Direct amide formation from unactivated carboxylic acids ... · PDF fileDirect amide formation...
Transcript of 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
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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.
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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 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
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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
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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
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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.
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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). 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
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).
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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).
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. 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.
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. 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.
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 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).
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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
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.
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. 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).
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, 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-
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(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
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. 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.
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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
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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.
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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). 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
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,
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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).
Analytical data was consistent with that above.
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)
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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.
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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
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.
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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.
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)-formamide (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. 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
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
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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). 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
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). 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;
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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.
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.
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
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
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
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(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
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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% 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.
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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.
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Electronic Supplementary Material (ESI) for Chemical CommunicationsThis journal is © The Royal Society of Chemistry 2011
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
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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
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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
Electronic Supplementary Material (ESI) for Chemical CommunicationsThis journal is © The Royal Society of Chemistry 2011
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
Electronic Supplementary Material (ESI) for Chemical CommunicationsThis journal is © The Royal Society of Chemistry 2011
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
Electronic Supplementary Material (ESI) for Chemical CommunicationsThis journal is © The Royal Society of Chemistry 2011
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
Electronic Supplementary Material (ESI) for Chemical CommunicationsThis journal is © The Royal Society of Chemistry 2011
[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
Electronic Supplementary Material (ESI) for Chemical CommunicationsThis journal is © The Royal Society of Chemistry 2011
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
Electronic Supplementary Material (ESI) for Chemical CommunicationsThis journal is © The Royal Society of Chemistry 2011
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
Electronic Supplementary Material (ESI) for Chemical CommunicationsThis journal is © The Royal Society of Chemistry 2011
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
Electronic Supplementary Material (ESI) for Chemical CommunicationsThis journal is © The Royal Society of Chemistry 2011
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
Electronic Supplementary Material (ESI) for Chemical CommunicationsThis journal is © The Royal Society of Chemistry 2011
(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
Electronic Supplementary Material (ESI) for Chemical CommunicationsThis journal is © The Royal Society of Chemistry 2011
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
Electronic Supplementary Material (ESI) for Chemical CommunicationsThis journal is © The Royal Society of Chemistry 2011
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
Electronic Supplementary Material (ESI) for Chemical CommunicationsThis journal is © The Royal Society of Chemistry 2011
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
Electronic Supplementary Material (ESI) for Chemical CommunicationsThis journal is © The Royal Society of Chemistry 2011
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
Electronic Supplementary Material (ESI) for Chemical CommunicationsThis journal is © The Royal Society of Chemistry 2011
[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
Electronic Supplementary Material (ESI) for Chemical CommunicationsThis journal is © The Royal Society of Chemistry 2011
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
Electronic Supplementary Material (ESI) for Chemical CommunicationsThis journal is © The Royal Society of Chemistry 2011
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
Electronic Supplementary Material (ESI) for Chemical CommunicationsThis journal is © The Royal Society of Chemistry 2011
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
Electronic Supplementary Material (ESI) for Chemical CommunicationsThis journal is © The Royal Society of Chemistry 2011
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
Electronic Supplementary Material (ESI) for Chemical CommunicationsThis journal is © The Royal Society of Chemistry 2011