stored under argon over 4 Å molecular sieves in a dark Schlenk bottle. For work-up purposes and quenching of reactions deionized water was used. Molecular sieves were activated by filling a 500 mL round-bottomed flask to one third of its volume with molecular sieves (Sigma-Aldrich, beads, 8-12 mesh) and heating the flask in a heating mantle (~150°C) under oil pump vacuum for ~3 days, followed by cooling to room temperature under an atmosphere of argon. Degassing was carried out by passing a stream of argon through the reaction mixture/solvent. This means, a balloon filled with argon was placed on a syringe with needle, and the needle was punched through a septum and dipped into the reaction mixture. Additionally the vessel was immersed in an ultrasonic bath. Temperatures were measured externally. When working at a temperature of 0°C, an ice-water bath served as the cooling agent. Temperatures of -5°C and -20°C were achieved with ice/MeOH, -78°C using dry-ice/acetone mixtures. Reactions carried out at higher

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temperatures than RT were heated in a silicon oil bath on a hot plate (RCT basic IKAMAG® safety control) equipped with a temperature controller. n-Butyllithium: n-Butyllithium was purchased from ACROS Organics as a 2.5 M solution in hexane. Before starting a reaction with n-BuLi the exact concentration of the solution was determined by a titration method from KOFRON and BACLAWSK.[1] A 100 mL Schlenk tube was dried under vacuum, filled with nitrogen and charged with 250.0 mg diphenyl acetic acid and 10 mL absolute THF. To this solution n-BuLi was added dropwise by using a syringe until the color of the solution turned from colorless to yellow. The added amount of n-BuLi corresponds to the weighed amount of diphenylacetic acid. This procedure was repeated twice and the average was used to calculate the exact concentration of n-BuLi. Reactions were carried out using standard Schlenk techniques under an inert atmosphere of argon or nitrogen unless otherwise indicated. The syntheses which are sensitive against oxidation were accomplished under nitrogen or argon atmosphere and absolute and degassed solvents (if necessary) were applied. 1,2-Diphenylethyne (2a)

In a flame-dried, evacuated and nitrogen-purged 10 mL Schlenk flask, equipped with a Teflon-coated stir bar, 200 μL (1.9 mmol, 1.0 eq) bromobenzene, 250 μL (2.3 mmol, 1.2 eq) phenylacetylene, 317 μL (3.8 mmol, 2.0 eq) pyrrolidine, 7 mg (0.038 mmol, 0.02 eq) palladium(II) chloride (PdCl2) and 20 mg (0.076 mmol, 0.04 eq) triphenylphosphine (PPh3) were added in 2 mL degasssed water. The black solution was heated to 120°C for 2 h. It was then cooled down to RT and extracted with ethyl acetate (2 × 10 mL). The organic phase was 7

washed with brine, dried over anhydrous Na2SO4 and filtered. The solvents were removed under reduced pressure using a rotary evaporator. The residue was purified via flash chromatography (cyclohexane, 23 g silica gel) to obtain the product. C14H10 [178.23 g/mol] Yield: 312 mg (1.75 mmol, 92%), colorless crystals Rf: 0.43 (cyclohexane) mp: 59-61°C 1

H-NMR (CDCl3): δ (ppm) = 7.59-7.49 (m, 4H, Ar-H), 7.41-7.29 (m, 6H, Ar-H).

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C-NMR (CDCl3): δ (ppm) = 131.8 (4 × CHAr), 128.5 (4 × CHAr), 128.4 (2 × CHAr), 123.4 (2

× Cq, CAr), 89.5 (2 × Cq).

1-Methyl-3-(phenylethynyl)benzene (2b)

In a flame-dried, evacuated and nitrogen-purged 10 mL Schlenk flask, equipped with a Teflon-coated stir bar, 200 μL (1.65 mmol, 1.0 eq) 3-bromotoluene, 217 μL (2.0 mmol, 1.2 eq) phenylacetylene, 275 μL (3.3 mmol, 2.0 eq) pyrrolidine, 6 mg (0.033 mmol, 0.02 eq) palladium(II) chloride (PdCl2) and 17 mg (0.066 mmol, 0.04 eq) triphenylphosphine (PPh3) were dissolved in 2 mL degasssed water. The black solution was heated to 120°C for 2 h. It was then cooled down to RT and extracted with ethyl acetate (2 × 10 mL). The organic phase was washed with brine, dried over anhydrous Na2SO4 and filtered. The solvents were

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removed under reduced pressure using a rotary evaporator. The residue was purified via flash chromatography (cyclohexane, 20 g silica gel) to obtain the product. C15H12 [192.26 g/mol] Yield: 270 mg (1.4 mmol, 85%), colorless oil Rf: 0.32 (cyclohexane) 1

H-NMR (CDCl3): δ (ppm) = 8.61 (dd, 3J = 6.5, 3.2 Hz, 2H, Ar-H), 7.40-7.31 (m, 5H, Ar-H),

7.23 (d, 3J = 7.5 Hz, 1H, Ar-H), 7.15 (d, 3J = 7.6 Hz, 1H, Ar-H), 2.36 (s, 3H, CH3). 13

C-NMR (CDCl3): δ (ppm) = 135.5 (Cq, CAr), 132.2 (CHAr), 131.6 (2 × CHAr), 129.2 (CHAr),

128.7 (CHAr), 128.5 (CHAr), 128.3 (2 × CHAr), 95.3 (Cq), 86.6 (Cq), 21.3 (CH3).

1-Methoxy-4-(phenylethynyl)benzene (2c)

In a flame-dried, evacuated and nitrogen-purged 10 mL Schlenk flask, equipped with a Teflon-coated stir bar, 200 μL (1.6 mmol, 1.0 eq) 4-bromoanisole, 210 μL (1.92 mmol, 1.2 eq) phenylacetylene, 267 μL (3.2 mmol, 2.0 eq) pyrrolidine, 5.7 mg (0.032 mmol, 0.02 eq) palladium(II) chloride (PdCl2) and 16.7 mg (0.064 mmol, 0.04 eq) triphenylphosphine (PPh3) were dissolved in 2 mL degasssed water. The black solution was heated to 120°C for 2 h. It was then cooled down to RT and extracted with ethyl acetate (2 × 10 mL). The organic phase was washed with brine, dried over anhydrous Na2SO4 and filtered. The solvents were removed under reduced pressure using a rotary evaporator. The residue was purified via flash chromatography (cyclohexane/ethyl acetate = 20:1, 20 g silica gel) to obtain the product. 9

C15H12O [208.26 g/mol] Yield: 245 mg (1.18 mmol, 75%), yellow oil Rf: 0.48 (cyclohexane/ethyl acetate = 20:1 (v/v)) 1

H-NMR (CDCl3): δ (ppm) = 7.56-7.44 (m, 4H, Ar-H), 7.38-7.30 (m, 3H, Ar-H), 6.88 (d, 3J =

8.8 Hz, 2H, Ar-H), 3.83 (s, 3H, CH3). 13

C-NMR (CDCl3): δ (ppm) = 159.8 (Cq, COCH3), 133.2 (2 × CHAr), 131.6 (2 × CHAr), 128.5

(2 × CHAr), 128.1 (CHAr), 123.8 (Cq, CAr), 115.5 (Cq, CAr), 114.2 (2 × CHAr), 89.5 (Cq), 88.2 (Cq), 55.4 (CH3). 4-(Phenylethynyl)benzonitrile (2d)

In a flame-dried, evacuated and nitrogen purged 10 mL Schlenk flask, equipped with a Teflon-coated stir bar, 182 mg (1.0 mmol, 1.0 eq) 4-bromobenzonitrile, 132 μL (1.2 mmol, 1.2 eq) phenylacetylene, 167 μL (2.0 mmol, 2.0 eq) pyrrolidine, 4 mg (0.02 mmol, 0.02 eq) palladium(II) chloride (PdCl2) and 11 mg (0.04 mmol, 0.04 eq) triphenylphosphine (PPh3) were dissolved in 2 mL degasssed water. The black solution was heated to 120°C for 2 h. It was then cooled down to RT and extracted with ethyl acetate (3 × 10 mL). The organic phase was washed with brine, dried over anhydrous Na2SO4, filtered. The solvent was removed under reduced pressure using a rotary evaporator. The residue was purified via flash chromatography (cyclohexane/ethyl acetate = 15:1 (v/v), 21 g silica gel) to obtain the product. C15H9N [203.24 g/mol] 10

Yield: 177 mg (0.87 mmol, 87%), brown crystals Rf: 0.40 (cyclohexane/ethyl acetate = 15:1 (v/v)) mp: 104-106°C 1

H-NMR (CDCl3): δ (ppm) = 7.68-7.58 (m, 4H, Ar-H), 7.57-7.51 (m, 2H, Ar-H), 7.43- 7.33

(m, 3H, Ar-H). 13

C-NMR (CDCl3) : δ (ppm) = 132.2 (2 × CHAr), 132.2 (2 × CHAr), 131.9 (2 × CHAr), 129.3

(CHAr), 128.7 (2 × CHAr), 128.4 (Cq, CAr), 122.4 (Cq, CAr ), 118.7 (Cq, CN), 111.6 (Cq, CAr), 93.9 (Cq), 87.9 (Cq). 1-Nitro-4-(phenylethynyl)benzene (2e)

In a flame-dried, evacuated and nitrogen-purged 150 mL Schlenk flask, equipped with a Teflon-coated stir bar, 14.3 g (70.0 mmol, 1.0 eq) 1-bromo-4-nitrobenzene, 9.41 mL (84.0 mmol, 1.2 eq) phenylacetylene, 11.8 mL (140.0 mmol, 2.0 eq) pyrrolidine, 247 mg (1.4 mmol, 0.02 eq) palladium(II) chloride (PdCl2) and 735 mg (2.8 mmol, 0.04 eq) triphenylphosphine (PPh3) were dissolved in 70 mL degasssed water. The black solution was heated to 120°C for 2 h. It was then cooled down to RT and extracted with ethyl acetate (3 × 80 mL). The organic phase was washed with brine, dried over anhydrous Na2SO4, filtered. The solvents were removed under reduced pressure using a rotary evaporator. The residue was purified via flash chromatography (cyclohexane/ethyl acetate = 50:1 (v/v), 175 g silica gel, size: 22.5 × 4.9 cm) to obtain the product. C14H9NO2 [223.23 g/mol] 11

Yield: 15.2 g (68.1 mmol, 97%), yellow solid Rf: 0.30 (cyclohexane/ethyl acetate = 50:1 (v/v)) mp: 139-141°C 1

H-NMR (CDCl3): δ (ppm) = 8.22 (d, 3J = 8.9 Hz, 2H, Ar-H), 7.68 (d, 3J = 8.9 Hz, 2H, Ar-H),

7.57 (dd, 3J = 6.6 Hz, 3.0 Hz, 2H, Ar-H), 7.45-7.34 (m, 3H, Ar- H). 13

C-NMR (CDCl3) : δ (ppm) = 147.0 (Cq, CAr), 132.4 (2 × CHAr), 132.0 (2 × CHAr), 130.4

(Cq, CAr), 129.4 (CHAr), 128.7 (2 × CHAr), 123.8 (2 × CHAr), 122.3 (Cq, CAr), 94.9 (Cq), 87.7 (Cq).

2-(Phenylethynyl)pyridine (2f)

In a flame-dried, evacuated and nitrogen-purged 100 mL Schlenk flask, equipped with a Teflon-coated stir bar, 4.82 mL (50.0 mmol, 1.0 eq) 2-bromopyridine, 6.72 mL (60.0 mmol, 1.2 eq) phenylacetylene, 8.43 mL (100.0 mmol, 2.0 eq) pyrrolidine, 177.0 mg (1.0 mmol, 0.02 eq) palladium(II) chloride (PdCl2) and 525 mg (2.0 mmol, 0.04 eq) triphenylphosphine (PPh3) were dissolved in 50 mL distilled water. The black solution was heated to 120°C for 2 h. It was then cooled down to RT and extracted with ethyl acetate (3 × 50 mL). The organic phase was washed with brine, dried over anhydrous Na2SO4 and filtered. The solvents were removed under reduced pressure using a rotary evaporator. The residue was purified via flash chromatography (cyclohexane/ethyl acetate = 6:1 (v/v), 175 g silica gel, size: 22.5 × 4.9 cm) to obtain the product. C13H9N [179.22 g/mol] 12

Yield: 7.4 g (41.3 mmol, 83%), brownish oil Rf: 0.28 (cyclohexane/ethyl acetate = 6:1 (v/v)) 1

H-NMR (CDCl3) : δ (ppm) = 8.62 (d, 3J = 4.2 Hz, 1H, Ar-H), 7.68 (td, 3J = 7.7 Hz, 1.7 Hz,

1H, Ar-H), 7.60 (dd, 3J = 6.6 Hz, 3.0 Hz, 2H, Ar-H ), 7.53 (d, 3J = 7.8 Hz, 1H, Ar-H), 13

C-NMR (CDCl3): δ (ppm) = 150.2 (CH, CAr), 143.6 (Cq, CAr), 136.3 (CH, CAr), 132.2 (2 ×

CHAr), 129.1 (CHAr), 128.5 (2 × CHAr), 127.3 (CH, CAr), 122.9 (CH, CAr), 122.4 (Cq, CAr), 89.4 (Cq, CAr), 88.8 (Cq, CAr).

4-(Phenylethynyl)pyridine (2g)

In a flame-dried, evacuated and nitrogen-purged 100 mL Schlenk flask, equipped with a Teflon-coated stir bar, 4.52 g (23 mmol, 1.0 eq) 4-bromopyridine hydrochloride, 3.06 mL (27.6 mmol, 1.2 eq) phenylacetylene, 3.9 mL (46.0 mmol, 2.0 eq) pyrrolidine, 82.8 mg (0.46 mmol, 0.02 eq) palladium(II)chloride (PdCl2) and 244 mg (0.92 mmol, 0.04 eq) triphenylphosphine (PPh3) were dissolved in 50 mL degasssed water. The black solution was heated to 120°C for 2 h. It was then cooled down to RT and extracted with ethyl acetate (3 × 50 mL). The organic phase was washed with brine, dried over anhydrous Na2SO4 and filtered. The solvents were removed under reduced pressure using a rotary evaporator. The residue was purified via flash chromatography (cyclohexane/ethyl acetate = 3:1 (v/v), 170 g silica gel, size: 22 × 4.9 cm) to obtain the product. C13H9N [179.22 g/mol] Yield: 3.88 g (21.6 mmol, 94%), brown solid 13

Rf: 0.30 (cyclohexane/ethyl acetate = 3:1 (v/v)) mp: 91-93°C 1

H-NMR (CDCl3): δ (ppm) = 8.61 (dd, 3J = 4.6 Hz, 1.5 Hz, 2H, Ar-H), 7.62-7.51 (m, 2H, Ar-

H), 7.44 (dd, 3J = 4.6 Hz, 1.6 Hz, 2H, Ar-H), 7.42-3.35 (m, 3H, Ar- H). 13

C-NMR (CDCl3): δ (ppm) = 148.9 (2 × CH, CAr), 132.8 (Cq, CAr), 132.1 (2 × CHAr), 129.6

(CHAr), 128.7 (2 × CHAr), 126.0 (2 × CH, CAr), 122.0 (Cq, CAr), 95.3 (Cq), 86.6 (Cq).

5-(Phenylethynyl)pyrimidine (2h)

In a flame-dried, evacuated and nitrogen-purged 10 mL Schlenk flask, equipped with a Teflon-coated stir bar, 164.0 mg (1.0 mmol, 1.0 eq) 5-bromopyrimidine, 132 μL (1.2 mmol, 1.2 eq) phenylacetylene, 167.0 μL (2.0 mmol, 2.0 eq) pyrrolidine, 4.0 mg (0.02 mmol, 0.02 eq) palladium(II) chloride (PdCl2) and 11.0 mg (0.04 mmol, 0.04 eq) triphenylphosphine (PPh3) were dissolved in 2 mL degasssed water. The black solution was heated to 120°C for 2 h. It was then cooled down to RT and extracted with ethyl acetate (2 × 10 mL). The organic phase was washed with brine, dried over anhydrous Na2SO4 and filtered. The solvents were removed under reduced pressure using a rotary evaporator. The residue was purified via flash chromatography (cyclohexane/ethyl acetate = 8:1 (v/v), 23 g silica gel, size: 14.5 × 2.4 cm) to obtain the product. C12H8N2 [180.21 g/mol] 14

Yield: 150 mg (68.1 mmol, 83%), brown oil 1

H-NMR (CDCl3): δ (ppm) = 9.14 (s, 1H, Ar-H), 8.86 (s, 2H, Ar-H), 7.57 (dd, 3J = 6.5 Hz,

3.1 Hz, 2H, Ar-H), 7.44-7.35 (m, 3H, Ar-H). 13

C-NMR (CDCl3): δ (ppm) = 158.8 (2 × CH, CAr), 156.8 (CH, CAr), 131.9 (2 × CHAr), 129.5

(CHAr), 128.7 (2 × CHAr), 121.9 (Cq, CAr), 120.1 (Cq, CAr), 96.5 (Cq), 82.4 (Cq). Diphenylethanedione (3a)

A 50 mL round-bottomed flask was charged with 178.0 mg (1.0 mmol, 1.0 eq) 1,2diphenylethyne (2a) and 15 mL reagent grade acetone. A solution of 50 mg NaHCO3 (0.6 mmol, 0.6 eq) and 246.0 mg (2 mmol, 2.0 eq) MgSO4∙7H2O in 5 mL H2O was added. The mixture was stirred with a Teflon-coated magnetic stir bar. 620.0 mg (3.9 mmol, 3.9 eq) powdered potassium permanganate (KMnO4) were added in one portion, and the mixture was stirred for 1 h. The reaction progress was monitored by TLC analysis and GC-MS. After complete conversion, the unreacted KMnO4 was reduced to Mn2+ ions by adding 300.0 mg NaNO2 and 2 ml 2M H2SO4 in small portions, stirred for 30 min. Then the reaction mixture was extracted with ethyl acetate (2 × 30 ml). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and filtered. The solvents were removed under reduced pressure using a rotary evaporator. The residue was purified via flash chromatography (cyclohexane/ethyl acetate = 3:1 (v/v), 27 g silica gel, size: 17 × 2.4 cm) to obtain the product. C14H10O2 [210.23 g/mol] Yield: 160 mg (0.76 mmol, 76%), light yellow crystals 15

Rf: 0.57 (cyclohexane/ethyl acetate = 6:1 (v/v)) mp: 94-95°C 1

H-NMR (CDCl3): δ (ppm) = 8.02-7.93 (m, 4H, Ar-H), 7.70-7.61 (m, 2H, Ar-H), 7.52 (t, 3J =

7.6 Hz, 4H, Ar-H). 13

C-NMR (CDCl3): δ (ppm) = 194.7 (2 × Cq, C=O), 135.0 (2 × CHAr), 133.1 (2 × Cq, CAr),

130.0 (4 × CHAr), 129.2 (4 × CHAr). 1-Phenyl-2-(m-tolyl)ethane-1,2-dione (3b)

A 25 mL round-bottomed flask was charged with 87 mg (0.45 mmol, 1.0 eq) 1-methyl-3(phenylethynyl)benzene (2b) and 10 mL reagent grade acetone. A solution of 23 mg NaHCO3 (0.27mmol, 0.6 eq) and 224 mg (0.91 mmol, 2.0 eq) MgSO4∙7H2O in 5 mL H2O was added. The mixture was stirred with a Teflon-coated magnetic stir bar. 280 mg (1.77 mmol, 3.9 eq) powdered potassium permanganate (KMnO4) were added in one portion, and the mixture was stirred for 2 h. The reaction progress was monitored by TLC analysis and GC-MS. After complete conversion, the unreacted KMnO4 was reduced to Mn2+ ions by adding a minimum quantity of 123 mg NaNO2 and 0.5 ml 2M H2SO4 in small portions, stirred for 30 min. Then the reaction mixture was filtered through a pad of Celite® and washed with acetone, the filtrate was concentrated in vacuo. The residue was extracted with ethyl acetate (2 × 20 ml). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and filtered. The solvents were removed under reduced pressure using a rotary evaporator. The

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residue was purified via flash chromatography (cyclohexane/ethyl acetate = 20:1 (v/v), 4.5 g silica gel) to obtain the product. C15H12O2 [224.26 g/mol] Yield: 84 mg (0.37 mmol, 82%), yellowish crystals Rf: 0.31 (cyclohexane/ethyl acetate = 20:1 (v/v)) mp: 56-57°C 1

H-NMR (CDCl3) : δ (ppm) = 8.01-7.94 (m, 2H, Ar-H), 7.77 (d, 3J = 8.0 Hz, 2H, Ar- H),

7.70-7.62 (m, 1H, Ar-H), 7.50 (dd, 3J = 15.6 Hz, 8.0 Hz, 3H, Ar- H), 7.40 (t, 3J = 7.6 Hz, 1H, Ar-H), 2.41 (s, 3H, CH3). 13

C-NMR (CDCl3): δ (ppm) = 195.0 (Cq, C=O), 194.9 (Cq, C=O), 139.2 (Cq, CAr), 135.9

(CHAr), 135.0 (CHAr), 133.2 (Cq, CAr), 133.1 (Cq, CAr), 130.4 (CHAr), 130.1 (2 × CHAr), 129.2 (2 × CHAr), 129.1 (CHAr), 127.4 (CHAr), 21.4 (CH3). 1-(4-Nitrophenyl)-2-phenylethane-1,2-dione (3c)

A 1 L round-bottomed flask was charged with 5.40 g (24.19 mmol, 1.0 eq) 1-nitro-4(phenylethynyl)benzene (2e) and 400 mL reagent grade acetone. A solution of 1.22 g NaHCO3 (14.47 mmol, 0.6 eq) and 12.14 g (48.24 mmol, 2.0 eq) MgSO4∙7H2O in 200 mL H2O was added. The mixture was stirred with a Teflon-coated magnetic stir bar. 9.7 g (60.3 mmol, 2.5 eq) powdered potassium permanganate (KMnO4) were added in one portion, and the mixture was stirred for 2 h. The reaction progress was monitored by TLC analysis and 17

GC-MS. After complete conversion, the unreacted KMnO4 was reduced to Mn2+ ions by adding a minimum quantity of 6.4 g NaNO2 and 15 ml 2M H 2SO4 in small portions, stirred for 30 min. Then the reaction mixture was filtered through a pad of Celite ® and washed with acetone, the filtrate was concentrated in vacuo. The residue was extracted with ethyl acetate (2 × 100 ml). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and filtered. The solvents were removed under reduced pressure using a rotary evaporator. The residue was purified via flash chromatography (cyclohexane/ethyl acetate = 14:1 (v/v)) to obtain the product. C14H9NO4 [255.23 g/mol] Yield: 5.5 g (21.55 mmol, 89%), yellow solid Rf: 0.30 (cyclohexane/ethyl acetate = 14:1 (v/v)) mp: 140-142°C 1


7.99 (d, 3J = 7.5 Hz, 2H, Ar-H), 7.71 (t, 3J = 7.4 Hz, 1H, Ar-H), 7.55 (t, 3J = 7.7 Hz, 2H, ArH). 13

C-NMR (CDCl3) : δ (ppm) = 193.0 (Cq, C=O), 192.2 (Cq, C=O), 151.3 (Cq, CAr), 137.4 (Cq,

CAr), 135.6 (CHAr), 132.5 (Cq, CAr), 131.1 (2 × CHAr), 130.2 (2 × CHAr), 129.4 (2 × CHAr), 124.3 (2 × CHAr).

1-(4-Methoxyphenyl)-2-phenylethane-1,2-dione (3d)

18

A 500 mL round-bottomed flask was charged with 2.18 g (10.5 mmol, 1.0 eq) 1-methoxy-4(phenylethynyl)benzene (2c) and 200 mL reagent grade acetone. A solution of 530 mg NaHCO3 (6.3 mmol, 0.6 eq) and 5.28 g (21.0 mmol, 2.0 eq) MgSO4∙7H2O in 100 mL H2O was added. The mixture was stirred with a Teflon-coated magnetic stir bar. 3.5 g (22 mmol, 2.1 eq) powdered potassium permanganate (KMnO4) were added in one portion, and the mixture was stirred for 2 h. The reaction progress was monitored by TLC analysis and GCMS. After complete conversion, the unreacted KMnO4 was reduced to Mn2+ ions by adding a minimum quantity of 2.6 g NaNO2 and 20 ml 2M H2SO4 in small portions, stirred for 30 min. Then the reaction mixture was filtered through a pad of Celite® and washed with acetone, the filtrate was concentrated in vacuo. The residue was extracted with ethyl acetate (2 × 100 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and filtered. The solvents were removed under reduced pressure using a rotary evaporator. The residue was purified via flash chromatography (cyclohexane/ethyl acetate = 15:1 (v/v), 79 g silica gel, size: 26.5 × 3.1 cm) to obtain the product. C15H12O3 [240.26 g/mol] Yield: 2.17 g (9.03 mmol, 86%), yellowish oil Rf: 0.20 (cyclohexane/ethyl acetate = 15:1 (v/v)) 1

H-NMR (CDCl3): δ (ppm) = 8.00-7.91 (m, 4H, Ar-H), 7.65 (ddd, 3J = 8.6 Hz, 2.4 Hz, 1.2 Hz,

1H, Ar-H), 7.50 (t, 3J = 7.6 Hz, 2H, Ar-H), 7.01-6.94 (m, 2H, Ar- H), 3.88 (s, 3H, CH3).

19

13


(CHAr), 133.3 (Cq, CAr), 132.5 (2 × CHAr), 130.0 (2 × CHAr), 129.1 (2 × CHAr), 126.2 (Cq, CAr), 114.5 (2 × CHAr), 55.8 (OCH3).

1-Phenyl-2-(pyridin-4-yl)ethane-1,2-dione (3e)

A 50 mL round-bottomed flask was charged with 360 mg (2.0 mmol, 1.0 eq) 4(phenylethynyl)pyridine (2g) and 10 mL reagent grade acetone. A solution of 100 mg NaHCO3 (1.2 mmol, 0.6 eq) and 1.01 g (4 mmol, 2.0 eq) MgSO4∙7H2O in 5 mL H2O was added. The mixture was stirred with a Teflon-coated magnetic stir bar. 800 mg (5.0 mmol, 2.5 eq) powdered potassium permanganate (KMnO4) were added in one portion, and the mixture was stirred for 2 h. The reaction progress was monitored by TLC analysis and GC-MS. After complete conversion, the reaction mixture was extracted with ethyl acetate (2 × 30 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and filtered. The solvents were removed under reduced pressure using a rotary evaporator. The residue was purified via flash chromatography (cyclohexane/ethyl acetate = 3:1 (v/v), 27 g silica gel, size: 17 × 2.4 cm) to obtain the product. C13H9NO2 [211.22 g/mol] Yield: 270 mg (1.28 mmol, 64%), yellowish oil Rf: 0.25 (cyclohexane/ethyl acetate = 3:1 (v/v))

20

1

H-NMR (CDCl3): δ (ppm) = 8.87 (dd, 3J = 4.5 Hz, 1.5 Hz, 2H, Ar-H), 8.03-7.90 (m, 2H, Ar-

H), 7.78 (dd, 3J = 4.4 Hz, 1.6 Hz, 2H, Ar-H), 7.70 (t, 3J = 7.4 Hz, 1H, Ar-H), 7.55 (t, 3J = 7.7 Hz, 2H, Ar-H). 13

C-NMR (CDCl3): δ (ppm) = 193.2 (Cq, C=O), 192.8 (Cq, C=O), 151.4 (2 × CHNCH, CAr),

138.9 (Cq, CAr), 135.5 (CHAr), 132.5 (Cq, CAr), 130.2 (2 × CHAr), 129.3 (2 × CHAr), 122.3 (2 × CHAr).

1-Phenyl-2-(pyridin-2-yl)ethane-1,2-dione (3f)

A 50 mL round-bottomed flask was charged with 100 mg (0.56 mmol, 1.0 eq) 2(phenylethynyl)pyridine (2f) and 22 mL reagent grade acetone. A solution of 28 mg NaHCO3 (0.33 mmol, 0.6 eq) and 281 mg (1.14 mmol, 2.0 eq) MgSO4∙7H2O in 12 mL H2O was added. The mixture was stirred with a Teflon-coated magnetic stir bar. 344 mg (2.18 mmol, 3.9 eq) powdered potassium permanganate (KMnO4) were added in one portion, and the mixture was stirred for 2 h. The reaction progress was monitored by TLC analysis and GC-MS. After complete conversion, the reaction mixture was filtered through a pad of Celite® and the filtrate was concentrated in vacuo. The residue was extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and filtered. The solvents were removed under reduced pressure using a rotary evaporator. The residue was purified via flash chromatography (cyclohexane/ethyl acetate = 5:1 (v/v), 5 g silica gel) to obtain the product. C13H9NO2 [211.22 g/mol] 21

Yield: 35 mg (0.17 mmol, 30%), yellow oil Rf: 0.23 (cyclohexane/ethyl acetate = 5:1 (v/v)) 1


8.04-7.86 (m, 3H, Ar-H), 7.71-7.58 (m, 1H, Ar-H), 7.59-7.45 (m, 3H, Ar-H). 13


(CH, CAr), 137.6 (CH, CAr), 134.8 (CHAr), 133.3 (CHAr), 129.8 (2 × CHAr), 129.1 (2 × CHAr), 128.3 (CH, CAr), 123.4 (CH, CAr). 2,6-Dimethylheptane-3,4-dione (3g)

In an oven dried, evacuated and nitrogen purged 250 mL Schlenk flask, 3.3 g (13.7 mmol, 1.0 eq) 2,6-dimethylhept-3-yne-2,5-diyl diacetate (8) were dissolved in 60 mL dry DCM at RT, then 60 mg (0.069 mmol, 0.5% eq) [(IPr)Au(NTf2)] were added. The mixture was stirred at RT for 2 h. Subsequently, 60 mL MeOH and 3.79 g (27.4 mmol, 2.0 eq) K2CO3 were added to the reaction mixture. The reaction was monitored by GC-MS analysis and running overnight at RT. The reaction mixture was filtered through a pad of Celite®, which was then rinsed with DCM. Most of the DCM was removed under reduced pressure using a rotary evaporator.* The residue was kept at 120°C at normal pressure for 2 h to remove most of the residual solvents. Upon standing at RT for 2 h, the oily residue separated into two phases whereby the lower phase solidified. The oily supernatant was taken off with a plastic pipette and identified as the desired product. The solid residue was washed with little amounts of n-pentane giving 30 mg of a second product. This second product was identified as the reaction catalyst. The isolated amount of the catalyst corresponds to a recovery rate of 50%. 22

C9H16O2 [156.22 g/mol] Yield: 1.66 g (10.6 mmol, 78%), yellow oil 1

H-NMR (CDCl3): δ (ppm) = 3.43-3.27 (m, 1H, (CH3)2CHC=O), 2.60 (d, 3J = 6.9 Hz, 2H,

CH2), 2.21-2.02 (m, 1H, (CH3)2CHCH2), 1.07 (d, 3J = 7.0 Hz, 6H, ((CH3)2CHC=O), 0.93 (d, 3

J = 6.7 Hz, 6H, ((CH3)2CHCH2).

13

C-NMR (CDCl3): δ (ppm) = 203.5 (Cq, C=O), 200.6 (Cq, C=O), 45.5 (CH2), 33.7

((CH3)2CHC=O), 24.3 ((CH3)2CHCH2), 22.7 ((CH3)2CHCH2), 17.5 ((CH3)2CHC=O). * The product is fairly volatile and would be partially lost upon applying high vacuum at elevated temperatures.

2,3-Diphenyl-1,4-diazaspiro[4.5]deca-1,3-diene (4a)

A 50 mL two-necked, round-bottom flask equipped with a Teflon-coated magnetic stir bar and a reflux condenser was charged with 3.16 g (15.0 mmol, 1.0 eq) benzil (3a), 8.0 g (103.8 mmol, 7.0 eq) ammonium acetate, 20 mL glacial acetic acid and 1.6 mL (15.4 mmol, 1.03 eq) cyclohexanone. The mixture was stirred and heated at reflux temperature for 2 h and then, while hot, poured into 50 mL ice-water. After reaching RT, the mixture was neutralized with 3M NaOH to pH >8. Then the mixture was extracted with ethyl acetate (2 × 50 mL), the organic phase was washed with brine and dried over anhydrous Na2SO4. The solvent was removed using a rotary evaporator. The crude product was purified via flash column 23

chromatography (cyclohexane/ethyl acetate = 10:1 (v/v), 200 g silica gel) to obtain the product. C20H20N2 [288.39 g/mol] Yield: 4.1 g (1.68 mmol, 95%), yellow crystals Rf: 0.22 (cyclohexane/ethyl acetate = 10:1 (v/v)) mp: 106-108°C (lit. 107-108°C) 1

H-NMR (CDCl3): δ (ppm) = 7.54-7.48 (m, 4H, Ar-H), 7.47-7.40 (m, 2H, Ar-H), 7.39-7.31

(m, 4H, Ar-H), 2.02-1.91 (m, 4H, CCH2), 1.87-1.79 (m, 4H, CCH2CH2), 1.78-1.69 (m, 2H, CCH2CH2 CH2). 13

C-NMR (CDCl3): δ (ppm) = 164.2 (2 × Cq, C=N), 133.2 (2 × Cq, CAr), 130.1 (2 × CHAr),

129.0 (4 × CHAr), 128.4 (4 × CHAr), 104.2 (Cq), 34.9 (2 × CCH2), 25.8 (CCH2CH2CH2), 24.3 (2 × CCH2CH2).

2-(4-Methoxyphenyl)-3-phenyl-1,4-diazaspiro[4.5]deca-1,3-diene (4b)

A 25 mL two-necked, round-bottom flask equipped with a Teflon-coated magnetic stir bar and a reflux condenser was charged with 135 mg (0.56 mmol, 1.0 eq) 1-(4-methoxyphenyl)-2phenylethane-1,2-dione (3d), 302 mg (3.92 mmol, 7.0 eq) ammonium acetate, 4.0 mL glacial acetic acid and 64 μL (0.62 mmol, 1.1 eq) cyclohexanone. The mixture was stirred and heated 24

at reflux temperature for 3 h and then, while hot, poured into 30 mL ice-water. After reaching RT, the mixture was extracted with ethyl acetate (2 × 30 mL), the organic phase was washed with 3M NaOH and saturated NaHCO3 and brine subsequently and finally dried over anhydrous Na2SO4. The solvent was removed using a rotary evaporator. The crude product was purified via flash column chromatography (cyclohexane/ethyl acetate = 8:1 (v/v), 28 g silica gel, size: 16.5 × 2.4 cm). C21H22N2O [318.42 g/mol] Yield: 120 mg (0.38 mmol, 67%), light yellow oil Rf: 0.21 (cyclohexane/ethyl acetate = 8:1 (v/v)) 1

H-NMR (CDCl3): δ (ppm) = 7.52-7.41 (m, 5H, Ar-H), 7.39-7.34 (m, 2H, Ar-H), 6.85 (d, 3J =

8.8 Hz, 2H, Ar-H), 3.83 (s, 3H, CH3), 1.95 (dd, 3J = 10.8, 5.3 Hz, 4H, CH2), 1.87-1.62 (m, 6H, CH2). 13

C-NMR (CDCl3): δ (ppm) = 164.4 (Cq, CH3OC), 163.4 (Cq, C=N), 161.2 (Cq, C=N), 133.7

(Cq, CAr), 130.7 (2 × CHAr), 130.0 (CHAr), 129.0 (2 × CHAr), 128.4 (2 × CHAr), 125.5 (Cq, CAr), 113.8 (2 × CHAr), 103.9 (Cq), 55.5 (CH3), 34.9 (2 × CCH2CH2), 25.9 (CCH2CH2CH2), 24.3 (2 × CCH2CH2). HRMS (EI): m/z: calculated for C21H22N2O [M]+: 318.1732; found: 318.1741.

2-(4-Nitrophenyl)-3-phenyl-1,4-diazaspiro[4.5]deca-1,3-diene (4c)

25

A 25 mL two-necked, round-bottomed flask equipped with a Teflon-coated magnetic stir bar and a reflux condenser was charged with 510 mg (2.0 mmol, 1.0 eq) 1-(4-nitrophenyl)-2phenylethane-1,2-dione (3c), 1.0 g (14.0 mmol, 7.0 eq) ammonium acetate, 8.0 mL glacial acetic acid and 248 μL (2.4 mmol, 1.2 eq) cyclohexanone. The mixture was stirred and heated at reflux temperature for 3 h and then, while hot, poured into 30 mL ice-water. After reaching RT, the mixture was neutralized with 3M NaOH solution to pH > 8. Then the mixture was extracted with ethyl acetate (2 × 30 mL). The organic phase was washed with brine and dried over anhydrous Na2SO4. The solvent was removed using a rotary evaporator. The crude product was purified via flash column chromatography (cyclohexane/ethyl acetate = 18:1 (v/v), 25 g silica gel, size: 16 × 2.4 cm). C20H19N3O2 [333.39 g/mol] Yield: 570 mg (1.71 mmol, 85%), brown solid Rf: 0.14 (cyclohexane/ethyl acetate = 18:1 (v/v)) 1


7.52-7.42 (m, 3H, Ar-H), 7.40-7.33 (m, 2H, Ar-H), 1.96 (dd, 3J = 10.8 Hz, 5.3 Hz, 4H, CH2), 1.90-1.67 (m, 6H, CH2). 13

C-NMR (CDCl3): δ (ppm) = 163.4 (Cq, C=N), 162.5 (Cq, C=N), 148.8 (Cq, O2NC-Ar), 139.4

(Cq, CAr), 132.5 (Cq, CAr), 130.5 (CHAr), 130.1 (2 × CHAr), 128.8 (2 × CHAr), 128.7 (2 ×

26

CHAr), 123.6 (2 × CHAr), 105.3 (Cq), 34.7 (2 × CCH2), 25.7 (CCH2CH2CH2), 24.2 (2 × CCH2CH2). HRMS (EI): m/z: calculated for C20H19N3O2 [M]+: 333.1477; found: 333.1480.

2,3-Bis(4-bromophenyl)-1,4-diazaspiro[4.5]deca-1,3-diene (4d)

A 25 mL two-necked, round-bottom flask equipped with a Teflon-coated magnetic stir bar and a reflux condenser was charged with 409 mg (1.0 mmol, 1.0 eq) 4,4’-dibromobenzil, 504 mg (7.0 mmol, 7.0 eq) ammonium acetate, 5 mL glacial acetic acid and 106 μL (1.02 mmol, 1.02 eq) cyclohexanone. The mixture was stirred and heated at reflux temperature for 3 h and then, while hot, poured into 30 mL ice-water. After reaching RT, the mixture was extracted with ethyl acetate (2 × 30 mL), the organic phase was washed with saturated NaHCO3 and brine subsequently and finally dried over anhydrous Na2SO4. The solvent was removed using a rotary evaporator. The crude product was purified via flash column chromatography (cyclohexane/ethyl acetate = 22:1 (v/v), 30 g silica gel, size: 25 × 2.2 cm) to obtain the product. C20H18Br2N2 [446.18 g/mol] Yield: 438 mg (0.98 mmol, 98%), yellowish crystals Rf: 0.25 (cyclohexane/ethyl acetate = 22:1 (v/v)) 27

mp: 149-151°C 1


1.93 (t, 3J = 6.0 Hz, 4H, CH2), 1.81-1.73 (m, 6H, CH2). 13

C-NMR (CDCl3): δ (ppm) = 162.7 (2 × Cq, C=N), 131.7 (4 × CHAr), 131.7 (2 × Cq, CAr),

130.5 (4 × CHAr), 124.9 (2 × Cq, CAr-Br ), 104.7 (Cq), 34.6 (2 × CH2), 25.6 (CH2), 24.1 (2 × CH2). HRMS (EI): m/z: calculated for C20H18Br2N2 [M]+: 445.9817; found: 445.9806. 2-Phenyl-3-(pyridin-2-yl)-1,4-diazaspiro[4.5]deca-1,3-diene (4e)

A 10 mL two-necked, round-bottom flask equipped with a Teflon-coated magnetic stir bar and a reflux condenser was charged with 38 mg (0.18 mmol, 1.0 eq) 1-phenyl-2-(pyridin-4yl)ethane-1,2-dione (3f), 97 mg (1.26 mmol, 7.0 eq) ammonium acetate, 5 mL glacial acetic acid and 19 μL (0.18 mmol, 1.0 eq) cyclohexanone. The mixture was stirred and heated at reflux temperature for 2 h and then, while hot, poured into 15 mL ice-water. After reaching RT, the mixture was extracted with ethyl acetate (2 × 20 mL). The organic phase was washed with saturated NaHCO3 and brine subsequently and finally dried over anhydrous Na2SO4. The solvent was removed using a rotary evaporator. The crude product was purified via flash column chromatography (cyclohexane/ethyl acetate = 3:1 (v/v), 9 g silica gel) to obtain the product. C19H19N3 [289.37 g/mol] 28

Yield: 45 mg (0.16 mmol, 86%), white crystals Rf: 0.25 (cyclohexane/ethyl acetate = 3:1 (v/v)) mp: 75-77°C 1

H-NMR (CDCl3): δ (ppm) = 8.66-8.59 (m, 1H, CH, Ar-H), 7.78 (td, 3J = 7.6 Hz, 1.7 Hz, 1H,

Ar-H), 7.78 (d, 3J = 7.7 Hz, 1H, Ar-H), 7.59-7.51 (m, 2H, Ar- H), 7.45-7.29 (m, 4H, Ar-H), 1.96 (dd, 3J = 11.2 Hz, 5.7 Hz, 4H, CH2), 1.90-1.69 (m, 6H, CH2). 13

C-NMR (CDCl3): δ (ppm) = 164.1 (Cq, C=N), 163.5 (Cq, C=N), 152.6 (Cq, CAr), 149.5 (CH,

CAr), 148.4 (Cq, CAr), 136.8 (CH, CAr), 130.2 (CHAr), 129.3 (2 × CHAr), 128.2 (2 × CHAr), 124.5 (CH, CAr), 124.3 (CH, CAr), 104.6 (Cq), 34.6 (2 × CH2), 25.8 (CH2), 24.2 (2 × CH2). HRMS (EI): m/z: calculated for C19H19N3 [M-H]+: 288.1579; found: 288.1574. 2-Phenyl-3-(pyridin-4-yl)-1,4-diazaspiro [4.5] deca-1, 3-diene (4f)

A 25 mL two-necked, round-bottom flask equipped with a Teflon-coated magnetic stir bar and a reflux condenser was charged with 46 mg (0.22 mmol, 1.0 eq) 1-phenyl-2-(pyridin-4yl)ethane-1,2-dione (3e), 119 mg (1.54 mmol, 7.0 eq) ammonium acetate, 5 mL glacial acetic acid and 23 μL (0.22 mmol, 1.0 eq) cyclohexanone. The mixture was stirred and heated at reflux temperature for 3 h and then, while hot, poured into 15 mL ice-water. After reaching RT, the mixture was extracted with ethyl acetate (2 × 20 mL). The organic phase was washed with saturated NaHCO3 and brine subsequently and finally dried over anhydrous Na2SO4. The

29

solvent was removed using a rotary evaporator. The crude product was purified via flash column chromatography (cyclohexane/ethyl acetate = 2:1 (v/v), 15 g silica gel). C19H19N3 [289.37 g/mol] Yield: 30 mg (0.10 mmol, 47%), light yellowish crystals Rf: 0.17 (cyclohexane/ethyl acetate = 2:1 (v/v)) mp: 138-141°C 1

H-NMR (CDCl3): δ (ppm) = 8.66 (dd, 3J = 4.6 Hz, 2H, Ar-H), 7.60-7.32 (m, 7H, Ar- H),

1.96 (dd, 3J = 11.2 Hz, 5.5 Hz, 4H, CH2), 1.87-1.68 (m, 6H, CH2). 13

C-NMR (CDCl3): δ (ppm) = 163.3 (Cq, C=N), 162.2 (Cq, C=N), 149.7 (2 × CH, CAr), 141.4

(Cq, CAr), 132.4 (Cq, CAr), 130.6 (CHAr), 128.9 (2 × CHAr), 128.7 (2 × CHAr), 123.3 (2 × CH, CAr), 105.5 (Cq), 34.7 (2 × CH2), 25.7 (CH2), 24.2 (2 × CH2). HRMS (EI): m/z: calculated for C19H19N3 [M-H]+: 288.1501; found: 288.1519. 2-(2-Chlorophenyl)-3-(3,4-dimethoxyphenyl)-1,4-diazaspiro[4.5]deca-1,3-diene (4g)

A 25 mL two-necked, round-bottom flask equipped with a Teflon-coated magnetic stir bar and a reflux condenser was charged with 314 mg (1.0 mmol, 1.0 eq) 2-chloro-3’,4’dimethoxybenzil, 504 mg (7.0 mmol, 7.0 eq) ammonium acetate, 5 mL glacial acetic acid and 107 μL (1.02 mmol, 1.02 eq) cyclohexanone. The mixture was stirred and heated at reflux temperature for 3 h and then, while hot, poured into 20 mL ice-water. After reaching RT, the 30

mixture was neutralized with 3M NaOH to pH >8, then the mixture was extracted with ethyl acetate (2 × 20 mL). The organic phase was washed with brine and dried over anhydrous Na2SO4. The solvent was removed using a rotary evaporator. The crude product was purified via flash column chromatography (cyclohexane/ethyl acetate = 3:1 (v/v), 25 g silica gel, size: 21 × 2.1 cm) to obtain the product. C22H23ClN2O2 [382.89 g/mol] Yield: 373 mg (0.97 mmol, 97%), grey crystals Rf: 0.25 (cyclohexane/ethyl acetate = 3:1 (v/v)) mp: 143-145°C 1

H-NMR (CDCl3): δ (ppm) = 7.49-7.35 (m, 4H, Ar-H), 7.13 (s, 1H, Ar-H), 7.07 (dd, 3J = 8.4

Hz, 1.6 Hz, 1H, Ar-H), 6.73 (d, 3J = 8.4 Hz, 1H, Ar-H), 3.86 (s, 3H, OCH3), 3.68 (s, 3H, OCH3), 1.96 (s, 6H, CH2), 1.80-1.64 (m, 4H, CH2). 13

C-NMR (CDCl3): δ (ppm) = 163.4 (Cq, C=N), 162.5 (Cq, C=N), 148.9 (2 × Cq, CAr- OCH3),

134.8 (Cq, CAr-Cl), 133.3 (2 × Cq, CAr), 130.7 (CHAr), 130.2 (CHAr), 129.9 (CHAr), 127.3 (CHAr), 121.6 (CHAr), 111.1100, (CHAr), 110.8(CHAr), 104.5 (Cq), 56.0 (OCH3), 55.7 (OCH3), 34.7 (2 × CCH2), 25.8 (CCH2CH2CH2), 24.2 (2 × CCH2CH2). One of the quaternary carbons could not be detected. HRMS (EI): m/z: calculated for C22H23ClN2O2 [M]+:382.1448; found: 382.1454.

2,2-Diethyl-4,5-diphenyl-2H-imidazole (4h) 31

A 50 mL two-necked, round-bottomed flask equipped with a Teflon-coated magnetic stir bar and a reflux condenser was charged with 2.11 g (10.0 mmol, 1.0 eq) benzil (3a), 5.04 g (69.7 mmol, 7.0 eq) ammonium acetate, 25 mL glacial acetic acid and 1.1 mL (10.3 mmol, 1.03 eq) 3-pentanone. The mixture was stirred and heated at reflux temperature for 2 h and then, while hot, poured into 40 mL ice-water. After reaching RT, the mixture was neutralized with 3M NaOH to pH >8. Then the mixture was extracted with ethyl acetate (2 × 40 mL), the organic phase was washed with brine and dried over anhydrous Na2SO4. The solvent was removed using a rotary evaporator. The crude product was purified via flash column chromatography (cyclohexane/ethyl acetate = 8:1 (v/v), 160 g silica gel) to obtain the product. C19H20N2 [276.38 g/mol] Yield: 2.66 g (9.6 mmol, 96%), purple solid Rf: 0.22 (cyclohexane/ethyl acetate = 8:1 (v/v)) mp: 98-100°C 1


7.3 Hz, 4H, Ar-H), 2.26 (q, 3J = 7.3 Hz, 4H, CH2CH3), 0.74 (t, 3J = 7.4 Hz, 6H, CH2CH3). 13


128.9 (4 × CHAr), 128.5 (4 × CHAr), 106.5 (Cq), 29.8 (2 × CH2CH3), 7.9 (2 × CH2CH3). HRMS (EI): m/z: calculated for C19H20N2 [M-H]+: 275.1548; found: 275.1561.

32

4,5-Diphenyl-2,2-dipropyl-2H-imidazole (4i)

A 50 mL two-necked, round-bottom flask equipped with a Teflon-coated magnetic stir bar and a reflux condenser was charged with 2.11 g (10.0 mmol, 1.0 eq) benzil (3a), 5.04 g (69.7 mmol, 7.0 eq) ammonium acetate, 25 mL glacial acetic acid and 1.44 mL (10.3 mmol, 1.03 eq) 4-heptanone. The mixture was stirred and heated at reflux temperature for 2 h and then, while hot, poured into 40 mL of ice-water. After reaching RT, the mixture was neutralized with 3M NaOH to pH >8. Then the mixture was extracted with ethyl acetate (2 × 40 mL), the organic phase was washed with brine and dried over anhydrous Na2SO4. The solvents were removed using a rotary evaporator. The crude product was purified via flash column chromatography (cyclohexane/ethyl acetate = 8:1 (v/v), 160 g silica gel) to obtain the product. C21H24N2 [304.44 g/mol] Yield: 2.89 g (9.5 mmol, 95%), brown solid Rf: 0.27 (cyclohexane/ethyl acetate = 15:1 (v/v)) mp: 34-36°C 1


7.3 Hz, 4H, Ar-H), 2.24-2.13 (m, 4H, CH2CH2CH3), 1.21-1.03 (m, 4H, CH2CH2CH3), 0.87 (t, 3

J = 7.3 Hz, 6H, CH2CH2CH3).

33

13


128.9 (4 × CHAr), 128.5 (4 × CHAr), 106.3 (Cq), 39.3 (2 × CH2CH2CH3), 16.7 (2 × CH2CH2CH3), 14.4 (2 × CH2CH2CH3). HRMS (EI): m/z: calculated for C21H24N2 [M]+: 304.1939; found: 304.1952.

8-Methyl-2,3-diphenyl-1,4,8-triazaspiro[4.5]deca-1,3-diene (4j)

A 100 mL two-necked, round-bottom flask equipped with a Teflon-coated magnetic stir bar and a reflux condenser was charged with 4.25 g (20.0 mmol, 1.0 eq) benzil (3a), 10.08 g (140 mmol, 7.0 eq) ammonium acetate, 50 mL glacial acetic acid and 2.36 mL (20.6 mmol, 1.03 eq) N-methyl-4-piperidone. The mixture was stirred and heated at reflux temperature for 3 h and then, while hot, poured into 150 mL ice-water. After reaching RT, the mixture was neutralized with 3M NaOH to pH >8. Then the mixture was extracted with ethyl acetate (3 × 50 mL), the organic phase was washed with brine and dried over anhydrous Na2SO4. The solvents were removed using a rotary evaporator. The crude product was purified via flash column chromatography (methanol/ethyl acetate = 1:2 (v/v), 89 g silica gel, size: 14.5 × 4.5 cm) to obtain the product. C20H21N3 [303.41 g/mol] Yield: 4.8 g (15.8 mmol, 80%), yellowish solid Rf: 0.25 (methanol/ethyl acetate = 1:2 (v/v)) 34

mp: 102-104°C 1

H-NMR (CDCl3): δ (ppm) = 7.54 (m, 4H, Ar-H), 7.43 (d, 3J = 7.2 Hz, 2H, Ar-H), 7.35 (t, 3J

= 7.2 Hz, 4H, Ar-H), 2.88 (t, 3J = 5.4 Hz, 4H, CCH2), 2.48 (s, 3H, CH3), 2.20-1.77 (m, 4H, CH2). 13


129.0 (4 × CHAr), 128.5 (4 × CHAr), 101.9 (Cq), 53.6 (2 × CH2), 46.4 (CH3), 34.3 (2 × CH2). HRMS (EI): m/z: calculated for C20H21N3 [M]+: 303.1736; found: 303.1740. Ethyl 2-(4-methoxyphenyl)-3-phenyl-1,4,8-triazaspiro[4.5]deca-1,3-diene-8- carboxylate (4k)

A 50 mL two-necked, round-bottom flask equipped with a Teflon-coated magnetic stir bar and a reflux condenser was charged with 2.15 g (8.95 mmol, 1.0 eq) 1-(4-methoxyphenyl)-2phenylethane-1,2-dione (3d), 4.88 g (63 mmol, 7.0 eq) ammonium acetate, 20 mL glacial acetic acid and 1.41 mL (9.13 mmol, 1.02 eq) 1-ethoxycarbonyl-4-piperidone. The mixture was stirred and heated at reflux temperature for 2 h and then, while hot, poured into 100 mL ice-water. After reaching RT, the mixture was neutralized with 3M NaOH to pH >8 and extracted with ethyl acetate (3 × 50 mL). The organic phase was washed with brine and dried over anhydrous Na2SO4. The solvents were removed using a rotary evaporator. The crude product was purified via flash column chromatography (cyclohexane/ethyl acetate = 2:1 (v/v), 115 g silica gel, size 18.5 × 4.5 cm) to obtain the product. 35

C23H25N3O3 [391.47 g/mol] Yield: 3.40 g (8.7 mmol, 97%), brownish oil Rf: 0.28 (cyclohexane/ethyl acetate = 2:1 (v/v)) 1

H-NMR (CDCl3): δ (ppm) = 7.55-7.43 (m, 5H, Ar-H), 7.38 (t, 3J = 7.1 Hz, 2H, Ar-H), 6.87

(d, 3J = 8.8 Hz, 2H, Ar-H), 4.20 (q, 3J = 7.1 Hz, 2H, CH3CH2), 3.90 (t, 3J = 4.3 Hz, 4H, CCH2CH2), 3.83 (s, 3H, CH3O), 1.91-1.81 (m, 4H, CCH2CH2), 1.30 (t, 3J = 7.1 Hz, 1H, CH3CH2). 13

C-NMR (CDCl3): δ (ppm) = 165.5 (Cq, CH3OC), 164.5 (Cq, C=N), 161.5 (Cq, C=N), 155.9

(Cq, C=O), 133.2 (Cq, CAr), 130.8 (2 × CH, CAr), 130.3 (CH, CAr), 129.0 (2 × CH, CAr), 128.5 (2 × CH, CAr), 125.0 (Cq, CAr), 113.9 (2 × CH, CAr ), 101.7 (Cq), 61.5 (CH3CH2O), 55.5 (CH3O), 42.3 (2 x CCH2CH2N), 34.0 (2 x CCH2 CH2N), 14.9 (CH3CH2O). HRMS (EI): m/z: calculated for C23H25N3O3 [M]+:391.1896; found: 391.1902. (6S,9R)-6-Isopropyl-9-methyl-2,3-diphenyl-1,4-diazaspiro[4.5]deca-1,3-diene (4 l)

A 50 mL two-necked, round-bottom flask equipped with a Teflon-coated magnetic stir bar and a reflux condenser was charged with 1.07 g (5.0 mmol, 1.0 eq) benzil (3a), 2.5 g (35.0 mmol, 7.0 eq) ammonium acetate, 20 mL glacial acetic acid and 1.04 mL (5.1 mmol, 1.02 eq) (-)-menthone. The mixture was stirred and heated at reflux temperature for 2 h and then, while 36

hot, poured into 50 mL ice-water. After reaching RT, the mixture was neutralized with 3M NaOH to pH >8 and extracted with ethyl acetate (2 × 40 mL). The organic phase was washed with brine and dried over anhydrous Na2SO4. The solvents were removed using a rotary evaporator. The

crude product

was

purified via flash

column chromatography

(cyclohexane/ethyl acetate = 28:1 (v/v), 88 g silica gel, size 20 × 4 cm) to obtain the product. C24H28N2 [344.50 g/mol] Yield: 1.30 g (3.77 mmol, 75%), colorless crystals Rf: 0.20 (cyclohexane/ethyl acetate = 28:1 (v/v)) mp: 90-92°C 1


(m, 4H, Ar-H), 2.42-2.30 (m, 1H, CCH2), 2.21-1.93 (m, 4H, CH2, CH), 1.86 (ddd, 3J = 13.1, 8.6 Hz, 3.1 Hz, 1H, CH2), 1.32-1.10 (m, 2H, CH2), 1.08-1.01 (m, 1H, CH), 0.95 (d, 3J = 5.8 Hz, 3H, CH3), 0.85 (d, 3J = 6.9 Hz, 3H, CH3), 0.63 (d, 3J = 6.9 Hz, 3H, CH3). 13

C-NMR (CDCl3): δ (ppm) = 164.7 (Cq, C=N), 164.6 (Cq, C=N), 133.6 (Cq, CAr), 133.1 (Cq,

CAr), 130.1 (CHAr), 129.9 (CHAr), 128.9 (2 × CHAr), 128.8 (2 × CHAr), 128.5 (2 × CHAr), 128.4 (2 × CHAr), 107.6 (Cq), 49.7 (CCHCH2), 45.7 (CCH2CH), 35.6 (CCH2CHCH2), 31.1 (CCH2CH), 25.5 (CH3CH), 23.7 (CCHCH2), 23.3 ((CH3)2CH), 22.5 ((CH3)2CH), 19.3 (CCH2CHCH3). HRMS (EI): m/z: calculated for C24H28N2 [M]+: 344.2253; found: 344.2254. [∝] : 0 ° (c= 1.00, MeOH). 2-Methyl-2-phenethyl-4,5-diphenyl-2H-imidazole (4m)

37

A 25 mL two-necked, round-bottom flask equipped with a Teflon-coated magnetic stir bar and a reflux condenser was charged with 212 mg (1.0 mmol, 1.0 eq) benzil (3a), 504 mg (7.0 mmol, 7.0 eq) ammonium acetate, 4.0 mL glacial acetic acid and 156 μL (1.02 mmol, 1.02 eq) 4-phenyl-2-butanone. The mixture was stirred and heated at reflux temperature for 5 h and then, while hot, poured into 20 mL ice-water. After reaching RT, the mixture was neutralized with 3M NaOH to pH >8 and extracted with ethyl acetate (2 × 20 mL). The organic phase was washed with brine and dried over anhydrous Na2SO4. The solvent was removed using a rotary evaporator. The

crude product

was

purified via flash


(cyclohexane/ethyl acetate = 8:1 (v/v), 27 g silica gel, size 17 × 2.4 cm) to obtain the product. C24H22N2 [338.44 g/mol] Yield: 280 mg (0.83 mmol, 83%), brownish oil Rf: 0.18 (cyclohexane/ethyl acetate = 8:1 (v/v)) 1

H-NMR (CDCl3): δ (ppm) = 7.64-7.56 (m, 4H, Ar-H), 7.54 (d, 3J = 7.2Hz, 2H, Ar-H), 7.46

(t, 3J = 7.2Hz, 4H, Ar-H), 7.34 (dd, 3J = 7.8, 6.8Hz, 2H, Ar-H), 7.25 (d, 3J = 6.6Hz, 3H, ArH), 2.67-2.46 (m, 4H, CCH2CH2), 1.79 (s, 3H, CCH3). 13

C-NMR (CDCl3): δ (ppm) = 165.2 (2 × Cq, C=N), 141.9 (Cq, CAr), 130.4 (2 × Cq, CAr),

129.0 (4 × CHAr), 128.5 (2 × CHAr), 128.4 (8 × CHAr), 126.0 (CHAr), 103.7 (Cq), 39.5 (CCH2CH2), 30.3 (CCH3), 23.5 (CCH2CH2). HRMS (EI): m/z: calculated for C24H22N2 [M]+:338.1783; found: 338.1792. 38

(rac)-2,3-Diphenyl-1,4-diazaspiro[4.5]dec-1-ene (5a)

An oven-dried, evacuated and nitrogen-purged 10 mL Schlenk tube, equipped with a Tefloncoated stir bar, was charged with 60 mg (1.5 mmol, 3.0 eq) lithium aluminium hydride. Addition of 2.0 mL dry THF resulted in a grey suspension, which was then cooled to ca. 0°C in an ice-water bath. Subsequently, a solution of 165 mg (0.5 mmol, 1.0 eq) 2,3-diphenyl-1,4diazaspiro[4.5]deca-1,3-diene (4a) in 2.0 mL dry THF was added slowly via a syringe over 10 min. The mixture was stirred vigorously in the thawing ice-bath until RT was reached. The reaction progress was monitored by TLC. The reaction was stopped after 4 h when TLC analysis did not indicate any remaining starting material. The reaction mixture was diluted with 2 mL diethyl ether and cooled to ca. 0°C in an ice-water bath. Subsequently, 60 μL ice cold water, 60 μL 15% aqueous NaOH solution and 180 μL ice cold water were added dropwise (n-n-3n work-up). The mixture was then stirred for 30 min. The formed white solid was filtrated off and washed with diethyl ether. The collected filtrates were dried over anhydrous Na2SO4. The solvent was removed in vacuo and the crude product was purified via flash column chromatography on silica (cyclohexane/ethyl acetate = 6:1 (v/v), 21 g silica gel, size: 13 × 2.4 cm) to obtain the product. C20H22N2 [290.41 g/mol] Yield: 250 mg (0.86 mmol, 86%), brownish oil Rf: 0.18 (cyclohexane/ethyl acetate = 6:1 (v/v)) 39

1

H-NMR (DMSO-d6): δ (ppm) = 7.66-7.58 (m, 2H, Ar-H), 7.48-7.37 (m, 2H, Ar-H), 7.33-

7.23 (m, 6H, Ar-H), 5.59 (s, 1H, CHN), 2.92 (s, 1H, CHNH), 1.92- 1.44 (m, 10H, CH2). 13

C-NMR (DMSO-d6): δ (ppm) = 167.4 (Cq, C=N), 142.7 (Cq, CAr), 132.8 (Cq, CAr), 130.0

(CHAr), 128.5 (2 × CHAr), 128.3 (2 × CHAr), 128.2 (2 × CHAr), 128.1 (2 × CHAr), 127.1 (CHAr), 91.1 (Cq), 69.5 (CHNH), 38.4 (CCH2), 34.3 (CCH2), 25.2 (CCH2CH2CH2), 23.1 (CCH2CH2), 23.0 (CCH2CH2). HRMS (EI): m/z: calculated for C20H22N2 [M-H]+: 289.1705; found: 289.1707. (rac)-8-Methyl-2,3-diphenyl-1,4,8-triazaspiro[4.5]dec-1-ene (5b)

An oven-dried, evacuated and nitrogen-purged 50 mL Schlenk tube, equipped with a Teflon coated stirring bar, was charged with 660 mg (17.4 mmol, 8.1 eq) lithium aluminium hydride. The addition of 10.0 mL dry THF resulted in a grey suspension, which was then cooled to ca. 0°C in an ice-water bath. Subsequently, a solution of 650 mg (2.14 mmol, 1.0 eq) 8-methyl2,3-diphenyl-1,4,8-triazaspiro[4.5]deca-1,3-diene (4j) in 10.0 mL dry THF was added slowly via a syringe over 60 min, upon the color turned dark red. The mixture was stirred vigorously in the thawing ice-bath until RT was reached. The reaction progress was monitored by TLC. The reaction was stopped after 18 h when TLC analysis did not indicate any remaining starting material. The solution was cooled to ca. 0°C in an ice-water bath. Subsequently, 660 μL ice cold water, 660 μL 15% aqueous NaOH solution and 1980 μL ice cold water were added dropwise (n-n-3n work-up). The mixture was then stirred for 30 min. The formed white solid was filtrated off and washed with diethyl ether. The collected filtrates were dried over 40

anhydrous Na2SO4. The solvent was removed in vacuo and the crude product was purified via flash column chromatography on silica (MeOH, 70 g silica gel, size: 25 × 3.0 cm) to obtain the product. C20H23N3 [305.43 g/mol] Yield: 359 mg (1.18 mmol, 55%), colorless solid Rf: 0.20 (MeOH) mp: 106- 107°C 1

H-NMR (CDCl3): δ (ppm) = 7.65 (m, 2H, Ar-H), 7.26 (m, 8H, Ar-H), 5.45 (s, 1H, CH), 2.87

– 2.70 (m, 2H, CH2), 2.56 – 2.40 (m, 1H, CHH), 2.35 (s, 3H, N-CH3), 2.23 (m, 1H, CHH), 1.94 (m, 2H, CH2), 1.76 (m, 2H, CH2). 13

C-NMR (CDCl3): δ (ppm)= 168.3 (Cq), 141.6 (Cq, CAr), 132.7 (Cq, CAr), 130.4 (CHAr), 129.3

(CHAr), 128.7 (CHAr), 128.4 (CHAr), 128.2 (CHAr), 128.1 (CHAr), 89.8 (Cq), 71.0 (CHN), 53.4 (CH2), 53.2 (CH2), 46.4 (N-CH3), 39.3 (CH2), 38.7 (CH2). HRMS (EI): m/z: calculated for C20H23N3 [M]+: 305.1892; found: 305.1905. (rac)-4,5-Diphenyl-2,2-dipropyl-2,5-dihydro-1H-imidazole (5c)

A yellow 0.15 M solution of the substrate was prepared by dissolving 2.36 g (7.77 mmol, 1.0 eq) 4,5-diphenyl-2,2-dipropyl-2H-imidazole (4i) in 52 mL THF and transferred into a 100 mL round-bottom flask. 41

For the reduction itself a continuous-flow hydrogenation reactor (H-Cube) with a 10% Pd/C catalyst cartridge was used with the following conditions: 1.0 mL/min, 80°C, 60 bar, controlled H2 The product solution (91% conversion) was collected in a 250 mL round-bottom flask, the solvents were removed using a rotary evaporator. The crude product was purified via flash column chromatography (cyclohexane/ethyl acetate = 15:1 (v/v), 110 g silica gel) to obtain the product. C21H26N2 [306.45 g/mol] Yield: 2.14 g (7.0 mmol, 90%), brownish oil Rf: 0.18 (cyclohexane/ethyl acetate = 15:1 (v/v)) 1

H-NMR (DMSO-d6): δ (ppm) = 7.63-7.53 (m, 2H, Ar-H), 7.36-7.14 (m, 8H, Ar-H), 5.56 (s,

1H, CHNH), 2.82 (s, 1H, CHNH), 1.76-1.12 (m, 8H, CH2), 0.89 (dt, 3J = 14.5 Hz, 7.2 Hz, 6H, CH3). 13


(CHAr), 128.5 (2 × CHAr), 128.1 (4 × CHAr), 128.0 (2 × CHAr), 127.1 (CHAr), 93.6 (Cq), 70.5 (CHNH), 43.5 (CCH2), 42.7 (CCH2), 17.3 (CH3), 16.5 (CH3), 14.6 (CCH2CH2), 14.4 (CCH2CH2). No HRMS data is given because of product instability. (rac)-2-Phenyl-3-(pyridin-4-yl)-1,4-diazaspiro[4.5]dec-1-ene (5d)

42

A yellow 5 mM solution of the substrate was prepared by dissolving 604 mg (2.09 mmol, 1.0 eq) 2-phenyl-3-(pyridin-4-yl)-1,4-diazaspiro[4.5]deca-1,3-diene (4f) in 400 mL MeOH and transferred into a 500 mL round-bottom flask. For the reduction itself a continuous-flow hydrogenation reactor (H-Cube) with a 10% Pd/C catalyst cartridge was used with the following conditions: 2.0 mL/min, 50°C, 40 bar, controlled H2. Reaction progress was monitored via TLC and the reaction was stopped after a single run (ca. 200 min). The product solution was collected in a 500 mL round-bottom flask, the solvents were removed using a rotary evaporator. The crude product was purified via flash column chromatography (ethyl acetate/methanol = 14:1 (v/v), 63 g silica gel) to obtain 146 mg of a beige powder. The obtained product (~ 15 mol% oxidized side-product) is prone to reoxidation and was therefore not further purified. C19H21N3 [291.40 g/mol] Yield: 146 mg (0.50 mmol, 24%, ~ 85% purity), beige sticky gum Rf: 0.11 (ethyl acetate) 1


7.41 – 7.24 (m, 3H, Ar-H), 7.21 (m, 2H, Ar-H), 5.50 (s, 1H, HCN), 2.15 – 1.39 (m, 10H).

43

13

C-NMR (CDCl3): δ (ppm) = 166.5 (Cq), 150.6 (CHAr), 130.7 (CHAr), 128.6 (CHAr), 128.5

(CHAr), 123.2 (CHAr), 92.9 (Cq), 69.5 (CHN), 39.6 (CH2), 38.9 (CH2), 25.5 (CH2), 23.7 (CH2), 23.5 (CH2). Two quaternary signals are not obtained (2x CAr). No HRMS data is given because of product instability. (rac)-2,2-Diethyl-4,5-diphenyl-2,5-dihydro-1H-imidazole (5e)

An oven-dried, evacuated and nitrogen-purged 80 mL Schlenk tube, equipped with a Tefloncoated stir bar, was charged with 1.38 g (5.0 mmol, 1.0 eq) 2,2-diethyl-4,5-diphenyl-2Himidazole (4h), 95.0 mg (2.5 mmol, 0.5 eq) sodium borohydride and 20.0 mL dry THF with a steam of nitrogen. The mixture was then cooled to ca. 0°C in an ice-water bath, 10.0 mL (10.0 mmol, 2.0 eq) 1M borane tetrahydrofuran solution were added slowly via a syringe over 30 min. The mixture was stirred vigorously in the thawing ice-bath until RT was reached. The reaction progress was monitored by GC- MS. The reaction was stopped after 16 h when GCMS analysis did not indicate more conversion (93%). The reaction mixture was quenched 20.0 mL 5% NaHCO3 solution, extracted with diethyl ether (2 × 40 mL) and washed with brine, the collected filtrates were dried over anhydrous Na2SO4. The solvent was removed in vacuo and the crude product was purified via flash column chromatography on silica (cyclohexane/ethyl acetate = 6:1 (v/v)) to obtain the product. C19H22N2 [278.40 g/mol] Yield: 1.17 g (4.2 mmol, 84%), brownish oil

44

Rf: 0.20 (cyclohexane/ethyl acetate = 4:1 (v/v)) 1

H-NMR (DMSO-d6): δ (ppm) = 7.66-7.60 (m, 2H, Ar-H), 7.31-7.22 (m, 8H, Ar-H), 5.45 (s,

1H, CHN), 2.14-1.75 (m, 5H, CHNH, CH2), 1.05-1.00 (m, 3H, CH3), 0.96 (t, 3J = 7.4 Hz, 3H, CH3). 13


(CHAr), 129.2 (2 × CHAr), 128.6 (2 × CHAr), 128.4 (2 × CHAr), 128.4 (2 × CHAr), 128.1 (CHAr), 95.4 (Cq), 72.3 (CHNH), 33.3 (CCH2), 33.0 (CCH2), 8.9 (CH3), 8.4 (CH3). No HRMS data is given because of product instability. (rac)-1-(2,3-Diphenyl-1,4-diazaspiro[4.5]dec-3-en-1-yl)prop-2-en-1-one (6a)

An oven-dried, evacuated and nitrogen purged 80 mL Schlenk tube, equipped with a Tefloncoated stir bar was charged with 328 mg (1.13 mmol, 1.0 eq) 2,3-diphenyl-1,4diazaspiro[4.5]dec-1-ene (5a), 8.0 mL dry DCM and 314 μL (2.26 mmol, 2.0 eq) Et3N subsequently. The Schlenk tube was then cooled to ca. -78°C in a dry-ice/acetone bath. A solution of 110 μL mg (1.36 mmol, 1.2 eq) acryloyl chloride in 8.0 mL dry DCM was added slowly via a syringe over 1 h. The reaction progress was monitored by TLC and GC-MS. The reaction was stopped after 30 min when TLC analysis did not indicate any remaining starting material. The mixture was quenched with 20 mL saturated NaHCO3 solution and extracted with ethyl acetate (2 × 20 mL). The organic layer was dried over anhydrous Na2SO4. The solvent was removed using a rotary evaporator. The crude product was purified via flash 45

column chromatography (cyclohexane/ethyl acetate = 6:1 (v/v), 24 g silica gel) to obtain the product. C23H24N2O [344.45 g/mol] Yield: 334 mg (0.97 mmol, 86%), white crystals Rf: 0.25 (cyclohexane/ethyl acetate = 6:1 (v/v)) mp: 153-155°C 1

H-NMR (DMSO-d6): δ (ppm) = 7.81-7.70 (m, 2H, Ar-H), 7.43 (d, 3J = 7.5 Hz, 2H, Ar- H),

7.39-7.25 (m, 5H, Ar-H), 7.18 (t, 3J = 7.2 Hz, 1H, Ar-H), 6.74 (s, 1H, CHN), 6.45 (dd, 3J = 16.6 Hz, 10.2 Hz, 1H, CH2=CH), 5.96 (dd, 3J = 16.6, 1.8 Hz, 1H, CH2=CH), 5.45 (dd, 3J = 10.2, 1.8 Hz, 1H, CH2=CH), 3.04-2.80 (m, 2H, CH2), 2.02-1.67 (m, 6H, CH2), 1.47- 1.27 (m, 2H, CH2). 13

C-NMR (DMSO-d6): δ (ppm) = 164.5 (Cq, C=N), 162.5 (Cq, C=O), 139.6 (Cq, CAr), 131.7

(Cq, CAr), 131.2 (CH2=CH), 130.7 (CHAr), 128.9 (2 × CHAr), 128.3 (2 × CHAr), 128.2 (2 × CHAr), 128.1 (2 × CHAr), 127.9 (CHAr), 126.8 (CH2=CH), 93.9 (Cq), 68.8 (CHNH), 35.3 (CCH2), 34.5 (CCH2), 25.2 (CCH2CH2CH2), 23.5 (CCH2CH2), 23.4 (CCH2CH2). HRMS (EI): m/z: calculated for C23H24N2O [M]+: 344.1889; found: 344.1884.

(rac)-1-(2,3-Diphenyl-1,4-diazaspiro[4.5]dec-3-en-1-yl)-2,2,2-trifluoroethan-1onecarboxamide (6b)

46

An oven-dried, evacuated and nitrogen-purged 15 mL Schlenk tube, equipped with a Tefloncoated stir bar was charged with 82.3 mg (0.28 mmol, 1.0 eq) 2,3-diphenyl-1,4diazaspiro[4.5]dec-1-ene (5a), 2.0 mL dry DCM and 77 µL (0.33 mmol, 2.0 eq) Et3N subsequently. The Schlenk tube was then cooled to ca. -78°C in a dry-ice/acetone bath. A solution of 47 μL (0.33 mmol, 1.2 eq) TFAA in 2.0 mL dry DCM was added slowly via a syringe over 60 min. It was slowly warmed to RT overnight in the cooling bath and the reaction progress was monitored by TLC. After 18 h TLC analysis did not indicate any remaining starting material. The mixture was quenched with 15 mL saturated NaHCO3 solution and extracted with ethyl acetate (3 × 15 mL) and the combined organic layers were dried over anhydrous Na2SO4. The solvents were removed using a rotary evaporator. The crude product was purified via flash column chromatography (cyclohexane/ethyl acetate = 100:1 (v/v), 4.7 g silica gel, size: 8.5 × 1.3 cm) to obtain the product. C22H21F3N2O [386.42 g/mol] Yield: 74.9 mg (0.19 mmol, 68%), colorless solid Rf: 0.60 (cyclohexane/ethyl acetate = 6:1 (v/v)) mp: 134-136°C 1

H-NMR (CDCl3): δ (ppm)= 7.76 – 7.60 (m, 2H, Ar-H), 7.42 – 7.14 (m, 8H, Ar-H), 6.29 (s,

1H, CHN), 2.96 (m, 2H, CH2), 2.18 – 1.68 (m, 6H, CH2), 1.45 (m, 2H, CH2).

47

13

C-NMR (CDCl3): δ (ppm)= 163.3 (Cq, C=N), 155.3 (q, J= 37 Hz, CCF3), 137.6 (Cq, CAr),

131.6 (Cq, CAr), 130.9 (CHAr), 129.0 (CHAr), 128.8 (CHAr), 128.7 (CHAr), 128.5 (2x CHAr), 115.8 (q, J= 289 Hz, CF3), 98.8 (Cq), 69.9 (2s,CHN), 35.1 (CH2), 34.7 (CH2), 25.4 (CH2), 24.2 (CH2), 24.1 (CH2). 19

F NMR (CDCl3) δ (ppm)= -71.3

HRMS (EI): m/z: calculated for C22H21F3N2O [M]+: 386.1606; found: 386.1590.

(rac)- (2,3-Diphenyl-1,4-diazaspiro[4.5]dec-3-en-1-yl)(thiophen-2-yl)methanone (6c)

An oven-dried, evacuated and nitrogen-purged 100 mL Schlenk tube, equipped with a Tefloncoated stir bar, was charged with 1.71 g (5.9 mmol, 1.0 eq) 2,3-diphenyl-1,4diazaspiro[4.5]dec-1-ene (5a), 20.0 mL dry DCM and 1.64 mL (11.8 mmol, 2.0 eq) Et3N subsequently. The Schlenk tube was then cooled to ca. -78°C in a dry-ice/acetone bath. A solution of 759 μL (7.1 mmol, 1.2 eq) 2-thiophencarbonyl chloride in 15.0 mL dry DCM was added slowly via a syringe over 30 min. The reaction progress was monitored by TLC and GC-MS. The reaction was run overnight at RT when TLC analysis did not indicate any remaining starting material. The mixture was quenched with 50 mL saturated NaHCO3 solution and extracted with DCM (2 × 50 mL). The organic layer was dried over anhydrous Na2SO4. The solvents were removed using a rotary evaporator. The crude product was

48

purified via flash column chromatography (cyclohexane/ethyl acetate = 9:1 (v/v), 80 g silica gel) to obtain the product. C25H24N2OS [400.54 g/mol] Yield: 2.25 g (5.6 mmol, 95%), colorless solid Rf: 0.24 (cyclohexane/ethyl acetate = 9:1 (v/v)) mp: 118-120°C 1


(m, 4H, Ar-H), 5.69 (ddd, 3J = 11.9 Hz, 5.5 Hz, 3.3 Hz, 3H, CH), 6.37 (s, 1 H, CHN), 3.223.04 (m, 1H, CH2), 2.88 (td, 3J = 12.9 Hz, 3.2 Hz, 1H, CH2), 2.17-1.94 (m, 3H, CH2), 1.83 (t, 3

J = 15.2 Hz, 3H, CH2), 1.68-1.39 (m, 2H, CH2).

13

C-NMR (CDCl3): δ (ppm) = 163.4 (Cq, C=O), 162.8 (Cq, C=N), 139.9 (Cq, CAr), 138.2 (Cq,

CAr), 136.2 (CHS), 132.0 (CH=CHS), 130.8 (CHAr), 128.7 (2 × CHAr), 128.4 (4 × CHAr), 128.3 (2 × CHAr), 127.9 (CS), 127.5 (CH=CHS), 127.4 (CH=CS), 126.4 (CHAr), 95.8 (Cq), 71.7 (CHN), 36.9 (CCH2), 35.3 (CCH2), 25.6 (CCH2CH2CH2), 24.2 (CCH2CH2), 24.1 (CCH2CH2). HRMS (EI): m/z: calculated for C25H24N2OS [M]+: 400.1609; found: 400.1615.

(rac)-1-(2,3-Diphenyl-1,4-diazaspiro[4.5]dec-3-en-1-yl)-2-methylpropan-1-one (6d)

49

An oven-dried, evacuated and nitrogen-purged 15 mL Schlenk tube, equipped with a Tefloncoated stir bar was charged with 63.4 mg (0.22 mmol, 1.0 eq) 2,3-diphenyl-1,4diazaspiro[4.5]dec-1-ene (5a), 2.0 mL dry DCM and 32 µL Et3N (0.43 mmol, 2.0 eq) subsequently. The Schlenk tube was then cooled to 0°C in an ice/water bath and 29.7 μL (0.28 mmol, 1.3 eq) isobutyryl chloride was added. It was slowly warmed to RT and stirred for 3h 30 min at this temperature, after which another 14.9 µL (0.14 mmol, 0.6 eq) isobutyryl chloride were added. The reaction progress was monitored by TLC. After 16 h TLC analysis did not indicate any remaining starting material. The mixture was quenched with 10 mL saturated NaHCO3 solution and extracted with ethyl acetate (3 × 10 mL) and the combined organic layers were dried over anhydrous Na2SO4. The solvents were removed using a rotary evaporator. The

crude product

was

purified via flash


(cyclohexane/ethyl acetate = 8:1 (v/v), 4.7 g silica gel, size: 8.5 × 1.3 cm) to obtain the product. C24H28N2O [360.50 g/mol] Yield: 63.4 mg (0.19 mmol, 68%), colorless solid Rf: 0.41 (cyclohexane/ ethyl acetate) = 6:1 (v/v)) mp: 172-173°C 1

H-NMR (CDCl3): δ (ppm)= two rotamers: δ 7.77 – 7.62 (m, 2H, Ar-H), 7.46 – 7.13 (m, 8H,

Ar-H), 6.31 (s, 0.2 H, HCN), 6.05 (s, 0.8 H, HCN), 3.15 – 2.86 (m, 1.8 H, ), 2.51 (dt, 3J = 50

13.2 Hz, 6.6 Hz, 0.8 H), 2.18 – 1.63 (m, 6.1 H), 1.59 – 1.27 (m, 1.9 H), 1.17 (d, 3J = 6.5 Hz, 0.6 H, CH3), 1.11 (d, 3J = 6.7 Hz, 2.3 H, CH3), 0.95 (d, 3J = 6.7 Hz, 0.5 H, CH3), 0.47 (d, 3J = 6.5 Hz, 2.4 H, CH3). 13

C-NMR (CDCl3): δ (ppm)= main rotamer: 176.0 (Cq), 163.4 (Cq), 139.5 (Cq, CAr), 132.4

(Cq, CAr), 130.5 (CHAr), 129.2 (CHAr), 128.5 (CHAr), 128.4 (CHAr), 128.3 (2x CHAr), 95.0 (Cq), 70.5 (CHN), 36.2 (CH2), 35.1 (CH2), 34.5 (CH), 25.7 (CH2), 24.2 (2xCH2), 19.9 (CH3), 18.4 (CH3). minor rotamer: 176.0 (Cq), 163.4 (Cq), 139.5 (Cq, CAr), 132.4 (Cq, CAr), 130.7 (CHAr), 129.1 (CHAr), 128.5 (CHAr), 128.4 (CHAr), 128.3 (CHAr), 127.7 (CHAr), 95.0 (Cq), 70.7 (CHN), 39.2 (CH2), 39.0 (CH2), 33.6 (CH), 25.8 (CH2), 24.5 (CH2), 24.3 (CH2), 21.0 (CH3), 18.9 (CH3). HRMS (EI): m/z: calculated for C24H28N2O [M]+: 360.2202; found: 360.2079.

(rac)-Ethyl 2-(2,3-diphenyl-1,4-diazaspiro[4.5]dec-3-en-1-yl)-2-oxoacetate (6e)

An oven-dried, evacuated and nitrogen-purged 15 mL Schlenk tube, equipped with a Tefloncoated stir bar was charged with 59.0 mg (0.20 mmol, 1.0 eq) 2,3-diphenyl-1,4diazaspiro[4.5]dec-1-ene (5a), 0.8 mL dry DCM and 170 µL pyridine (2.1 mmol, 10 eq) subsequently. The Schlenk tube was then cooled to 0°C in an ice/water bath and 116 μL (1.0 mmol, 5.1 eq) ethyl 2-chloro-2-oxoacetate was added. It was slowly warmed to RT and the 51

reaction progress was monitored by TLC. After 2 h TLC analysis did not indicate any remaining starting material. The mixture was quenched with 7 mL saturated NaHCO3 solution and extracted with ethyl acetate (4 × 8 mL) and the combined organic layers were dried over anhydrous Na2SO4. The solvents were removed using a rotary evaporator. The crude product was purified via flash column chromatography (cyclohexane/ethyl acetate = 6:1 (v/v), 4.7 g silica gel, size: 7.5 × 1.5 cm) to obtain the product. C24H26N2O3 [390.48 g/mol] Yield: 62.5 mg (0.16 mmol, 79%), colorless solid Rf: 0.32 (cyclohexane/ ethyl acetate) = 6:1 (v/v)) mp: 117-119°C 1

H-NMR (CDCl3):

δ (ppm)= δ 7.72-7.63 (m, 2H, Ar-H), 7.34-7.18 (m, 8H, Ar-H), 6.36 (s,

1H, HCN), 4.06–3.90 (m, 1H, CHH), 3.87–3.69 (m, 1H, CHH), 3.08–2.92 (m, 1H, CHH), 2.84 (m, 1H, CHH), 2.16–1.71 (m, 6H, 3x CH2), 1.63–1.42 (m, 2H, CH2), 0.97 (t, J = 7.1 Hz, 3H, CH3). 13

C-NMR (CDCl3):

δ (ppm)= 163.4 (Cq), 162.7 (Cq), 159.1 (Cq), 137.9 (Cq, CAr), 131.8 (Cq,

CAr), 130.8 (CHAr), 129.4 (CHAr), 129.1(CHAr), 128.6 (CHAr), 128.5 (CHAr), 128.4 (CHAr), 96.1 (Cq), 70.1 (CHN), 61.8 (CH2), 35.4 (CH2), 35.1 (CH2), 25.4 (CH2), 24.0 (2x CH2), 13.7 (CH3). HRMS (EI): m/z: calculated for C24H26N2O3 [M]+: 390.1943; found: 390.1857.

52

(rac)-N-Cyclohexyl-2,3-diphenyl-1,4-diazaspiro[4.5]dec-3-ene-1-carboxamide (6f)

An oven-dried, evacuated and nitrogen-purged 15 mL Schlenk tube, equipped with a Tefloncoated stir bar was charged with 84.2 mg (0.29 mmol, 1.0 eq) 2,3-diphenyl-1,4diazaspiro[4.5]dec-1-ene (5a) and 2.0 mL dry DCM. The Schlenk tube was then cooled to 0°C in an ice bath and 110 μL (0.86 mmol, 3.0 eq) cyclohexylisocyanate was added. It was slowly warmed to RT overnight in the cooling bath and the reaction progress was monitored by TLC. After 18 h TLC analysis did not indicate any remaining starting material. The solvents were removed using a rotary evaporator. The crude product was purified via flash column chromatography (cyclohexane/ethyl acetate = 8:1 (v/v), 4.7 g silica gel, size: 8.5 × 1.3 cm) to obtain the product. C27H33N3O [415.58 g/mol] Yield: 104 mg (0.25 mmol, 86%), colorless solid Rf: 0.65 (cyclohexane/ethyl acetate = 2:1 (v/v)) mp: 144-146°C

53

1

H-NMR (CDCl3): δ (ppm) = δ 7.69 (m, 2H, Ar-H), 7.36 (m, 8H, Ar-H), 5.85 (s, 1H, CH),

4.07 (d, J = 7.4 Hz, 1H, N-H), 3.63–3.39 (m, 1H, CH), 3.13–2.82 (m, 2H, CH2), 2.23–1.68 (m, 7H, CH2), 1.66 – 0.92 (m, 10H, CH2), 0.64 (m, 1H, CHH).

13

C-NMR (CDCl3): δ (ppm)= 163.1 (Cq), 154.4 (Cq), 139.0 (Cq, CAr), 132.5 (Cq, CAr), 130.4

(CHAr), 129.6 (CHAr), 128.8 (CHAr), 128.4 (CHAr), 128.3 (2x CHAr), 94.4 (Cq), 69.6 (CHN), 48.7 (CHN), 37.4 (CH2), 35.9 (CH2), 33.8 (CH2), 32.9 (CH2), 25.8 (CH2), 25.7 (CH2), 24.7 (CH2), 24.5 (CH2), 24.4 (CH2). HRMS (EI): m/z: calculated for C27H33N3O [M]+: 415.2624; found: 415.2620. (rac)-N-Hexyl-2,3-diphenyl-1,4-diazaspiro[4.5]dec-3-ene-1-carboxamide (6g)

An oven-dried, evacuated and nitrogen-purged 15 mL Schlenk tube, equipped with a Tefloncoated stir bar was charged with 47.4 mg (0.16 mmol, 1.0 eq) 2,3-diphenyl-1,4diazaspiro[4.5]dec-1-ene (5a) and 2.0 mL dry DCM. The Schlenk tube was then cooled to 0°C in an ice bath and 72 μL (0.49 mmol, 3.0 eq) hexylisocyanate was added. After 50 min, the ice bath was removed and the reaction progress was monitored by TLC. The reaction was stirred for 2 h at RT when TLC analysis did not indicate any remaining starting material. The solvents were removed using a rotary evaporator. The crude product was purified via flash column chromatography (cyclohexane/ethyl acetate = 6:1 (v/v), 2.0 g silica gel, size: 7.0 × 0.5 cm) to obtain the product. 54

C27H35N3O [417.60 g/mol] Yield: 49.7 mg (0.12 mmol, 73%), colorless solid Rf: 0.23 (cyclohexane/ethyl acetate = 6:1 (v/v)) mp: 163-164°C 1

H-NMR (CDCl3):

δ (ppm) = 7.64 (m, 2H, Ar-H), 7.49–7.14 (m, 8H, Ar-H), 5.82 (s, 1H,

C-H), 4.08 (s, 1H, N-H), 3.21–2.77 (m, 4H, CH2), 2.18–1.63 (m, 6H, CH2), 1.49 (m, 2H, CH2), 1.33–1.01 (m, 6H, CH2), 1.02–0.73 (m, 5H, CH3, CH2). 13

C-NMR (CDCl3):

δ (ppm) 163.1 (Cq), 155.1 (Cq), 138.9 (Cq, CAr), 132.5 (Cq, CAr), 130.4

(CHAr), 129.6 (CHAr), 128.9 (CHAr), 128.4 (CHAr), 128.3 (CHAr), 128.2 (CHAr), 94.4 (Cq), 69.7 (CHN), 40.4 (CH2), 40.2 (CH2), 37.4 (CH2), 35.9 (CH2), 31.6 (CH2), 29.8 (CH2), 26.4 (CH2), 25.7 (CH2), 24.4 (CH2), 22.6 (CH2), 14.2 (CH3). HRMS (EI): m/z: calculated for C27H35N3O [M]+: 417.2780; found: 417.2762. (rac)-N,2,3-Triphenyl-1,4-diazaspiro[4.5]dec-3-ene-1-carboxamide (6h)

An oven-dried, evacuated and nitrogen-purged 15 mL Schlenk tube, equipped with a Tefloncoated stir bar was charged with 58.9 mg (0.20 mmol, 1.0 eq) 2,3-diphenyl-1,4diazaspiro[4.5]dec-1-ene (5a) and 2.0 mL dry DCM. The Schlenk tube was then cooled to 0°C in an ice bath and 67 μL (0.62 mmol, 3.0 eq) phenylisocyanate was added. After 50 min, 55

the ice bath was removed and the reaction progress was monitored by TLC. The reaction was stirred for 2 h at RT when TLC analysis did not indicate any remaining starting material. The solvents were removed using a rotary evaporator. The crude product was purified via flash column chromatography (cyclohexane/ethyl acetate = 20:1 (v/v), 4.6 g silica gel, size: 8.5 × 1.3 cm) to obtain the product. C27H27N3O [409.53 g/mol] Yield: 64.5 mg (0.16 mmol, 78%), colorless solid Rf: 0.31 (cyclohexane/ethyl acetate = 6:1 (v/v)) mp: 169-170°C 1

H-NMR (CDCl3): δ (ppm) = 7.62 (m, 2H, Ar-H), 7.49–7.01 (m, 10H, Ar-H), 7.00–6.76 (m,

3H, Ar-H), 6.12 (s, 1H, N-H), 5.88 (s, 1H, CH), 3.02, 2.85 (2x td, 3J = 12.9 Hz, 4.0 Hz, 2H, CH2), 2.16–1.58 (m, 6H, CH2), 1.58–1.29 (m, 2H, CH2). 13

C-NMR (CDCl3): δ (ppm) = δ 162.7 (Cq), 152.2 (Cq), 138.9 (Cq, CAr), 138.4 (Cq, CAr), 132.2

(Cq, CAr), 130.6 (CHAr), 130.0 (CHAr), 129.4 (CHAr), 128.8 (CHAr), 128.4 (2x CHAr), 128.3 (CHAr), 123.1 (CHAr), 119.7 (CHAr), 95.0 (Cq), 69.7 (CHN), 36.9 (CH2), 35.9 (CH2), 25.6 (CH2), 24.4 (CH2). HRMS (EI): m/z: calculated for C27H27N3O [M]+: 409.2154; found: 409.2130. (rac)-4-(2,3-Diphenyl-1,4-diazaspiro[4.5]dec-3-en-1-yl)-4-oxobutanoic acid (6i)

56

An oven-dried, evacuated and nitrogen-purged 15 mL Schlenk tube, equipped with a Tefloncoated stir bar was charged with 123.2 mg (0.42 mmol, 1.0 eq) 2,3-diphenyl-1,4diazaspiro[4.5]dec-1-ene (5a), 1.6 mL dry DCM and 340 µL pyridine (4.2 mmol, 10 eq) subsequently. The Schlenk tube was then cooled to 0°C in an ice/water bath and 215.3 μL (2.6 mmol, 6.3 eq) succinic anhydride was added. It was slowly warmed to RT overnight and the reaction progress was monitored by TLC. After 16 h TLC analysis did not indicate any remaining starting material. The mixture was quenched with 15 mL of a 5% formic acid solution and extracted with ethyl acetate (4 × 10 mL) and the combined organic layers were concentrated in vacuo. The crude product was further purified via preparative HPLC (column: Nucleodur C-18, flow: 12 mL/min, 30°C; a: 0.01% formic acid in water, b: acetonitrile, time: 0-3 min: 70% a, 30% b, -9 min: 25% a, 75% b, -14 min: 25% a, 75% b, - 17 min 5% a, 95% b, - 21 min 5% a, 95% b). The solvent was removed using a rotary evaporator. C24H26N2O3 [390.48 g/mol] Yield: 98 mg (0.34 mmol, 80%), colorless solid Rf: 0.45 (cyclohexane/ ethyl acetate/ acetic acid) = 1:1:0.01 (v/v/v)) mp: 173-175°C

57

1

H-NMR (CDCl3):

δ (ppm) = 7.66 (d, J = 6.8 Hz, 2H, Ar-H), 7.44– .14 (m, 8H, Ar-H), 6.04

(s, 1H, HCN), 3.05–2.82 (m, 2H, CH2), 2.58 (m, 2H, CH2), 2.40 (m, 1H, CHH), 2.14 – 1.64 (m, 7H, 3x CH2, 1x CHH), 1.44 (m, 2H, CH2). 13

C-NMR (CDCl3):

δ (ppm)= 176.4 (Cq), 170.6 (Cq), 163.1 (Cq), 138.0 (Cq, CAr), 132.1 (Cq,

CAr), 130.7 (CHAr), 129.4 (CHAr), 128.7 (CHAr), 128.6 (CHAr), 128.5 (CHAr), 128.3 (CHAr), 95.9 (Cq), 70.9 (CHN), 35.8 (CH2), 35.1 (CH2), 32.0 (CH2), 29.6 (CH2), 25.5 (CH2), 24.2 (CH2), 24.1 CH2). HRMS (EI): m/z: calculated for C24H26N2O3 [M]+: 390.1943; found: 390.1932. (rac)-4-Allyl-2,3-diphenyl-1,4-diazaspiro[4.5]dec-1-ene (6j)

An oven-dried, evacuated and nitrogen-purged 10 mL Schlenk tube, equipped with a Tefloncoated stir bar was charged with 145 mg (0.5 mmol, 1.0 eq) 2,3-diphenyl-1,4diazaspiro[4.5]dec-1-ene (5a), 2.0 mL dry DMF, 138 mg (1.0 mmol, 2.0 eq) potassium carbonate, 19 mg (0.05 mmol, 0.1 eq) tetrabutylammonium iodide and 131 μL (1.5 mmol, 3.0 eq) allyl bromide subsequently. The mixture was heated to 60°C and run overnight. The reaction mixture was quenched with 5.0 mL distilled water, extracted with diethyl ether (3 × 20 ml). The ether phase was dried over anhydrous Na2SO4 and the solvent was removed using a rotary evaporator. The crude product was purified via flash column chromatography (cyclohexane/ethyl acetate = 40:1 (v/v), 20 g silica gel, size: 12.5 × 2.4 cm) to obtain the pure product. C23H26N2 [330.48 g/mol] 58

Yield: 129 mg (0.39 mmol, 86%), yellowish solid Rf: 0.28 (cyclohexane/ethyl acetate = 40:1 (v/v)) mp: 69-71°C 1

H-NMR (CDCl3): δ (ppm) = 7.70-7.61 (m, 2H, Ar-H), 7.37-7.19 (m, 8H, Ar-H), 5.69 (ddt,

1H, 3J = 17.0 Hz, 10.0 Hz, 6.6 Hz, 1H, CH2=CHCH2), 5.25 (s, 1H, CHN), 5.13 (d, 3J = 17.1 Hz, 1H, CH2=CH), 5.01 (d, 3J = 9.9 Hz, 1H, CH2=CH), 3.50-3.30 (m, 2H, CH2=CHCH2), 2.26-2.08 (m, 1H, CH2), 2.00-1.71 (m, 7H, CH2), 1.64 (d, 3J = 12.6 Hz, 1H, CH2), 1.40-1.23 (m, 1H, CH2). 13

C-NMR (CDCl3): δ (ppm) = 167.1 (Cq, C=N), 141.4 (Cq, CAr), 138.1 (CH2=CH), 133.7 (Cq,

CAr), 129.8 (CHAr), 129.4 (2 × CHAr), 128.4 (2 × CHAr), 128.3 (2 × CHAr), 128.1 (2 × CHAr), 127.4 (CHAr), 115.9 (CH2=CH), 91.7 (Cq), 74.1 (CHNH), 49.1 (CH2=CHCH2), 39.3 (CCH2), 35.9 (CCH2), 26.4 (CCH2CH2CH2), 24.7 (CCHCH2), 24.2 (CCH2CH2). HRMS (EI): m/z: calculated for C23H26N2 [M]+:330.2096; found: 330.2094. (rac)-1-(4,5-Diphenyl-2,2-dipropyl-2,5-dihydro-1H-imidazol-1-yl)prop-2-en-1-one (6k)

An oven-dried, evacuated and nitrogen-purged 100 mL Schlenk tube, equipped with a Tefloncoated stir bar was charged with 1.11 g (3.63 mmol, 1.0 eq) 4,5-diphenyl-2,2-dipropyl-2,5dihydro-1H-imidazole (5c), 20.0 mL dry DCM and 1.01 mL (7.26 mmol, 2.0 eq) Et3N subsequently. The Schlenk tube was then cooled to ca. -78°C in a dry-ice/acetone bath. A 59

solution of 354 μL mg (4.36 mmol, 1.2 eq) acryloyl chloride in 20.0 mL dry DCM was added slowly via a syringe over 1 h. The reaction progress was monitored by TLC and GC-MS. The reaction was stopped after 30 min when TLC analysis did not indicate any remaining starting material. The mixture was quenched with 20 mL saturated NaHCO3 solution and extracted with ethyl acetate (2 × 40 mL). The organic layer was dried over anhydrous Na2SO4. The solvent was removed using a rotary evaporator. The crude product was purified via flash column chromatography (cyclohexane/ethyl acetate = 12:1 (v/v), 72 g silica gel) to obtain the product. C24H28N2O [360.49 g/mol] Yield: 1.09 g (3.02 mmol, 86%), white crystals Rf: 0.20 (cyclohexane/ethyl acetate = 12:1 (v/v)) mp: 141-143°C 1

H-NMR (DMSO-d6): δ (ppm) = 7.70 (dd, 3J = 9.7 Hz, 8.2 Hz, 2H, Ar-H), 7.43 (d, 3J = 7.4

Hz, 2H, Ar-H), 7.41-7.27 (m, 5H, Ar-H), 7.20 (t, 3J = 7.2 Hz, 1H, Ar-H), 6.66 (s, 1H, CHN), 6.47 (dd, 3J = 16.6 Hz, 10.2 Hz, 1H, CH2=CH), 5.98 (dd, 3J = 16.6 Hz, 1.9 Hz, 1H, CH2=CH), 5.47 (dd, J = 10.2 Hz, 1.9 Hz, 1H, CH2=CH), 2.65 (td, J = 12.7 Hz, 5.1 Hz, 1H, CH2), 2.101.81 (m, 3H, CH2), 1.79-1.55 (m, 2H, CH2), 1.06-0.92 (m, 5H, CH2, CH3), 0.81 (t, 3J = 7.0 Hz, 3H, CH3). 13

C-NMR (DMSO-d6): δ (ppm) = 165.8 (Cq, C=N), 162.7 (Cq, C=O), 139.5 (Cq, CAr), 131.4

(Cq, CAr), 130.6 (CH2=CH), 130.5 (CHAr), 128.9 (2 × CHAr), 128.3 (2 × CHAr), 128.2 (2 × CHAr), 128.0 (2 × CHAr), 127.9 (CHAr), 127.0 (CH2=CH), 96.4 (Cq), 69.7 (CHNH), 42.3 (CCH2), 36.3 (CCH2), 17.9 (CCH2CH2), 15.6 (CCH2CH2), 14.7 (CH3), 13.7 (CH3). HRMS (EI): m/z: calculated for C24H28N2O [M]+: 360.2202; found: 360.2210. 60

(rac)-1-(8-Methyl-2,3-diphenyl-1,4,8-triazaspiro[4.5]dec-3-en-1-yl)ethan-1-one (6l)

An oven-dried, evacuated and nitrogen-purged 15 mL Schlenk tube, equipped with a Tefloncoated stir bar was charged with 44 mg (0.14 mmol, 1.0 eq) 8-methyl-2,3-diphenyl-1,4,8triazaspiro[4.5]dec-1-ene (5b), 0.6 mL dry DCM and 25 µL pyridine (0.31 mmol, 2.2 eq) subsequently. The Schlenk tube was then cooled to ca. -78°C in a dry-ice/acetone cooling bath and 16 μL (0.23 mmol, 1.6 eq) acetyl chloride was added. It was slowly warmed to RT over 16 h, after which another 240 µL pyridine (2.97 mmol, 21 eq) and 51 µL (0.72 mmol, 5.0 eq) acetyl chloride were added at 0°C (ice/water bath). The reaction progress was monitored by TLC. After 8 h TLC analysis did not indicate any remaining starting material. The mixture was quenched with 15 mL saturated NaHCO3 solution and extracted with ethyl acetate (5 × 15 mL) and the combined organic layers were dried over anhydrous Na2SO4. The solvents were removed using a rotary evaporator. The crude product was purified via flash column chromatography (MeOH, 4.7 g silica gel, size: 7.5 × 1.5 cm) to obtain the product. C22H25N3O [347.46 g/mol] Yield: 41 mg (0.12 mmol, 82%), red-brown solid Rf: 0.25 (MeOH) mp: 180-181°C 1

H-NMR (CDCl3):

δ (ppm)= main rotamer: 7.68 (m, 2H, Ar-H), 7.40–7.17 (m, 8H, Ar-H),

5.99 (s, 1H, NH), 3.51–3.25 (m, 2H, CH2), 3.02–2.56 (m, 2H, CH2), 2.41 (s, 3H, N-CH3), 61

2.23 (s, 1H, CHH), 1.83 (s, 3H, CH3), 1.32 (m, 1H, CHH). minor rotamer: 7.68 (m, 2H, ArH), 7.40–7.17 (m, 8H, Ar-H), 6.35 (s, 1H, NH), 3.51–3.25 (m, 2H, CH2), 3.02–2.56 (m, 2H, CH2), 2.41 (s, 3H, N-CH3), 2.23 (s, 1H, CHH), 1.83 (s, 3H, CH3), 1.32 (m, 1H, CHH). 13

C-NMR (CDCl3):

δ (ppm)= main rotamer: 168.8 (Cq), 163.9 (Cq), 138.4 (Cq,CAr), 132.0

(Cq,CAr), 130.7 (CHAr), 129.2 (CHAr), 128.5 (CHAr), 128.4 (2x CHAr), 128.3 (CHAr), 92.5 (Cq), 71.5 (CHN), 53.5 (CH2), 53.4 (CH2), 46.1 (N-CH3), 35.3 (CH2), 34.2 (CH2), 25.8 (CH3). minor rotamer: 168.8 (Cq), 163.9 (Cq), 138.4 (Cq,CAr), 132.0 (Cq,CAr), 130.9 (CHAr), 129.2 (CHAr), 128.5 (CHAr), 128.4 (2x CHAr), 128.3 (CHAr), 89.7 (Cq), 70.8 (CHN), 53.8 (CH2), 53.5 (CH2), 46.3 (N-CH3), 38.1 (CH2), 37.6 (CH2), 24.0 (CH3). HRMS (EI): m/z: calculated for C22H25N3O [M]+: 347.1998; found: 347.2004. (rac)-2,2,2-Trifluoro-1-(8-methyl-2,3-diphenyl-1,4,8-triazaspiro[4.5]dec-3-en-1-yl)ethan1-one (6m)

An oven-dried, evacuated and nitrogen-purged 15 mL Schlenk tube, equipped with a Tefloncoated stir bar was charged with 32.5 mg (0.11 mmol, 1.0 eq) 8-methyl-2,3-diphenyl-1,4,8triazaspiro[4.5]dec-1-ene (5b), 0.9 mL dry DCM and 50 µL (0.36 mmol, 3.4 eq) Et3N subsequently. The Schlenk tube was then cooled to ca. -78°C in a dry-ice/acetone bath and a solution of 17.4 μL (0.13 mmol, 1.2 eq) TFAA in 0.9 mL dry DCM was added slowly via a syringe over 30 min. It was slowly warmed to RT overnight in the cooling bath and the reaction progress was monitored by TLC. After 14 h it was again cooled to ca. -78°C in a dryice/acetone bath and further 17.4 μL (0.13 mmol, 1.2 eq) TFAA were added. The cooling bath 62

was removed and it was stirred at RT for 3 h. The mixture was quenched with 2 mL saturated NaHCO3 solution and extracted with ethyl acetate (5 × 4 mL) and the combined organic layers were dried over anhydrous Na2SO4. The solvents were removed using a rotary evaporator. The crude product was purified via flash column chromatography (ethyl acetate/ MeOH= 2:1 (v/v), 1.0 g silica gel, size: 5.0 × 0.5 cm) to obtain the product. C22H22F3N3 [401.43 g/mol] Yield: 29.5 mg (0.073 mmol, 69%), colorless solid Rf: 0.52 (MeOH) mp: 132 - 133°C 1

H-NMR (CDCl3):

δ (ppm) = 7.75–7.65 (m, 2H, Ar-H), 7.40– .21 (m, 8H, Ar-H), 6.34 (s,

1H, CHN), 3.39 (m, 2H, CH2), 3.28–2.94 (m, 4H, CH2), 2.60 (s, 3H, N-CH3), 1.97 (dd, J = 13.0, 2.2 Hz, 1H, CHH), 1.46 (d, 3J = 12.2 Hz, 1H, CHH). 13

C-NMR (CDCl3):

δ (ppm)= 164.9 (Cq, C=N), 137.0 (Cq), 131.4 (Cq, HCAr), 131.0 (Cq),

129.2 (CHAr), 129.1 (CHAr), 128.6 (CHAr), 128.5 (2x CHAr), 115.6 (q, J= 287 Hz, CF3), 95.1 (Cq), 70.2 (CHN), 52.7 (CH2), 52.5 (CH2), 44.5 (N-CH3), 33.2 (CH2), 32.6 (CH2). O=CCF3 is not observed. 19

F-NMR (CDCl3):

δ (ppm)= -71.3, -75.4 (two rotamers)

HRMS (EI): m/z: calculated for C22H22F3N3O [M]+: 401.1715; found: 401.1739. (rac)-2-Methyl-1-(8-methyl-2,3-diphenyl-1,4,8-triazaspiro[4.5]dec-3-en-1-yl)propan-1one (6n)

63

An oven-dried, evacuated and nitrogen-purged 15 mL Schlenk tube, equipped with a Tefloncoated stir bar was charged with 59.6 mg (0.20 mmol, 1.0 eq) 8-methyl-2,3-diphenyl-1,4,8triazaspiro[4.5]dec-1-ene (5b), 0.8 mL dry DCM and 160 µL pyridine (1.98 mmol, 10.1 eq) subsequently. The Schlenk tube was then cooled to 0°C in an ice/water bath and 103.6 μL (0.99 mmol, 5.1 eq) isobutyryl chloride was added. It was slowly warmed to RT overnight and the reaction progress was monitored by TLC. After 14 h TLC analysis did not indicate any remaining starting material. The mixture was quenched with 10 mL saturated NaHCO3 solution and extracted with ethyl acetate (5 × 15 mL) and the combined organic layers were dried over anhydrous Na2SO4. The solvents were removed using a rotary evaporator. The crude product was purified via flash column chromatography (MeOH, 6.0 g silica gel, size: 13.0 × 1.2 cm) to obtain the product. C24H29N3O [375.52 g/mol] Yield: 47.3 mg (0.13 mmol, 65%), colorless solid Rf: 0.31 (MeOH) mp: 200 - 201°C 1

H-NMR (CDCl3):

δ (ppm)= two rotamers: 7.70 (m, 2H, Ar-H), 7.42 – 7.13 (m, 8 H, Ar-

H), 6.33, 6.06 (2x s, 1H, CHN), 3.53 – 3.23, 3.06-2.53 (m, 6H), 2.44 (d, J = 9.5 Hz, 3H), 2.20 (m, 1H), 2.04 (m, 1H, 0.5 H), 1.80 (m, 0.5 H), 1.66 (m, 0.5 H), 1.26 (m, 0.5 H), 1.13 (m, 3H), 0.93 (d, J = 6.5 Hz, 1.5 H), 0.48 (d, J = 6.4 Hz, 1.5 H). 64

13

C-NMR (CDCl3):

δ (ppm)= main rotamer: 175.8 (Cq), 163.9 (Cq), 139.3 (Cq, CAr), 132.2

(Cq, CAr), 130.7 (CHAr), 129.2 (CHAr), 128.5 (CHAr), 128.5 (CHAr), 128.4 (CHAr), 127.8 (CHAr), 92.5 (Cq), 70.6 (CHN), 53.8 (CH2), 53.3 (CH2), 45.8 (N-CH3), 38.3 (CH2), 34.5 (CH2), 33.8 (CH), 19.9 (CH3), 18.4 (CH3). minor rotamer: 176.1 (Cq), 165.1 (Cq), 138.6 (Cq, CAr), 130.9 (Cq, CAr), 129.0 (CHAr), 128.5 (2x CHAr), 128.4 (2x CHAr), 127.8 (CHAr), 89.5 (Cq), 70.8 (CHN), 54.0 (CH2), 53.4 (CH2), 46.4 (N-CH3), 38.7 (CH2), 35.1 (CH), 33.5 (CH2), 20.9 (CH3), 18.9 (CH3). HRMS (EI): m/z: calculated for C24H29N3O [M]+: 375.2310; found: 375.2331.

(rac)-(8-Methyl-2,3-diphenyl-1,4,8-triazaspiro[4.5]dec-3-en-1-yl)(thiophen-2yl)methanone (6o)

An oven-dried, evacuated and nitrogen-purged 15 mL Schlenk tube, equipped with a Tefloncoated stir bar was charged with 52.6 mg (0.17 mmol, 1.0 eq) 8-methyl-2,3-diphenyl-1,4,8triazaspiro[4.5]dec-1-ene (5b), 0.8 mL dry DCM and 139 µL pyridine (1.72 mmol, 10.0 eq) subsequently. The Schlenk tube was then cooled to 0°C in an ice/water bath and 92 μL (0.86 mmol, 5.0 eq) 2-thiophene carbonyl chloride was added. It was slowly warmed to RT overnight and the reaction progress was monitored by TLC. After 14 h TLC analysis did not indicate any remaining starting material. The mixture was quenched with 10 mL saturated NaHCO3 solution and extracted with ethyl acetate (5 × 15 mL) and the combined organic 65

layers were dried over anhydrous Na2SO4. The solvents were removed using a rotary evaporator. The crude product was purified via flash column chromatography (methanol/ethyl acetate = 4:5 (v/v), 4.7 g silica gel, size: 7.5 × 1.5 cm) to obtain the product. C25H25N3OS [415.56 g/mol] Yield: 30.0 mg (0.07 mmol, 42%), colorless solid Rf: 0.29 (ethyl acetate/ MeOH) = 5:4 (v/v)) mp: 168-170°C (decomposition) 1

H-NMR (CDCl3):

δ 7.60 (m, 2H, Ar-H), 7.29–7.15 (m, 5H, Ar-H), 7.08–6.75 (m, 6H, Ar-

H), 6.31 (s, 1H, HCN), 3.45 (m, 1H, CHH), 3.18 (m, 1H, CHH), 3.03–2.71 (m, 4H, 2x CH2), 2.42 (s, 3H, N-CH3), 1.85 (d, 3J = 12.9 Hz, 1H, CHH), 1.49 (d, 3J = 11.6 Hz, 1H, CHH). 13

C NMR (CDCl3)

δ 164.2 (Cq), 162.9 (Cq), 139.5 (Cq, CAr), 138.0 (Cq, CAr), 131.8 (Cq,

CAr), 131.0 (CHAr), 128.8 (CHAr), 128.5 (2x CHAr), 128.2 (CHAr), 127.6 (CHAr), 127.5 (CHAr), 126.5 (CHAr), 93.1 (Cq), 71.9 (CHN), 53.3 (2x CH2), 45.8 (N-CH3), 36.0 (CH2), 34.3 (CH2). HRMS (EI): m/z: calculated for C25H25N3OS [M]+: 415.1718; found: 415.1737. (rac)-Methyl 8-methyl-2,3-diphenyl-1,4,8-triazaspiro[4.5]dec-3-ene-1-carboxylate (6p)

An oven-dried, evacuated and nitrogen-purged 15 mL Schlenk tube, equipped with a Tefloncoated stir bar was charged with 46 mg (0.15 mmol, 1.0 eq) 8-methyl-2,3-diphenyl-1,4,8triazaspiro[4.5]dec-1-ene (5b), 0.6 mL dry DCM and 240 µL pyridine (2.97 mmol, 19.7 eq) 66

subsequently. The Schlenk tube was then cooled to ca. -78°C in a dry-ice/acetone cooling bath and 57 μL (0.74 mmol, 4.9 eq) methyl chloroformate was added. It was slowly warmed to RT over 16 h and TLC analysis did not indicate any remaining starting material. The mixture was quenched with 15 mL saturated NaHCO3 solution and extracted with ethyl acetate (5 × 15 mL) and the combined organic layers were dried over anhydrous Na2SO4. The solvents were removed using a rotary evaporator. The crude product was purified via flash column chromatography (MeOH, 4.7 g silica gel, size: 7.5 × 1.5 cm) to obtain the product. C22H25N3O2 [363.46 g/mol] Yield: 36 mg (0.10 mmol, 66%), colorless solid Rf: 0.32 (MeOH) mp: 134-136°C 1

H-NMR (CDCl3):

δ (ppm)= main rotamer: 7.68 (m, 2H, Ar-H), 7.30 (m, 8H, Ar-H), 6.07

(s, 1H, H-C-N), 3.67 (s, 3H, O-CH3), 3.19–2.54 (m, 6H, CH2), 2.42 (s, 3H, NCH3), 1.78 (m, 1H, CHH), 1.51–1.31 (m, 1H, CHH). minor rotamer: 7.68 (m, 2H, Ar-H), 7.30 (m, 8 H, ArH), 5.96 (s, 1H, H-C-N), 3.52 (s, 3H, O-CH3), 3.20–2.53 (m, 6H, CH2), 2.42 (s, 3H, NCH3), 1.78 (m, 1H, CHH), 1.52–1.30 (m, 1H, CHH). 13

C-NMR (CDCl3):

δ (ppm)= main rotamer: 164.4 (Cq), 153.9 (Cq), 138.3 (Cq,CAr), 131.9

(Cq,CAr), 130.8 (CHAr), 129.0 (CHAr), 128.7 (CHAr), 128.6 (CHAr), 128.4 (CHAr), 128.1 (CHAr), 90.4 (Cq), 70.7 (CHN), 53.8 (CH2), 53.6 (CH2), 52.4 (N-CH3), 46.4 (O-CH3), 37.1 (CH2), 36.0 (CH2). minor rotamer: 164.4 (Cq), 153.9 (Cq), 139.1 (Cq,CAr), 131.9 (Cq,CAr), 130.8 (CHAr), 129.0 (CHAr), 128.7 (CHAr), 128.5 (CHAr), 128.4 (CHAr), 128.1 (CHAr), 91.0 (Cq), 70.0 (CHN), 53.6 (CH2), 53.4 (CH2), 51.8 (N-CH3), 46.1 (O-CH3), 36.0 (CH2), 34.5 (CH2). 67

HRMS (EI): m/z: calculated for C22H25N3O2 [M]+: 363.1947; found: 363.1930. (rac)-N-Hexyl-8-methyl-2,3-diphenyl-1,4,8-triazaspiro[4.5]dec-3-ene-1-carboxamide (6q)

An oven-dried, evacuated and nitrogen-purged 15 mL Schlenk tube, equipped with a Tefloncoated stir bar was charged with 35.0 mg (0.12 mmol, 1.0 eq) 8-methyl-2,3-diphenyl-1,4,8triazaspiro[4.5]dec-1-ene (5b) and 2.0 mL dry DCM. The Schlenk tube was then cooled to 0°C in an ice bath and 51 μL (0.35 mmol, 3.0 eq) hexylisocyanate was added. The reaction progress was monitored by TLC and the reaction was warmed to RT overnight, when TLC analysis did not indicate any remaining starting material. The solvents were removed using a rotary evaporator. The crude product was purified via flash column chromatography (MeOH, 1.0 g silica gel, size: 5.0 × 0.5 cm) to obtain the product. C27H36N4O [432.61 g/mol] Yield: 36.0 mg (0.083 mmol, 72%), brownish solid Rf: 0.29 (MeOH) mp: 175-177°C 1

H-NMR (CDCl3):

δ (ppm) = 7.70–7.62 (m, 2H, Ar-H), 7.40-7.22 (m, 8H, Ar-H), 5.93 (s,

1H, H-C-N), 3.66 (s, 1H, NH), 3.35–2.63 (m, 7H, CH2), 2.43 (s, 3H, N-CH3), 1.83 (dd, J = 12.7, 1.9 Hz, 1H, CHH), 1.54–0.92 (m, 10H, CH2), 0.85 (t, J = 6.9 Hz, 3H).

68

13

C-NMR (CDCl3):

δ (ppm) = 164.0 (Cq), 154.9 (Cq), 138.9 (Cq, CAr), 132.2 (Cq, CAr), 130.6

(CHAr), 129.5 (CHAr), 128.7 (CHAr), 128.4 (CHAr), 128.3 (2x CHAr), 91.4 (Cq), 70.0 (CHN), 53.6 (2xCH2), 45.9 (N-CH3), 40.5 (CH2), 36.8 (CH2), 34.8 (CH2), 31.6 (CH2), 29.9 (CH2), 26.5 (CH2), 22.6 (CH2), 14.1 (CH3). HRMS (EI): m/z: calculated for C27H36N4O [M]+: 432.2889; found: 432.2887.

(rac)-8-Methyl-N,2,3-triphenyl-1,4,8-triazaspiro[4.5]dec-3-ene-1-carboxamide (6r)

An oven-dried, evacuated and nitrogen-purged 15 mL Schlenk tube, equipped with a Tefloncoated stir bar was charged with 45.0 mg (0.15 mmol, 1.0 eq) 8-methyl-2,3-diphenyl-1,4,8triazaspiro[4.5]dec-1-ene (5b) and 2.0 mL dry DCM. The Schlenk tube was then cooled to 0°C in an ice bath and 49 μL (0.45 mmol, 3.1 eq) phenylisocyanate was added. The reaction progress was monitored by TLC and the reaction was warmed to RT overnight, when TLC analysis did not indicate any remaining starting material. The solvents were removed using a rotary evaporator. The crude product was purified via flash column chromatography (MeOH, 4.7 g silica gel, size: 7.5 × 1.5 cm) to obtain the product. C27H28N4O [424.55 g/mol]

69

Yield: 46.0 mg (0.11 mmol, 74%), colorless solid Rf: 0.31 (MeOH) mp: 194-196°C (decomposition) 1

H-NMR (CDCl3):

δ (ppm) = 7.69 (m, 2H, Ar-H), 7.56–6.85 (m, 13H, Ar-H), 6.26 (s, 1H,

NH), 6.05 (s, 1H, H-C-N), 3.53–3.32 (m, 1H, CHH), 3.29–3.09 (m, 1H, CHH), 3.02–2.61 (m, 4H, CHH), 2.45 (s, 3H, N-CH3), 1.85 (d, 3J = 12.0 Hz, 1H, CHH), 1.47 (d, 3J = 11.7 Hz, 1H, CHH). 13

C-NMR (CDCl3):

δ (ppm) = 163.6 (Cq), 152.1 (Cq), 138.9 (Cq,CAr), 138.4 (Cq,CAr), 132.0

(Cq,CAr), 130.8 (CHAr), 129.9 (CHAr), 129.3 (CHAr), 128.9 (CHAr), 128.5 (CHAr), 128.4 (2x CHAr), 123.1 (CHAr), 119.7 (CHAr), 92.1 (Cq), 70.0 (CHN), 53.6 (2xCH2), 46.0 (N-CH3), 36.4 (CH2), 34.9 (CH2). HRMS (EI): m/z: calculated for C27H28N4O [M]+: 424.2263; found: 424.2273.

(rac)-N,3-Diphenyl-2-(pyridin-4-yl)-1,4-diazaspiro[4.5]dec-3-ene-1-carboxamide (6s)

An oven-dried, evacuated and nitrogen-purged 15 mL Schlenk tube, equipped with a Tefloncoated stir bar was charged with 65 mg (0.22 mmol, 1.0 eq) 2-phenyl-3-(pyridin-4-yl)-1,4diazaspiro[4.5]dec-1-ene (5d) and 1.0 mL dry DCM. The Schlenk tube was then cooled to 70

0°C in an ice bath and 73 μL (0.67 mmol, 3.0 eq) phenylisocyanate was added. After 5 min, the ice bath was removed and the reaction progress was monitored by TLC. The reaction was stirred for 14 h at RT when TLC analysis did not indicate any remaining starting material. The solvents were removed using a rotary evaporator. The crude product was purified via flash column chromatography (cyclohexane/ethyl acetate = 2:1 (v/v), 4.7 g silica gel, size: 8.7 × 1.3 cm) to obtain a crude product (62.4 mg). A portion (49.2 mg) of the crude product was further purified via preparative HPLC (column: Nucleodur C-18, flow: 12 mL/min, 30°C; a: 0.01% formic acid in water, b: acetonitrile, time: 0-3 min: 70% a, 30% b, -9 min: 25% a, 75% b, -14 min: 25%a, 75%b, - 17 min 5%a, 95% b, - 21 min 5%a, 95% b). The solvent was removed using a rotary evaporator. The obtained solid was redissolved in 20 mL diethyl ether and it was washed with a sat. NaHCO3 solution (1x 20 mL) and the aqueous layer was extracted with diethyl ether (2x 20 mL). The combined organic layers were dried over anhydrous Na2SO4 and the solvents were removed using a rotary evaporator. C26H26N4O [410.52 g/mol] Calculated yield: 36.5 mg (0.089 mmol, 51%), colorless solid Rf: 0.16 (cyclohexane/ethyl acetate = 2:1 (v/v)) mp: 162-164°C (decomposition) 1

H-NMR (CDCl3):

δ (ppm) = 8.60 (d, 3J = 4.6 Hz, 2H, Ar-H), 7.72–7.59 (m, 2H, Ar-H),

7.43–7.27 (m, 5H, Ar-H), 7.27–7.18 (m, 2H, Ar-H), 7.13 (m, 2H, Ar-H), 7.00 (m, 1H, Ar-H), 6.13 (s, 1H, HCN), 6.06 (s, 1H, N-H), 2.88 (m, 1H, CHH), 2.79–2.63 (m, 1H, CHH), 2.22– 1.71 (m, 6H, 3x CH2), 1.60 (m, 1H, CHH), 1.47 (m, 1H, CHH). 13

C-NMR (CDCl3):

δ (ppm) = 162.3 (Cq), 152.1 (Cq), 150.9 (CHAr), 147.6 (Cq, CAr), 138.3

(Cq, CAr), 131.5 (Cq, CAr), 131.2 (CHAr), 129.1 (CHAr), 128.7 (CHAr), 128.2 (CHAr), 123.7 71

(CHAr), 123.3 (CHAr), 120.0 (CHAr), 95.1 (Cq), 69.0 (CHN), 38.3 (CH2), 36.1 (CH2), 25.7 (CH2), 24.4 (CH2), 24.3 (CH2). HRMS (EI): m/z: calculated for C26H26N4O [M]+: 410.2107; 410.2103. (rac)-N-Cyclohexyl-3-phenyl-2-(pyridin-4-yl)-1,4-diazaspiro[4.5]dec-3-ene-1carboxamide (6t)

An oven-dried, evacuated and nitrogen-purged 15 mL Schlenk tube, equipped with a Tefloncoated stir bar was charged with 65 mg (0.22 mmol, 1.0 eq) 2-phenyl-3-(pyridin-4-yl)-1,4diazaspiro[4.5]dec-1-ene (5d) and 1.0 mL dry DCM. The Schlenk tube was then cooled to 0°C in an ice bath and 85 μL (0.67 mmol, 3.0 eq) cyclohexylisocyanate was added. After 5 min, the ice bath was removed and the reaction progress was monitored by TLC. The reaction was stirred for 14 h at RT when TLC analysis did not indicate any remaining starting material. The solvents were removed using a rotary evaporator. The crude product was purified via flash column chromatography (cyclohexane/ethyl acetate = 2:1 (v/v), 7.0 g silica gel, size: 14.0 × 1.1 cm) to obtain a crude product (80.5 mg). A portion (74.3 mg) of the crude product was further purified via preparative HPLC (column: Nucleodur C-18, flow: 12 mL/min, 30°C; a: 0.01% formic acid in water, b: acetonitrile, time: 0-3 min: 70% a, 30% b, -9 min: 25% a, 75%b, -14 min: 25% a, 75% b, - 17 min 5% a, 95% b, - 21 min 5% a, 95% b). The solvent was removed using a rotary evaporator. The obtained solid was redissolved in 20 mL diethyl ether and it was washed with a sat. NaHCO3 solution (1x 20 mL) and the aqueous layer was 72

extracted with diethyl ether (2x 20 mL). The combined organic layers were dried over anhydrous Na2SO4 and the solvents were removed using a rotary evaporator. C26H32N4O [416.57 g/mol] Calculated yield: 50.2 mg (0.12 mmol, 66%), colorless solid Rf: 0.20 (cyclohexane/ethyl acetate = 2:1 (v/v)) mp: 81-83°C 1

H-NMR (CDCl3):

δ (ppm) = 8.55 (d, J = 4.9 Hz, 2H, Ar-H), 7.73–7.53 (m, 2H, Ar-H),

7.45–7.17 (m, 5H, Ar-H), 5.95 (s, 1H, HCN), 3.94 (d, J = 7.4 Hz, 1H), 3.66–3.39 (m, 1H), 2.92–2.55 (m, 2H), 2.06–1.67 (m, 6H), 1.56 (m, 3H), 1.50–1.17 (m, 6H), 1.14–0.93 (m, 2H), 0.78 (m, 1H). 13

C-NMR (CDCl3):

δ (ppm) = 162.4 (Cq), 153.9 (Cq), 150.6 (CHAr), 148.1 (Cq, CAr), 131.8

(Cq, CAr), 130.9 (CHAr), 128.6 (CHAr), 128.1(CHAr), 123.2 (CHAr), 94.5 (Cq), 68.9 (CHN), 49.1 (CH), 38.3 (CH2), 35.9 (CH2), 33.8 (CH2), 33.3 (CH2), 25.7 (CH2), 25.6 (CH2), 24.8 (CH2), 24.6 (CH2), 24.4 (CH2), 24.3 (CH2). HRMS (EI): m/z: calculated for C26H32N4O [M]+: 416.2576; found: 416.2589.

(rac)-N-Hexyl-3-phenyl-2-(pyridin-4-yl)-1,4-diazaspiro[4.5]dec-3-ene-1-carboxamide (6u)

73

An oven-dried, evacuated and nitrogen-purged 15 mL Schlenk tube, equipped with a Tefloncoated stir bar was charged with 65 mg (0.22 mmol, 1.0 eq) 2-phenyl-3-(pyridin-4-yl)-1,4diazaspiro[4.5]dec-1-ene (5d) and 1.0 mL dry DCM. The Schlenk tube was then cooled to 0°C in an ice bath and 98 μL (0.67 mmol, 3.0 eq) hexylisocyanate was added. After 5 min the ice bath was removed and the reaction progress was monitored by TLC. The reaction was stirred for 14 h at RT when TLC analysis did not indicate any remaining starting material. The solvents were removed using a rotary evaporator. The crude product was purified via flash column chromatography (cyclohexane/ethyl acetate = 2:1 (v/v), 7.0 g silica gel, size: 14.0 × 1.1 cm) to obtain a crude product (76.7 mg). A portion (64.4 mg) of the crude product was further purified via preparative HPLC (column: Nucleodur C-18, flow: 12 mL/min, 30°C; a: 0.01% formic acid in water, b: acetonitrile, time: 0-3 min: 70% a, 30% b, -9 min: 25% a, 75% b, -14 min: 25% a, 75% b, - 17 min 5% a, 95% b, - 21 min 5% a, 95% b). The solvent was removed using a rotary evaporator. The obtained solid was redissolved in 20 mL diethyl ether and it was washed with a sat. NaHCO3 solution (1x 20 mL) and the aqueous layer was extracted with diethyl ether (2x 20 mL). The combined organic layers were dried over anhydrous Na2SO4 and the solvents were removed using a rotary evaporator. C26H34N4O [418.59 g/mol] Calculated yield: 47.8 mg (0.12 mmol, 73%), colorless solid Rf: 0.20 (cyclohexane/ethyl acetate = 2:1 (v/v))

74

mp: 142-145°C 1

H-NMR (CDCl3): δ (ppm) = 8.56 (d, J = 5.7 Hz, 2H, Ar-H), 7.63 (d, J = 6.6 Hz, 2H, Ar-H),

7.44– .19 (m, 5H, Ar-H), 5.96 (s, 1H, HCN), 4.03 (s, 1H, N-H), 3.24–2.89 (m, 2H, CH2), 2.75 (m, 2H, CH2), 2.17–1.64 (m, 6H, CH2), 1.55-0.95 (m, 10H, CH2), 0.84 (t, J = 6.8 Hz, 3H, CH3). 13

C-NMR (CDCl3):

δ (ppm) = 162.5 (Cq), 154.6 (Cq), 150.8 (CHAr), 147.8 (Cq, CHAr), 131.8

(Cq, CHAr), 130.9 (CHAr), 128.6 (CHAr), 128.1 (CHAr), 123.1 (CHAr), 94.5 (Cq), 68.9 (CHN), 40.5 (CH2), 38.2 (CH2), 35.9 (CH2), 31.5 (CH2), 29.9 (CH2), 26.5 (CH2), 25.7 (CH2), 24.4 (CH2), 24.3 (CH2), 22.6 (CH2), 14.1 (CH3). HRMS (EI): m/z: calculated for C26H34N4O [M]+: 418.2733; found: 418.2732. 2,6-Dimethylhept-3-yne-2,5-diol (7)

In an oven-dried, evacuated and nitrogen-purged 250 mL Schlenk flask, 1.98 mL (20.0 mmol, 1.0 eq) 2-methyl-3-butyn-2-ol were dissolved in 30 mL dry THF at -78°C using a dryice/acetone bath. Then 20.0 mL (44.0 mmol, 2.2 M in hexane, 2.2 eq) n-BuLi were added dropwise with a syringe over 40 min. The reaction mixture was allowed to stir at this temperature for 2 h. Then 3.64 mL (39 mmol, 1.95 eq) isobutyraldehyde were added dropwise with a syringe over 40 min, and the reaction was allowed to run overnight at RT. The reaction mixture was then poured into 15 mL saturated NH4Cl solution. The THF was removed in vacuo using a rotary evaporator. The remaining aqueous layer was extracted with ethyl acetate (2 × 30 mL). The combined organic extracts were dried over Na2SO4, filtered and 75

concentrated under reduced pressure. The crude product was purified via flash chromatography (cyclohexane/EtOAc = 2:1, 150 g silica gel, size: 20 × 5 cm) to obtain the product. C9H16O2 [156.22 g/mol] Yield: 2.84 g (18.2 mmol, 91%), light-green oil Rf: 0.18 (cyclohexane/ethyl acetate = 2:1 (v/v)) 1

H-NMR (CDCl3) : δ (ppm) = 4.17 (d, 3J = 5.7 Hz, 1H, CHOH), 2.42 (s, br, 1H, OH), 2.40 (s,

br, 1H, OH), 1.91-1.80 (m, 1H, CH(CH3)2), 1.51 (s, 6H, CH3), 0.99 (d, 3J = 4.8 Hz, 3H, CH3), 0.96 (d, 3J = 4.8 Hz, 3H, CH3). 13

C-NMR (CDCl3): δ (ppm) = 90.5 (Cq, C≡C), 82.0 (Cq, C≡C), 67.9 (CHOH), 65.3 (Cq,

(CH3)2COH), 34.6 (CHCH(CH3)2), 31.6 (CH3), 31.5 (CH3), 18.3 (CH3), 17.6 (CH3). 2,6-Dimethylhept-3-yne-2,5-diyl diacetate (8)

In an oven-dried, evacuated and nitrogen-purged 250 mL Schlenk flask, 2.82 g (18.0 mmol, 1.0 eq) 2,6-dimethylhept-3-yne-2,5-diol (7) were dissolved in 50 mL dry DCM at 0°C using an ice-water bath. Subsequently, 25.1 mL (180 mmol, 10.0 eq) triethylamine, 444 mg (3.6 mmol, 0.2 eq) 4-(dimethylamino)pyridine and 10.3 mL (108 mmol, 6.0 eq) acetic anhydride were added. The resulting mixture was stirred for 4 h at RT until complete conversion was detected by GC-MS. The reaction was quenched with 30 mL saturated NaHCO3, and the aqueous phase was extracted with DCM (2 × 50 mL). The combined organic layers were 76

washed with brine and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified via flash chromatography (cyclohexane/EtOAc = 11:1, 124 g silica gel, size 16.5 × 5 cm) to obtain the product. C13H20O4 [240.30 g/mol] Yield: 3.89 g (16.2 mmol, 90%), colorless oil Rf: 0.30 (cyclohexane/ethyl acetate = 11:1 (v/v)) 1

H-NMR (CDCl3) : δ (ppm) = 5.25 (d, 3J = 6.4 Hz, 1H, CH), 2.09 (s, 3H, CH3), 1.99 (s, 3H,

CH3 ), 1.96-1.92 (m, 1H, CH(CH3)2), 1.64 (s, 6H, CH3), 0.99 (d, 3J = 6.6 Hz, 3H, CH3), 0.96 (d, 3J = 6.9 Hz, 3H, CH3). 13

C-NMR (CDCl3): δ (ppm) = 170.1 (Cq, C=O), 169.2 (Cq, C=O), 87.1 (Cq, C≡C), 80.4 (Cq,

C≡C), 71.9 (Cq, (CH3)2C), 69.0 (CHOCOCH3), 32.6 (CHCH(CH3)2), 29.1 (CH3), 29.0 (CH3), 22.0 (CH3), 21.2 (CH3), 18.3 (CH3), 17.5 (CH3). trans-2,3-Diphenyl-1,4-diazaspiro[4.5]decane (rac9a)

An oven-dried, evacuated and argon-purged 100 mL three-necked, round-bottomed flask, equipped with a Teflon-coated stir bar, a dry-ice condenser, and a thermometer was charged with 1.44 g (5.0 mmol, 1.0 eq) 2,3-diphenyl-1,4-diazaspiro[4.5]deca-1,3-diene (4a) and 8.0 mL dry THF. The mixture was stirred until all solids dissolved, cooled to -78°C in a dry-ice/acetone bath, and treated with a stream of gaseous ammonia until the volume of liquid increases by about 10 mL. Then 142 mg (20.0 mmol, 4.0 eq) lithium was slowly introduced 77

by cutting the wire with scissors in a gentle stream of argon. The pieces were added at such a rate that the temperature did not rise above -65°C. Following the addition of lithium, the blue mixture was stirred for 30 min and 0.6 mL (10.0 mmol, 2.0 eq) ethanol were slowly added. The yellow mixture was stirred for an additional 20 min and 1.4 g ammonium chloride were added. The cooling bath was removed, the yellow mixture was allowed to warm to RT, and 10 mL distilled water were introduced. After extraction with ethyl acetate (3 × 30 mL), the organic phase was washed with brine and dried over anhydrous Na2SO4. The solvents were removed using a rotary evaporator. The product was received without further purification. C20H24 [292.42 g/mol] Yield: 1.45 g (4.96 mmol, 99%), white crystals mp: 64-66°C 1

H-NMR (CDCl3): δ (ppm) = 7.32-7.18 (m, 10H, Ar-H), 4.18 (s, 2H, CHN), 2.11 (s, 2H, NH),

1.89-1.75 (m, 4H, CH2), 1.74-1.61 (m, 4H, CH2), 1.52- 1.40 (m, 2H, CH2). 13

C-NMR (CDCl3): δ (ppm) = 141.0 (2 × Cq, CAr), 128.5 (4 × CHAr), 127.4 (2 × CHAr), 127.2

(4 × CHAr), 76.8 (Cq), 69.9 (2 × CHNH), 40.0 (2 × CCH2), 25.7 (CH2), 24.1 (2 × CCH2CH2). HRMS (EI): m/z: calculated for C20H24N2 [M]+:292.1939; found: 292.1955.

trans-8-Methyl-2,3-diphenyl-1,4,8-triazaspiro[4.5]decane (rac9b)

78

An oven-dried, evacuated and argon-purged 100 mL three-necked, round-bottomed flask, equipped with a Teflon-coated stir bar, dry-ice condenser, and a thermometer was charged with 2.43 g (8.0 mmol, 1.0 eq) 8-methyl-2,3-diphenyl-1,4,8-triazaspiro[4.5]deca-1,3-diene (4k) and 20.0 mL dry THF. The mixture was stirred until all solids dissolved, cooled to -78°C in a dry-ice/acetone bath, and treated with a stream of gaseous ammonia until the volume of liquid increases by about 20 mL. Then 222 mg (32.0 mmol, 4.0 eq) lithium was slowly introduced by cutting the wire with scissors in a gentle stream of argon. The pieces were added at such a rate that the temperature did not rise above -65°C. Following the addition of lithium, the blue mixture was stirred for 30 min and 1.2 mL (20.0 mmol, 2.5 eq) ethanol were slowly added. The brown mixture was stirred for an additional 20 min and 2.5 g ammonium chloride were added. The cooling bath was removed, the mixture was allowed to warm to RT and 30 mL distilled water were added. After extraction with ethyl acetate (2 × 50 mL), the organic phase was washed with brine and dried over anhydrous Na2SO4. The solvents were removed using a rotary evaporator. The product was received without further purification. C20H25N3 [307.44 g/mol] Yield: 2.40 g (7.8 mmol, 98%), brownish oil 1

H-NMR (CDCl3): δ (ppm) = 7.33-7.19 (m, 10H, Ar-H), 4.22 (s, 2H, CHN), 2.68-2.47 (m,

4H, CH2CH2N), 2.34 (s, 3H, CH3), 2.13 (s, 2H, NH), 1.96 (t, 3J = 7.9 Hz, 4H, CCH2). 13

C-NMR (CDCl3): δ (ppm) = 140.8 (2 × Cq, CAr), 128.6 (4 × CHAr), 127.6 (2 × CHAr), 127.2

(4 × CHAr), 75.3 (Cq), 69.8 (2 × CHNH), 53.7 (2 × CCH2CH2), 46.3 (CH3), 39.6 (2 × CCH2). HRMS (EI): m/z: calculated for C20H25N3 [M]+: 307.2048, found: 307.2046.

N-(2-(3-Hexylureido)-1,2-diphenylethyl)heptanamide (10) 79

An oven-dried, evacuated and nitrogen-purged 15 mL Schlenk tube, equipped with a Tefloncoated stir bar was charged with 82.2 mg (0.28 mmol, 1.0 eq) 2,3-diphenyl-1,4diazaspiro[4.5]decane (rac-9a) and 0.8 mL dry DCM. The Schlenk tube was then cooled to 0°C in an ice bath and 90 μL (0.62 mmol, 2.2 eq) hexylisocyanate were added. It was warmed to RT and the reaction progress was monitored by HPLC-MS. The reaction was stopped after 7 d stirring at RT. The solvents were removed using a rotary evaporator. The crude product was purified via flash column chromatography (cyclohexane/ethyl acetate = 10:1 (v/v), 4.7 g silica gel, size: 8.5 × 1.3 cm) to obtain the product. C28H41N3O2 [466.67 g/mol] Yield: 84 mg (0.18 mmol, 64%), colorless solid Rf: 0.42 (cyclohexane/ethyl acetate = 1:1 (v/v)) mp: 170-173°C (decomposition) 1

H-NMR (CDCl3):

δ (ppm) = 7.14–6.86 (m, 10H, Ar-H), 6.16 (s, 2H, 2xN-H), 4.94 (m, 3H,

2xHCN, N-H), 3.17–2.84 (m, 4H, 2x CH2), 1.44–0.91 (m, 16H, 8x CH2), 0.79 (t, 3J = 6.4 Hz, 3H, CH3). 13

C-NMR (CDCl3):

δ (ppm) = 159.3 (Cq), 140.3 (Cq, CAr), 128.4 (CHAr), 127.6 (CHAr), 127.5

(CHAr), 61.0 (CHN), 40.8 (CH2), 31.7 (CH2), 30.3 (CH2), 26.7 (CH2), 22.7 (CH2), 14.2 (CH3). HRMS (EI):

m/z: calculated for C28H41N3O2 [M]+: 466.3308; found: 466.3340. 80

References

[1] Kofron, W. G., Baclawski, L. M. A convenient method for estimation of alkyllithium concentrations. J. Org. Chem. 1976, 41, 1879-1880.

List of Abbreviations:

DCM dichloromethane RT

room temperature

TFAA trifluoroacetic anhydride THF

tetrahydrofuran

81

NMR-spectra

1,2-Diphenylethyne (2a)

82

1-Methyl-3-(phenylethynyl)benzene (2b)

83

1-Methoxy-4-(phenylethynyl)benzene (2c)

84

4-(Phenylethynyl) benzonitrile (2d)

85

1-Nitro-4- (phenylethynyl) benzene (2e)

86

2-(Phenylethynyl) pyridine (2f)

87

4-(Phenylethynyl) pyridine (2g)

88

5-(Phenylethynyl)pyrimidine (2h)

89

Benzil (3a)

90

1-Phenyl-2-(m-tolyl) ethane-1, 2-dione (3b)

91

1-(4-Nitrophenyl)-2-phenylethane-1, 2-dione (3c)

92

1-(4-Methoxyphenyl)-2-phenylethane-1,2-dione (3d)

93

1-Phenyl-2-(pyridin-4-yl) ethane-1, 2-dione (3e)

94

1-Phenyl-2-(pyridin-2-yl) ethane-1, 2-dione (3f)

95

2,6-Dimethylheptane-3,4-dione (3g)

96

2,3-Diphenyl-1,4-diazaspiro[4.5]deca-1,3-diene (4a)

97

2-(4-Methoxyphenyl)-3-phenyl-1,4-diazaspiro[4.5]deca-1,3-diene (4b)

98

2-(4-Nitrophenyl)-3-phenyl-1,4-diazaspiro[4.5]deca-1,3-diene (4c)

99

2,3-Bis(4-bromophenyl)-1,4-diazaspiro[4.5]deca-1,3-diene (4d)

100

2-Phenyl-3-(pyridin-2-yl)-1,4-diazaspiro[4.5]deca-1,3-diene (4e)

101

2-Phenyl-3-(pyridin-4-yl)-1,4-diazaspiro[4.5]deca-1,3-diene (4f)

102

2-(2-Chlorophenyl)-3-(3,4-dimethoxyphenyl)-1,4-diazaspiro[4.5]deca-1,3-diene (4g)

103

2,2-Diethyl-4,5-diphenyl-2H-imidazole (4h)

104

4,5-Diphenyl-2,2-dipropyl-2H-imidazole (4i)

105

8-Methyl-2,3-diphenyl-1,4,8-triazaspiro[4.5]deca-1,3-diene (4j)

106

Ethyl 2-(4-methoxyphenyl)-3-phenyl-1,4,8-triazaspiro[4.5]deca-1,3-diene-8carboxylate (4k)

107

(6S,9R)-6-Isopropyl-9-methyl-2,3-diphenyl-1,4-diazaspiro[4.5]deca-1,3-diene (4l)

108

2-Methyl-2-phenethyl-4,5-diphenyl-2H-imidazole (4m)

109

2,3-Diphenyl-1,4-diazaspiro[4.5]dec-1-ene (5a)

110

8-Methyl-2,3-diphenyl-1,4,8-triazaspiro[4.5]dec-1-ene (5b)

111

4,5-Diphenyl-2, 2-dipropyl-2, 5-dihydro-1H-imidazole (5c)

112

2-Phenyl-3-(pyridin-4-yl)-1,4-diazaspiro[4.5]dec-1-ene (5d)

113

2,2-Diethyl-4,5-diphenyl-2,5-dihydro-1H-imidazole (5e)

114

1-(2,3-Diphenyl-1, 4-diazaspiro [4.5] dec-3-en-1-yl) prop-2-en-1-one (6a)

115

1-(2,3-Diphenyl-1,4-diazaspiro[4.5]dec-3-en-1-yl)-2,2,2-trifluoroethan-1-one (6b)

116

117

(2,3-Diphenyl-1, 4-diazaspiro [4.5] dec-3-en-1-yl)(thiophen-2-yl) methanone (6c)

118

1-(2,3-Diphenyl-1,4-diazaspiro[4.5]dec-3-en-1-yl)-2-methylpropan-1-one (6d)

119

Ethyl 2-(2,3-diphenyl-1,4-diazaspiro[4.5]dec-3-en-1-yl)-2-oxoacetate (6e)

120

N-Cyclohexyl-2,3-diphenyl-1,4-diazaspiro[4.5]dec-3-ene-1-carboxamide (6f)

121

N-Hexyl-2,3-diphenyl-1,4-diazaspiro[4.5]dec-3-ene-1-carboxamide (6g)

122

N,2,3-Triphenyl-1,4-diazaspiro[4.5]dec-3-ene-1-carboxamide (6h)

123

4-(2,3-Diphenyl-1,4-diazaspiro[4.5]dec-3-en-1-yl)-4-oxobutanoic acid (6i)

124

4-Allyl-2, 3-diphenyl-1, 4-diazaspiro [4.5] dec-1-ene (6j)

125

1-(4, 5-Diphenyl-2, 2-dipropyl-2, 5-dihydro-1H-imidazol-1-yl) prop-2-en-1-one (6k)

126

1-(8-Methyl-2,3-diphenyl-1,4,8-triazaspiro[4.5]dec-3-en-1-yl)ethan-1-one (6l)

127

2,2,2-Trifluoro-1-(8-methyl-2,3-diphenyl-1,4,8-triazaspiro[4.5]dec-3-en-1yl)ethan-1-one (6m)

128

129

2-Methyl-1-(8-methyl-2,3-diphenyl-1,4,8-triazaspiro[4.5]dec-3-en-1-yl)propan1-one (6n)

130

(8-Methyl-2,3-diphenyl-1,4,8-triazaspiro[4.5]dec-3-en-1-yl)(thiophen-2yl)methanone (6o)

131

Methyl 8-methyl-2,3-diphenyl-1,4,8-triazaspiro[4.5]dec-3-ene-1-carboxylate (6p)

132

N-Hexyl-8-methyl-2,3-diphenyl-1,4,8-triazaspiro[4.5]dec-3-ene-1-carboxamide (6q)

133

8-Methyl-N,2,3-triphenyl-1,4,8-triazaspiro[4.5]dec-3-ene-1-carboxamide (6r)

134

N,3-Diphenyl-2-(pyridin-4-yl)-1,4-diazaspiro[4.5]dec-3-ene-1-carboxamide (6s)

135

N-Cyclohexyl-3-phenyl-2-(pyridin-4-yl)-1,4-diazaspiro[4.5]dec-3-ene-1carboxamide (6t)

136

N-Hexyl-3-phenyl-2-(pyridin-4-yl)-1,4-diazaspiro[4.5]dec-3-ene-1-carboxamide (6u)

137

2,6-Dimethylhept-3-yne-2,5-diol (7)

138

2,6-Dimethylhept-3-yne-2,5-diyl diacetate (8)

139

2,3-Diphenyl-1,4-diazaspiro[4.5]decane (rac-9a)

140

8-Methyl-2,3-diphenyl-1,4,8-triazaspiro[4.5]decane (rac-9b)

141

1,1'-(1,2-Diphenylethane-1,2-diyl)bis(3-hexylurea) (10)

142