Supporting Information. 2-Amino-1,3,5-triazine Chemistry: Hydrogen-Bond-Networks, Takemoto

Transcription

1 S1 Supporting Information 2-Amino-1,3,5-triazine Chemistry: Hydrogen-Bond-etworks, Takemoto Thiourea Catalyst Analogs, and Olfactory Mapping of a Sweet-Smelling Triazine Li Xiao, Alexander Pöthig, and Lukas Hintermann*

2 S2 Contents 1 General information... 3! 2 General Procedures... 4! 2.1 General procedures for synthesis of heterocyclic alkoxy derivatives by S Ar... 4! 2.2 General procedure for the chlorination of pyridones/pyrimidones (GP-2)... 4! 2.3 General procedure for tert-butylation of pyridines and pyrimidines (GP-3)... 5! 3 Synthesis of Triazinyl-thioureas... 6! 3.1 Triazinyl-isothiocyanates... 6! 3.2 Syntheses of thioureas... 7! 4 Olfactory mapping of an alkoxytriazine... 10! 4.1 Syntheses of various starting materials... 10! Amino-1,3,5-triazines... 13! Aminopyrimidines... 17! 4.4 4,6-Di-tert-butyl-1,3,5-triazinyl ethers... 18! 4.5 Other Ethoxytriazines... 22! 4.6 Alkoxypyrimidines... 24! 4.7 De-aza- and de-alkyl analogues of 10a... 27! 5 MR spectra... 32! 6 References... 87!

3 S3 1 General information Chemicals: Unless otherwise specified, all reagents and solvents were obtained from commercial suppliers and used without further purification. Solvents used in catalytic reactions were dried by passing through a column of Al 2 O 3 and then kept over 3 Å molecular sieves under an argon atmosphere. [1] Chromatography: Column chromatography (CC) was performed on silica gel 60 (35 70 µm particle size), usually as a flash chromatography with 0.2 bar positive air pressure. Thin layer chromatography was performed on glass plates coated with silica gel 60 F 254 and visualized with UV light (254 nm). For certain substrates, it was necessary to use MeOH-deactivated SiO 2 for chromatographic purification. This was prepared as follows: Silica gel 60 for chromatography was washed with MeOH and dried in an oven at 120 C for 1 h (or until constant weight). To this dried SiO 2, 3 5% by weight of MeOH was added and the material was left standing in a closed vessel. Analytical data: MR spectra were recorded at 250, 360, or 500 MHz ( 1 H) at ambient temperature (19 25 C). 1 H MR spectra were internally referenced to tetramethylsilane (TMS, δ = 0.00 ppm) or residual solvent peaks (in CDCl 3 : δ = 7.26 ppm; in [D 6 ]-DMSO: δ = 2.50 ppm). 13 C MR spectra were referenced to solvent peaks (CDCl 3, δ = ppm; [D 6 ]-DMSO, δ = ppm). IR spectra of liquids were recorded neat in a capillary. Abbreviations tbuome CC DDQ DMF THF TLC tert-butyl methyl ether (flash) column chromatography 2,3-dichloro-5,6-dicyano-1,4-benzoquinone,-dimethylformamide tetrahydrofuran thin-layer chromatography

4 S4 2 General Procedures 2.1 General procedures for synthesis of heterocyclic alkoxy derivatives by S Ar GP-1A: The halogenated starting material (1 equiv.) was added to an alkoxide solution, freshly prepared by slow addition of alcohol (1.5 3 equiv.) to a suspension of ah (60% in mineral oil, 1.1 equiv. relative to the alcohol) in THF at 0 C. The reaction mixture was stirred at r.t. until completion of the reaction (1 48 h, TLC-control). The reaction was quenched by addition of water and extracted twice with tbuome. The combined organic phases were dried over MgSO 4. After filtration and evaporation, the residue was purified by CC (tbuome/hexanes, typically 1:30). GP-1B: The corresponding halogenated triazine, pyrimidine or pyridine (1 equiv.) was added to an alkoxide solution prepared by dissolving sodium (3 equiv.) in the respective alcohol (5 ml) and the reaction mixture stirred at r.t. until completion of the reaction (1 48 h, TLC-control). After quenching by addition of water, the reaction mixture was extracted twice with tbuome and the combined organic phases were dried over MgSO 4. After filtration and evaporation, the residue was purified by CC (tbuome/hexanes, typically 1:30). GP-1C: After sodium (3 5 equiv.) has been totally dissolved in hot ethanol, the solvent was removed under vacuum; DMF was then added, followed by corresponding pyridine derivative (1 equiv.) and catalytic amount of CuI (5 mol-% to the substrate). The mixture was heated at 90 C till the completion of the reaction (16 24 h, TLC-control). After cooling to r.t., the reaction was quenched with water (2 ml), extracted twice with tbuome, the combined organic phases were dried over MgSO 4. After filtration and evaporation, the residue was purified by CC. 2.2 General procedure for the chlorination of pyridones/pyrimidones (GP-2) POCl 3 was added to the corresponding substrate, the mixture was heated to 90 C for 16 h, after cooling to r.t., the reaction mixture was poured into crushed ice, and an aqueous solution of 25% ammonia was added carefully to neutralize the mixture. The mixture was then extracted twice with CH 2 Cl 2, and the organic layers were dried over MgSO 4. After evaporation of the solvent, the residue was purified by CC.

5 S5 2.3 General procedure for tert-butylation of pyridines and pyrimidines (GP-3) Adapted from refs. [2,3] A solution of tbuli (15% in Hexane, 1.48 M, 1.1 equiv.) was added drop-wise to a solution of the substrate (1 equiv.) in hexane (1 ml/mmol) at 15 C. After stirring at this temperate for 30 min., the mixture was allowed to warm up to 0 C. A solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (1 equiv.) in THF (1 ml/mmol) was added carefully to quench the reaction. The mixture was diluted with tbuome, washed with water (1 x), aqueous 2 M aoh (2 x) and water (1 x). The organic layer was dried over MgSO 4, filtered, and evaporated. The residue was purified by CC.

6 S6 3 Synthesis of Triazinyl-thioureas 3.1 Triazinyl-isothiocyanates ,4-Di-tert-butyl-6-isothiocyanato-1,3,5-triazine (7a) Triazinylamine 8a (2.08 g, 10 mmol) was added to a suspension of ah (1.28 g, 32 mmol, 3.2 equiv) in THF (30 ml). After 30 min of stirring at r.t., CS 2 (3.02 ml, 50 mmol, 5 equiv.) was added at 0 C and the mixture C S stirred overnight for 20 h at r.t. Ethyl chloroformate (1.43 ml, 15 mmol, 1.5 equiv.) was added, followed by Et 3 (2.8 ml, 20 mmol, 2 equiv.), and the mixture stirred at r.t. for 30 min. The reaction was quenched by addition of 2.4 M aq HCl (18 ml) and tbuome for extraction of the product. Washing of the organic phase with water, drying (a 2 SO 4 ), filtration and evaporation gave 3.63 g of crude product. Purification by CC (150 g of MeOH-deactivated SiO 2 ; hexanes, then tbuome/hexanes 1:50) gave 1.45 g (58%) of slightly brown-yellowish liquid. 1 H MR (300 MHz, CDCl 3 ): δ = 1.37 (s, 18 H) ppm. 13 C MR (75 MHz, CDCl 3 ): δ = (CH 3 ), (C), (C), (C), (C-2/4) ppm. IR (capillary): ν = 2965m, 2929w, 2870w, 2125sh, 1983s (br ), 1537s, 1507s, 1372s, 11347s, 912m, 845m cm 1. GC-MS (EI + ): m/z (%) = 250 (14) M +, 235 (100), 208 (6), 84 (10). Analysis calcd for C 12 H 18 4 S (250.36): C 57.57, H 7.25, 22.38; found C 57.53, H 7.33, ,4-Diisopropyl-6-isothiocyanato-1,3,5-triazine (7g) a) 0.5 mmol scale reaction: Triazinylamine 8g (90 mg, 0.50 mmol), ah (60% in oil; 60 mg, 1.5 mmol, 3 equiv.) and CS 2 (0.15 ml, 2.5 mmol, 5 equiv.) were stirred in THF (2 ml) overnight (16 h). Ethyl chloroformate C S (71 µl, 1.5 equiv.) and Et 3 (0.14 ml, 1 mmol, 2 equiv.) were added and the mixture was stirred for 0.5 h at r.t., when TLC showed little remaining starting material. The reaction was quenched with H 2 O and extracted with tbuome. After drying of the organic phase (a 2 SO 4 ), filtration and evaporation, a crude yield of 187 mg was obtained. CC (SiO 2 ; tbuome/hexanes 1:50) gave 47 mg (42%) of product 7g. b) 5 mmol scale reaction with inadequate workup: Triazinylamine 8g (901 mg, 5.0 mmol), ah (640 mg, 16 mmol, 3.2 equiv) and CS 2 (1.5 ml, 25 mmol) were stirred in THF (20 ml) overnight. Ethyl chloroformate (0.71 ml, 7.5 mmol, 1.5 equiv.) and Et 3 (1.4 ml, 10 mmol) were

7 S7 successively added, followed by stirring for 30 min at r.t. and workup as above. During the CC purification (SiO 2 ; tbuome/hexanes 1:50 1:30), the product showed partial decomposition. It was also noticed that washing of the organic product phase with aq H 4 Cl led to decomposition of the product. c) 5 mmol scale synthesis: Reaction performed as in b) on a 5 mmol scale. Chromatography of the crude product was performed on MeOH-deactivated SiO 2 (tbuome/hexanes 1:50) to give oily product (499 mg, 45%). 1 H MR (400 MHz, CDCl 3 ): δ = 1.32 (d, J = 6.9 Hz, 12 H), 3.07 (sept, J = 6.9 Hz, 2 H) ppm. 13 C MR (100 MHz, CDCl 3 ): δ = (CH 3 ), (CH), (C), (C) ppm; 1 C (presumed at 162 ppm) not detected. IR (capillary): ν = 2972m, 2932m, 2875w, 1983s (br ), 1542s, 1516s, 1378s cm 1. GC-MS (EI+): m/z (%) = 222 (35) M +, 207 (100), 194 (10), 111 (7), 85 (16), 70 (14). Analysis calcd for C 10 H 14 4 S (222.31): C 54.03, H 6.35, 25.20; found C 54.02, H 6.49, Syntheses of thioureas (4,6-Di-tert-butyl-1,3,5-triazin-2-yl)-3-phenylthiourea (12) Obtained by reaction of distilled aniline (70 µl, 0.77 mmol) with isothiocyanate 7a (160 mg, 0.64 mmol) neat for 5 minutes. Addition of H S hexanes (5 ml), filtration gave 132 mg colorless solid. The filtrate was H evaporated and the residue crystallized from CH 2 Cl 2 /hexanes (overlayering) to give 30 mg needles. Total yield 162 mg (74%) of 12 as colorless solid. 1 H MR (400 MHz, CDCl 3 ): δ = 1.35 (br s, 9 H, tbu), 1.39 (br s, 9 H, tbu), 7.27 (t, J = 7.5 Hz, 1 H-Ar), 7.43 (t, J 7.8 Hz, 2 H-Ar), 7.71 (d, J = 7.7 Hz, 2 H-Ar), 8.59 (br s, 1 H), (br s, 1 H) ppm. 13 C MR (100 MHz, CDCl 3 ): δ = (br s, CH 3 ), (br s, CH 3 ), (br s, 39.81), (CH), (CH), (CH), (C), (C), (C), (br s, C), (br s, C) ppm. IR (ATR): ν = 3184m, 3071w, 2963m, 1581m, 1516s, 1322m, 1175s, 1153s, 744m, 685m cm 1. MS (CI, CH 4 ): m/z (%) = (20) [M+C 2 H 5 ] +, (100) [M+H] +, (34) M +, 251 (20), 209 (15). Analysis calcd for C 18 H 25 5 S (343.49): C 62.94, H 7.34, 20.39; found C62.72, H 7.34,

8 S ((1S,2S)-2-(Dimethylamino)cyclohexyl)-3-(4,6-dimethylpyrimidin-2-yl)thiourea (5-1) a) Small scale reaction: (1S,2S)-2-(Dimethylamino)-cyclohexylamine H (4; 115 mg, 0.81 mmol) was added to a solution of isothiocyanate Me S 11 [4] (90 mg, 0.54 mmol) in toluene (1 ml) and stirred for 1 h at r.t. The solvent was removed and the residue separated by CC H Me Me 2 (CH 2 Cl 2 /MeOH 30:1 20:1 12.5:1). Product fractions were evaporated to give a colorless foam which was crushed and washed with tbuome and dried in high vacuum to give colorless solid 5-1 (164 mg, 99%). b) Larger scale: (1S,2S)-2-(Dimethylamino)-cyclohexylamine (4; 1.07 g, 7.5 mmol) was added to a solution of isothiocyanate 11 (830 mg, 5.02 mmol) in toluene (10 ml) and stirred for 3 h at r.t. Purification as above gave crude product, which retained some tbuome (1.598 g, quantitative). 1 H MR (400 MHz, CDCl 3 ): δ = (m, 4 H), (m, 1 H), (m, 2 H), 2.29 (s, 6 H, Me 2 ), 2.39 (s, 6 H, 2 Me), 2.56 (td, J = 10.5, 3.4 Hz, 1 H), (m, 1 H), 4.15 (ddd, J = 10.5, 6.6, 4.0 Hz, 1 H), 6.66 (s, 1 H), 8.37 (br s, 1 H), (br d, J = 5.7 Hz, 1 H). 13 C MR (100 MHz, CDCl 3 ): δ = (CH 2 ), (CH 3 ), (CH 2 ), (CH 2 ), (CH 2 ), (CH 3 ), (CH), (CH), (CH), (C), br (C), (C=S) ppm. MS (CI, CH 4 ): m/z (%) = (10) [M+H] +, 166 (40), 124 (100). IR (ATR): ν = 3429w, 3178m, 3030m, 2929s, 2858m, 1598s, 1511s br, 1371m, 1164s br, 1040m, 788m, 706m cm 1. Analysis calcd for C 15 H 25 5 S (307.46): C 58.60, H 8.20, 22.78; found C 58.47, H 8.22, (4,6-Diisopropyl-1,3,5-triazin-2-yl)-3-((1S,2S)-2-(dimethylamino)cyclohexyl)thiourea (5-2) (1S,2S)-2-(Dimethylamino)-cyclohexylamine (4; 594 mg, 4.18 H mmol) was added to a solution of isothiocyanate 7g (773 mg, 3.48 S mmol) in toluene (5 ml) and the reaction mixture stirred overnight. Evaporation and purification by CC (CH 2 Cl 2, then CH 2 Cl 2 /MeOH 30:1 20:1) gave a foam which was crushed to powder, washed with H Me 2 tbuome and dried in vacuum to give colorless solid (1300 mg, quant.) retaining some tbuome. A sample for analysis was further dried in vacuum. 1 H MR (400 MHz, CDCl 3 ): δ = (m, 1 H), (m, 16 H), (m, 1 H), (m, 2 H), 2.25 (s, 6 H, Me 2 ), 2.55 (td, J = 10.9, 3.3 Hz, 1 H), (m, 1 H), 1.98

9 S9 (br s, 2 H, ipr-ch), 4.21 (m, 1 H), 8.38 (s, 1 H), (d, J = 6.3 Hz, 1 H) ppm. 13 C MR (100 MHz, CDCl 3 ): δ = (CH 3 ), (CH 3 ), (CH 2 ), (CH 2 ), (CH 2 ), (CH 2 ), br (CH 3 ), (CH), (CH), (CH), (C), (C), br (C) ppm. MS (CI, CH 4 ): (6) [M+C 2 H 5 ] +, (100) [M+H] +. IR (ATR): ν = 3419m, 3198s, 2931s, 2861s, 1570s br, 1536s br, 1391s, 1150m, 840m cm 1. Analysis calcd for C 18 H 32 6 S (364.55): C 59.30, H 8.85, 23.05; found 59.83, H 9.06, (4,6-Di-tert-butyl-1,3,5-triazin-2-yl)-3-((1S,2S)-2-(dimethylamino)cyclohexyl)thiourea (5-3) Isothiocyanate 7a (116 mg, 0.46 mmol) was combined with (1S,2S)- 2-(dimethylamino)-cyclohexylamine (4; 79 mg, 0.56 mmol) in PhMe H S (1 ml) and stirred overnight. Evaporation and purification by CC (CH 2 Cl 2 CH 2 Cl 2 /MeOH 30:1 20:1) gave colorless solid (136 mg, 75%). X-ray quality crystals were obtained by slow evaporation from a concentrated solution in toluene. H Me 2 1 H MR (400 MHz, CDCl 3 ): δ = (m, 4 H), 1.33 (br s, 18 H, tbu), (m, 3 H), 2.24 (br s, 6 H, Me 2 ), (m, 2 H), (m, 1 H), 8.37 (br s, 1 H), (br d, J = 6.1 Hz, H) ppm. 13 C MR (100 MHz, CDCl 3 ): δ = (CH 2 ), (CH 2 ), (CH 2 ), (CH 3 ), (CH 2 ), (C), (CH 3 ), (CH), (CH), (C), (C), br (C) ppm. MS (CI, CH 4 ): m/z (%) = (100), [M+H] +. IR (ATR): ν = 3190m, 3127w, 3047w, 2935m, 2862w, 1573m, 1510s, 1173m, 1151s, 683m cm 1. Analysis calcd for C 20 H 36 6 S (392.61): C 61.18, H 9.24, 21.41; found C 61.13, H 9.16, 21.2.

10 S10 4 Olfactory mapping of an alkoxytriazine 4.1 Syntheses of various starting materials The compounds in this section are not listed or numbered in the main article. 2-Chloro-4,6-di-tertbutyl-1,3,5-triazin was prepared from cyanuric chloride and tbumgcl by the copper catalyzed cross-coupling described in ref. [5] ,6-Dimethylpyrimidin-2(1H)-one hydrochloride (S1) Older syntheses use hydrochloric acid [6] whereas we used Me 3 SiCl as source of HCl (cf. [7] ): To a stirred solution of acetylacetone (21.5 g, 215 mmol) and urea (12.9 g, 215 mmol) in ethanol (100 ml) at 50 C, Me 3 SiCl H O H Cl (30 ml, 237 mmol) was added dropwise over 30 min. The mixture was heated to reflux for 1 h and cooled to r.t. with addition of tbuome (100 ml). The resulting white crystal suspension was filtered, the solid washed with tbuome and dried in vacuum to give pure product (29.3 g, 85%). The structure of this compound as -protonated chloride salt has been previously established by X-ray crystallography; [8] the 1 H MR data in DMSO solution is in line with the free base (1 H-signal, 1 J,H discernible), but shows higher symmetry. M.p. 280 C (dec). 1 H MR (400 MHz, [D 6 ]-DMSO): δ = 2 4 ppm (br s, H + /H 2 O), 2.48 (s, 6 H, CH 3 ), 6.74 (s, 1 H, CH), 7.42 (t, 1 J,H = 50.7 Hz, 1 H, H) ppm. 13 C MR (100 MHz, [D 6 ]- DMSO): δ = (CH 3 ), (CH), (C), (C) ppm. Known compound, CAS Chloro-4,6-dimethylpyrimidine (S2) Prepared from 4,6-dimethylpyridinone hydrochloride (S1) and POCl 3 according to literature methods. [6b,9] M.p C (Lit.: [6b] C). 1 H MR (300 MHz, CDCl 3 ): δ = 2.50 (d, J = 0.6 Cl Hz, 6 H, CH 3 ), 7.04 (sept, J = 0.5 Hz, 1 H, CH) ppm. 13 C MR (75 MHz, CDCl 3 ): δ = (CH 3 ), (CH), (C), (C) ppm. GC-MS (EI + ): m/z (%) = 142/144 (100) M +, 107 (15). Known compound, CAS

11 S ,6-Diisopropylpyrimidin-2(1H)-one (S3) Concentrated HCl (3 ml, 37%) was added to a stirred solution of 2,6-dimethyl-3,5-heptanedione (3.61 g, 21 mmol) and urea (1.38 g, 23 mmol) in EtOH (10 ml) at 100 C. The mixture was reflux for 36 h. After cooling, EtOAc (100 ml) was added, followed by aqueous 2 M aoh (ca 18 ml) for O H neutralization. The mixture was extracted with CH 2 Cl 2 (3 100 ml) and the combined organic phase was dried over a 2 SO 4. After filtration and removal of the solvent, the residue was purified by CC (CH 2 Cl 2 /MeOH 30:1 10:1) to give a colorless solid (3.24 g, 78%). M.p C. 1 H MR (400 MHz, CDCl 3 ): δ = 1.30 (d, J = 6.8 Hz, 12 H, CH 3 ), 2.91 (br s, 2 H, CH), 6.15 (s, 1 H, CH), (br s, 1 H, H) ppm. 13 C MR (100 MHz, CDCl 3 ): δ = (4 CH 3 ), (br., CH), (br., CH), (CH), (C), (br., C), (br, C) ppm. IR (KBr): ν = 2967m, 1616s, 1446m, 1016w, 938m cm 1. GC-MS (EI + ): m/z (%) = 180 (20) M +, 165 (100), 152 (14). Analysis calcd for C 10 H 16 2 O (180.25): C 66.63, H 8.95, 15.54; found C 65.90, H 8.87, 15.49; calculated for C 10 H 16 2 O+0.1 H 2 O (182.05): C 65.98, H 8.97, CAS (hydroxypyrimidine tautomer): Chloro-4,6-diisopropylpyrimidine (S4) Prepared according to the GP-3, from 4,6-diisopropylpyridinone (3.08 g, 17 mmol) and POCl 3 (10 ml). Purification by CC (tbuome/hexanes 1:30) gave a colorless liquid (2.74 g, 81%). 1 H MR (400 MHz, CDCl 3 ): δ = 1.30 (d, J = 6.9 Hz, 12 H, CH 3 ), 2.98 (sept, J Cl = 6.9 Hz, 2 H, CH 2 ), 6.97 (s, 1 H, CH) ppm. 13 C MR (100 MHz, CDCl 3 ): δ = (CH 3 ), (CH), (CH), (C), (C) ppm. IR (capillary): ν = 2969s, 1583s, 1523s, 1321m, 1245s, 904m, 840m cm 1. GC-MS (EI + ): m/z (%) = 198/200 (9) M +, 183/185 (100), 170/172 (31). Analysis calcd for C 10 H 15 Cl 2 (198.69): C 60.45, H 7.61, 14.10; found C 60.46, H 7.67, Chloro-4,6-diethyl-1,3,5-triazine (S5) Synthesized from cyanuric chloride and EtMgCl according to ref. [10] 1 H MR (300 MHz, CDCl 3 ): δ = 1.39 (t, J = 7.4 Hz, 6 H, CH 3 ), 2.90 (q, J = 7.4 Hz, 2 H, CH 2 ) ppm. 13 C MR (75 MHz, CDCl 3 ): δ = (CH 3 ), (CH 2 ), (C), (C) ppm. MS (GC-MS): m/z (%) = 171/173 (100) M +, 156/158 (31), 56 (92). Known compound, CAS Cl

12 S Chloro-4,6-diisopropyl-1,3,5-triazine (S6) The synthesis was performed similarly to that of the diethyl derivative, see above: [10] a solution of isopropylmagnesium chloride (3 M in THF, 10 ml, 30 mmol) was added drop-wise to a solution of cyanuric chloride (1.84 g, 10 mmol) in THF (10 ml) at 15 C. After stirring at 15 C for 1 h, the mixture Cl was allowed to warm to 0 C and quenched by careful addition of saturated H 4 Cl aq. The mixture was extracted twice with tbuome, the organic layers were dried (MgSO 4 ), filtered and evaporated. Purification of the residue by CC (tbuome/hexanes 1:90 1:30) gave a colorless liquid (1.09 g, 55%) that solidified upon standing in the refrigerator (4 C). ote: reactant-ratio and -temperature were optimized to minimize the amount of trisubstitution product being formed. 1 H MR (400 MHz, CDCl 3 ): δ = 1.34 (d, J = 6.9 Hz, 12 H, CH 3 ), 3.09 (sept, J = 6.9 Hz, 2 H, 2 CH) ppm. 13 C MR (100 MHz, CDCl 3 ): δ = (CH 3 ), (CH), (C), (C) ppm. IR (capillary): ν = 2973s, 1542s, 1509s, 1374s, 1208s, 1254s, 1085m, 938s, 837s cm 1. GC-MS (EI + ): m/z (%) = 199/201 (11) M +, 184/186 (100). Analysis calcd for C 9 H 14 Cl 3 (199.68): C 54.13, H 7.07, 21.04; found C 53.94, H 7.07, ,4-Di-tert-butyl-6-chloropyridine (S7) The target compound was accessed by the following multistep sequence relying on direct or modified literature procedures: [11] C ah 2 H Et 3 H 2 O O tbu aome OEt tbu tbu H O POCl 3 tbu tbu S7 Cl a) Pivalamidine: Pivalonitrile (10 g, 0.12 mol) and sodium amide (20 g, 0.48 mol) were refluxed in Et 3 (10 ml) for 45 h. After cooling, the mixture was diluted with CH 2 Cl 2 and carefully quenched carefully with water (ca. 50 ml). The organic layer H H 2 was separated and the water phase extracted with CH 2 Cl 2. The combined organic phase was dried (a 2 SO 4 ). After filtration and evaporation of the solvent, a slightly brown solid (2.7 g) resulted that was used without further purification. 1 H MR (300 MHz, CDCl 3 ): δ = 0.96 (s, 9 H, tbu), 5.58 (br s, 3 H, H) ppm. 13 C MR (75 MHz, CDCl 3 ): δ = (CH 3 ), (C), (C) ppm.

13 S13 b) 2,6-Di-tert-butylpyrimidin-4(3H)-one: [11] A solution of ethyl 4,4-dimethyl-3- oxovalerate (4.1 g, 4.4 ml, 24 mmol) in MeOH (5 ml) was added dropwise to a stirred solution of a (552 mg, 24 mmol) in MeOH (10 ml) at 0 C. Crude pivalamidine (2.0 g, 20 mmol) was added in small portions. The mixture was stirred at r.t. for 2 days, the solvent removed under vacuum, and the residue H O partitioned between CH 2 Cl 2 and water and the mixture neutralized with aq HCl (2.4 M; ca 10 ml). The organic layer was separated and the water phase was extracted with CH 2 Cl 2. The combined organic phase was dried over MgSO 4, filtered and evaporated. The residual solid (4.3 g) was used in the next step without further purification. Known compound, CAS c) 2,4-Di-tert-butyl-6-chloropyridine (S7): POCl 3 (9.2 g, 5.5 ml, 60 mmol) was added to a suspension of crude 2,4-di-tert-butyl-6-pyrimidinone (4.3 g) at r.t. The mixture was heated at 60 C for 2.5 h. After cooling to r.t., the reaction mixture was poured over crushed ice and neutralized by careful addition of Cl 25% aqueous ammonia. The mixture was extracted with tbuome (2 x). The organic layers were dried (MgSO 4 ), filtered and evaporated. The residue was purified by CC (tbuome/hexanes 1:50) to give a colorless liquid (3.1 g, 15% overall yield based on pivalonitrile). 1 H MR (400 MHz, CDCl 3 ): δ = 1.32 (s, 9 H, tbu), 1.38 (s, 9 H, tbu), 7.09 (s, 1 H, Ar-H) ppm. 13 C MR (100 MHz, CDCl 3 ): δ = (CH 3 ), (CH 3 ), (C), (C), (CH), (C), (C), (C) ppm. Known compound, Amino-1,3,5-triazines Amino-4,6-di-tert-butyl-1,3,5-triazine (8a) a) Aqueous ammonia (25%, 10 ml) was added to a solution of 2-chloro-4,6- di-tert-butyl-1,3,5-triazine (1; 1.61 g, 7.07 mmol) in ethanol (15 ml). The reaction mixture was stirred at 45 C for 24 h. After cooling to r.t., the volume of the reaction mixture was reduced to ca 50% in vacuum. Extraction with H 2 CH 2 Cl 2, washing of the organic phase with water and removal of the solvent in vacuum gave white crystalline powder (1.47 g, 99%).

14 S14 b) Large scale synthesis: 2-Chloro-4,6-di-tert-butyl-1,3,5-triazine (1; 8.66 g, 38.0 mmol) was dissolved in 70 ml EtOH. Aqueous 25% H 3 (50 ml) was added and the mixture stirred at 45 C for 7.5 h. After cooling, the volume was reduced to ca 50 ml in vacuum and the resulting crystals were filtered off (fraction 1, 6.16 g). The filtrate was extracted with CH 2 Cl 2, the extract dried over MgSO 4, filtered and evaporated to dryness (fraction 2, 1.68 g). Total yield 7.84 g (99%). X-ray quality crystals were obtained by slow evaporation from a CH 2 Cl 2 /- hexanes solution in an open flask. Larger crystals were washed with hexanes, crushed into smaller parts and dried in air. Some of this material (see picture) was used for the X-ray structure analysis. M.p C. 1 H MR (400 MHz, CDCl 3 ): δ = 1.29 (s, 18 H, CH 3 ), 5.37 (br s, 2 H, H 2 ) ppm. 13 C MR (100 MHz, CDCl 3 ): δ = (CH 3 ), (C), (C), (C) ppm. IR (KBr): ν = 3435m, 3309m, 3202m, 2967s, 1632s, 1535s, 1232m, 1186m, 1001w, 846 cm 1. GC-MS (EI + ): m/z (%) = 208 (20) M +, 193 (100). Analysis calcd for C 11 H 20 4 (208.30): C 63.43, H 9.68, 26.90; found C 63.41, H 9.61, ,6-Di-tert-butyl--methyl-1,3,5-triazin-2-amine (8b) A mixture of 2-chloro-4,6-di-tert-butyl-1,3,5-triazine (1; 627 mg, 2.75 mmol), triethylamine (3 ml, 21.5 mmol), methylammonium chloride (1.50 g, 22 mmol), EtOH (10 ml) and water (3 ml) was heated at 60 C for 12 h. After cooling to r.t., the reaction mixture was diluted with water and extracted with H Me tbuome (2 x). The organic phase was washed with water, dried (MgSO 4 ), filtered and the filtrate evaporated to give 603 mg (99%) crude product. Recrystallization from aqueous methanol with final cooling to 0 C, filtration, washing with a MeOH/ice mixture ( 10 C) and air-drying afforded 487 mg of material. The mother liquor was concentrated, cooled and filtered to give another 78 mg of material. Combined yield of white solid: 565 mg (92%). M.p C. 1 H MR (300 MHz, CDCl 3 ): δ = 1.29 (s, 18 H, CH 3 ), 3.00 (d, J = 5.1 Hz, CH 3 ), 5.17 (br s, 1 H, H) ppm. 13 C MR (75 MHz, CDCl 3 ): δ = (CH 3 ), (CH 3 ), (br, C), (br, C), (C), (br, C), (br, C) ppm. IR (KBr): ν = 3281m, 2962s, 1601s,

15 S s, 1353m cm 1. MS (EI): m/z (%) = 222 (27) M +, 207 (100). Analysis calcd for C 12 H 22 4 (222.33): C 64.83, H 9.97, 25.20; found C 64.74, H 9.96, Amino-4,6-di-tert-pentyl-1,3,5-triazine (8c) Aqueous ammonia (25%, 0.4 ml) was added to a solution of 2-chloro- 4,6-di-tert-butyl-1,3,5-triazine [5] (318 mg, 1.24 mmol) in tert-butanol (3 ml) and the mixture heated at 55 C for 3 h. After cooling to r.t., the reaction mixture was diluted with tbuome and water. The organic H 2 phase was separated, washed with water, and dried over MgSO 4. Removal of the solvent gave analytically pure product as a white crystal (303 mg, quant.). M.p C. 1 H MR (300 MHz, CDCl 3 ): δ = 0.72 (t, J = 7.5 Hz, 6 H, CH 3 ), 1.25 (s, 12 H, CH 3 ), 1.71 (q, J = 7.5 Hz, 4 H, CH 2 ), 5.35 (br s, 2 H, H 2 ) ppm. 13 C MR (75 MHz, CDCl 3 ): δ = 9.11 (CH 3 ), (CH 3 ), (CH 3 ), (C), (C), (C) ppm. IR (KBr): ν = 3400m, 3214m, 2969s, 1646s, 1540s, 1460m, 1390m, 1009m cm 1. GC-MS (EI + ): m/z (%) = 236 (8) M +, 221 (100), 208 (66), 193 (15). Analysis calcd for C 13 H 24 4 (236.36): C 66.06, H 10.23, 23.70; found C 66.01, H 10.23, ,6-Dimethyl-1,3,5-triazin-2-amine (8d) Prepared according to the method of Kabbe et al [12] from guanidine hydrochloride H 2 (14.3 g, 149 mmol), a (5.5 g, 239 mmol) in EtOH (80 ml) and acetonitrile (15.9 g, 20 ml, 387 mmol), as described in more detail below for 8g. The solid residue was recrystallized from MeOH/H 2 O to give 8d (10.0 g, 54 %) as white solid. 1 H MR (400 MHz, [D 6 ]-DMSO): δ = 2.22 (s, 6 H, 2 Me), 7.26 (br s, 2 H, H 2 ) ppm. 13 C MR (100 MHz, [D 6 ]-DMSO): δ = (CH 3 ), (C) (C) ppm. Known compound, CAS Amino-4,6-diethyl-1,3,5-triazine (8e) Prepared according to the method of Kabbe et al [12] from guanidine hydrochloride (14.3 g, 149 mmol), a (5.50 g, 239 mmol) in EtOH (80 ml) and H 2 propionitrile (21.3 g, 27.6 ml, 387 mmol) as described in more detail below for 8g. The solid residue was recrystallized from CH 2 Cl 2 /hexanes to give a white solid (12.5 g, 55 %). M.p C. (Lit. [12] C). 1 H MR (400 MHz, CDCl 3 ): δ = 1.28 (t, J = 7.7 Hz, 6 H, 2

16 S16 Me), 2.67 (q, J = 7.7 Hz, 4 H, 2 CH 2 ), 6.31 (br s, 2 H, H 2 ) ppm. 13 C MR (100 MHz, CDCl 3 ): δ = (CH 3 ), (CH 2 ), (C-2), (C-4/6) ppm. Known compound, CAS Amino-4,6-dipropyl-1,3,5-triazine (8f) Prepared according to the procedure of Kabbe et al [12] from guanidine H 2 hydrochloride (14.3 g, 149 mmol), a (5.5g, 239 mmol) in EtOH (80 ml) and butyronitrile (26.8 g, 33.7 ml, 387 mmol), as described in more detail below for 8g. The solid residue was recrystallized from CH 2 Cl 2 /hexanes to give a white solid (11.9 g, 44 %). M.p C. 1 H MR (400 MHz, CDCl 3 ): δ = 0.98 (t, J = 7.4 Hz, 6 H, CH 3 ), 1.77 (sext, J 7.4 Hz, 4 H, CH 2 ), 2.61 (t, J = 7.7 Hz, 4 H, CH 3 ), 5.86 (br s, 2 H, H 2 ) ppm. 13 C MR (100 MHz, CDCl 3 ): δ = (CH 3 ), (CH 2 ), (CH 2 ), (C), (C) ppm. IR (KBr): ν = 2963m, 1661m, 1532s, 1381m, 1193w, 1092w, 981w cm 1. GC-MS (EI + ): m/z (%) = 180 (3) M +, 179 (8), 165 (38), 152 (100), 124 (20). Analysis calcd for C 9 H 16 4 (180.25): C 59.97, H 8.95, 31.08; found C 59.62, H 8.76, Amino-4,6-diisopropyl-1,3,5-triazine (8g) Synthesis according to Kabbe et al: [12] Guanidine-hydrochloride (15.9 g, 166 mmol) was added to a solution of sodium metal (6.0 g, 0.26 mol) in EtOH (150 ml) at 80 C. The mixture was stirred at 85 C for 30 min., cooled to r.t., and the solvent partly removed in vacuum to a volume of ca. 100 ml. After H 2 filtration and washing of the filter with EtOH, the filtrate was concentrated to a small volume, leaving an oily residue. To this, isobutyronitrile (29.7 g, 429 mmol) was added and the mixture refluxed at 110 C for 18 h. After cooling to r.t. and addition of water, the mixture was extracted with CH 2 Cl 2 (3 x 100 ml). The organic phase was evaporated and the solid residue recrystallized from CH 2 Cl 2 /tbuome to give the title compound (21.6 g, 72 %) as white solid. M.p C (Lit.: [ 12] C). 1 H MR (300 MHz, CDCl 3 ): δ = 1.26 (d, J = 6.9 Hz, 12 H, CH 3 ), 2.85 (sept, J = 6.9 Hz, 2 H, CH 2 ), 5.77 (br s, 2 H, H 2 ) ppm. 13 C MR (75 MHz, CDCl 3 ): δ = (CH 3 ), (CH), (C), (C) ppm. Known compound, CAS

17 S Aminopyrimidines Amino-4,6-di-tert-butyl-pyrimidine (9a) Aqueous ammonia (25%, 5 ml), H 4 Cl (1.0 g) and CuI (0.20 g) were added to a solution of 2-chloro-4,6-di-tert-butyl-pyrimidine [5] (354 mg, 1.6 mmol) in ethanol (5 ml), and was heated in a pressure-tube at 120 C for 24 h. After cooling to r.t., the solvent was removed partly under vacuum and the mixture H 2 extracted with CH 2 Cl 2. After separation of the organic phase and evaporation in vacuum, the residue was separated by CC (SiO 2, tbuome/hexanes 1:30 1:10 1:5) to give starting material (40 mg, 11%) followed by the product as colorless solid (183 mg, 57%). The synthesis was not further optimized. M.p C (Lit.: [13] 127 C). 1 H MR (400 MHz, CDCl 3 ): δ = 1.27 (s, 18 H, CH 3 ), 4.83 (br s, 2 H, H 2 ), 6.65 (s, 1 H, CH) ppm. 13 C MR (100 MHz, CDCl 3 ): δ = 29.7 (CH 3 ), 37.4 (C), (CH), (C?, broad), (C) ppm. GC-MS (EI + ): m/z (%) = 207 (37) [M+], 192 (85), 176 (17), 165 (100). Known compound, CAS Amino-4,6-dimethylpyrimidine (9b) Synthesis adapted from Combes et al.: [14] To a solution of acetylacetone (14.3 g, 143 mmol) in ethanol (60 ml), guanidine hydrochloride (13.6 g, 142 mmol) and K 2 CO 3 (10 g, 72 mmol) was added and the mixture heated at reflux for 6 h. After cooling, the suspension was filtered, the filter washed with ethanol, and Me H 2 Me the filtrate evaporated to dryness. Recrystallization of the residue from hot ethanol/water (50 ml) with cooling ( 10 C), filtration and washing with little ice water gave the title compound as white crystals (9.71 g). The mother liquor was evaporated to dryness and the residue recrystallized from tbuome (washing with hexanes) to give 3.20 g; combined yield g (74%). M.p.: C. 1 H MR (300 MHz, CDCl 3 ): δ = 2.28 (s, 6 H, CH 3 ), 5.73 (br s, 2 H, H 2 ), 6.35 (s, 1 H, CH) ppm. 13 C MR (75 MHz, CDCl 3 ): δ = (CH 3 ), (CH), (C), (C) ppm. Known compound, CAS

18 4.4 4,6-Di-tert-butyl-1,3,5-triazinyl ethers S ,4-Di-tert-butyl-6-ethoxy-1,3,5-triazine (10a) a) Synthesis according to the GP-1A from 2-chloro-4,6-di-tert-butyl-1,3,5- triazine (1) [5] (342 mg, 1.50 mmol), EtOH (l ml) and ah (110 mg, 60%, 2.9 mmol) in THF (5 ml), reaction time: 1 h. Purification by CC (tbuome/hexanes 1:30) gave the product (373 mg, 99%) as colorless liquid. OEt b) Synthesis from chlorotriazine 1 (5.00 g, 22.0 mmol) and a solution of sodium metal (1.01 g, 44.0 mmol) in EtOH (30 ml) at r.t., stirring for 1 h. EtOH was removed, water added (10 ml) and the mixture extracted with tbuome (3 x 50 ml) to give crude product (5.279 g); purification by CC (tbuome/hexanes 1:50) gave g (99.6%) of a slightly yellow oil, which was further purified by Kugelrohr distillation (130 C, ca. 10 mbar) to give a colorless oil. 1 H MR (300 MHz, CDCl 3 ): δ = 1.35 (s, 18 H, CH 3 ), 1.44 (t, J = 7.0 Hz, 3 H, CH 3 ), 4.49 (q, J = 7.0 Hz, 2 H, CH 2 ) ppm. 13 C MR (75 MHz, CDCl 3 ): δ = (CH 3 ), (CH 3 ), (C), (CH 2 ), (C), (C) ppm. IR (capillary): ν = 2965s, 1537s, 1336m, 1239m, 1069m, 920w cm 1. GC-MS (EI + ): m/z (%) = 237 (20) M +, 222 (100), 208 (9), 194 (18). Analysis calcd for C 13 H 23 3 O (237.34): C 65.79, H 9.77, 17.70; found C 65.99, H 9.65, ,4-Di-tert-butyl-6-methoxy-1,3,5-triazine (10b) Synthesized according to the GP-1B from 2-chloro-4,6-di-tert-butyl-1,3,5- triazine (1) [5] (363 mg, 1.60 mmol) and aome (6.5 mmol) in MeOH (7 ml), reaction time: 2 h. Purification by CC (tbuome/hexanes 1:30) gave the product as colorless liquid (338 mg, 95%). OMe 1 H MR (300 MHz, CDCl 3 ): δ = 1.36 (s, 18 H, CH 3 ), 4.03 (s, 3 H, CH 3 ) ppm. 13 C MR (75 MHz, CDCl 3 ): δ = 28.8 (CH 3 ), 39.5 (C), 54.5 (CH 3 ), (C) (C). ppm. IR (capillary): ν = 3261m, 1669s, 1541s, 1468s, 1239s, 1172s, 1074s, 849m cm 1. GC-MS (EI + ): m/z (%) = 223 (15) M +, 208 (100). Analysis calcd for C 12 H 21 3 O (223.31): C 64.54, H 9.48, 18.82; found C 64.45, H 9.77,

19 S ,4-Di-tert-butyl-6-propoxy-1,3,5-triazine (10c) Synthesis according to the GP-1A from 2-chloro-4,6-di-tert-butyl-1,3,5- O triazine (1) [5] (342 mg, 1.50 mmol), 1-propanol (150 mg, 2.5 mmol) and ah (91.5 mg, 60%, 2.3 mmol) in THF (5 ml), time: 1 h. Purification by CC (hexanes/tbuome 30:1) gave the product as colorless liquid (347 mg, 95%). 1 H MR (400 MHz, CDCl 3 ): δ = 1.03 (t, J = 7.4 Hz, 3 H, CH 3 ), 1.35 (s, 18 H, CH 3 ), 1.85 (sext, J 7 Hz, 2 H, CH 2 ), 4.37 (t, J = 6.9 Hz, 2 H, CH 2 ) ppm. 13 C MR (100 MHz, CDCl 3 ): δ = 10.7 (CH 3 ), 22.2 (CH 2 ), 29.0 (CH 3 ), 39.6 (C), 69.3 (CH 2 ), (C), (C) ppm. IR (capillary): ν = 2964s, 1536s, 1363s, 1240m, 1070s, 942w cm 1. GC-MS (EI + ): m/z (%) = 251 (29) M +, 236 (100), 208 (18), 194 (64). Analysis calcd for C 14 H 25 3 O (251.37): C 66.89, H 10.02, 16.72; found C 66.97, H 10.08, Butoxy-4,6-di-tert-butyl-1,3,5-triazine (10d) Synthesis according to the GP-1A from 2-chloro-4,6-di-tert-butyl-1,3,5- O triazine (1) [5] (342 mg, 1.5 mmol), 1-butanol (200 mg, 0.25 ml, 2.7 mmol) and ah (98 mg, 60%, 2.5 mmol) in THF (5 ml), reaction time: 1 h. Purification by CC (tbuome/hexanes 1:30) gave the product (362 mg, 91%) as colorless liquid. 1 H MR (300 MHz, CDCl 3 ): δ = 0.97 (t, J = 7.4 Hz, 3 H, CH 3 ), 1.35 (s, 18 H, CH 3 ), (m, 2 H, CH 2 ), (m, 2 H, CH 2 ), 4.42 (t, J = 6.9 Hz, 2 H, CH 2 ) ppm. 13 C MR (75 MHz, CDCl 3 ): δ = (CH 3 ), (CH 2 ), (CH 3 ), (CH 2 ), (C), (CH 2 ), (C), (C) ppm. IR (capillary): ν = 2962s, 1536s, 1340m, 1240w, 1072m, 848w cm 1. GC-MS (EI + ): m/z (%) = 265 (31) M +, 250 (100), 194 (75). Analysis calcd for C 15 H 27 3 O (265.39): C 67.88, H 10.25, 15.83; found C 68.03, H 10.32, ,4-Di-tert-butyl-6-(pentyloxy)-1,3,5-triazine (10e) Synthesis according to the GP-1A from 2-chloro-4,6-di-tert-butyl-1,3,5- triazine (1) [5] (342 mg, 1.5 mmol), ah (101 mg, 60%, 2.5 mmol) and 1-pentanol (246 mg, 0.30 ml, 2.8 mmol) in THF (5 ml), reaction time: 1 h. Purification by CC (tbuome/hexanes 1:30) gave a colorless liquid (404 mg, 96%). O

20 S20 1 H MR (300 MHz, CDCl 3 ): δ = 0.92 (t, J = 7.2 Hz, 3 H, CH 3 ), 1.35 (s, 18 H, CH 3 ), (m, 4 H, CH 2 ), 1.83 (pent, J 7 Hz, 2 H, CH 2 ), 4.41 (t, J = 6.9 Hz, 2 H, CH 2 ) ppm. 13 C MR (75 MHz, CDCl 3 ): δ = 14.2 (CH 3 ), 22.6 (CH 2 ), 28.3 (CH 2 ), 28.6 (CH 2 ), 29.0 (CH 3 ), 39.6 (C), 67.8 (CH 2 ), (C), (C) ppm. IR (capillary): ν = 2961s, 1537s, 1341s, 1240m, 1069s, 848w cm 1. GC- MS (EI + ): m/z (%) = 279 (32) M +, 264 (100), 210 (34), 194 (86). Analysis calcd for C 16 H 29 3 O (279.42): C 68.77, H 10.46, 15.04; found C 68.96, H 10.45, ,4-Di-tert-butyl-6-isopropoxy-1,3,5-triazine (10f) Synthesis according to the GP-1A from 2-chloro-4,6-di-tert-butyl-1,3,5- triazine (1) [5] (341 mg, 1.5 mmol), 2-propanol (162 mg, 0.21 ml, 2.7 mmol) and ah (98 mg, 60%, 2.5 mmol) in THF (5 ml), time: 1 h. Purification by CC (tbuome/hexanes 1:30) gave a colorless liquid (352 mg, 94%). 1 H MR (300 MHz, CDCl 3 ): δ = 1.35 (s, 18 H, CH 3 ), 1.41 (d, J = 6.2 Hz, 6 H, O 2 Me, ipr), 5.37 (sept, J = 6.2 Hz, 1 H, CHMe 2 ) ppm. 13 C MR (75 MHz, CDCl 3 ): δ = (CH 3 ), (CH 3 ), (C), (CH 2 ), (C), (C) ppm. IR (capillary): ν = 2966s, 1537s, 1322m, 1239w, 1054m, 924w cm 1. GC-MS (EI + ): m/z (%) = 251 (14) M +, 236 (12), 208 (9), 194 (100). Analysis calcd. for C 14 H 25 3 O (251.37): C 66.89, H 10.02, 16.72; found C 67.00, H 10.16, ,4-Di-tert-butyl-6-isobutoxy-1,3,5-triazine (10g) Synthesis according to the GP-1A from 2-chloro-4,6-di-tert-butyl-1,3,5- O triazine (1) [5] (336 mg, 1.5 mmol), iso-butanol (198 mg, 0.25 ml, 2.7 mmol) and ah (97 mg, 60%, 2.4 mmol) in THF (5 ml), reaction time: 1 h. Purification by CC (tbuome/hexanes 1:30) gave a colorless liquid (360 mg, 92%). 1 H MR (300 MHz, CDCl 3 ): δ = 1.03 (d, J = 6.9 Hz, 6 H, CH 3 ), 1.35 (s, 18 H, 2 tbu), 2.17 (nonett, J 6.7 Hz, 1 H, CHMe 2 ), 4.19 (d, J = 6.7 Hz, 2 H, CH 2 ) ppm. 13 C MR (75 MHz, CDCl 3 ): δ = (CH 3 ), (CH), (CH 3 ), (C), (CH 2 ), (C), (C) ppm. IR (capillary): ν = 2963s, 1536s, 1433m, 1337m, 1064m, 911w cm -1. GC-MS (EI + ): m/z (%) = 265 (21) M +, 250 (43), 210 (40), 194 (100). Analysis calcd for C 15 H 27 3 O (265.39): C 67.88, H 10.25, 15.83; found C 68.12, H 10.43,

21 S ,4-Di-tert-butyl-6-(isopentyloxy)-1,3,5-triazine (10h) Synthesis according to the GP-1A from 2-chloro-4,6-di-tert-butyl-1,3,5-triazine (1) [5] (336 mg, 1.5 mmol), isoamyl alcohol (269 mg, 3.1 mmol) and ah (111 mg, 60%, 2.8 mmol) in THF (5 ml), reaction time: 1 h. Purification by CC (tbuome/hexanes 1:30) gave a colorless liquid (376 mg, 91%). The compound was a mixture of the isopentyl (82 mol-%) and O 2-methylbutyl (18 mol-%) ethers, resulting from use of a technical quality of isoamyl alcohol. 1 H MR (300 MHz, CDCl 3 ): δ = 0.97 (d, J = 6.5 Hz, 6 H, CH 3 ), 1.35 (s, 18 H, 2 tbu), (m, 3 H, CH + CH 2 ), 4.46 (t, J = 6.7 Hz, 2 H, CH 2 ) ppm; selected signals for the isomeric 2- methylbutyl ether (18 mol-%): δ = 0.95 (t, J = 7.7 Hz, 3 H), 1.01 (d, J = 6.7 Hz, 3 H), (m, 1 H), 4.18 (dd, J = 10.6, 7.0 Hz, 1 H), 4.33 (dd, J = 10.6, 6.2 Hz, 1 H) ppm. 13 C MR (75 MHz, CDCl 3 ): δ = (CH 3 ), (CH), (CH 3 ), (CH 2 ), (C), (CH 2 ), (C), (C) ppm; selected signals for the 2-methylbutyl-isomer: δ = (CH 3 ), (CH 3 ), (CH 2 ), (CH), (CH) ppm. IR (capillary): ν = 2962s, 1536s, 1433m, 1339m, 1069m, 848w cm 1. GC-MS (EI + ): m/z (%) = 279 (27) M +, 264 (81), 210 (50), 194 (100). Analysis calcd for C 16 H 29 3 O (279.42): C 68.77, H 10.46, 15.04; found C 68.75, H 10.61, (sec-Butoxy)-4,6-di-tert-butyl-1,3,5-triazine (10i) Synthesis according to GP-1A from 2-chloro-4,6-di-tert-butyl-1,3,5-triazine (1) [5] (330 mg, 1.4 mmol), 2-butanol (198 mg, 0.24 ml, 2.7 mmol) and ah (97 mg, 60%, 2.4 mmol) in THF (5 ml), reaction time: 1 h. Purification by CC (tbuome/hexanes 1:30) gave a colorless liquid (465 mg, 95%). 1 H MR (300 MHz, CDCl 3 ): δ = 0.98 (t, J = 7.4 Hz, 3 H, CH 3 ), 1.35 (s, 18 H, O 2 tbu), 1.37 (d, J = 6.2 Hz, 3 H, CH 3 ), (m, 1 H, CH 2 ), (m, 1 H, CH 2 ), 5.20 (sext, J = 6.3 Hz, 1 H, CH) ppm. 13 C MR (75 MHz, CDCl 3 ): δ = (CH 3 ), (CH 3 ), (CH 2 ), (CH 3 ), (C), (CH), (C), (C) ppm. IR (capillary): ν = 2967s, 1536s, 1431m, 1332m, 1239w, 1056m, 921w cm 1. GC-MS (EI + ): m/z (%) = 265 (11) M +, 250 (4), 194 (100). Analysis calcd for C 15 H 27 3 O (265.39): C 67.88, H 10.25, 15.83; found C 68.18, H 10.39,

22 S (tert-Butoxy)-4,6-di-tert-butyl-1,3,5-triazine (10j) Synthesis according to the GP-1A from 2-chloro-4,6-di-tert-butyl-1,3,5- triazine (1) [5] (340 mg, 1.5 mmol), tert-butanol (208 mg, 0.27 ml, 2.8 mmol) and ah (102 mg, 60%, 2.6 mmol) in THF (5 ml), reaction time: 1 h. Purification by CC (tbuome/hexanes 1:30) gave a white solid (367 mg, 93%). M.p C. 1 H MR (300 MHz, CDCl 3 ): δ = 1.35 (s, 18 H, 2 tbu), 1.66 O (s, 9 H, tbu) ppm. 13 C MR (75 MHz, CDCl 3 ): δ = (CH 3 ), (CH 3 ), (C), (C), (C), (C) ppm. IR (capillary): ν = 2963m, 1530s, 1422m, 1356m, 1162s, 1052m, 919w cm 1. GC-MS (EI + ): m/z (%) = 265 (1) M +, 250 (1), 210 (40), 194 (100). Analysis calcd for C 15 H 27 3 O (265.39): C 67.88, H 10.25, 15.83; found C 67.76, H 10.32, ,4-Di-tert-butyl-6-(ethylthio)-1,3,5-triazine (15) 2-Chloro-4,6-di-tert-butyl-1,3,5-triazine (1) [5] (342 mg, 1.50 mol) and sodium ethanethiolate (189 mg, 2.3 mmol) were mixed in DMF (2 ml) and stirred at r.t. for 2 h. Water was added and the mixture extracted with tbuome. The organic layer was washed with water, dried over MgSO 4, and evaporated to dryness. The residue was purified by CC (tbuome/hexanes 1:50) to give a colorless liquid (358 mg, 94%). S 1 H MR (300 MHz, CDCl 3 ): δ = 1.34 (s, 18 H, 2 tbu), 1.41 (t, J = 7.4 Hz, 3 H, CH 3 ), 3.14 (q, J = 7.4 Hz, 2 H, CH 2 ) ppm. 13 C MR (75 MHz, CDCl 3 ): δ = (CH 3 ), (CH 2 ), (CH 3 ), (C), (C), (C) ppm. IR (capillary): ν = 2965m, 1517s, 1365w, 1290m, 1262m, 878w cm 1. GC-MS (EI + ): m/z (%) = 253 (59) M +, 238 (100), 211 (13). Analysis calcd for C 13 H 23 3 S (253.41): C 61.62, H 9.15, 16.58; found C 61.55, H 9.29, Other Ethoxytriazines Ethoxy-4,6-di-tert-pentyl-1,3,5-triazine (16a) Synthesis according to the GP-1A from 2-chloro-4,6-di-tert-pentyl- 1,3,5-triazine [5] (297 mg, 1.20 mmol), EtOH (0.5 ml) and ah (87 mg, O 60%, 2.3 mmol) in THF (2 ml), reaction time: 2 h. Purification by CC (tbuome/hexanes 1:50) gave a colorless liquid (300 mg, 97%). 1 H MR (400 MHz, CDCl 3 ): δ = 0.73 (t, J = 7.4 Hz, 6 H, CH 3 ), 1.31 (s,

23 S23 12 H, CH 3 ), 1.44 (t, J = 7.1 Hz, 3 H, CH 3 ), 1.76 (q, J = 7.4 Hz, 4 H, CH 2 ), 4.48 (q, J = 7.1 Hz, 2 H, CH 2 ) ppm. 13 C MR (100 MHz, CDCl 3 ): δ = 9.33 (CH 3 ), (CH 3 ), (CH 3 ), (CH 2 ), (C), (CH 2 ), (C), (C) ppm. IR (capillary): ν = 2968s, 1535s, 1433m, 1327m, 1072m, 848w cm 1. GC-MS (EI + ): m/z (%) = 265 (6) M +, 250 (100), 237 (99), 222 (17). Analysis calcd for C 15 H 27 3 O (265.39): C 67.88, H 10.25, 15.83; found C 68.15, H 10.24, (tert-Butyl)-4-ethoxy-6-(tert-pentyl)-1,3,5-triazine (16b) Synthesis according to the GP-1A, from 6-tert-butyl-2-chloro-4-tertpentyl-1,3,5-triazine [5] (725 mg, 3.0 mmol), EtOH (1 ml) and ah (172 mg, 60%, 4.5 mmol) in THF (5 ml), reaction time: 1 h. Purification by CC (tbuome/hexanes 1:30) gave a colorless liquid (702 mg, 93%). OEt 1 H MR (400 MHz, CDCl 3 ): δ = 0.74 (t, J = 7.4 Hz, 3 H, CH 3 ), 1.31 (s, 6 H, CH 3 ), 1.36 (s, 9 H, CH 3 ), 1.44 (t, J = 7.1 Hz, 3 H, CH 3 ), 1.78 (q, J = 7.4 Hz, 2 H, CH 2 ), 4.49 (q, J = 7.1 Hz, 2 H, CH 2 ) ppm. 13 C MR (100 MHz, CDCl 3 ): δ = 9.27 (CH 3 ), (CH 3 ), (CH 3 ), (CH 3 ), (CH 2 ), (C), (C), (CH 2 ), (C), (C), (C) ppm. IR (capillary): ν = 2967m, 1535s, 1433m, 1337m, 1071m, 848w cm 1. GC-MS (EI + ): m/z (%) = 251 (7) M +, 236 (100), 223 (82), 208 (19), 194 (12). Analysis calcd for C 14 H 25 3 O (251.37): C 66.89, H 10.02, 16.72; found C 67.15, H 10.11, Ethoxy-4,6-bis(3-ethylpentan-3-yl)-1,3,5-triazine (16c) Synthesis according to the GP-1A from 2-chloro-4,6-bis(3-ethylpentan- 3-yl)-1,3,5-triazine [5] (134 mg, 0.43 mmol), EtOH (0.5 ml) and ah (36 mg, 60%, 0.94 mmol) in THF (2 ml), time: 2 h. Purification by CC (tbuome/hexanes 1:30) gave a colorless liquid (141 mg, quant). O 1 H MR (400 MHz, CDCl 3 ): δ = 0.67 (t, J = 7.5 Hz, 18 H, Me), 1.44 (t, J = 7.1 Hz, 3 H, OCH 2 CH 3 ), 1.81 (q, J = 7.4 Hz, 12 H, CH 2 ), 4.47 (q, J = 7.1 Hz, 2 H, OCH 2 CH 3 ) ppm. 13 C MR (100 MHz, CDCl 3 ): δ = 8.36 (CH 3 ), (CH 3 ), (CH 3 ), (CH 2 ), (CH 2 ), (C), (C) ppm. IR (Kap): ν = 2966s, 1532s, 1431m, 1339m, 1064m, 846w cm 1. GC-MS (EI + ): m/z (%) = 321 (6) M +, 306 (72), 292 (100), 278 (71). Analysis calcd for C 19 H 35 3 O (321.50): C 70.98, H 10.97, 13.07, found: C 70.88, H 11.12,

24 S Ethoxy-4,6-diisopropyl-1,3,5-triazine (16d) Synthesized according to the GP-1A from 2-chloro-4,6-di-iso-propyl-1,3,5- triazine (S6; 479 mg, 2.4 mmol), EtOH (1 ml) and ah (184 mg, 60%, 4.8 mmol) in THF (5 ml), reaction time: 1 h. Purification by CC (tbuome/hexanes 1:30) gave the product (456 mg, 91%) as colorless liquid. OEt 1 H MR (400 MHz, CDCl 3 ): δ = 1.31 (d, J = 6.9 Hz, 12 H, 4 CH 3 ), 1.44 (t, J = 7.1 Hz, 3 H, CH 3 ), 3.00 (sept, J = 6.9 Hz, 2 H, 2 CH), 4.49 (q, J = 7.1 Hz, 2 H, CH 2 ) ppm. 13 C MR (100 MHz, CDCl 3 ): δ = (CH 3 ), (CH 3 ), (CH), (CH 2 ), (C), (C) ppm. IR (capillary): ν = 2972s, 1548s, 1438m, 1340s, 1053s, 842w cm 1. GC-MS (EI + ): m/z (%) = 209 (30) M +, 194 (100), 166 (22). Analysis calcd for C 11 H 19 3 O (209.29): C 63.13, H 9.15, 20.08; found C 62.92, H 9.09, Ethoxy-4,6-diethyl-1,3,5-triazine (16e) Synthesis according to the GP-1A from 2-chloro-4,6-diethyl-1,3,5-triazine OEt (S5; 230 mg, 1.3 mmol), EtOH (1 ml) and ah (154 mg, 60%, 4 mmol) in THF (5 ml), reaction time: 2 h. Purification by CC (tbuome/hexanes 1:10) gave a colorless liquid (226 mg, 93%). 1 H MR (400 MHz, CDCl 3 ): δ = 1.33 (t, J = 7.5 Hz, 6 H, CH 3 ), 1.44 (t, J = 7.1 Hz, 3 H, CH 3 ), 2.80 (q, J = 7.6 Hz, 4 H, CH 2 ), 4.49 (q, J = 7.1 Hz, 2 H, CH 2 ) ppm. 13 C MR (100 MHz, CDCl 3 ): δ = (CH 3 ), (CH 3 ), (CH 2 ), (CH 2 ), (C), (C) ppm. IR (capillary): ν = 2979s, 1546s, 1339m, 1174m, 1110s, 1048s, 909m, 837s cm 1. GC-MS (EI + ): m/z (%) = 181 (100) M +, 151 (65), 138 (37), 122 (48). Analysis calcd for C 9 H 15 3 O (181.23): C 59.64, H 8.34, 23.19; found C 59.60, H 8.43, Known compound, CAS Alkoxypyrimidines ,6-Di-tert-butyl-2-ethoxypyrimidine (17-1a) Synthesis according to the GP-1A from 2-chloro-4,6-di-tert-butyl-pyrimidine [5,15] (454 mg, 2.00 mmol), EtOH (1 ml) and ah (139 mg, 60%, 3.6 mmol) in THF (5 ml), reaction time: 36 h. Purification by CC (tbuome/hexanes 1:10) gave the product (438 mg, 93%) as colorless liquid. O 1 H MR (400 MHz, CDCl 3 ): δ = 1.32 (s, 18 H, 2 tbu), 1.44 (t, J = 7.1 Hz, 3 H, CH 3 ), 4.44 (q, J =

25 S Hz, 2 H, OCH 2 ), 6.91 (s, 1 H, CH) ppm. 13 C MR (100 MHz, CDCl 3 ): δ = (CH 3 ), (CH 3 ), (C), (CH 2 ), (CH), (C), (C) ppm. IR (capillary): ν = 2961s, 1582s, 1376s, 1066s, 908m, 856m cm 1. GC-MS (EI + ): m/z (%) = 236 (40) M +, 221 (100), 207 (25), 193 (75). Analysis calcd for C 14 H 24 2 O (236.35): C 71.14, H 10.23, 11.85; found C 71.33, H 10.41, Ethoxy-4,6-diisopropylpyrimidine (17-2a) Synthesis according to the GP-1A from 2-chloro-4,6-diisopropylpyrimidine (S4; 322 mg, 1.6 mmol), EtOH (l ml) and ah (96 mg, 60%, 2.4 mmol) in THF (2 ml), reaction time: 26 h. Purification by CC (tbuome/hexanes 1:30) gave a colorless liquid (300 mg, 90%). OEt 1 H MR (400 MHz, CDCl 3 ): δ = 1.27 (d, J = 6.9 Hz, 12 H, CH 3 ), 1.43 (t, J = 7.1 Hz, 3 H, CH 3 ), 2.89 (sept, J = 6.9 Hz, 2 H, CH), 4.43 (q, J = 7.1 Hz, 2 H, CH 2 ), 6.63 (s, 1 H, CH) ppm. 13 C MR (100 MHz, CDCl 3 ): δ = (CH 3 ), (CH 3 ), (CH), (CH 2 ), (CH), (C), (C) ppm. IR (capillary): ν = 2967s, 1586s, 1551s, 1413s, 1378s, 1226s, 1054s, 854m cm 1. GC-MS (EI + ): m/z (%) = 208 (36) M +, 193 (94), 180 (24), 165 (100). Analysis calcd for C 12 H 24 2 O (208.30): C 69.19, H 9.68, 13.45; found C 68.98, H 9.65, Ethoxy-4,6-dimethylpyrimidine (17-3a) Synthesis according to the GP-1A from 2-chloro-4,6-dimethylpyrimidine (S2; 713 mg, 5.0 mmol), EtOH (1 ml) and ah (314 mg, 60%, 7.8 mmol) in THF (10 ml), reaction time: 3 h. Purification by CC (tbuome/hexanes 1:2) gave a colorless liquid (717 mg, 94%). O 1 H MR (300 MHz, CDCl 3 ): δ = 1.41 (t, J = 7.1 Hz, 3 H, CH 3 ), 2.39 (s, 6 H, CH 3 ), 4.39 (q, J = 7.1 Hz, 2 H, CH 2 ), 6.64 (s, 1 H, CH) ppm. 13 C MR (75 MHz, CDCl 3 ): δ = (CH 3 ), (CH 3 ), CH 2 ), (CH), (C), (C) ppm. IR (capillary): ν = 2981m, 1559s, 1417s, 1332s, 1103s, 1029s, 836w cm 1. GC-MS (EI + ): m/z (%) = 152 (53) M +, 137 (41), 124 (42), 108 (100). Analysis calcd for C 8 H 12 2 O (152.19): C 63.13, H 7.95, 18.41; found C 63.04, H 8.04, Known compound, CAS

26 S Methoxy-4,6-dimethylpyrimidine (17-3b) Synthesis according to the GP-1A from 2-chloro-4,6-dimethylpyrimidine (S2; 713 mg, 5 mmol), MeOH (2 ml) and ah (321 mg, 60%, 7.5 mmol) in THF (5 ml), reaction time: 2 h. Purification by CC (tbuome/hexanes 1:2) gave the product (664 mg, 96%) as a colorless solid. Me OMe Me M.p C (Lit.: [16] C). 1 H MR (400 MHz, CDCl 3 ): δ = 2.40 (s, 6 H, CH 3 ), 3.98 (s, 3 H, CH 3 ), 6.66 (s, 1 H, CH) ppm. 13 C MR (100 MHz, CDCl 3 ): δ = (CH 3 ), (CH 3 ), (CH), (C), (C) ppm. IR (KBr): ν = 2956w, 1587s, 1465s, 1336s, 1096s, 1030m, 874w, 690s cm 1. GC-MS (EI + ): m/z (%) = 138 (100) M +, 108 (82), 93 (53). Analysis calcd for C 7 H 10 2 O (138.17): C 60.85, H 7.30, 20.28; found C 60.61, H 7.25, Known compounds, CAS Isopropoxy-4,6-dimethylpyrimidine (17-3c) Synthesis according to the GP-1A from 2-chloro-4,6-dimethylpyrimidine (S2; 713 mg, 5 mmol), 2-propanol (564 mg, 0.72 ml, 9.4 mmol) and ah (60% in oil; 300 mg, 7.8 mmol) in THF (5 ml), reaction time: 24 h. Purification by CC (tbuome/- hexanes 1:3) gave a colorless liquid (789 mg, 95%). O 1 H MR (400 MHz, CDCl 3 ): δ = 1.37 (d, J = 6.6 Hz, 6 H, CH 3 ), 2.38 (s, 6 H, 2 CH 3 ), 5.31 (sept, J = 6.6 Hz, 1 H, CH 2 ), 6.61 (s, 1 H, CH) ppm. 13 C MR (100 MHz, CDCl 3 ): δ = (CH 3 ), (CH 3 ), (CH), (CH), (C), (C) ppm. IR (capillary): ν = 2980m, 1591s, 1407s, 1379s, 1319s, 1093s, 834w cm 1. GC-MS (EI + ): m/z (%) = 166 (15) M +, 151 (26), 124 (38), 108 (100), 96 (72). Analysis calcd for C 9 H 14 2 O (166.22): C 65.03, H 8.49, 16.85; found C 64.93, H 8.63, ,6-Dimethyl-2-(pentyloxy)pyrimidine (17-3d) Synthesis according to the GP-1A from 2-chloro-4,6-dimethylpyrimidine (S2; 713 mg, 5 mmol), 1-pentanol (860 mg, 1.06 ml, 9.7 mmol) and ah (324 mg, 60%, 8.1 mmol) in THF (5 ml), reaction time: 1 h. Purification by CC (tbuome/hexanes 1:3) gave a colorless solid (912 mg, 94%). O M.p C. 1 H MR (400 MHz, CDCl 3 ): δ = 0.92 (t, J = 7.1 Hz, 3 H, CH 3 ), (m, 4 H, CH 2 ), 1.80 (pent, J 7 Hz, 2 H, CH 2 ), 2.39 (s, 6 H, CH 3 ), 4.32 (t, J = 6.9 Hz, 2 H, CH 2 ), 6.64 (s, 1