Supporting Information

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1 Supporting Information Divergent Reactivity of gem-difluoro-enolates towards Nitrogen Electrophiles: Unorthodox Nitroso Aldol Reaction for Rapid Synthesis of -Ketoamides Mallu Kesava Reddy, Isai Ramakrishna, and Mahiuddin Baidya* Department of Chemistry, Indian Institute of Technology Madras, Chennai , Tamil Nadu, India S1

2 Table of Contents Page General procedure S3 General procedure for the synthesis of -ketoamides S3 General procedure for the -amination of gem-difluro-enolates S6 Gram scale synthesis of -ketoamide 3q S9 Synthesis of imidazolidinone 6 S9 Synthesis of orexin receptor antagonists (7 and 8) S9 Synthesis of substituted maleimides 9 S10 Crystallographic experimental section S11 NMR Spectra S14 S2

3 General Procedure All non-aqueous reactions were carried out under an atmosphere of nitrogen in flame-dried glassware and were stirred using a magnetic stir plate. CH 3 CN, DCE, and 1,4 dioxane were dried over calcium hydride. Dry THF was prepared by distilling over sodium ketyl. All reactions were monitored by thin layer chromatography (TLC) on WhatmanPartisil K6F TLC plates (silica gel 60 Å, 0.25 mm thickness) and visualized using a UV lamp (366 or 254 nm) or by use of one of the following visualization reagents: PMA: 10 g phosphomolybdic acid/ 100 ml ethanol; KMnO 4 : 0.75 g potassium permanganate, 5 g K 2 CO 3, / 100mL water. Products were isolated by column chromatography (Merck silica gel μm). Yields refer to chromatographically and spectroscopically homogenous materials unless noted otherwise. 13 C and 1 H NMR spectra were recorded on a Bruker 400 or Bruker 500 MHz spectrometers. Chemical shift values (δ) are reported in ppm and calibrated to the residual solvent peak CDCl 3 δ = ppm for 1 H, δ = for 13 C or calibrated to tetramethylsilane (δ = 0.00). All NMR spectra were recorded at ambient temperature (290 K) unless otherwise noted. 1 H NMR spectra are reported as follows: chemical shift (multiplicity, coupling constant, integration). The following abbreviations are used to indicate multiplicities: s, singlet; d, doublet; t, triplet; q, quartet; quint, quintet; sext, sextet; sept, septet; m, multiplet; dd, doublet of doublet; dt, doublet of triplet; dq, doublet of quartet; td, triplet of doublet; tt, triplet of triplet; dq, doublet of quartet; ddt, doudlet of doublet of triplet; b, broad; app, apparent; m, multiplet. Mass spectra were recorded by electrospray ionization (ESI) method on a Q-TOF Micro with lock spray source. The -fluorinated gem-diol derivatives were synthesized following literature procedures (J. Am. Chem. Soc. 2011, 133, 5802). Nitrosobezene and Azadicarboxylates were purchased from sigma Aldrich company. Other nitrosobenzene derivatives were synthesized following literature procedures (J. Org. Chem. 2005, 70, 2350). General procedure for the synthesis of -ketoamides: In an oven dried reaction tube equipped with a magnetic stir bar, -fluorinated gem-diol (1, 0.3 mmol, 1.0 equiv), aryl nitroso compound (2, 0.36 mmol, 1.2 equiv), and Lithium bromide (3.0 equiv) were taken. Then, anhydrous CH 3 CN (4 ml) followed distilled Et 3 N (2.0 equiv) were added and the reaction mixture was stir at room temperature. After 5 min (TLC monitored), volatiles were removed under reduced pressure. The crude product was purified by silica gel column chromatography (1 5% EtOAc : hexane) to provide pure product 3. 1 H and 13 C NMR data were reported for all compounds 3 and mass-spectroscopy data were reported only for new compounds 3l-q. Compound 3a was prepared following the general procedure of synthesis of -keto amides described above and purified by silica gel column chromatography (1 5% EtOAc : hexane) to provide pure compound as yellow solid (61 mg, 92%). 1 H NMR (400 MHz, CDCl 3 ): δ 9.01 (s, 1H), (m, 2H), 7.71 (d, J = 7.7 Hz, 2H), (m, 1H), 7.50 (t, J = 7.8 Hz, 2H), 7.40 (t, J = 7.9 Hz, 2H), 7.20 (t, J = 7.4 Hz, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ , , , , , , , , , Compound 3b was prepared following the general procedure of synthesis of -keto amides described above and purified by silica gel column chromatography (1 5% EtOAc : hexane) to provide pure compound as yellow solid (63 mg, 88%). 1 H NMR S3

4 (400 MHz, CDCl 3 ): δ 8.97 (s, 1H), 8.34 (d, J = 8.3 Hz, 2H), 7.70 (dd, J = 8.6, 1.0 Hz, 2H), (m, 2H), 7.30 (d, J = 8.1 Hz, 2H), (m, 1H), 2.44 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ): δ , , , , , , , , , , Compound 3c was prepared following the general procedure of synthesis of -keto amides described above and purified by silica gel column chromatography (1 5% EtOAc : hexane) to provide pure compound as yellow solid (72 mg, 94%). 1 H NMR (400 MHz, CDCl 3 ): δ 9.03 (s, 1H), (m, 2H), 7.69 (dd, J = 8.5, 0.9 Hz, 2H), 7.39 (t, J = 7.9 Hz, 2H), 7.19 (t, J = 7.4 Hz, 1H), (m, 2H), 3.90 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ): δ , , , , , , , , , , Compound 3d was prepared following the general procedure of synthesis of -keto amides described above and purified by silica gel column chromatography (1 5% EtOAc : hexane) to provide pure compound as yellow solid (66 mg, 84%). 1 H NMR (400 MHz, CDCl 3 ): δ 8.95 (s, 1H), 8.42 (d, J = 8.6 Hz, 2H), 7.69 (d, J = 7.9 Hz, 2H), 7.51 (t, J = 13.3 Hz, 2H), 7.41 (t, J = 7.9 Hz, 2H), 7.21 (t, J = 7.5 Hz, 1H); 13 C NMR (100 MHz, CDCl 3 ): δ , , , , , , , , , Compound 3e was prepared following the general procedure of synthesis of -keto amides described above and purified by silica gel column chromatography (1 5% EtOAc : hexane) to provide pure compound as yellow solid (75 mg, 82%). 1 H NMR (400 MHz, CDCl 3 ): δ 8.95 (s, 1H), (m, 2H), 7.68 (dd, J = 8.6, 1.0 Hz, 2H), (m, 2H), 7.40 (t, J = 7.9 Hz, 2H), (m, 1H); 13 C NMR (100 MHz, CDCl 3 ): δ , , , , , , , , , Compound 3f was prepared following the general procedure of synthesis of -keto amides described above and purified by silica gel column chromatography (1 5% EtOAc : hexane) to provide pure compound as yellow solid (55 mg, 75%). 1 H NMR (400 MHz, CDCl 3 ): δ 8.98 (s, 1H), 8.53 (dd, J = 8.0, 5.7 Hz, 2H), 7.69 (d, J = 7.9 Hz, 2H), 7.40 (t, J = 7.7 Hz, 2H), 7.19 (dd, J = 17.4, 8.5 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ): δ , (d, J = Hz), , , (d, J = 9.7 Hz), , , , , (d, J = 21.8 Hz). Compound 3g was prepared following the general procedure of synthesis of -keto amides described above and purified by silica gel column chromatography (1 5% EtOAc : hexane) to provide pure compound as yellow solid (82 mg, 78%). 1 H NMR (400 MHz, CDCl 3 ): δ 8.95 (s, 1H), (m, 2H), (m, 2H), (m, 2H), (m, 2H), (m, 1H); 13 C NMR (100 MHz, CDCl 3 ): δ , , , , , , , , , Compound 3h was prepared following the general procedure of synthesis of -keto amides described above and purified by silica gel column chromatography (1 5% EtOAc : hexane) to provide pure compound as yellow solid (62 mg, 80%). 1 H NMR (400 MHz, CDCl 3 ): δ 8.97 (s, 1H), 8.06 (d, J = 7.8 Hz, 1H), 7.90 (s, 1H), 7.70 (d, J = 7.8 Hz, 2H), (m, 3H), (m, 2H), 3.87 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ): δ , , , , , , , , , , , , Compound 3i was prepared following the general procedure of synthesis of -keto amides described above and purified by silica gel column chromatography (1 5% EtOAc : hexane) to provide pure compound as yellow solid (71 mg, 77%). 1 H NMR (400 MHz, CDCl 3 ): δ 8.93 (s, 1H), 8.55 (s, 1H), 8.38 (d, J = 6.9 Hz, 1H), 7.77 (d, J = 5.9 Hz, 1H), 7.69 (d, J = 6.8 Hz, 2H), (m, 3H), (m, 1H); 13 C NMR (100 MHz, CDCl 3 ): δ , , , , , , (2 C), , , , S4

5 Compound 3j was prepared following the general procedure of synthesis of -keto amides described above and purified by silica gel column chromatography (1 5% EtOAc : hexane) to provide pure compound as yellow solid (69 mg, 75%). 1 H NMR (500 MHz, CDCl 3 ): δ 8.83 (s, 1H), (m, 4H), (m, 4H), 7.20 (t, J = 7.5 Hz, 1H); 13 C NMR (100 MHz, CDCl 3 ): δ = , , , , , , , , , , , Compound 3k was prepared following the general procedure of synthesis of -keto amides described above and purified by silica gel column chromatography (1 5% EtOAc : hexane) to provide pure compound as yellow solid (75 mg, 91%). 1 H NMR (400 MHz, CDCl 3 ): δ 9.30 (s, 1H), 9.04 (s, 1H), 8.25 (d, J = 8.7 Hz, 1H), 8.03 (d, J = 8.2 Hz, 1H), 7.90 (dd, J = 15.3, 8.4 Hz, 2H), 7.74 (d, J = 7.9 Hz, 2H), 7.65 (t, J = 7.6 Hz, 1H), 7.57 (t, J = 7.5 Hz, 1H), 7.42 (t, J = 7.7 Hz, 2H), 7.22 (t, J = 7.5 Hz, 1H); 13 C NMR (100 MHz, CDCl 3 ): δ , , , , , , , , , , , , , , , Compound 3l was prepared following the general procedure of synthesis of -keto amides described above and purified by silica gel column chromatography (1 5% EtOAc : hexane) to provide pure compound as yellow solid (70 mg, 82%). 1 H NMR (400 MHz, CDCl 3 ): δ 9.00 (s, 1H), 8.50 (d, J = 9.0 Hz, 2H), (m, 2H), 7.39 (t, J = 7.9 Hz, 2H), 7.19 (dd, J = 10.6, 4.3 Hz, 1H), 6.99 (d, J = 9.0 Hz, 2H), 6.06 (ddt, J = 16.9, 10.5, 5.3 Hz, 1H), 5.44 (dd, J = 17.3, 1.4 Hz, 1H), 5.34 (dd, J = 10.5, 1.3 Hz, 1H), 4.64 (dt, J = 5.3, 1.4 Hz, 2H); 13 C NMR (100 MHz, CDCl 3 ): δ , , , , , , , , , , , , 69.00; HRMS (ESI/TOF-Q) m/z: [M+Na] + Calcd for C 17 H 15 NO 3 Na ; Found Compound 3m was prepared following the general procedure of synthesis of -keto amides described above and purified by silica gel column chromatography (1 5% EtOAc : hexane) to provide pure compound as yellow solid (85 mg, 86%). 1 H NMR (400 MHz, CDCl 3 ): δ 9.00 (s, 1H), 8.50 (d, J = 8.9 Hz, 2H), 7.69 (d, J = 8.0 Hz, 2H), (m, 7H), 7.18 (t, J = 7.5 Hz, 1H), 7.04 (d, J = 9.0 Hz, 2H), 5.16 (s, 2H); 13 C NMR (100 MHz, CDCl 3 ): δ , , , , , , , , , , , , , , Compound 3n was prepared following the general procedure of synthesis of -keto amides described above and purified by silica gel column chromatography (1 5% EtOAc : hexane) to provide pure compound as yellow solid (58 mg, 77%). 1 H NMR (400 MHz, CDCl 3 ): δ 9.02 (s, 1H), 8.01 (d, J = 16.2 Hz, 1H), 7.88 (d, J = 16.1 Hz, 1H), (m, 4H), (m, 5H), 7.18 (t, J = 7.3 Hz, 1H); 13 C NMR (100 MHz, CDCl 3 ): δ , , , , , , , , , , , ; HRMS (ESI/TOF-Q) m/z: [M+Na] + Calcd for C 16 H 13 NO 2 Na ; Found Compound 3o was prepared following the general procedure of synthesis of -keto amides described above and purified by silica gel column chromatography (1 5% EtOAc : hexane) to provide pure compound as yellow solid (83 mg, 85%). 1 H NMR (400 MHz, CDCl 3 ): δ 8.95 (s, 1H), 8.44 (d, J = 8.4 Hz, 2H), 7.70 (dd, J = 8.6, 1.0 Hz, 2H), 7.64 (d, J = 8.4 Hz, 2H), (m, 2H), (m, 5H), (m, 1H); 13 C NMR (100 MHz, CDCl 3 ): δ , , , , , , , , , , , , , , 94.21, 88.84; HRMS (ESI/TOF-Q) m/z: [M+Na] + Calcd for C 22 H 15 NO 2 Na ; Found Compound 3p was prepared following the general procedure of synthesis of -keto amides described above and purified by silica gel column chromatography (1 5% EtOAc : hexane) to provide pure compound as yellow solid (51 mg, 73%). 1 H NMR (400 MHz, CDCl 3 ): δ 9.13 (s, 1H), 8.48 (d, J = 3.4 Hz, 1H), 7.88 (d, J = 4.6 Hz, 1H), 7.71 (d, J = 7.9 Hz, 2H), 7.40 (t, J = 7.7 Hz, 2H), (m, 2H); 13 C NMR (100 MHz, CDCl 3 ) δ , , , , , , , , , ; HRMS (ESI/TOF-Q) m/z: [M+Na] + Calcd for C 12 H 17 NO 2 Na ; Found S5

6 Compound 3q was prepared following the general procedure of synthesis of -keto amides described above and purified by silica gel column chromatography (1 5% EtOAc : hexane) to provide pure compound as yellow solid (66 mg, 87%). 1 H NMR (400 MHz, CDCl 3 ): δ 8.87 (s, 1H), 8.40 (d, J = 7.4 Hz, 2H), 7.63 (t, J = 7.3 Hz, 1H), (m, 3H), 7.41 (d, J = 7.9 Hz, 1H), 7.13 (d, J = 8.0 Hz, 1H), 2.27 (s, 3H), 2.24 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ): δ , , , , , , , , , , , , 20.02, 19.40; HRMS (ESI/TOF-Q) m/z: [M+Na] + Calcd for C 16 H 15 NO 2 Na ; Found Compound 3r was prepared following the general procedure of synthesis of -keto amides described above and purified by silica gel column chromatography (1 5% EtOAc : hexane) to provide pure compound as yellow solid (65 mg, 90%). 1 H NMR (500 MHz, CDCl 3 ): δ 8.94 (s, 1H), 8.40 (d, J = 8.3 Hz, 2H), 7.63 (t, J = 7.4 Hz, 1H), 7.58 (d, J = 8.4 Hz, 2H), (m, 2H), 7.18 (d, J = 8.1 Hz, 2H), 2.34 (s, 3H); 13 C NMR (125 MHz, CDCl 3 ): δ , , , , , , , , , , Compound 3s was prepared following the general procedure of synthesis of -keto amides described above and purified by silica gel column chromatography (1 5% EtOAc : hexane) to provide pure compound as yellow solid (56 mg, 76%). 1 H NMR (400 MHz, CDCl 3 ): δ 8.98 (s, 1H), 8.40 (d, J = 7.9 Hz, 2H), (m, 3H), 7.50 (t, J = 7.8 Hz, 2H), 7.08 (t, J = 8.5 Hz, 2H); 13 C NMR (100 MHz, CDCl 3 ): δ , (d, J = Hz), , , , (d, J = 2.9 Hz), , , (d, J = 8.0 Hz), (d, J = 22.6 Hz). Compound 3t was prepared following the general procedure of synthesis of -keto amides described above and purified by silica gel column chromatography (1 5% EtOAc : hexane) to provide pure compound as yellow solid (75 mg, 82%). 1 H NMR (500 MHz, CDCl 3 ): δ 9.00 (s, 1H), (m, 2H), 7.99 (t, J = 1.9 Hz, 1H), (m, 1H), 7.57 (ddd, J = 8.0, 2.0, 0.9 Hz, 1H), (m, 2H), 7.32 (ddd, J = 8.0, 1.8, 1.0 Hz, 1H), 7.24 (t, J = 10.7 Hz, 1H); 13 C NMR (126 MHz, CDCl 3 ) δ , , , , , , , (2 C), , , Compound 3u was prepared following the general procedure of synthesis of -keto amides described above and purified by silica gel column chromatography (1 5% EtOAc : hexane) to provide pure compound as yellow solid (63 mg, 80%). 1 H NMR (400 MHz, CDCl 3 ): δ 8.99 (s, 1H), 8.40 (d, J = 8.1 Hz, 2H), (m, 3H), 7.51 (t, J = 7.7 Hz, 2H), 7.35 (d, J = 8.7 Hz, 2H); 13 C NMR (100 MHz, CDCl 3 ) δ , , , , , , , , , Compound 3v was prepared following the general procedure of synthesis of -keto amides described above and purified by silica gel column chromatography (1 5% EtOAc : hexane) to provide pure compound as yellow solid (72 mg, 84%). 1 H NMR (400 MHz, CDCl 3 ): δ 9.20 (s, 1H), 8.39 (d, J = 7.8 Hz, 2H), 8.07 (d, J = 8.5 Hz, 2H), 7.79 (d, J = 8.5 Hz, 2H), 7.66 (t, J = 7.4 Hz, 1H), 7.51 (t, J = 7.7 Hz, 2H), 3.91 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ): δ , , , , , , , , , , , General procedure for the -amination of gem-difluoro-enolates: In an oven dried reaction tube equipped with a magnetic stir bar, -fluorinated gem-diol (1, 0.3 mmol, 1.0 equiv), azadicarboxylate (4, 0.36 mmol, 1.2 equiv), and Lithium bromide (3.0 equiv) were taken. Then, anhydrous CH 3 CN (4 ml) followed distilled Et 3 N (2.0 equiv) were added and the reaction mixture was allowed to stir at room temperature. After 5 min (TLC monitored), volatiles were removed under reduced pressure. The S6

7 crude product was purified by silica gel column chromatography (1 15% EtOAc : hexane) to provide pure product 5. Compound 5a was prepared following the general procedure for synthesis of -amino ketones described above and purified by silica gel column chromatography (1 15% EtOAc : hexane) to provide pure compound as white solid (91 mg, 92%). 1 H NMR (400 MHz, CDCl 3 ): δ (m, 2H), 7.62 (t, J = 7.4 Hz, 1H), 7.51 (t, J = 7.5 Hz, 2H), 6.92 (s, 1H), 4.31 (q, J = 6.7 Hz, 2H), 4.12 (q, J = 7.0 Hz, 2H), 1.34 (t, J = 6.3 Hz, 3H), 1.11 (s, 3H); 13 C NMR (125 MHz, CDCl 3 ): δ (t, J = 29.5 Hz), , , , , , , (t, J = Hz), 63.62, 62.04, 13.49, 12.88; HRMS (ESI/TOF-Q) m/z: [M+Na] + Calcd for C 14 H 16 N 2 O 5 F 2 Na ; Found Compound 5b was prepared following the general procedure for synthesis of -amino ketones described above and purified by silica gel column chromatography (1 15% EtOAc : hexane) to provide pure compound as yellow oil (95 mg, 88%). 1 H NMR (500 MHz, CDCl 3 ): δ (m, 2H), 7.62 (t, J = 7.4 Hz, 1H), 7.51 (t, J = 7.0 Hz, 2H), 6.74 (s, 1H), 5.07 (s, 1H), 4.86 (quint, J = 12.1, 6.1 Hz, 1H), 1.33 (s, 6H), (m, 6H); 13 C NMR (125 MHz, CDCl 3 ): δ (t, J = 28.2 Hz), , , , , , , (t, J = Hz), 73.54, 71.02, 22.08, 21.48; HRMS (ESI/TOF-Q) m/z: [M+H] + Calcd for C 16 H 20 N 2 O 5 F 2 H ; Found Compound 5c was prepared following the general procedure for synthesis of -amino ketones described above and purified by silica gel column chromatography (1 15% EtOAc : hexane) to provide pure compound as yellow oil (103 mg, 89%). 1 H NMR (400 MHz, CDCl 3 ): δ (m, 2H), 7.60 (t, J = 7.3 Hz, 1H), (m, 2H), 6.61 (s, 1H), 1.52 (s, 9H), 1.27 (s, 9H); 13 C NMR (100 MHz, CDCl 3 ): δ (t, J = 31.0 Hz), , , , , , , (t, J = Hz), 86.06, 82.38, 28.22, HRMS (ESI/TOF-Q) m/z: [M+Na] + Calcd for C 18 H 24 N 2 O 5 F 2 Na ; Found Compound 5d was prepared following the general procedure for synthesis of -amino ketones described above and purified by silica gel column chromatography (1 15% EtOAc : hexane) to provide pure compound as white solid (94 mg, 91%). 1 H NMR (400 MHz, CDCl 3 ): δ (m, 2H), 7.31 (d, J = 7.7 Hz, 2H), 7.21 (s, 1H), 4.30 (q, J = 6.7 Hz, 2H), 4.12 (q, J = 6.9 Hz, 2H), 2.42 (s, 3H), 1.33 (t, J = 6.8 Hz, 3H), 1.12 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ): δ (t, J = 25.4 Hz), , , , , , , (t, J = Hz), 64.49, 62.90, 21.85, 14.43, 13.81; HRMS (ESI/TOF-Q) m/z: [M+Na] + Calcd for C 15 H 18 N 2 O 5 F 2 Na ; Found Compound 5e was prepared following the general procedure for synthesis of -amino ketones described above and purified by silica gel column chromatography (1 15% EtOAc : hexane) to provide pure compound as colourless oil (101 mg, 93%). 1 H NMR (400 MHz, CDCl 3 ): δ (m, 2H), 7.33 (s, 1H), 6.98 (d, J = 8.2 Hz, 2H), 4.29 (q, J = 6.6 Hz, 2H), 4.12 (q, J = 7.0 Hz, 2H), 3.87 (s, 3H), 1.32 (t, J = 6.6 Hz, 3H), 1.11 (t, J = 6.0 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ): δ (t, J = 29.4 Hz), , , , , , , (t, J = Hz), 64.41, 62.85, 55.58, 14.38, 13.77; HRMS (ESI/TOF-Q) m/z: [M+Na] + Calcd for C 15 H 18 N 2 O 6 F 2 Na ; Found Compound 5f was prepared following the general procedure for synthesis of -amino ketones described above and purified by silica gel column chromatography (1 15% EtOAc : hexane) to provide pure compound as yellow oil (93 mg, 85%). 1 H NMR (400 MHz, CDCl 3 ): δ (m, 2H), 7.60 (d, J = 8.1 Hz, 2H), 7.38 (s, 1H), 4.41 (q, J = 6.5 Hz, 2H), 4.24 (q, J = 7.0 Hz, 2H), 1.44 (t, J = 6.7 Hz, 3H), 1.25 (t, J = 6.3 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ): δ (t, J = 30.1 Hz), , , , , , , (t, J = Hz), 64.69, 63.05, 14.44, Compound 5g was prepared following the general procedure for synthesis of -amino ketones described above and purified by silica gel column chromatography (1 15% EtOAc : hexane) to provide pure compound as yellow solid (106 mg, 86%). 1 H NMR S7

8 (400 MHz, CDCl 3 ): δ (m, 2H), 7.49 (d, J = 8.1 Hz, 2H), 7.27 (s, 1H), 4.30 (q, J = 6.5 Hz, 2H), 4.13 (q, J = 7.0 Hz, 2H), 1.33 (t, J = 6.7 Hz, 3H), 1.14 (t, J = 6.3 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ): δ (t, J = 29.5 Hz), , , , , , , (t, J = Hz), 64.66, 63.02, 14.42, 13.85; HRMS (ESI/TOF-Q) m/z: [M+Na] + Calcd for C 14 H 15 BrN 2 O 5 F 2 Na ; Found Compound 5h was prepared following the general procedure for synthesis of -amino ketones described above and purified by silica gel column chromatography (1 15% EtOAc : hexane) to provide pure compound as white solid (88 mg, 84%). 1 H NMR (400 MHz, CDCl 3 ): δ (m, 2H), 7.47 (s, 1H), (m, 2H), 4.30 (q, J = 6.7 Hz, 2H), 4.13 (q, J = 6.7 Hz, 2H), 1.33 (t, J = 5.6 Hz, 3H), 1.13 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ): δ (t, J = 29.8 Hz), (d, J = Hz), , , (d, J = 8.9 Hz), , (d, J = 22.0 Hz), (t, J = Hz), 64.60, 62.95, 14.36, 13.76; HRMS (ESI/TOF-Q) m/z: [M+Na] + Calcd for C 14 H 15 N 2 O 5 F 3 Na ; Found Compound 5i was prepared following the general procedure for synthesis of -amino ketones described above and purified by silica gel column chromatography (1 15% EtOAc : hexane) to provide pure compound as yellow oil (105 mg, 90%). 1 H NMR (400 MHz, CDCl 3 ): δ (m, 2H), 6.98 (d, J = 8.5 Hz, 2H), 6.85 (s, 1H), 6.04 (ddt, J = 17.1, 10.5, 5.3 Hz, 1H), 5.42 (dd, J = 17.3, 1.4 Hz, 1H), 5.32 (d, J = 9.7 Hz, 1H), 4.61 (d, J = 5.3 Hz, 2H), 4.29 (q, J = 7.0 Hz, 2H), 4.12 (q, J = 7.0 Hz, 2H), 1.33 (t, J = 6.9 Hz, 3H), 1.11 (s, 3H); 13 C NMR (125 MHz, CDCl 3 ): δ (t, J = 29.4 Hz), , , , , , , , , (t, J = Hz), 69.08, 64.55, 63.01, 14.50, 13.90; HRMS (ESI/TOF-Q) m/z: [M+Na] + Calcd for C 17 H 20 N 2 O 6 F 2 Na ; Found Compound 5j was prepared following the general procedure for synthesis of -amino ketones described above and purified by silica gel column chromatography (1 15% EtOAc : hexane) to provide pure compound as yellow oil (94 mg, 88%). 1 H NMR (400 MHz, CDCl 3 ): δ 7.95 (d, J = 15.8 Hz, 1H), (m, 2H), (m, 3H), 7.31 (d, J = 15.9 Hz, 1H), 6.99 (s, 1H), (m, 4H), 1.30 (t, J = 7.0 Hz, 3H), 1.23 (t, J = 7.1 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ): δ (t, J = 30.9 Hz), , , , , , (2 C), , (t, J = Hz), 64.42, 62.93, 14.45, 14.09; HRMS (ESI/TOF- Q) m/z: [M+H] + Calcd for C 16 H 18 N 2 O 5 F 2 H ; Found Compound 5k was prepared following the general procedure for synthesis of - amino ketones described above and purified by silica gel column chromatography (1 15% EtOAc : hexane) to provide pure compound as yellow solid (111 mg, 86%). 1 H NMR (400 MHz, CDCl 3 ): δ (m, 2H), 7.64 (d, J = 7.8 Hz, 2H), (m, 2H), (m, 3H), 6.96 (s, 1H), 4.30 (q, J = 6.6 Hz, 2H), 4.13 (q, J = 7.0 Hz, 2H), 1.33 (t, J = 6.6 Hz, 3H), 1.13 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ): δ (t, J = 30.3 Hz), , , , , , , , , , , (t, J = Hz), 93.63, 88.68, 64.67, 63.05, 14.49, 13.91; HRMS (ESI/TOF-Q) m/z: [M+K] + Calcd for C 22 H 20 N 2 O 5 F 2 K ; Found compound 5l was prepared following the general procedure for synthesis of -amino ketones described above and purified by silica gel column chromatography (1 15% EtOAc : hexane) to provide pure compound as white solid (83 mg, 82%). 1 H NMR (400 MHz, CDCl 3 ): δ (m, 1H), 7.78 (d, J = 4.8 Hz, 1H), 7.21 (t, J = 4.2 Hz, 1H), 6.88 (s, 1H), 4.30 (q, J = 7.0 Hz, 2H), 4.17 (q, J = 7.1 Hz, 2H), 1.34 (t, J = 7.0 Hz, 3H), (m, 3H); 13 C NMR (100 MHz, CDCl 3 ): δ (t, J = 31.7 Hz), , , , , , , (t, J = Hz), 64.49, 62.85, 14.31, 13.71; HRMS (ESI/TOF-Q) m/z: [M+Na] + Calcd for C 12 H 14 N 2 O 5 F 2 Na ; Found compound 5m was prepared following the general procedure for synthesis of -amino ketones described above and purified by silica gel column chromatography (1 15% EtOAc : hexane) to provide pure compound as yellow oil (79 mg, 75%). 1 H NMR (400 MHz, CDCl 3 ): δ 7.96 (s, 1H), 7.73 (s, 1H), 6.97 (s, 1H), 6.60 (dd, J = 3.6, 1.5 Hz, 1H), 4.27 (q, J = 7.0 Hz, 2H), 4.16 (q, J = 5.9 Hz, 2H), 1.31 (t, J = 7.1 Hz, 3H), 1.14 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ): δ (t, J = 31.6 Hz), , , (2 C), , , (t, J = Hz), 64.61, 63.07, 14.50, 13.97; HRMS (ESI/TOF-Q) m/z: [M+Na] + Calcd for C 12 H 14 N 2 O 6 F 2 Na ; Found S8

9 Gram scale synthesis of -ketoamide 3q: In an oven dried 100 ml round bottom flask equipped with a magnetic stir, -fluorinated gem-diol 1a (1.5 g, 1.0 equiv), 3,4-dimethylnitrosobenzene (0.713 g, 1.2 equiv), and Lithium bromide (1.43 g, 3.0 equiv) were taken. Then, anhydrous CH 3 CN (20 ml) followed distilled Et 3 N (1.65 ml, 2.0 equiv) were added and the reaction mixture was allowed to stir at room temperature. After 5 min (TLC monitored), the volatiles were removed under reduced pressure. The crude product was purified by silica gel column chromatography (1 5% EtOAc : hexane) to provide pure product 3q as yellow solid (1.2 g, 85%). Synthesis of imidazolidinone 6: In an oven dried 50 ml round bottom flask equipped with a magnetic stir, -ketoamide (3q, 76 mg, 0.3 mmol), 1,2,3,4-tetrahydroisoquilonine (48 mg, 0.36 mmol, 1.2 equiv), and benzoic acid (3.7 mg, 0.1 equiv) were taken. Then, toluene (4 ml) was added and the reaction mixture was allowed to stir at 100 o C. After completion (10 h, TLC monitored), the reaction mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (1 10% EtOAc : hexane) to provide pure product 6 (104 mg, 94%). 1 H NMR (400 MHz, CDCl 3 ): δ 7.57 (d, J = 7.3 Hz, 2H), 7.39 (t, J = 7.3 Hz, 2H), 7.33 (d, J = 7.1 Hz, 1H), (m, 3H), 7.13 (d, J = 8.0 Hz, 1H), 7.06 (d, J = 8.0 Hz, 1H), 6.99 (t, J = 7.1 Hz, 1H), 6.76 (d, J = 7.7 Hz, 1H), 6.19 (s, 1H), 4.54 (s, 1H), (m, 1H), (m, 2H), (m, 1H), 2.25 (s, 3H), 2.24 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ): δ , , , , , , , , , , , , , , , , , 74.81, 67.33, 45.18, 24.61, 20.01, 19.50; HRMS (ESI/TOF-Q) m/z: [M+Na] + Calcd for C 25 H 24 CN 2 ONa ; Found Synthesis of orexin receptor antagonists (7 and 8): In an oven dried reaction tube equipped with a magnetic stir, -ketoamide (3q, 76 mg, 0.3 mmol), respective homobenzyl bromo compound (0.45 mmol, 1.5 equiv), Cs 2 CO 3 (147 mg, 1.5 equiv) were taken. Then, toluene (4 ml) was added and the reaction mixture was allowed to stir at 100 o C temperature. After 24 h, the reaction mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (1 10% EtOAc : hexane) to provide pure product 7 or 8. S9

10 Compound 7 was prepared following the procedure described above and purified by silica gel column chromatography (1 10% EtOAc : hexane) to provide pure compound (87 mg, 68%). 1 H NMR (400 MHz, CDCl 3 ): δ (m, 5H), (m, 4H), 6.93 (d, J = 8.0 Hz, 1H), 6.75 (s, 1H), (m, 1H), 4.22 (t, J = 7.4 Hz, 2H), 3.02 (t, J = 7.4 Hz, 2H), 2.16 (s, 3H), 2.09 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ): δ , , , , , , , , , , , , , (q, J = 3.6 Hz), , 48.79, 33.62, 19.79, 19.49; HRMS (ESI/TOF-Q) m/z: [M+H] + Calcd for C 24 H 23 F 3 NO 2 H ; Found Compound 8 was prepared following procedure described above and purified by silica gel column chromatography (1 10% EtOAc : hexane) to provide pure compound as white solid (99 mg, 84%). 1 H NMR (500 MHz, CDCl 3 ): δ 7.61 (dd, J = 8.2, 1.2 Hz, 2H), (m, 1H), 7.38 (t, J = 7.8 Hz, 2H), (m, 2H), (m, 2H), 6.92 (d, J = 8.0 Hz, 1H), 6.77 (d, J = 2.1 Hz, 1H), 6.67 (dd, J = 8.0, 2.2 Hz, 1H), 4.17 (t, J = 7.5 Hz, 2H), 2.91 (t, J = 7.4 Hz, 2H), 2.14 (s, 3H), 2.08 (s, 3H); 13 C NMR (125 MHz, CDCl 3 ): δ , , , , , , , , , , , , , , , 48.79, 33.01, 19.71, 19.40; HRMS (ESI/TOF-Q) m/z: [M+Na] + Calcd for C 24 H 22 ClNO 2 Na ; Found Synthesis of substituted maleimides 9: In an oven dried 15 ml reaction tube equipped with a magnetic stir bar, -keto amide (3, 0.3 mmol), dimethyl malonate (0.45 mmol, 1.5 equiv), Cs 2 CO 3 (2.5 equiv) were taken under nitrogen. Toluene (4 ml) was added. The reaction tube was caped and the reaction mixture was allowed to stir at 100 o C. After 10 h, the reaction mixture was concentrated under reduced pressure and the crude product was purified by silica gel column chromatography (1 10% EtOAc : hexane) to provide pure product 9. Compound 9a was prepared from -ketoamide 3a following the procedure described above and purified by silica gel column chromatography (1 10% EtOAc : hexane) to provide pure compound as yellow solid (76 mg, 82%). 1 H NMR (500 MHz, CDCl 3 ): δ (m, 2H), (m, 5H), (m, 3H), 3.92 (s, 3H); 13 C NMR (125 MHz, CDCl 3 ): δ , , , , , , , , , , , , , 53.25; HRMS (ESI/TOF-Q) m/z: [M+Na] + Calcd for C 18 H 13 NO 4 Na ; Found Compound 9b was prepared from -ketoamide 3r following the procedure described above and purified by silica gel column chromatography (1 10% EtOAc : hexane) to provide pure compound as yellow solid (82 mg, 85%). 1 H NMR (400 MHz, CDCl 3 ): δ 7.74 (d, J = 7.0 Hz, 2H), (m, 3H), (m, 4H), 3.91 (s, 3H), 2.40 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ): δ , , , , , , , , , , , , , 53.18, 21.31; HRMS (ESI/TOF-Q) m/z: [M+H] + Calcd for C 19 H 15 NO 4 H ; Found S10

11 Crystallographic experimental section: Crystal data and structure refinement for 5g (CCDC number: , Ellipsoid Probability 30): Identification code 5g Empirical formula C 1 4 H 15 Br F2 N 2 O 5 Formula weight Temperature Wavelength Crystal system, space group Unit cell dimensions 296(2) K A Orthorhombic, P2(1)2(1)2(1) a = (4) A alpha = 90 deg. b = (5) A beta = 90 deg. c = (11) A gamma = 90 deg. Volume (15) A^3 Z, Calculated density 4, Mg/m^3 Absorption coefficient mm^-1 F(000) 824 Crystal size Theta range for data collection Limiting indices x x mm to deg. -10<=h<=10, -11<=k<=11, -24<=l<=23 Reflections collected / unique / 3066 [R(int) = ] Completeness to theta = % Absorption correction Refinement method None Full-matrix least-squares on F^2 Data / restraints / parameters 3066 / 0 / 223 S11

12 Goodness-of-fit on F^ Final R indices [I>2sigma(I)] R1 = , wr2 = R indices (all data) R1 = , wr2 = Absolute structure parameter 0.007(7) Extinction coefficient Largest diff. peak and hole n/a and e.a^-3 Crystal data and structure refinement for 9b (CCDC Ellipsoid Probability 30). Identification code Empirical formula 9b C19 H15 N O4 Formula weight Temperature Wavelength 296(2) K A Crystal system, space group Triclinic, P-1 Unit cell dimensions a = (4) A alpha = (2) deg. b = (4) A beta = (2) deg. c = (5) A gamma = (2) deg. Volume (6) A^3 Z, Calculated density 2, Mg/m^3 Absorption coefficient mm^-1 F(000) 336 Crystal size Theta range for data collection x x mm to deg. S12

13 Limiting indices -8<=h<=10, -11<=k<=11, -13<=l<=12 Reflections collected / unique 9670 / 2789 [R(int) = ] Completeness to theta = % Absorption correction Refinement method None Full-matrix least-squares on F^2 Data / restraints / parameters 2789 / 0 / 220 Goodness-of-fit on F^ Final R indices [I>2sigma(I)] R1 = , wr2 = R indices (all data) R1 = , wr2 = Extinction coefficient 0.009(3) S13

14 NMR Spectra S14

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