direct amide formation from unactivated carboxylic acids ... · pdf filedirect amide formation...

Direct amide formation from unactivated carboxylic acids and amines

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

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

Materials and Methods

All reactions requiring an anhydrous, inert atmosphere were carried out under a

nitrogen 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 ninhydrin 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.

1H NMR / 13C 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 water:acetonitrile 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.


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 acid (1.0 mmol) was added to an oven dried Radleys carousel tube,

followed by the appropriate amine (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


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

spectrometry data.

IV. Zirconium catalyzed coupling of carboxylic acids and amines: The carboxylic

acid 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


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

NH

O

PhOH

Solvent

110 oC, 20 hPh TolH2N Tol

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


Table S2 Additional examples of substrates

Entry Amide Conversion

(%)a

neat

Conversion

(%)a

in toluene

Catalyst Time

(h)

Conversion

(%)a

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 56 (150 oC)b

32 100 (91) (150 oC)b

ZrCl4

18

57

5 0 45 (150 oC) b

0 53 (150 oC) b

ZrCl4 24

27

a Determined by 1H NMR spectroscopy, isolated yields shown in parentheses where

appropriate; b Reaction at 150 oC were run on xylenes.


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). 1H 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

Hz, NHCH2(4-Me)Ph), 7.06 – 7.32 (9H, m, 2xPh); 13C 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


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).


1H 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).


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


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. 1H 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),

5.35 (1H, br. s., NH), 7.23 - 7.31 (5H, m, Ph); 13C 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.


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.


N-(5-Methylfurfuryl)-3-phenylpropionamide (Table 2, Entry 4)


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. 1H 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,

Furyl), 7.09 - 7.18 (5H, m, Ph); 13C 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.


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


used as the acid species and aniline (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. 1H 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).



used as the acid species and aniline (0.17 mL, 2.0 mmol) was used as the amine

species. 10 mol% ZrCl4 (0.046g) was used. An 1H 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.


N-(Morpholino)-3-phenylpropionamide (Table 2, Entry 6)1


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. 1H 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,

J = 6.3 Hz), 3.55 (s, 4H), 7.13 - 7.22 (m, 5H, Ph); 13C 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).



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.


N-(Benzyl)-propionamide (Table 2, Entry 7)4

Following general procedure III, 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 (0.293 g, 90 %) removal of

toluene and recrystallisation (dichloromethane/hexane). 1H 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 –

7.22 (5H, m, aromatic); 13C 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


(Benzyl)-propionamide was recovered as a white solid (0.264 g, 81%) after filtration


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. 1H 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.


N-(Benzyl)-benzamide (Table 2, Entry 9)5

Following general procedure III, benzoic acid (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.

1H 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

mol% ZrCl4 (0.046g) was used. An 1H 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). 13C 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. 1H NMR (300 MHz, DMSO-d6): δ = 3.46 (2H, s, CH2C(O)), 4.24 – 4.26 (2H, d, J =

6.0 Hz, NHCH2Ph), 7.08 – 7.32 (9H, m, 2xPh), 8.54 (1H, br. s., NH); 13C NMR (75


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). 1H 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.


3-Benzoyl-N-morpholinopropionic acid (Table 2, Entry 12)7

Following general procedure III, 3-benzoylpropionic acid (0.178 g, 1.0 mmol) was


species. 3-Benzoyl-N-morpholinopropionamide was recovered as a dark yellow oil

(0.193 g, 78 %) after removal of toluene and recrystallization

(dichloromethane/hexane). 1H 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


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.


[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


[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,


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

[M+H]+ = 305.148; IR: ν (cm-1) = 1675.75 cm-1 (C=O stretch, amide); [α]D25 = 80.3o

(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)-cyanoacetamide (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. 1H 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,

NHCH2CHCH2), 6.29 (1H, br. s., NH); 13C 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).


N-(Phenylacetyl)-valine methyl ester (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)


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 base. 1H 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),

7.19 – 7.28 (5H, m, Ph); 13C 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 (Paracetamol) (Table 2, Entry 16)10

Following general procedure III, 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. 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. 1H 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.


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. 1H 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,

3285.8 cm-1. 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


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.


1H 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,

N(CH3)CH2Ph, major rotamer), 7.23 - 7.36 (10H, m, 2xPh); 13C 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.


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)-formamide (Table S2, Entry 2)13

Following general procedure III, formic acid (0.06 mL, 1.0 mmol) was used as the


(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. 1H 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

(major rotamer), s, HC(O)NH); 13C 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


(Benzyl)-formamide was recovered as a white solid (0.251 g, 93 %) after filtration



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


N-(Benzyl)-phenylacetamide was recovered as a white solid (0.410 g, 91 %) after

removal of toluene and recrystallization (dichloromethane/hexane). 1H NMR (300 MHz, CDCl3): δ = 3.56 (2H, s, PhCH2C(O)), 4.33 – 4.35 (2H, d, J =

5.7 Hz, NHCH2Ph), 5.63 (1H, br. s., NH), 7.09 – 7.28 (10H, m, 2xPh); 13C 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


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


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). 1H 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;


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


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.

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 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.

1H 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


10 mol% ZrCl4 (0.046g) was used. An 1H 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. 1H 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

NH

O

PhI


(br. s, 1H, NH), 7.16 - 7.35 (m, 10H, aromatic); 13C 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 (%)

Uncatalysed

Conversion (%)

Catalysed

1 1 7 42

2 2 13 48

3 3 16 74

4 4 32 83

5 6 39 100


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% hydrolysis 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.


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.


1H NMR and 13C NMR Spectra

N-(4-Methylbenzyl)-3-phenylpropionamide (Table 2, Entry 1)

ppm (t1)1.02.03.04.05.06.07.08.09.0

7.32

27.

315

7.30

97.

300

7.29

1

7.26

57.

260

7.24

4

7.21

5

7.15

5

7.12

3

7.09

0

7.05

7

5.60

1

4.39

84.

375

3.05

5

3.02

5

2.99

42.

561

2.52

9

2.50

0

2.35

9

2.00

2.05

3.15

1.98

0.94

10.09

ppm (t1)050100150200

171.

768

140.

825

137.

205

135.

126

129.

341

128.

564

128.

410

127.

794

126.

256

43.3

8238

.569

31.7

42

21.0

92


N-(4-Methoxybenzyl)-3-phenylpropionamide (Table 2, Entry 2)

ppm (t1)0.05.010.0

7.32

57.

318

7.31

07.

302

7.29

17.

284

7.28

17.

263

7.25

77.

238

7.21

37.

207

7.12

3

7.08

8

6.87

0

6.83

55.

668

4.36

64.

343

3.82

0

3.04

63.

017

2.98

6

2.56

1

2.53

02.

500

2.00

3.00

2.00

0.96

1.92

1.927.56

ppm (t1)050100150200

171.

971

159.

021

140.

768

130.

187

129.

145

128.

568

128.

414

128.

297

126.

329

126.

269

114.

059

55.3

21

43.1

2138

.536

31.7

50


N-(Pentyl)-3-phenylpropionamide (Table 1, Entry 3)

ppm (t1)0.05.0

7.31

47.

309

7.29

1

7.25

07.

243

7.23

3

5.34

6

3.26

33.

235

3.21

23.

184

3.02

42.

994

2.96

3

2.52

0

2.48

82.

458

1.46

81.

440

1.41

2

1.33

51.

308

1.28

31.

277

1.26

51.

249

1.22

20.

930

0.90

30.

874

2.03

3.00

6.25

5.77

0.82

2.00

1.96

ppm (t1)050100150200

172.

029

140.

914

128.

527

128.

374

128.

294

126.

241

39.5

34

38.6

44

31.8

21

29.2

4428

.980

22.3

36

13.9

62


N-(5-Methylfurfuryl)-3-phenylpropionamide (Table 2, Entry 4)

ppm (t1)1.02.03.04.05.06.07.08.09.0

7.18

27.

160

7.13

07.

115

7.10

47.

086

5.95

85.

946

5.80

15.

797

5.78

95.

785

5.66

9

4.26

94.

248

2.92

1

2.89

2

2.85

9

2.43

8

2.40

5

2.37

6

2.17

0

2.00

2.07

2.00

2.99

0.83

1.000.97

5.75

ppm (t1)050100150200

171.

809

151.

881

149.

310

140.

833

128.

525

128.

354

126.

220

108.

302

106.

273

38.3

77

36.6

33

31.6

32

13.5

29


N-(Morpholino)-3-phenylpropionamide (Table 2, Entry 6)

ppm (t1)1.02.03.04.05.06.07.0

7.22

17.

198

7.18

9

7.16

17.

157

7.14

47.

133

3.55

1

3.45

53.

438

3.41

7

3.30

03.

279

3.26

2

2.94

1

2.91

2

2.87

9

2.57

4

2.54

1

2.51

2

2.001.964.08

1.94

2.26

ppm (t1)050100150

170.

890

141.

055

128.

562

128.

494

126.

292

66.7

9666

.435

45.9

45

41.9

37

34.7

58

31.4

92


N-(Benzyl)-propionamide (Table 2, Entry 7)

ppm (t1)0.01.02.03.04.05.06.07.08.09.0

7.22

8

7.20

07.

183

7.15

77.

143

7.12

77.

118

5.59

95.

595

4.32

04.

301

2.15

5

2.13

0

2.10

5

2.07

9

1.07

8

1.05

3

1.02

7

2.00

1.98

2.97

5.30

0.93

ppm (t1)050100150200

173.

947

138.

791

129.

114

128.

233

127.

911

44.0

17

30.1

14

10.2

50


[N-(Benzyl)N’-Boc]-glycinamide (Table 2, Entry 8)

ppm (t1)1.02.03.04.05.06.07.08.09.0

8.31

5

7.32

27.

316

7.30

77.

294

7.28

07.

268

7.25

47.

237

7.01

8

4.31

44.

291

3.61

33.

588

1.40

6

2.00

1.02

0.90

5.14

9.04

2.04

ppm (t1)050100150200

169.

396

155.

802

139.

391

128.

146

127.

114

126.

669

78.0

15

43.3

55

41.9

51

28.1

54


N-Benzylbenzamide (Table 2, Entry 9)

ppm (t1)5.010.0

7.73

47.

730

7.72

57.

707

7.70

27.

428

7.41

97.

409

7.40

47.

399

7.37

47.

370

7.35

57.

350

7.33

27.

327

7.32

1

7.29

27.

277

7.26

17.

248

7.23

77.

230

7.22

0

7.18

4

6.36

3

4.58

54.

566

2.00

0.95

2.02

8.33

ppm (t1)050100150

167.

346

138.

209

134.

431

131.

563

128.

817

128.

616

127.

947

127.

656

126.

968

44.1

70


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

ppm (t1)5.010.0

8.54

2

7.31

6

7.28

8

7.26

4

7.22

0

7.19

5

7.13

2

7.10

3

7.07

5

4.26

14.

242

3.46

0

2.00

2.65

1.01

11.24

ppm (t1)050100150

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

42.5

70

41.7

00


N-(Benzyl)-4-methoxyphenylacetamide (Table 2, Entry 11)

ppm (t1)1.02.03.04.05.06.07.08.09.0

8.46

8

7.36

8

7.33

3

7.30

8

7.28

2

7.25

9

7.21

2

7.18

8

7.16

0

7.12

26.

855

6.82

7

4.24

44.

225

3.70

4

3.38

0

2.00

0.87

9.83

2.14

3.41

2.20

ppm (t1)050100150200

170.

809

158.

250

139.

864

130.

626

130.

335

128.

672

128.

604

128.

321

127.

655

127.

543

127.

083

113.

990

55.3

66

42.5

15

41.8

16


3-Benzoyl-N-morpholinopropionamide (Table 2, Entry 12)

ppm (t1)5.010.0

8.01

1

7.98

87.

983

7.57

17.

554

7.54

67.

539

7.52

67.

522

7.51

7

7.46

97.

448

7.44

47.

425

7.42

0

3.72

53.

710

3.69

33.

676

3.66

03.

646

3.62

23.

607

3.58

23.

565

3.55

0

3.37

83.

356

3.33

4

2.78

22.

760

2.73

8

2.00

2.08

7.98

3.01

2.08

ppm (t1)050100150200

199.

113

170.

497

136.

715

133.

180

128.

628

128.

598

128.

133

128.

050

66.8

8266

.604

45.8

66

42.1

50

33.5

27

26.9

10


(Table 2, Entry 13)

ppm (t1)0.01.02.03.04.05.06.07.08.0

8.37

08.

351

8.33

0

8.30

6

7.28

4

7.25

17.

230

7.20

8

4.35

24.

331

4.30

24.

281

4.22

54.

208

4.18

9

4.15

84.

139

4.12

34.

114

4.08

04.

070

4.05

14.

042

3.41

6

3.38

23.

366

3.34

5

3.30

43.

295

3.28

23.

267

3.24

82.

119

2.10

62.

092

2.07

9

2.04

5

1.97

0

1.78

61.

771

1.76

01.

748

1.39

2

1.26

6

ppm (t1)050100150

172.

773

161.

665

139.

982

128.

488

127.

644

127.

058

78.7

84

60.2

6960

.146

46.8

35

42.3

82

31.4

5231

.426

28.3

08

23.5

02


N-(Allyl)-cyanoacetamide (Table 2, Entry 14)8

ppm (t1)0.05.0

6.29

7

5.83

65.

817

5.80

25.

798

5.78

35.

779

5.77

45.

760

5.75

05.

745

5.74

15.

726

5.71

65.

707

5.20

45.

200

5.19

5

5.16

15.

157

5.15

35.

148

5.14

35.

137

5.12

35.

119

5.10

45.

099

3.88

63.

882

3.87

73.

867

3.86

33.

858

3.84

83.

843

3.33

9

0.85

1.00

2.19

1.94

1.88

ppm (t1)050100150200

160.

781

133.

475

132.

814

117.

584

42.6

77

25.8

42


N-(Phenylacetyl)-valine methyl ester (Table 2, Entry 15)

ppm (t1)1.02.03.04.05.06.07.0

7.27

8

7.25

47.

249

7.24

07.

229

7.22

4

7.20

37.

191

5.85

6

5.82

8

4.49

34.

477

4.46

44.

448

3.63

03.

557

3.55

2

2.07

5

2.05

22.

036

2.02

92.

013

2.00

61.

990

1.96

7

0.78

9

0.76

60.

694

0.67

1

1.00

0.95

3.213.13

1.13

3.012.12

ppm (t1)050100150

172.

410

170.

996

134.

639

129.

395

129.

036

128.

589

127.

458

56.9

85

52.1

78

43.7

11

31.1

91

18.8

95

17.5

85


Paracetamol (Table 2, Entry 16)

ppm (t1)0.05.010.0

9.67

3

9.15

8

7.36

3

7.32

8

6.69

8

6.66

3

1.98

7

2.00

1.98

0.90

2.95

0.88

ppm (t1)50100150

167.

839

153.

455

131.

383

121.

119

115.

315

24.0

77


Moclobemide (Table 2, Entry 17)

ppm (t1)1.02.03.04.05.06.07.08.0

7.79

2

7.76

4

7.40

6

7.37

7

3.52

53.

509

3.49

4

3.45

03.

428

3.41

03.

388

2.70

8

2.48

02.

458

2.43

6

2.38

12.

366

2.35

1

2.00

1.07

4.162.21

2.184.14

2.04

ppm (t1)050100150200

166.

764

138.

108

129.

331

129.

243

129.

205

128.

820

67.0

96

57.3

9453

.693

36.2

53


[N-(Benzyl)-N-methyl]-3-phenylpropionamide (Table S2, Entry 1)

ppm (t1)0.05.010.0

7.35

77.

349

7.33

07.

317

7.30

77.

291

7.27

17.

256

7.24

67.

231

4.64

1

4.49

7

3.07

53.

043

3.01

22.

994

2.88

22.

768

2.73

42.

718

11.75

0.781.22

1.812.17

3.18

ppm (t1)050100150200

172.

351

141.

386

137.

359

128.

932

128.

583

128.

537

128.

491

128.

064

127.

335

126.

261

126.

149

50.9

10

35.4

05

31.5

7831

.409


N-(Benzyl)-formamide (Table S2, Entry 2)

ppm (t1)1.02.03.04.05.06.07.08.09.0

8.13

5

7.25

17.

232

7.20

47.

183

6.11

46.

110

4.38

14.

361

4.31

14.

290

2.00

0.91

5.05

0.97

ppm (t1)50100150

164.

728

161.

116

137.

629

137.

519

128.

935

128.

777

127.

784

127.

672

126.

986

45.6

7042

.158


N-(Benzyl)-phenylacetamide (Table S2, Entry 3)

ppm (t1)1.02.03.04.05.06.07.08.09.0

7.27

6

7.25

3

7.22

67.

210

7.20

27.

186

7.17

0

7.11

3

7.09

0

5.63

15.

628

4.35

04.

331

3.56

0

2.00

2.09

0.91

11.97

ppm (t1)050100150200

170.

921

138.

111

134.

758

129.

482

129.

094

128.

679

127.

499

127.

456

43.8

5643

.614


N-(Benzyl)-cinnamamide (Table S2, Entry 4)

ppm (t1)1.02.03.04.05.06.07.08.0

7.62

4

7.56

17.

423

7.40

97.

404

7.39

47.

385

7.37

67.

289

7.28

07.

266

7.25

47.

245

6.38

9

6.32

66.

047

4.49

4

4.47

1

2.00

1.00

0.93

10.80

1.15

ppm (t1)50100150

165.

831

141.

415

138.

221

134.

804

129.

734

128.

835

128.

769

127.

936

127.

826

127.

597

120.

482

43.8

82


N-(Benzyl)-3-phenylpropanamide (Scale up procedure).

ppm (t1)1.02.03.04.05.06.07.08.09.0

7.35

37.

349

7.34

37.

333

7.32

67.

312

7.30

57.

298

7.29

17.

286

7.26

57.

260

7.24

67.

235

7.21

87.

193

7.18

37.

162

5.68

65.

683

4.44

14.

418

3.06

1

3.03

2

3.00

0

2.57

8

2.54

7

2.51

7

2.00

0.96

1.92

2.14

11.30

ppm (t1)050100150

171.

890

140.

789

138.

169

128.

679

128.

578

128.

423

127.

767

127.

478

126.

279

43.6

11

38.5

43

31.7

41


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