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Home , Amide, Benzylamine

Electronic Supplementary Material (ESI) for Chemical Communications This journal is © The Royal Society of Chemistry 2011

Direct formation from unactivated carboxylic and

C. Liana Allen, A. Rosie Chhatwal and Jonathan M. J. Williams

Department of Chemistry, University of Bath, Claverton Down, Bath, BA2 7AY

Materials and Methods

General Procedures

Table S1 – Solvent screen

Table S2 – Additional products

Characterisations of Products

Rate Enhancement Study

Reversibility Study

References

1H and 13C NMR Spectra of Products

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Materials and Methods

All reactions requiring an anhydrous, inert atmosphere were carried out under a atmosphere using evacuated carousel or ampules. Unless preparative details are provided, all reagents were purchased from commercial suppliers Aldrich, Fluka, Lancaster, TCI and Acros Organics and used without further purification. All solvents were distilled and degassed and stored in the presence of 3 Å molecular sieves prior to use. Thin layer chromatography was carried out on aluminium or glass backed silica plates, purchased from Aldrich. The plates were visualised under UV (254 nm) light, sometimes followed by staining with potassium permanganate or dip and gentle heating. During compound separations, column chromatography was carried out using 60 micron dry silica purchased from Aldrich. Organic layers were routinely

dried with anhydrous MgSO4 and concentrated using a Büchi rotary evaporator.

1 13 H NMR / C NMR spectra were run in CDCl3, unless stated otherwise, on either a Bruker Avance 250 (250 MHz) or a Bruker Avance 300 (300 MHz). Any chemical shifts (δ) are reported as parts per million (ppm) with reference to tetramethylsilane

(TMS) (δH = 0.00 ppm) unless otherwise stated. The coupling constants (J) are reported in Hz and signal multiplicities are reported as singlet (s) , doublet (d), triplet (t), quartet (q), quintet (qu), doublet of doublets (dd), doublet of triplets (dt), triplet of triplets (tt), multiplet (m), or broad (br. s).

For mass spectrometry data aquisition a micrOTOF electrospray time-of-flight (ESI- TOF) mass spectrometer (Bruker Daltonik GmbH, Bremen, Germany) was used; this was coupled to an Agilent 1200 LC system (Agilent Technologies, Waldbronn, Germany). The LC system was used as an autosampler only. 10 µL of sample was injected into a 30:70 flow of : at 0.3 mL/min to the mass spectrometer. For each acquisition 10 μL of a calibrant of 5 mM sodium formate was injected after the sample. The observed mass and isotope pattern matched the corresponding theoretical values as calculated from the expected elemental formula.

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Infra-red spectra were recorded on a Perkin Elmer Spectrum 100 FT-IR spectrometer, using a Universal ATR accessory for sampling, with relevant absorbances quoted as ν in cm-1.

Enantiomeric excess was measured using a Perkin Elmer 200 Series HPLC machine fitted with a Chiralcel OD-H column (25 cm), eluting with HPLC grade hexane and isopropylalcohol.

All characterization data was consistent with that reported in the literature.

General Procedures

I. Solvent screening: 3-Phenylpropionamide (0.150 g, 1 mmol) was added to an oven dried Radleys carousel tube. 4-Methylbenzylamine (0.13 mL, 1 mmol) and the appropriate solvent (1 mL, see Table S1) was added then the tube was sealed and heated at reflux for 20 hours. The reaction mixture was allowed to cool to room temperature before the solvent was removed in vacuo on a rotary evaporator and the crude reaction mixtures were analysed by their 1H NMR and 13C NMR spectra.

II. Catalyst screening: 3-Phenylpropionamide (0.150 g, 1 mmol) was added to an oven dried Radleys carousel tube. Benzylamine (0.11 mL, 1 mmol), the appropriate catalyst (10 mol %, see Table 3) and toluene (1 mL) was added then the tube was sealed and heated at reflux for 4 hours. The reaction mixture was allowed to cool to room temperature before the solvent was removed in vacuo on a rotary evaporator and the crude reaction mixtures were analysed by their 1H NMR and 13C NMR spectra.

III. Catalyst free direct coupling of carboxylic acids and amines: The appropriate carboxylic (1.0 mmol) was added to an oven dried Radleys carousel tube, followed by the appropriate (1.0 mmol) and 0.5 mL toluene (unless otherwise stated). The tube was then sealed and the reaction mixture heated at reflux for 22 hours before being allowed to cool to room temperature. The solvent was then removed on a rotary evaporator and the products were isolated by column chromatography and recrystallized where appropriate. The resulting amides were Electronic Supplementary Material (ESI) for Chemical Communications This journal is © The Royal Society of Chemistry 2011

characterised by their IR, 1H NMR and 13C NMR spectroscopy and mass spectrometry data.

IV. Zirconium catalyzed coupling of carboxylic acids and amines: The species (2 mmol) was added to an oven dried Radleys carousel tube, followed by

the zirconium catalyst (ZrCl4: 0.023 g, 5 mol% unless otherwise stated; ZrCp2Cl2: 0.029 g, 5 mol%; see Table 2), toluene (2 mL) and the amine species (2 mmol). The carousel tube was then sealed before the reaction mixture was heated at reflux for the appropriate time (see Table 2). After being allowed to cool to room temperature, the solvent was removed in vacuo on a rotary evaporator and the resulting crude reaction mixtures were analysed by their 1H NMR and 13C NMR spectroscopy and mass spectrometry data. Where the reaction had gone to 100% conversion, the reaction mixture was passed through a short plug of silica to remove the catalyst; otherwise the amides were purified by column chromatography where appropriate.

V. Scale up reaction: 3-Phenylpropionamide (62.74 g, 418 mmol) was added to an oven dried single neck 500 mL round bottom flask. Benzylamine (45.6 mL, 418 mmol) and toluene (210 mL) were added and the flask was fitted with a reflux condenser (and left open to the air) before being heated at reflux for 28 hours. The reaction mixture was allowed to cool to room temperature before the solvent was removed in vacuo on a rotary evaporator and the resulting amide was recrystallized from dichloromethane.

VI. Rate study: 3-Phenylpropionamide (0.150 g, 1 mmol) was added to an oven dried

Radleys carousel tube. Benzylamine (0.11 mL, 1 mmol), ZrCl4 (0.012 g, 5 mol%) and toluene (1 mL) was added then the tube was sealed and heated at reflux for the appropriate number of hours. The reaction mixture was allowed to cool to room temperature before the solvent was removed in vacuo on a rotary evaporator and the crude reaction mixtures were analysed by their 1H NMR and 13C NMR spectra.

VII. Reversibility study: The appropriate secondary amide (0.15 mmol) and water (0.004 mL, 0.2 mmol) were added to an oven dried Radleys carousel tube. Toluene

(0.2 mL) and, if required, ZrCl4 (0.0012 g, 5 mol%) were added and the tube was sealed and heated at reflux for 22 hours. The reaction mixture was allowed to cool to Electronic Supplementary Material (ESI) for Chemical Communications This journal is © The Royal Society of Chemistry 2011

room temperature before the solvent was removed on a rotary evaporator and the products analysed by their 1H NMR and 13C NMR spectra.

Table S1 Direct amide bond formation in a range of solvents after 20 hours O O Solvent H2N Tol 110 oC, 20 h Ph N Tol Ph OH H 1.0 M

Entry Solvent Conversion (%)a 1 Toluene 92 2 Cyclohexane 4 3 Isopropanol 3 4 Dimethylsulfoxide 0 5 Water 0 6 1,2-Dichloroethane 12 7 1,4-Dioxane 66 8 Acetonitrile 50 9 No solvent 58 10 Toluene 100b aDetermined by analysis of the 1H NMR spectra. bRun at 2.0M for 22 h

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Table S2 Additional examples of substrates

Entry Amide Conversion Conversion Catalyst Time Conversion (%)a (%)a (h) (%)a neat in toluene 1 18 100 (95) ZrCl4 18 96 (81)

2 100 100 (89) ZrCl4 5 100 (93)

3 48 100 (91) ZrCl4 5 100 (88)

4 <1 32 ZrCl4 18 57 56 (150 oC)b 100 (91) (150 oC)b 5 0 0 ZrCl4 24 27 45 (150 oC) b 53 (150 oC) b a Determined by 1H NMR spectroscopy, isolated yields shown in parentheses where appropriate; b Reaction at 150 oC were run on xylenes.

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Characterisations of Products

N-(4-Methylbenzyl)-3-phenylpropionamide (Table 2, Entry 1) Following general procedure III, 3-phenylpropionic acid (0.150 g, 1.0 mmol) was used as the acid species and 4-methylbenzylamine (0.13 mL, 1.0 mmol) was used as the amine species. N-(4-Methylbenzyl)-3-phenylpropionamide was recovered as an off-white solid (0.205 g, 81 %) after removal of toluene and recrystallisation (dichloromethane/hexane). 1 H NMR (250 MHz, CDCl3): δ = 2.36 (3H, s, CH3), 2.50 – 2.56 (2H, t, J = 7.5 Hz,

PhCH2CH2), 2.99 – 3.06 (2H, t, J = 7.5 Hz, PhCH2CH2), 4.38 – 4.40 (2H, d, J = 5.75 13 Hz, NHCH2(4-Me)Ph), 7.06 – 7.32 (9H, m, 2xPh); C NMR (75 MHz, CDCl3): δ = 21.1, 31.7, 38.6, 43.4, 126.3, 127.8, 128.4, 128.6, 129.3, 135.1, 137.2, 140.8, 171.8; + + ESI-MS of [C17H20NO] ; theoretical m/z of [M+H] = 254.15, measured m/z of [M+H]+ = 254.14; IR: ν (cm-1) = 1636.58 cm-1 (C=O stretch); Elemental analysis: predicted C:80.60, H:7.56, N:5.53; Found C:80.58, H:7.55, N:5.54. Following general procedure IV, 3-phenylpropionic acid (0.300 g, 2.0 mmol) was used as the acid species and 4-methylbenzylamine (0.26 mL, 2.0 mmol) was used as the amine species. N-(4-Methylbenzyl)-3-phenylpropionamide was recovered as an

off-white solid (0.476 g, 94 %, ZrCp2Cl2; 0.466 g, 92 %, ZrCl4) after filtration through a pad of silica (eluting with dichloromethane) and recrystallisation (dichloromethane/hexane).

N-(4-Methoxybenzyl)-3-phenylpropionamide (Table 2, Entry 2)1 Following general procedure III, 3-phenylpropionic acid (0.150 g, 1.0 mmol) was used as the acid species and 4-methyoxybenzylamine (0.14 mL, 1.0 mmol) was used as the amine species. N-(4-Methoxybenzyl)-3-phenylpropionamide was recovered as a yellow solid (0.194 g, 72 %) after column chromatography (eluting with dichloromethane/methanol 95:5). Electronic Supplementary Material (ESI) for Chemical Communications This journal is © The Royal Society of Chemistry 2011

1 H NMR (250 MHz, CDCl3): 2.50 - 2.56 (2H, t, J = 7.75 Hz, PhCH2CH2), 2.99 - 3.05

(2H, t, J = 7.75 Hz, PhCH2CH2), 3.82 (3H, s, OCH3), 4.34 - 4.37 (2H, d, J = 5.75 Hz,

NHCH2Ph), 5.67 (1H, br. s., NH), 6.84 - 6.87 (2H, d, J = 8.75 Hz, (4-OMe)Ph), 7.09 - 7.12 (2H, d, J = 8.75 Hz, (4-OMe)Ph), 7.21 - 7.33 (m, 5H, Ph); 13C NMR (75 MHz,

CDCl3): δ = 31.8, 38.5, 43.1, 55.3, 114.1, 126.3, 128.3, 128.4, 128.6, 129.1, 130.2, + + 140.8, 159.0, 172.0; ESI-MS of [C17H20NO2] ; theoretical m/z of [M+H] = 270.157, measured m/z of [M+H]+ = 270.157; IR: ν (cm-1) = 1637.37 cm-1 (C=O stretch). Following general procedure IV, 3-phenylpropionic acid (0.300 g, 2.0 mmol) was used as the acid species and 4-methyoxybenzylamine (0.27 mL, 2.0 mmol) was used as the amine species. N-(4-Methoxybenzyl)-3-phenylpropionamide was recovered as

a pale yellow solid (0.323 g, 60 % ZrCp2Cl2; 0.479 g, 89 %, ZrCl4) after filtration through a pad of silica, eluting with dichloromethane. Analytical data was consistent with that above.

N-(Pentyl)-3-phenylpropionamide (Table 2, Entry 3)2 Following general procedure III, 3-phenylpropionic acid (0.150 g, 1.0 mmol) was used as the acid species and pentylamine (0.13 mL, 1.0 mmol) was used as the amine species. N-(Pentyl)-3-phenylpropionamide was recovered as a dark brown oil (0.199 g, 94 %) after removal of toluene. 1 H NMR (250 MHz, CDCl3): δ = 0.87 - 0.93 (3H, t, J = 6.75 Hz, CH2CH2CH3), 1.22 -

1.47 (6H, m, CH2CH2CH2CH2CH3), 2.46 - 2.52 (2H, t, J = 8.0 Hz, PhCH2CH2), 2.96 -

3.02 (2H, t, J = 8.0 Hz, PhCH2CH2), 3.18 - 3.26 (2H, q, J = 7.0 Hz, NHCH2CH2), 13 5.35 (1H, br. s., NH), 7.23 - 7.31 (5H, m, Ph); C NMR (75 MHz, CDCl3): δ = 14.0, 22.3, 29.0, 29.2, 31.8, 38.6, 39.5, 126.2, 128.3, 128.4, 128.5, 140.9, 172.0; ESI-MS of + + + [C14H22NO] ; theoretical m/z of [M+H] = 220.128, measured m/z of [M+H] = 220.127. Following general procedure IV, 3-phenylpropionic acid (0.300 g, 2.0 mmol) was used as the acid species and pentylamine (0.26 mL, 2.0 mmol) was used as the amine species. N-(Pentyl)-3-phenylpropionamide was isolated as a brown oil (0.301g, 71%) after column chromatography (eluting with 95:5 dichloromethane:methanol). Analytical data was consistent with that above.

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N-(5-Methylfurfuryl)-3-phenylpropionamide (Table 2, Entry 4) Following general procedure III, 3-phenylpropionic acid (0.150 g, 1.0 mmol) was used as the acid species and 5-methylfurfurylamine (0.18 mL, 1.0 mmol) was used as the amine species. N-(5-Methylfurfuryl)-3-phenylpropionamide was recovered as a brown oil (0.454 g, 92 %) after removal of the solvent. 1 H NMR (250 MHz, CDCl3): δ = 2.17 (3H, s, CH3), 2.38 - 2.44 (2H, t, J = 8.25 Hz,

PhCH2CH2), 2.86 - 2.92 (2H, t, J = 8.25 Hz, PhCH2CH2), 4.25 - 4.27 (2H, d, J = 5.25

Hz, NHCH2Furyl), 5.67 (1H, br. s., NH), 5.79 - 5.80 (1H, d, Furyl), 5.95 -5.96 (1H, d, 13 Furyl), 7.09 - 7.18 (5H, m, Ph); C NMR (75 MHz, CDCl3): δ = 13.5, 31.6, 36.6, 38.4, 106.3, 108.3, 126.2, 128.4, 128.5, 140.8, 149.3, 151.9, 171.8; ESI-MS of + + + [C15H18NO2] ; theoretical m/z of [M+H] = 244.130, measured m/z of [M+H] = 244.130; IR: ν (cm-1) = 1647.39 cm-1 (C=O stretch); Elemental analysis: predicted C:74.05, H:7.04, N:5.76; Found C:74.05, H:7.05, N:5.74. Following general procedure IV, 3-phenylpropionic acid (0.300 g, 2.0 mmol) was used as the acid species and 5-methylfurfurylamine (0.36 mL, 2.0 mmol) was used as the amine species. N-(5-Methylfurfuryl)-3-phenylpropionamide was recovered as a brown oil (0.442 g, 91 %) after filtration through a pad of silica, eluting with dichloromethane. Analytical data was consistent with that above.

N-(Phenyl)-3-phenylpropionamide (Table 2, Entry 5)3 Following general procedure III, 3-phenylpropionic acid (0.150 g, 1.0 mmol) was used as the acid species and (0.09 mL, 1.0 mmol) was used as the amine species. The reaction mixture was heated at reflux in 0.5 mL p-xylene. An 1H NMR of the crude reaction mixture showed a 73 % conversion into N-(phenyl)-3- phenylpropionamide. 1 H NMR (250 MHz, CDCl3): δ = 2.66 – 2.72 (2H, t, J = 7.25 Hz, PhCH2CH2), 3.06 –

3.12 (2H, t, J = 7.25 Hz, PhCH2CH2), 5.60 (1H, br. S., NH), 7.30 – 7.37 (8H, m, + 2xPh), 7.45 – 7.48 (2H, d, J = 7.5 Hz, Ph); ESI-MS of [C15H16NO] ; theoretical m/z of [M+H]+ = 226.135, measured m/z of [M+H]+ = 226.135; IR: ν (cm-1) = 1649.38 cm-1 (C=O stretch). Electronic Supplementary Material (ESI) for Chemical Communications This journal is © The Royal Society of Chemistry 2011

Following general procedure IV, 3-phenylpropionic acid (0.300 g, 2.0 mmol) was used as the acid species and aniline (0.17 mL, 2.0 mmol) was used as the amine 1 species. 10 mol% ZrCl4 (0.046g) was used. An H NMR of the crude reaction mixture

showed a 45 % conversion into N-(phenyl)-3-phenylpropionamide when ZrCp2Cl2

was used as catalyst and a 41 % conversion when ZrCl2 was used as catalyst. Analytical data was consistent with that above.

N-(Morpholino)-3-phenylpropionamide (Table 2, Entry 6)1 Following general procedure III, 3-phenylpropionic acid (0.150 g, 1.0 mmol) was used as the acid species and morpholine (0.08 mL, 1.0 mmol) was used as the amine species. The reaction mixture was heated at reflux in 0.5 mL p-xylene. N- (Morpholino)-3-phenylpropionamide was recovered as a colourless oil (0.206 g, 94 %) after removal of p-xylene. 1 H NMR (250 MHz, CDCl3): δ = 2.51 - 2.57 (t, 2H, J = 8.3 Hz, PhCH2CH2), 2.88 -

2.94 (t, 2H, J = 8.3 Hz, PhCH2CH2), 3.26 - 3.30 (t, 2H, J = 6.3 Hz), 3.42 - 3.46 (t, 2H, 13 J = 6.3 Hz), 3.55 (s, 4H), 7.13 - 7.22 (m, 5H, Ph); C NMR (75 MHz, CDCl3): δ = 31.49, 34.76, 41.94, 45.95, 66.44, 66.80, 126.29, 128.49, 128.56, 141.06, 170.89; + + ESI-MS of [C13H17NO2] ; theoretical m/z of [M+H] = 220.134, measured m/z of [M+H]+ = 220.132; IR: ν (cm-1) = 1635.83 (C=O stretch). Following general procedure IV, 3-phenylpropionic acid (0.300 g, 2.0 mmol) was used as the acid species and morpholine (0.17 mL, 2.0 mmol) was used as the amine species. N-(Morpholino)-3-phenylpropionamide was recovered as a colourless oil (0.386 g, 88 %) after filtration through a pad of silica, eluting with dichloromethane. Analytical data was consistent with that above.

N-(Benzyl)-propionamide (Table 2, Entry 7)4 Following general procedure III, (0.15 mL, 2.0 mmol) was used as the acid species and benzylamine (0.22 mL, 2.0 mmol) was used as the amine species. N- Electronic Supplementary Material (ESI) for Chemical Communications This journal is © The Royal Society of Chemistry 2011

(Benzyl)-propionamide was recovered as a white solid (0.293 g, 90 %) removal of toluene and recrystallisation (dichloromethane/hexane). 1 H NMR (250 MHz, CDCl3, 25 °C): δ = 1.02 – 1.07 (3H, t, J = 6.0, CH3CH2), 2.08 –

2.14 (2H, q, J = 6.0 Hz, CH3CH2C(O)), 4.31 (2H, d, J = 9.0 Hz, PhCH2NH), 7.08 – 13 7.22 (5H, m, aromatic); C NMR (75.5 MHz, CDCl3, 25 °C): δ = 10.2, 30.1, 40.0, + 127.9, 128.2, 129.1, 138.8, 173.9; ESI-MS of [C10H13NO] ; theoretical m/z of [M+H]+ = 164.11, measured m/z of [M+H]+ = 164.11; IR : ν (cm-1) = 1642.09 cm-1 (C=O stretch). Following general procedure IV, propionic acid (0.15 mL, 2.0 mmol) was used as the acid species and benzylamine (0.22 mL, 2.0 mmol) was used as the amine species. N- (Benzyl)-propionamide was recovered as a white solid (0.264 g, 81%) after filtration through a pad of silica, eluting with dichloromethane. Analytical data was consistent with that above.

[N-(Benzyl)N’-Boc]-glycinamide (Table 2, Entry 8)5 Following general procedure III, N-Boc-glycine (0.350 g, 2.0 mmol) was used as the acid species and benzylamine (0.22 mL, 2.0 mmol) was used as the amine species. An 1H NMR of the crude reaction mixture showed a 71% conversion into [N-(Benzyl)N’- Boc]-glycinamide. 1 H NMR (250 MHz, DMSO-d6): δ = 1.41 (9H, s, 3xCH3), 3.59 - 3.61 (2H, d, J = 6.25

Hz, NHCH2C(O)NH), 4.29 - 4.31 (2H, d, J = 5.75 Hz, C(O)NHCH2Ph), 7.02 (1H, br. s., NH), 7.24 - 7.32 (5H, m, Ph), 8.32 (1H, br. s., NH). Following general procedure IV, N-Boc-glycine (0.350 g, 2.0 mmol) was used as the acid species and benzylamine (0.22 mL, 2.0 mmol) was used as the amine species. [N- (Benzyl)N’-Boc]-glycinamide was recovered as a pale yellow viscous oil (0.423 g, 80 %) after column chromatography (eluting with 97:3 dichloromethane: methanol) and washing with hexanes. 13C NMR (75 MHz, DMSO-d6): δ = 28.2, 42.0, 43.4, 78.0, 126.7, 127.1, 128.1, 139.4, + + 155.8, 169.4; ESI-MS of [C14H21N2O3] ; theoretical m/z of [M+H] = 265.153, measured m/z of [M+H]+ = 265.153.

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N-(Benzyl)-benzamide (Table 2, Entry 9)5 Following general procedure III, (0.246 g, 2.0 mmol) was used as the acid species and benzylamine (0.22 mL, 2.0 mmol) was used as the amine species. The reaction mixture was heated at reflux in 0.5 mL p-xylene. An 1H NMR of the crude reaction mixture showed a 44% conversion into N-(benzyl)-benzamide. 1 H NMR (300 MHz, CDCl3): δ = 4.57 - 4.59 (d, 2H, J = 5.7 Hz, PhCH2NH), 6.36 (br. s, 1H, NH), 7.18 - 7.43 (m, 8H, 2Ph), 7.70 - 7.73 (m, 2H, Ph). Following general procedure IV, benzoic acid (0.241 g, 2.0 mmol) was used as the acid species and benzylamine (0.22 mL, 2.0 mmol) was used as the amine species. 10 1 mol% ZrCl4 (0.046g) was used. An H NMR of the crude reaction mixture showed

55 % conversion into N-(benzyl)-benzamide when ZrCl4 was used as catalyst.

N-(Benzyl)-benzamide was recovered as a white solid (0.304 g, 72 %, ZrCp2Cl2) after column chromatography (eluting with 92:8 dichloromethane:methanol). 13 C NMR (75 MHz, CDCl3): δ = 44.17, 126.97, 127.66, 127.95, 128.62, 128.82, + + 131.56, 134.43, 138.21, 167.35; ESI-MS of [C14H13NO] ; theoretical m/z of [M+H] = 212.107, measured m/z of [M+H]+ = 212.106.

N-(Benzyl)-4-fluorophenylacetamide (Table 2, Entry 10) Following general procedure III, 4-fluorophenylacetic acid (0.308 g, 2.0 mmol) was used as the acid species and benzylamine (0.22 mL, 2.0 mmol) was used as the amine species. N-(Benzyl)-4-fluorophenylacetamide was recovered as an off white solid (0.435 g, 90 %) after removal of toluene. 1 H NMR (300 MHz, DMSO-d6): δ = 3.46 (2H, s, CH2C(O)), 4.24 – 4.26 (2H, d, J = 13 6.0 Hz, NHCH2Ph), 7.08 – 7.32 (9H, m, 2xPh), 8.54 (1H, br. s., NH); C NMR (75 Electronic Supplementary Material (ESI) for Chemical Communications This journal is © The Royal Society of Chemistry 2011

MHz, DMSO-d6): δ = 41.7, 42.5, 114.9, 115.1, 115.2, 115.4, 127.1, 127.6, 127.9, 128.6, 128.7, 131.1, 131.2, 131.5, 131.6, 132.9, 132.9, 139.8, 159.8, 162.9, 170.4; + + ESI-MS of [C15H15NOF] ; theoretical m/z of [M+H] = 244.109, measured m/z of [M+H]+ = 244.109; IR: ν (cm-1) = 1640.13 cm-1 (C=O stretch); Elemental analysis: predicted C:74.06, H:5.80, N:5.76; Found C:74.08, H:5.85, N:5.74. Following general procedure IV, 4-fluorophenylacetic acid (0.308 g, 2.0 mmol) was used as the acid species and benzylamine (0.22 mL, 2.0 mmol) was used as the amine species. N-(Benzyl)-4-fluorophenylacetamide was recovered as an off white solid (0.442 g, 91 %) after filtration through a pad of silica, eluting with dichloromethane and methanol. Analytical data was consistent with that above.

N-(Benzyl)-4-methoxyphenylacetamide (Table 2, Entry 11)6 Following general procedure III, 4-methoxyphenylacetic acid (0.333 g, 2.0 mmol) was used as the acid species and benzylamine (0.22 mL, 2.0 mmol) was used as the amine species. N-(Benzyl)-4-methoxyphenylacetamide was recovered as a yellow solid (0.469 g, 92 %) after removal of toluene and recrystallization (dichloromethane/hexane). 1 H NMR (300 MHz, DMSO-d6): δ = 3.38 (2H, s, (4-OMe)PhCH2C(O)), 3.70 (3H, s,

OCH3), 4.22 – 4.24 (2H, d, J = 5.7 Hz, NHCH2Ph), 6.83 – 6.86 (2H, d, J = 8.4 Hz, (4- OMe)Ph), 7.12 – 7.37 (7H, m, 2xPh), 8.47 (1H, br. s., NH); 13C NMR (75 MHz, DMSO-d6): δ = 41.8, 42.5, 55.4, 114.0, 127.1, 127.5, 128.3, 128.6, 130.3, 130.6, + + 139.9, 158.3, 170.8; ESI-MS of [C16H18NO2] ; theoretical m/z of [M+H] = 256.135, measured m/z of [M+H]+ = 256.137; IR: ν (cm-1) = 1634.93 cm-1 (C=O stretch). Following general procedure IV, 4-methoxyphenylacetic acid (0.333 g, 2.0 mmol) was used as the acid species and benzylamine (0.22 mL, 2.0 mmol) was used as the amine species. N-(Benzyl)-4-methoxyphenylacetamide was recovered as a yellow solid (0.455 g, 91 %) after filtration through a pad of silica, eluting with dichloromethane. Analytical data was consistent with that above.

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3-Benzoyl-N-morpholinopropionic acid (Table 2, Entry 12)7 Following general procedure III, 3-benzoylpropionic acid (0.178 g, 1.0 mmol) was used as the acid species and morpholine (0.08 mL, 1.0 mmol) was used as the amine species. 3-Benzoyl-N-morpholinopropionamide was recovered as a dark yellow oil (0.193 g, 78 %) after removal of toluene and recrystallization (dichloromethane/hexane). 1 H NMR (300 MHz, CDCl3): δ = 2.74 – 2.78 (2H, t, J = 6.6 Hz, PhC(O)CH2), 3.33 –

3.38 (2H, t, J = 6.6 Hz, PhC(O)CH2CH2), 3.55 – 3.73 (8H, m, morpholine ring), 7.42 – 7.57 (3H, m, PhC(O)), 7.99 – 8.01 (2H, d, J = 6.9 Hz, PhC(O)); 13C NMR (75 MHz,

CDCl3): δ = 26.9, 33.5, 42.1, 45.9, 128.0, 128.1, 128.5, 128.6, 133.2, 136.7, 170.5, + + 199.1; ESI-MS of [C16H18NO2] ; theoretical m/z of [M+H] = 248.124, measured m/z of [M+H]+ = 248.122; IR: ν (cm-1) = 1682.76 cm-1 (C=O stretch, amide). Following general procedure IV, 3-benzoylpropionic acid (0.356 g, 2.0 mmol) was used as the acid species and morpholine (0.16 mL, 2.0 mmol) was used as the amine species. 3-Benzoyl-N-morpholinopropionamide was recovered as a dark yellow oil (0.386 g, 78 %) after filtration through a pad of silica, eluting with dichloromethane. Analytical data was consistent with that above.

[N-(Benzyl)N’-Boc]-D-prolinamide (Table 2, Entry 13)5 Following general procedure IV, N-Boc-D-proline (0.431 g, 2.0 mmol) was used as the acid species and benzylamine (0.22 mL, 2.0 mmol) was used as the amine species. The reaction was heated at reflux in 0.5 mL p-xylene. An 1H NMR of the crude reaction mixture showed 79 % conversion into [N-(Benzyl)N’-Boc]-D-prolinamide. Following general procedure IV, N-Boc-D-proline (0.323 g, 1.5 mmol) was used as the acid species and benzylamine (0.22 mL, 2.0 mmol) was used as the amine species. [N-(Benzyl)N’-Boc]-D-prolinamide was recovered as a white solid (0.256 g, 56 %) after column chromatography eluting with 1:1 hexane : ethyl acetate. 1H NMR (250 MHz, DMSO-d6): δ = 1.30 (5.5H, s, tBu), 1.42 (3.5H, s, tBu), 1.79 - 1.82 (3H, m, pyrrolidine ring), 2.07 - 2.18 (1H, m, pyrrolidine ring), 3.25 - 3.43 (2H, Electronic Supplementary Material (ESI) for Chemical Communications This journal is © The Royal Society of Chemistry 2011

m, pyrrolidine ring), 4.07 - 4.39 (3H, m, NHCH2Ph and (Boc)NCHC(O)), 7.24 - 7.32 (5H, m, Ph), 8.36 - 8.43 (1H, m, NH); 13C NMR (75 MHz, DMSO-d6): δ = 23.5, 28.3, 31.4, 31.5, 42.4, 46.8, 60.1, 60.3, 78.8, 127.1, 127.6, 128.5, 139.9, 161.7, 172.8; ESI- + + MS of [C17H23N2O3] ; theoretical m/z of [M+H] = 305.154, measured m/z of + -1 -1 25 o [M+H] = 305.148; IR: ν (cm ) = 1675.75 cm (C=O stretch, amide); [α]D = 80.3

(CHCl3, c = 0.09); HPLC: Chiralcel AD column (25 cm), 90:10 hexane : isopropylalcohol, 0.5 mL min-1 flow rate, 16.39 min (D-enantiomer). No peak observed for L-enantiomer @ 22.94 min.

N-(Allyl)- (Table 2, Entry 14)8 Following general procedure III, cyanoacetic acid (0.085 g, 1.0 mmol) was used as the acid species and allylamine (0.08 mL, 1.0 mmol) was used as the amine species. N-(Allyl)-cyanoacetamide was recovered as a light brown solid (0.095 g, 76 %) after removal of toluene. 1 H NMR (300 MHz, CDCl3): δ = 3.34 (2H, s, NCCH2C(O)), 3.84 – 3.88 (2H, m,

NHCH2CH), 5.09 – 5.21 (2H, m, NHCH2CHCH2), 5.71 – 5.84 (1H, m, 13 NHCH2CHCH2), 6.29 (1H, br. s., NH); C NMR (75 MHz, CDCl3): δ = 25.8, 42.7, + + 117.6, 132.8, 133.5, 160.8; ESI-MS of [C6H9N2O] ; theoretical m/z of [M+H] = 125.069 measured m/z of [M+H]+ = 125.068; IR: ν (cm-1) = 1657.64 cm-1 (C=O stretch). Following general procedure VI, cyanoacetic acid (0.085 g, 1.0 mmol) was used as the acid species and allylamine (0.08 mL, 1.0 mmol) was used as the amine species. N-(Allyl)-cyanoacetamide was recovered as a light brown solid (0.104 g, 84 %) after filtration through a short pad of silica (eluting with 97:3 dichloromethane : methanol). Analytical data was consistent with that above.

N-(Phenylacetyl)-valine methyl (Table 2, Entry 15)9 Following general procedure III, phenylacetic acid (0.135 g, 1.0 mmol) was used as the acid species and valine methyl ester hydrochloride (0.167 g, 1.0 mmol) was used as the amine species. One equivalent of N,N-diisopropylethylamine (0.17 mL, 1 mmol) Electronic Supplementary Material (ESI) for Chemical Communications This journal is © The Royal Society of Chemistry 2011

was included in the reaction. N-(Phenylacetyl)-valine methyl ester was recovered as a yellow oil (0.218 g, 88 %) after removal of toluene and washing with water to remove the . 1 H NMR (300 MHz, CDCl3): δ = 0.67 – 0.69 (3H, d, J = 6.0 Hz, (CH3)CH(CH3)CH),

0.77 – 0.79 (3H, d, J = 6.0 Hz, (CH3)CH(CH3)CH), 1.97 – 2.08 (1H, m,

(CH3)CH(CH3)CH), 3.55 – 3.56 (2H, d, J = 3.0 Hz, PhCH2C(O)), 3.63 (3H, s, OCH3),

4.45 – 4.49 (1H, dd, J = 4.8 Hz, 8.7 Hz, (CH3)CH(CH3)CHNH), 5.83 (1H, br. s, NH), 13 7.19 – 7.28 (5H, m, Ph); C NMR (75 MHz, CDCl3): δ = 17.6, 18.9, 31.2, 43.7, 52.2, + 57.0, 127.5, 128.6, 129.0, 129.4, 134.6, 171.0, 172.4; ESI-MS of [C14H20NO3] ; theoretical m/z of [M+H]+ = 249.136, measured m/z of [M+H]+ = 249.136. Following general procedure VI, phenylacetic acid (0.135 g, 1.0 mmol) was used as the acid species and valine methyl ester hydrochloride (0.167 g, 1.0 mmol) was used as the amine species. One equivalent of N,N-diisopropylethylamine (0.17 mL, 1 mmol) was included in the reaction. N-(Phenylacetyl)-valine methyl ester was recovered as a yellow oil (0.202 g, 81 %) after filtration through a short pad of silica and washing with water to remove the base. Analytical data was consistent with that above.

N-(Acetyl)-4-hydroxyaniline () (Table 2, Entry 16)10 Following general procedure III, (0.12 mL, 2.0 mmol) was used as the acid species and 4-aminophenol (0.218 g, 2.0 mmol) was used as the amine species. The reaction mixture was heated at reflux in 1.0 mL p-xylene. An 1H NMR of the crude reaction mixture showed 69 % conversion into N-(acetyl)-4-hydroxyaniline. Following general procedure IV, acetic acid (0.12 mL, 2.0 mmol) was used as the acid species and 4-aminophenol (0.218 g, 2.0 mmol) was used as the amine species. N- (Acetyl)-4-hydroxyaniline was recovered as a dark brown solid (0.266 g, 88 %) after filtration through a pad of celite, eluting with dichloromethane. 1 H NMR (300 MHz, DMSO-d6): δ = 1.99 (3H, s, C(O)CH3), 6.66 - 6.70 (2H, d, J = 8.75 Hz, Ph), 7.33 - 7.36 (2H, d, J = 8.75 Hz, Ph), 9.16 (1H, s, NH), 9.67 (1H, s, OH); 13C NMR (75 MHz, DMSO-d6): δ = 24.1, 115.3, 121.1, 131.4, 153.5, 167.8; ESI-MS + + + of [C8H9NO2] ; theoretical m/z of [M+H] = 152.071, measured m/z of [M+H] = 152.072. Electronic Supplementary Material (ESI) for Chemical Communications This journal is © The Royal Society of Chemistry 2011

N-(2-morpholinoethyl)-4-chlorobenzamide (Moclobemide) (Table 2, Entry 17)11 Following general procedure III, 4-chlorobenzoic acid (0.312 g, 2.0 mmol) was used as the acid species and benzylamine (0.22 mL, 2.0 mmol) was used as the amine species. The reaction mixture was heated at reflux in 1.0 mL p-xylene. An 1H NMR of the crude reaction mixture showed 66 % conversion into N-(2-morpholinoethyl)-4- chlorobenzamide. Following general procedure IV, 4-chlorobenzoic acid (0.313 g, 2.0 mmol) was used as the acid species and 2-(morpholino)ethylamine (0.26 mL, 2.0 mmol) was used as the amine species. N-(2-morpholinoethyl)-4-chlorobenzamide was recovered as an off white solid (0.462 g, 86 %) after filtration through a pad of silica, eluting with dichloromethane. 1 H NMR (300 MHz, CDCl3, 25 °C): δ = 2.54 – 2.58 (4H, t, J = 4.3 Hz, CH2NCH2),

2.63 – 2.68 (2H, t, J = 6.0 Hz, NCH2CH2), 3.56 – 3.62 (2H, q, J = 5.6 Hz,

NHCH2CH2), 3.76 – 3.79 (4H, t, J = 4.6 Hz, CH2OCH2), 6.83 (1H, br. s, NH), 7.43 – 7.47 (2H, d, J = 8.6 Hz, aromatic), 7.73 – 7.77 (2H, d, J = 8.6 Hz, aromatic). 13C

NMR (75.5 MHz, CDCl3, 25 °C): δ = 36.5, 53.6, 57.5, 67.1, 128.8, 129.2, 129.3, 133.4, 138.2, 166.7. IR: 1117.04, 1486.97, 1540.68, 1594.76, 1634.53, 2968.43, -1 + + 3285.8 cm . ESI-MS of [C13H18N2 O2Cl] ; theoretical m/z of [M+H] = 269.105, measured m/z of [M+H]+ = 269.104; IR: ν (cm-1) = 1634.53 (C=O stretch).

[N-(Benzyl)-N-methyl]-3-phenylpropionamide (Table S2, Entry 1)12 Following general procedure III, 3-phenylpropionic acid (0.150 g, 1.0 mmol) was used as the acid species and N-methylbenzylamine (0.13 mL, 1.0 mmol) was used as the amine species. [N-(Benzyl)-N-methyl]-3-phenylpropionamide was recovered as a yellow oil (0.241 g, 95 %) after removal of toluene. The product was observed as two rotamers in its 1H and 13C NMR spectra. Electronic Supplementary Material (ESI) for Chemical Communications This journal is © The Royal Society of Chemistry 2011

1 H NMR (250 MHz, CDCl3): δ = 2.72 - 2.77 (2H, t, J = 8.0 Hz, PhCH2CH2), 2.88

(1.8H, s, CH3 major rotamer), 2.99 (1.2H, s, CH3 minor rotamer), 3.01 - 3.07 (2H, t, J

= 8.0 Hz, PhCH2CH2), 4.50 (0.8H, s, N(CH3)CH2Ph, minor rotamer), 4.64 (1.2H, s, 13 N(CH3)CH2Ph, major rotamer), 7.23 - 7.36 (10H, m, 2xPh); C NMR (75 MHz,

CDCl3): δ = 31.4, 31.6, 35.4, 50.9, 126.1, 126.3, 127.3, 128.1, 128.5, 128.6, 128.9, + + 137.4, 141.3, 172.4; ESI-MS of [C17H20NO] ; theoretical m/z of [M+H] = 254.154, measured m/z of [M+H]+ =254.155. Following general procedure IV, 3-phenylpropionic acid (0.150 g, 1.0 mmol) was used as the acid species and N-methylbenzylamine (0.13 mL, 1.0 mmol) was used as the amine species. [N-(Benzyl)-N-methyl]-3-phenylpropionamide was recovered as a yellow oil (0.206 g, 81 %) after column chromatography (eluting with 98:2 dichloromethane:methanol). Analytical data was consistent with that above.

N-(Benzyl)- (Table S2, Entry 2)13 Following general procedure III, formic acid (0.06 mL, 1.0 mmol) was used as the acid species and benzylamine (0.11 mL, 1.0 mmol) was used as the amine species. N- (Benzyl)-formamide was recovered as a white solid (0.132 g, 89 %) after removal of toluene and recrystallisation (dichloromethane/hexane). The product was observed as 2 rotamers in its NMR spectra. 1 H NMR (300 MHz, CDCl3): δ = 4.29 - 4.31 (2H (minor rotamer), d, J = 6.3 Hz,

NHCH2Ph), 4.36 - 4.38 (2H (major rotamer), d, J = 6.3 Hz, NHCH2Ph), 6.11 (1H, br. s., NH), 7.18 - 7.25 (5H, m, Ph), 8.03 (1H (minor rotamer), s, HC(O)NH), 8.14 (1H 13 (major rotamer), s, HC(O)NH); C NMR (75 MHz, CDCl3): δ = 42.2 (major rotamer), 45.7 (minor rotamer), 126.9, 127.7, 127.8, 128.8, 128.9, 137.5 (major rotamer), 137.6 (minor rotamer), 161.1 (major rotamer), 164.7 (minor rotamer); ESI-MS of + + + [C8H10NOCl] ; theoretical m/z of [M+H] = 136.076, measured m/z of [M+H] = 136.078; IR: ν (cm-1) = 1649.88 cm-1 (C=O stretch). Following general procedure IV, formic acid (0.11 mL, 2.0 mmol) was used as the acid species and benzylamine (0.22 mL, 2.0 mmol) was used as the amine species. N- (Benzyl)-formamide was recovered as a white solid (0.251 g, 93 %) after filtration Electronic Supplementary Material (ESI) for Chemical Communications This journal is © The Royal Society of Chemistry 2011

through a pad of silica, eluting with dichloromethane. Analytical data was consistent with that above.

N-(Benzyl)-phenylacetamide (Table S2, Entry 3)5 Following general procedure III, phenylacetic acid (0.272 g, 2.0 mmol) was used as the acid species and benzylamine (0.22 mL, 2.0 mmol) was used as the amine species. N-(Benzyl)-phenylacetamide was recovered as a white solid (0.410 g, 91 %) after removal of toluene and recrystallization (dichloromethane/hexane). 1 H NMR (300 MHz, CDCl3): δ = 3.56 (2H, s, PhCH2C(O)), 4.33 – 4.35 (2H, d, J = 13 5.7 Hz, NHCH2Ph), 5.63 (1H, br. s., NH), 7.09 – 7.28 (10H, m, 2xPh); C NMR (75

MHz, CDCl3): δ = 43.6, 43.9, 127.5, 128.7, 129.1, 129.5, 134.8, 138.1, 170.9; ESI- + + + MS of [C15H16NO] ; theoretical m/z of [M+H] = 226.132, measured m/z of [M+H] = 226.133; IR: ν (cm-1) = 1636.35 cm-1 (C=O stretch). Following general procedure IV, phenylacetic acid (0.272 g, 2.0 mmol) was used as the acid species and benzylamine (0.22 mL, 2.0 mmol) was used as the amine species. N-(Benzyl)-phenylacetamide was recovered as a white solid (0.396 g, 88 %) after filtration through a pad of silica, eluting with dichloromethane. Analytical data was consistent with that above.

N-(Benzyl)-cinnamamide (Table S2, Entry 4)14 Following general procedure III, cinnamic acid (0.296 g, 2.0 mmol) was used as the acid species and benzylamine (0.22 mL, 2.0 mmol) was used as the amine species. The reaction was heated at reflux in 0.5 mL p-xylene. N-(Benzyl)-cinnamamide was recovered as an off-white solid (0.216 g, 91 %) after removal of p-xylene and recrystallization (dichloromethane/hexane). 1 H NMR (250 MHz, CDCl3): δ = 4.47 – 4.49 (2H, d, J = 5.75 Hz, NHCH2Ph), 6.05 (1H, br. s., NH), 6.33 – 6.39 (1H, d, J = 15.75 Hz, PhCHCHC(O)), 7.25 – 7.42 (10H, m, 2xPh), 7.56 – 7.62 (1H, d, J = 15.75 Hz, PhCHCHC(O)); 13C NMR (75 MHz,

CDCl3): δ = 42.3, 120.5, 127.6, 127.8, 127.9, 128.8, 129.7, 134.8, 138.2, 141.4, 165.8; Electronic Supplementary Material (ESI) for Chemical Communications This journal is © The Royal Society of Chemistry 2011

+ + ESI-MS of [C16H16NO] ; theoretical m/z of [M+H] = 238.131, measured m/z of [M+H]+ = 238.132; IR: ν (cm-1) = 1650.39 cm-1 (C=O stretch). Following general procedure IV, cinnamic acid (0.296 g, 2.0 mmol) was used as the acid species and benzylamine (0.22 mL, 2.0 mmol) was used as the amine species. An 1H NMR of the crude reaction mixture showed a 57 % conversion into N-(benzyl)-

cinnamamide when ZrCl4 was used as catalyst and 72 % conversion when ZrCp2Cl2 was used as catalyst. Analytical data was consistent with that above.

O I N Ph H

N-(Benzyl)-3-iodobenzamide (Table S2, Entry 5) Following general procedure III, 3-iodobenzoic acid (0.248 g, 1.0 mmol) was used as the acid species and benzylamine (0.11 mL, 1.0 mmol) was used as the amine species. The reaction mixture was heated at reflux in 0.5 mL p-xylene. An 1H NMR of the crude reaction mixture showed a 53% conversion into N-(benzyl)-benzamide. 1 H NMR (250 MHz, DMSO-d6): δ = 4.47 - 4.50 (2H, d, J = 5.75 Hz, PhCH2NH), 7.20 - 7.41 (6H, m, 2Ph), 8.24 - 8.27 (2H, d, J = 7.25 Hz, (m-I)Ph), 8.52 (1H, s, (m- + + I)Ph), 9.19 (br. s, 1H, NH), ESI-MS of [C14H13NOI] ; theoretical m/z of [M+H] = 238.131, measured m/z of [M+H]+ = 238.132. Following general procedure IV, 3-iodobenzoic acid (0.496 g, 2.0 mmol) was used as the acid species and benzylamine (0.22 mL, 2.0 mmol) was used as the amine species. 1 10 mol% ZrCl4 (0.046g) was used. An H NMR of the crude reaction mixture showed

27 % conversion into N-(benzyl)-3-iodobenzamide when ZrCl4 was used as catalyst. Analytical data was consistent with that shown above.

N-(Benzyl)-3-phenylpropionamide (Scale up example)11 Following general procedure V, (N-benzyl)-3-phenylpropionamide was recovered as a pale yellow solid (0.439 g, 92 %) after removal of toluene in vacuo. 1 H NMR (250 MHz, CDCl3): δ = 2.52 - 2.58 (t, 2H, J = 7.8 Hz, CH2CH2Ph), 3.00 -

3.06 (t, 2H, J = 7.8 Hz, CH2CH2Ph), 4.42 - 4.44 (d, 2H, J = 5.8 Hz, PhCH2NH), 5.68 Electronic Supplementary Material (ESI) for Chemical Communications This journal is © The Royal Society of Chemistry 2011

13 (br. s, 1H, NH), 7.16 - 7.35 (m, 10H, aromatic); C NMR (75 MHz, CDCl3): δ = 31.74, 38.54, 43.61, 126.28, 127.48, 127.77, 128.42, 128.58, 128.68, 138.17, 140.79, + + 171.89; ESI-MS of [C16H17NO] ; theoretical m/z of [M+H] = 240.139, measured m/z of [M+H]+ = 240.139; IR: ν (cm-1) = 1637.28 (C=O stretch).

Rate Study Results were obtained following general procedure VI.

Entry Time (h) Conversion (%) Conversion (%) Uncatalysed Catalysed 1 1 7 42 2 2 13 48 3 3 16 74 4 4 32 83 5 6 39 100

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Reversibility study:

Following general procedure VII, N-benzyl-4-chlorobenzamide (0.035 g, 0.15 mmol) was used as the secondary amide species. With no catalyst, no reaction was observed.

With ZrCl4 (0.0012 g, 5 mol%), 5% into 4-chlorobenzoic acid and benzylamine was observed.

Following general procedure VII, N-benzyl-3-phenylpropionic acid (0.024 g, 0.15 mmol) was used as the secondary amide species. No reaction was observed with or without the catalyst.

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References 1) A. J. A. Watson, A. C. Maxwell and J. M. J. Williams, Org. Lett., 2009, 11, 2667. 2) R. Ballini, G. Bosica, D. Fiorini, Tetrahedron, 2003, 59, 1143. 3) P.-C. Chiang, Y. Kim, J. W. Bode, Chem. Commun. 2009, 4566. 4) D. C. Johnson, T. S. Widlanski, Tetrahedron Lett., 2004, 45, 8483. 5) L. U. Nordstrom, H. Vogt, R. masden, J. Am. Chem. Soc, 2008, 130, 17672. 6) S. C. Ghosh, S. H. Hong, Eur. J. Org. Chem., 2010, 22, 4266. 7) A. R. Balaban, T.-S. Balaban, G. V. Boyd, Synthesis, 1987, 6, 577. 8) T. Sasaki, A. Kojima, M. Ohta, J. Chem. Soc. C, 1971, 196. 9) W.-J. Yoo, C.-J. Li, J. Am. Chem. Soc.,2006, 128, 13064. 10) H. Liu, X. Wang, Y. Gu, Org. Biomol. Chem., 2011, 9, 1614. 11) C. L. Allen, S. D. Davulcu, J. M. J. Williams, Org. Lett, 2010, 12, 5096. 12) C. Han, J. P. Lee, E. Lobkovsky, J. A. Porco, J. Am. Chem. Soc., 2005, 127, 10039. 13) Y. Wan, M. Alterman, M. Larhed, A. Hallberg, J. Org. Chem., 2002, 67, 6232. 14) L. J. Goossen, D. M. Ohlmann, P. P. Lange, Synthesis, 2009, 1, 160.

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1H NMR and 13C NMR Spectra

N-(4-Methylbenzyl)-3-phenylpropionamide (Table 2, Entry 1) 7.322 7.315 7.309 7.300 7.291 7.265 7.260 7.244 7.215 7.155 7.123 7.090 7.057 5.601 4.398 4.375 3.055 3.025 2.994 2.561 2.529 2.500 2.359 10.09 0.94 2.00 1.98 2.05 3.15

9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 ppm (t1) 171.768 140.825 137.205 135.126 129.341 128.564 128.410 127.794 126.256 43.382 38.569 31.742 21.092

200 150 100 50 0 ppm (t1) Electronic Supplementary Material (ESI) for Chemical Communications This journal is © The Royal Society of Chemistry 2011

N-(4-Methoxybenzyl)-3-phenylpropionamide (Table 2, Entry 2) 7.325 7.318 7.310 7.302 7.291 7.284 7.281 7.263 7.257 7.238 7.213 7.207 7.123 7.088 6.870 6.835 5.668 4.366 4.343 3.820 3.046 3.017 2.986 2.561 2.530 2.500 7.56 1.92 1.92 0.96 2.00 3.00 2.00

10.0 5.0 0.0 ppm (t1) 171.971 159.021 140.768 130.187 129.145 128.568 128.414 128.297 126.329 126.269 114.059 55.321 43.121 38.536 31.750

200 150 100 50 0 ppm (t1)

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N-(Pentyl)-3-phenylpropionamide (Table 1, Entry 3) 7.314 7.309 7.291 7.250 7.243 7.233 5.346 3.263 3.235 3.212 3.184 3.024 2.994 2.963 2.520 2.488 2.458 1.468 1.440 1.412 1.335 1.308 1.283 1.277 1.265 1.249 1.222 0.930 0.903 0.874 5.77 0.82 1.96 2.03 2.00 6.25 3.00

5.0 0.0 ppm (t1) 172.029 140.914 128.527 128.374 128.294 126.241 39.534 38.644 31.821 29.244 28.980 22.336 13.962

200 150 100 50 0 ppm (t1)

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N-(5-Methylfurfuryl)-3-phenylpropionamide (Table 2, Entry 4) 7.182 7.160 7.130 7.115 7.104 7.086 5.958 5.946 5.801 5.797 5.789 5.785 5.669 4.269 4.248 2.921 2.892 2.859 2.438 2.405 2.376 2.170 5.75 1.00 0.97 0.83 2.00 2.07 2.00 2.99

9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 ppm (t1)

171.809 151.881 149.310 140.833 128.525 128.354 126.220 108.302 106.273 38.377 36.633 31.632 13.529

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N-(Morpholino)-3-phenylpropionamide (Table 2, Entry 6) 7.221 7.198 7.189 7.161 7.157 7.144 7.133 3.551 3.455 3.438 3.417 3.300 3.279 3.262 2.941 2.912 2.879 2.574 2.541 2.512 4.08 1.96 2.00 2.26 1.94

7.0 6.0 5.0 4.0 3.0 2.0 1.0 ppm (t1)

170.890 141.055 128.562 128.494 126.292 66.796 66.435 45.945 41.937 34.758 31.492

150 100 50 0 ppm (t1)

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N-(Benzyl)-propionamide (Table 2, Entry 7) 7.228 7.200 7.183 7.157 7.143 7.127 7.118 5.599 5.595 4.320 4.301 2.155 2.130 2.105 2.079 1.078 1.053 1.027 5.30 0.93 2.00 1.98 2.97

9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0 ppm (t1) 173.947 138.791 129.114 128.233 127.911 44.017 30.114 10.250

200 150 100 50 0 ppm (t1)

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[N-(Benzyl)N’-Boc]-glycinamide (Table 2, Entry 8) 8.315 7.322 7.316 7.307 7.294 7.280 7.268 7.254 7.237 7.018 4.314 4.291 3.613 3.588 1.406 1.02 5.14 0.90 2.00 2.04 9.04

9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 ppm (t1) 169.396 155.802 139.391 128.146 127.114 126.669 78.015 43.355 41.951 28.154

200 150 100 50 0 ppm (t1)

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N-Benzylbenzamide (Table 2, Entry 9) 7.734 7.730 7.725 7.707 7.702 7.428 7.419 7.409 7.404 7.399 7.374 7.370 7.355 7.350 7.332 7.327 7.321 7.292 7.277 7.261 7.248 7.237 7.230 7.220 7.184 6.363 4.585 4.566 2.02 8.33 0.95 2.00

10.0 5.0 ppm (t1)

167.346 138.209 134.431 131.563 128.817 128.616 127.947 127.656 126.968 44.170

150 100 50 0 ppm (t1)

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N-(Benzyl)-4-fluorophenylacetamide (Table 2, Entry 10)

8.542 7.316 7.288 7.264 7.220 7.195 7.132 7.103 7.075 4.261 4.242 3.460 1.01 11.24 2.00 2.65

10.0 5.0 ppm (t1) 170.372 162.985 159.781 139.759 132.935 132.894 131.556 131.450 131.231 131.125 128.722 128.624 127.567 127.126 115.376 115.194 115.096 114.914 42.570 41.700

150 100 50 0 ppm (t1)

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N-(Benzyl)-4-methoxyphenylacetamide (Table 2, Entry 11) 8.468 7.368 7.333 7.308 7.282 7.259 7.212 7.188 7.160 7.122 6.855 6.827 4.244 4.225 3.704 3.380 0.87 9.83 2.14 2.00 3.41 2.20

9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 ppm (t1) 170.809 158.250 139.864 130.626 130.335 128.672 128.604 128.321 127.655 127.543 127.083 113.990 55.366 42.515 41.816

200 150 100 50 0 ppm (t1)

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3-Benzoyl-N-morpholinopropionamide (Table 2, Entry 12) 8.011 7.988 7.983 7.571 7.554 7.546 7.539 7.526 7.522 7.517 7.469 7.448 7.444 7.425 7.420 3.725 3.710 3.693 3.676 3.660 3.646 3.622 3.607 3.582 3.565 3.550 3.378 3.356 3.334 2.782 2.760 2.738 2.08 3.01 7.98 2.08 2.00

10.0 5.0 ppm (t1)

199.113 170.497 136.715 133.180 128.628 128.598 128.133 128.050 66.882 66.604 45.866 42.150 33.527 26.910

200 150 100 50 0 ppm (t1)

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(Table 2, Entry 13) 8.370 8.351 8.330 8.306 7.284 7.251 7.230 7.208 4.352 4.331 4.302 4.281 4.225 4.208 4.189 4.158 4.139 4.123 4.114 4.080 4.070 4.051 4.042 3.416 3.382 3.366 3.345 3.304 3.295 3.282 3.267 3.248 2.119 2.106 2.092 2.079 2.045 1.970 1.786 1.771 1.760 1.748 1.392 1.266

8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0 ppm (t1)

172.773 161.665 139.982 128.488 127.644 127.058 78.784 60.269 60.146 46.835 42.382 31.452 31.426 28.308 23.502

150 100 50 0 ppm (t1) Electronic Supplementary Material (ESI) for Chemical Communications This journal is © The Royal Society of Chemistry 2011

N-(Allyl)-cyanoacetamide (Table 2, Entry 14)8 6.297 5.836 5.817 5.802 5.798 5.783 5.779 5.774 5.760 5.750 5.745 5.741 5.726 5.716 5.707 5.204 5.200 5.195 5.161 5.157 5.153 5.148 5.143 5.137 5.123 5.119 5.104 5.099 3.886 3.882 3.877 3.867 3.863 3.858 3.848 3.843 3.339 0.85 1.00 2.19 1.94 1.88

5.0 0.0 ppm (t1)

160.781 133.475 132.814 117.584 42.677 25.842

200 150 100 50 0 ppm (t1) Electronic Supplementary Material (ESI) for Chemical Communications This journal is © The Royal Society of Chemistry 2011

N-(Phenylacetyl)-valine methyl ester (Table 2, Entry 15) 7.278 7.254 7.249 7.240 7.229 7.224 7.203 7.191 5.856 5.828 4.493 4.477 4.464 4.448 3.630 3.557 3.552 2.075 2.052 2.036 2.029 2.013 2.006 1.990 1.967 0.789 0.766 0.694 0.671 0.95 1.00 3.01 2.12 1.13 3.21 3.13

7.0 6.0 5.0 4.0 3.0 2.0 1.0 ppm (t1) 172.410 170.996 134.639 129.395 129.036 128.589 127.458 56.985 52.178 43.711 31.191 18.895 17.585

150 100 50 0 ppm (t1) Electronic Supplementary Material (ESI) for Chemical Communications This journal is © The Royal Society of Chemistry 2011

Paracetamol (Table 2, Entry 16) 9.673 9.158 7.363 7.328 6.698 6.663 1.987 0.90 0.88 2.00 1.98 2.95

10.0 5.0 0.0 ppm (t1)

167.839 153.455 131.383 121.119 115.315 24.077

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Moclobemide (Table 2, Entry 17) 7.792 7.764 7.406 7.377 3.525 3.509 3.494 3.450 3.428 3.410 3.388 2.708 2.480 2.458 2.436 2.381 2.366 2.351 2.00 2.04 4.16 2.21 1.07 2.18 4.14

8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 ppm (t1) 166.764 138.108 129.331 129.243 129.205 128.820 67.096 57.394 53.693 36.253

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[N-(Benzyl)-N-methyl]-3-phenylpropionamide (Table S2, Entry 1) 7.357 7.349 7.330 7.317 7.307 7.291 7.271 7.256 7.246 7.231 4.641 4.497 3.075 3.043 3.012 2.994 2.882 2.768 2.734 2.718 11.75 1.22 0.78 3.18 1.81 2.17

10.0 5.0 0.0 ppm (t1) 172.351 141.386 137.359 128.932 128.583 128.537 128.491 128.064 127.335 126.261 126.149 50.910 35.405 31.578 31.409

200 150 100 50 0 ppm (t1)

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N-(Benzyl)-formamide (Table S2, Entry 2) 8.135 7.251 7.232 7.204 7.183 6.114 6.110 4.381 4.361 4.311 4.290 0.97 5.05 0.91 2.00

9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 ppm (t1) 164.728 161.116 137.629 137.519 128.935 128.777 127.784 127.672 126.986 45.670 42.158

150 100 50 ppm (t1)

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N-(Benzyl)-phenylacetamide (Table S2, Entry 3) 7.276 7.253 7.226 7.210 7.202 7.186 7.170 7.113 7.090 5.631 5.628 4.350 4.331 3.560 11.97 0.91 2.00 2.09

9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 ppm (t1)

170.921 138.111 134.758 129.482 129.094 128.679 127.499 127.456 43.856 43.614

200 150 100 50 0 ppm (t1) Electronic Supplementary Material (ESI) for Chemical Communications This journal is © The Royal Society of Chemistry 2011

N-(Benzyl)-cinnamamide (Table S2, Entry 4) 7.624 7.561 7.423 7.409 7.404 7.394 7.385 7.376 7.289 7.280 7.266 7.254 7.245 6.389 6.326 6.047 4.494 4.471 1.15 10.80 1.00 0.93 2.00

8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 ppm (t1) 165.831 141.415 138.221 134.804 129.734 128.835 128.769 127.936 127.826 127.597 120.482 43.882

150 100 50 ppm (t1)

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N-(Benzyl)-3-phenylpropanamide (Scale up procedure). 7.353 7.349 7.343 7.333 7.326 7.312 7.305 7.298 7.291 7.286 7.265 7.260 7.246 7.235 7.218 7.193 7.183 7.162 5.686 5.683 4.441 4.418 3.061 3.032 3.000 2.578 2.547 2.517 11.30 0.96 2.00 2.14 1.92

9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 ppm (t1)

171.890 140.789 138.169 128.679 128.578 128.423 127.767 127.478 126.279 43.611 38.543 31.741

150 100 50 0 ppm (t1)