Direct amide formation using radiofrequency heating

Article abstract of DOI:10.1039/c2ob26930a

We present a simple method for direct and solvent-free formation of amides from carboxylic acids and amines using radiofrequency heating. The direct energy coupling of the AC magnetic field via nickel ferrite magnetic nanoparticles enables fast and controllable heating, as well as enabling facile work-up via magnetic separation.

Full text of DOI:10.1039/c2ob26930a

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Direct amide formation using radiofrequency heating†
Cite this: DOI: 10.1039/c2ob26930a
Thomas K. Houlding, Kirill Tchabanenko, Md. Taifur Rahman and Evgeny V. Rebrov*
Received 1st October 2012,
We present a simple method for direct and solvent-free formation of amides from carboxylic acids and
amines using radiofrequency heating. The direct energy coupling of the AC magnetic field via nickel
ferrite magnetic nanoparticles enables fast and controllable heating, as well as enabling facile work-up
via magnetic separation.
Accepted 7th November 2012
DOI: 10.1039/c2ob26930a
www.rsc.org/obc
efficient recyclability of the heat source via magnetic
separation.
1 Introduction
Amide bond formation ranks as one of the most important
chemical transformations and is of crucial importance for the
pharmaceutical industry.1,2 Of all the routes available to the
synthetic chemist3,4 the direct coupling of an amine and a car-
boxylic acid, yielding water as the only by product (Fig. 1), is
the most desirable due to its simplicity and high atom-
efficiency. Due to the stable nature of the salts initially formed
by the substrates, high temperatures of over 160 °C5–8 or long
reaction times9–11 are required to allow the reaction to occur
spontaneously. The two methods that can be employed to over-
come this issue are (1) high temperature, possibly solvent-free
conditions using i.e. microwave heating;12,13 (2) use of a cata-
lyst; or a combination thereof.14 To date published catalysts
2 Results and discussion
2.1 Optimisation
Optimisation of the reaction conditions was carried out using
benzylamine (BnNH2) and 4-phenylbutyric acid (PBA) as sub-
strates (reaction 1, Table 2). Nickel ferrite nanoparticles syn-
thesised according to methods reported elsewhere28 were used
as the heat source. The as-synthesised ferrite was calcined for
4 hours at 973 K to obtain magnetic properties well suited to
generate high temperatures under RF heating. In a typical
experiment 100 mg of ferrite and 1 mmol of each starting
material were loaded into a test tube equipped with a fibre
optic temperature probe, and placed inside an RF coil (Fig. 2).
The extent of the reactions was monitored by NMR analysis of
the crude reaction mixtures. On completion of the reactions,
ethyl acetate was added to the still warm reaction mixtures to
avoid crystallisations, and the ferrite was removed by magnetic
separation. After 8 iterative runs the amount of ferrite lost was
minimal at 5% and the RF heating capability of the ferrite was
include enzymes,15 boronic acids and esters,9,10,16,17 Lewis
18,19
acidic metal salts such as ZrCl4
and heterogeneous cata-
lysts such as hydrophobic silica20 and supported Lewis
acids.14,21–23
In this paper we present radiofrequency (RF) heating as an
alternative method of energy transfer to chemical transform-
ations, applied to amide bond formation. RF heating employs
the coupling of AC magnetic fields to dedicated RF absorbing
magnetic materials to generate large amounts of heat locally
within a chemical reactor.24 This method has recently been
applied by the group of Kirschning to many chemical trans-
formations, both stoichiometric and catalytic.25–27 By careful
selection of the combination of equipment and RF absorbing
material we have achieved the high temperatures necessary to
drive the direct formation of amides from amines and car-
boxylic acids in solvent-free conditions. Added benefits of the
developed method are ease of product isolation and facile and
Fig. 1 Direct amide bond formation from carboxylic acids and amines.
School of Chemistry & Chemical Engineering, Queens University Belfast, Stranmillis
Road, Belfast, BT9 5AG, UK. E-mail: e.rebrov@qub.ac.uk
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c2ob26930a
Fig. 2 Schematic representation of the experimental setup.
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Table 1 Effect of RF field parameters on heating rate and amine conversion
after 5 minutes
5-turn (287 kHz)
4-turn (312 kHz)
Coil (frequency)
RF current
200 A
250 A
200 A
250 A
Time to 200 °C (s)
Amine conversion (%)
226
87
72
95
140
89
53
96
reach 200 °C. Subsequently an increase in amine conversion
was observed. Increasing the frequency had a smaller effect on
amine conversion. Modifying the RF current is a more effective
and operationally more facile way of optimising the RF field
parameters.
2.2 Substrate scope
Multiple substrates were used to test the versatility of the RF
heating method (Table 2). Isobutyric, benzoic and substituted
benzoic acids 2–6 gave high yields comparable to the opti-
mised 4-phenylbutyric acid 1 when reacted with benzylamine.
Aniline 7 gave a distinctively lower yield due to its lower intrin-
sic reactivity. The conversion of the starting materials in this
case was only around 60% and isolation of the product
required column chromatography. Slightly better yield was
achieved in the reaction of 4-aminophenol producing paraceta-
mol as the isolated product 14. The method also works very
well with secondary amines such as morpholine and pyrroli-
▲
Fig. 3 (a) Reaction temperature and amine conversion ( , NMR) as a function
of reaction time, conditions: 100 mg ferrite, 1 mmol PBA and BnNH2, RF 200
□
▲
A@287 kHz; (b) final reaction temperature ( ) and amine conversion ( , NMR)
as a function of the amount of ferrite, conditions: 5 minutes, 1 mmol PBA and
BnNH2, RF 200 A@287 kHz.
not compromised. Hence no regeneration step was necessary. dine 8–10, while piperazine gave a high yield of a symmetric
Less than 1.5 g of nickel ferrite was used for the entire study, dibenzamide on treatment with two equivalents of benzoic
most of which was retained. Analytically pure products were acid 11. The chiral methylbenzylamine 13 showed similar
obtained either by direct crystallisation on addition of pet- yields to benzylamine. Purification of the product via crystalli-
roleum ether to the ethyl acetate solutions (for the solid amide sation gave highly enantiomerically pure material.
products) or by filtration through a short plug of silica and
elution with 2 : 1 ethyl acetate–petroleum ether and evapor- glycine and proline were also tested 15–18. Owing to their
ation for oils. greater stability the Cbz protected substrates gave higher
Protected amino acids in the form of Cbz and Boc protected
In Fig. 3a a typical temperature profile is shown for a reac- yields. Overall however the yields were not high, presumably
tion carried out at the given reaction conditions, along with due to decomposition of either the substrates or products. The
the conversions for different respective reaction times. After an products were formed as single diastereoisomers showing no
initial delay of approximately two minutes the mixture reached epimerisation at the α-stereogenic centre of the amino acids.
a temperature (100 °C) above which the reaction proceeded Separation of the products in these cases required column
and a conversion of 80% was reached after a further three chromatography.
minutes. After a total of eight minutes the conversion ceased
to increase above 92%. In Fig. 3b we show the relation between
2.3 Scale-up
the amount of ferrite, reaction temperature and amine conver-
sion. A purely thermal effect was observed for a fixed amount
of reactants and a fixed 5 min of RF heating time: in other
words the amount of ferrite proportionally influences the reac-
tion temperature, which in turn determines the amine conver-
sion. The optimal amount of ferrite lies between the
minimum needed to create reflux conditions (80 mg) and the
limit set by safety concerns due to overheating.
Reaction 1 was scaled from 1 up to 2 and 5 mmol (Table 3). At
all three scales the reaction went to near completion, with
high isolated yields of over 90%. Most notably the amount of
ferrite only needed to be scaled three times when the amount
of substrate was scaled fivefold in order to obtain similar
heating behaviour and product yields.
2.4 Synthesis of diamide 19
The effect of the RF field parameters, field strength and fre-
quency, was also investigated (Table 1). The field strength is
proportional to the electrical current applied to the coil. As a
consequence an increase of the RF current resulted in a dra-
matic decrease in the time needed for the reaction mixture to
Finally we demonstrated the applicability of our method in the
synthesis of more complex molecules. The synthesis of an
unsymmetrically substituted piperazine diamide 19 (Fig. 4)
was chosen, requiring two independent amidation steps. First
we prepared the monobenzamide 18 by treatment of
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Table 2 Substrates used for solvent-free amide synthesis using RF heatinga
Carboxylic acid
Amine
Reaction time (min)
10
Isolated yield (%)
94
Purification methodb
A
1
2
15
10
91
94
B
A
3
4
10
10
15
20
10
10
10
92
87
86
49
91
87
95
A
A
A
C
B
B
A
5
6
7
8
9
10
11c
12
10
10
96d
A
A
96 (e.e. > 99%)
13
14
15
16
10
10
10
10
51
C
C
C
C
52
60
43 (d.e. > 99%)
17
10
58 (d.e. > 99%)
C
a Conditions: RF 200 A@287 kHz; 100 mg nickel ferrite. b Purification methods: A = direct crystallisation from ethyl acetate solution; B = filtration
through a short pad of silica; C = column chromatography. c 2 : 1 molar equivalents of acid–amine. d Diamide product.
Table 3 Scale-up of reaction 1a
contributed to a lower yield of the monoamide and sub-
sequently column chromatography was required to separate
the products. Next the benzamide 18 was reacted with com-
mercially available ( )-ibuprofen giving the complex diamide
19 in a moderate yield after column chromatography.
Scale mmol
Amount of ferrite mg
Yield mg (%)
1
2
5
100
200
300
237 (94)
465 (92)
1243 (98)
2.5 Product metals analysis
a Conditions: RF 200 A@287 kHz.
Analysis of the metal content of the product of reaction 1
(Table 4) showed very little leaching of the nickel ferrite into
the crystallised amide. This result clearly illustrates the
reliability of magnetic separation and the high thermal
piperazine with one equivalent of benzoic acid. Competing
diamidation to form dibenzamide 11 in 10% isolated yield
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NMR spectral data were collected on Bruker DRX-500 or
Bruker AV-400 spectrometers. IR spectra were collected on a
Perkin-Elmer Spectrum One FT-IR spectrometer, optical
rotations were measured on a Perkin-Elmer Model 341 polari-
meter and mass-spec data were collected on a Waters GCT-
Premier spectrometer with nanomate attachment. For metals
analysis, an accurate weight of the sample was ashed and dis-
solved in concentrated nitric acid. The diluted solution was
analysed using a Thermo Elemental IRIS Intrepid Inductively
Coupled Plasma–Optical Emission Spectrometer coupled with
a Timberline IIL Autosampler. Calibration was performed
using solutions prepared from certified reference standards.
General procedures
Fig. 4 Synthesis of the non-symmetrical piperazine diamide 19.
Table 4 Metals analysis of amide 1
OPTIMISATION. The desired amount of ferrite, 1 mmol of PBA
and 1 mmol of BnNH2 were added to a test tube which was
positioned inside the centre of the RF coil. The tube was
sealed and the experiment was started by starting the current
supply at the desired current set point. After the desired reac-
tion time the sheathed temperature probe was removed and
the reaction mixture was allowed to cool briefly. 3 mL of
acetone was added to the reaction mixture under vigorous stir-
ring. The ferrite was removed by magnetic separation, rinsed
with 2 mL of the solvent, magnetically separated again and
dried in an oven at 120 °C for re-use. All of the liquid was col-
lected and after solvent removal in vacuo by rotary evaporation
the crude product was dissolved in CDCl3 for 1H NMR
analysis.
Sample
Fe mg kg−1
Ni mg kg−1
Crystallised product
Filtered producta
49
<10
36
<10
a Filtered through a short plug of silica.
stability of the nickel ferrite during RF heating and the result-
ing harsh reaction conditions. Moreover, the small amount
remaining could be easily removed down to a level below the
detection limit of the analysis method, by simple filtration
through a short plug of silica.
SUBSTRATE SCREENING. 100 mg of ferrite and 1 mmol of each of
the substrates were added to a test tube which was positioned
inside the centre of the 5-turn RF coil. The tube was sealed
and the experiment was started by starting the current supply
set to 200 A. After the required reaction time the sheathed
temperature probe was removed and the reaction mixture was
allowed to cool briefly. 3 mL of ethyl acetate or dichloro-
methane was added to the reaction mixture under vigorous
stirring. The ferrite was removed by magnetic separation,
rinsed with 2 mL of the solvent, magnetically separated again
and dried in an oven at 120 °C for re-use. All of the liquid was
collected for purification. Final products were obtained either
by direct crystallisation on addition of petroleum ether to the
ethyl acetate solutions (for the solid amide products) or by fil-
tration through a short plug of silica and elution with 2 : 1
ethyl acetate–petroleum ether and evaporation for oils.
3 Conclusions
In summary, RF heating provides a simple method for the
direct formation of amides from carboxylic acids and amines.
The method is versatile, easily optimisable and operationally
facile. The use of nickel ferrite magnetic nanoparticles enables
direct energy transfer into the reaction mixture resulting in
fast and controllable heating, and additionally allows for easy
and efficient product isolation and recycling of the heating
material via magnetic separation.
Experimental
Materials and methods
SCALE-UP. For the scale-up experiments 200 and 300 mg of
ferrite, and 2 mmol and 5 mmol of the substrates (BnNH2 and
All reactions were performed in glass test tubes sealed by a PBA) respectively were added to a test tube which was posi-
rubber septum. A fibre optic temperature probe was sheathed tioned inside the centre of the 5-turn RF coil. The tube was
in a glass tube and inserted into the test tube, sealed by the sealed and the experiment was started by starting the current
septum. The radiofrequency (RF) field was produced using an supply set to 200 A. After the required reaction time the
Ambrell Easyheat 1 kW induction heater in conjunction with a sheathed temperature probe was removed and the reaction
4 or 5-turn copper solenoid coil applicator. Cooling water was mixture was allowed to cool briefly. 5 and 10 mL of ethyl
circulated through the coil at 20 °C. Monitoring of the reaction acetate were added to the reaction mixture under vigorous stir-
temperature was done using a Fiso FOT-L-SD fibre optic probe ring. The ferrite was removed by magnetic separation, rinsed
and a Fiso FPI-HR signal conditioner. All reagents were pur- with 5 mL of the solvent, magnetically separated again and
chased from Aldrich and were used without purification. All dried in an oven at 120 °C for re-use. All of the liquid was
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collected for purification by direct crystallisation on addition
of petroleum ether to the ethyl acetate solution.
N-BENZYL-P-METHYLBENZAMIDE (6). From the reaction of p-toluic
acid (136 mg, 1 mmol) and benzylamine (107 mg, 1 mmol)
after crystallisation from EtOAc–petrol ether product
6
(193 mg, 86%) was obtained as a white solid; m.p. 127–129 °C;
νmax (KBr discs, cm−1) 3313 (br s), 1640 (s), 1547 (m), 1507 (m);
Product characterisation
N-BENZYL-4-PHENYL-BUTYRAMIDE (1). From the reaction of 4-phe- 1H NMR (400 MHz, CDCl3) δ = 2.39 (3H, s), 4.64 (2H, d, J
nylbutyric acid (164 mg, 1 mmol) and benzylamine (107 mg, 5.5 Hz), 6.37 (1H, br s), 7.22 (2H, d, J 8.0 Hz), 7.34 (5H, m),
1 mmol) after crystallisation from EtOAc–petrol ether product 7.68 (2H, d, J 8.0 Hz); 13C NMR (135 MHz, CDCl3) 21.5, 44.2,
1 (238 mg, 94%) was obtained as a white solid; m.p. 76–79 °C; 126.9, 127.6, 127.9, 128.8, 129.3, 131.5, 138.3, 142.0, 167.5; m/z
νmax (KBr discs, cm−1) 2389 (s br), 1643 (s), 1547 (m), 1495 (m); (ES+) MH+ found 226.2941, C15H16NO requires 226.2937.
1H NMR (400 MHz, CDCl3) δ = 1.98 (2H, m), 2.20 (2H, t, J
N-PHENYL-4-PHENYL-BUTYRAMIDE (7). From the reaction of 4-phe-
7.5 Hz), 2.65 (2H, t, J 7.5 Hz), 4.41 (2H, s), 5.74 (1H, br s), nylbutyric acid (164 mg, 1 mmol) and aniline (93 mg, 1 mmol)
7.13–7.34 (5H, m); 13C NMR (135 MHz, CDCl3) 27.1, 35.2, 35.9, after column chromatography (2 : 1 petrol ether–EtOAc)
43.7, 126.0, 127.6, 127.9, 128.4, 128.5, 128.7, 138.4, 141.5, product 7 (117 mg, 49%) was obtained as a white solid; m.p.
172.8; m/z (ES+) MH+ found 254.1519, C17H20NO requires 91–93 °C; νmax (KBr discs, cm−1) 3324 (s), 1664 (s), 1599 (m),
1
254.1545.
1533 (m), 1501 (m), 1445 (m); H NMR (400 MHz, CDCl3) δ =
N-BENZYL-ISOBUTYRAMIDE (2). From the reaction of isobutyric 2.03 (2H, m), 2.32 (2H, t, J 8.0 Hz), 2.67 (2H, t, J 7.0 Hz),
acid (88 mg, 1 mmol) and benzylamine (107 mg, 1 mmol) after 7.05–7.50 (11H, m); 13C NMR (135 MHz, CDCl3) 26.9, 35.1,
filtration through a short pad of silica and solvent evaporation 36.8, 120.0, 124.2, 126.0, 1284, 128.5, 128.9, 138.0, 131.4,
product 2 (162 mg, 91%) was obtained as a white solid; m.p. 171.2; m/z (ES+) MH+ found 240.1398, C16H18NO requires
84–86 °C; νmax (KBr discs, cm−1) 3287 (br m), 1641 (s), 1544 240.1388.
(m), 1455 (m); 1H NMR (400 MHz, CDCl3) δ = 1.18 (6H, d, J
4-PHENYL-1-(PYRROLIDINE-1-YL)BUTANONE (8). From the reaction of
7.0 Hz), 2.38 (1H, sepr., J 7.0 Hz), 4.42 (2H, s), 5.85 (1H, br s), 4-phenylbutyric acid (164 mg, 1 mmol) and pyrrolidine
7.23–7.34 (5H, m); 13C NMR (135 MHz, CDCl3) 19.6, 35.7, 43.4, (71 mg, 1 mmol) after filtration through a short pad of silica
127.4, 127.7, 128.7, 138.5, 176.8; m/z (ES+) MH+ found product 8 (197 mg, 91%) was obtained as a colourless oil; νmax
178.1240, C11H16NO requires 178.1232.
(thin film, cm−1) 2970 (m), 1641 (s), 1544 (m); 1H NMR
N-BENZYL-BENZAMIDE (3). From the reaction of benzoic acid (400 MHz, CDCl3) δ = 1.83 (2H, m), 1.91 (2H, m), 1.99 (2H, m),
(122 mg, 1 mmol) and benzylamine (107 mg, 1 mmol) after 2.25 (2H, t, J 7.5 Hz), 2.68 (2H, t, J 7.0 Hz), 3.31 (2H, t, J
crystallisation from EtOAc–petrol ether product 3 (198 mg, 7.0 Hz), 3.45 (2H, t, J 7.0 Hz), 7.15–7.29 (5H, m); 13C NMR
94%) was obtained as a white solid; m.p. 103–105 °C; νmax (135 MHz, CDCl3) 24.4, 26.2, 33.9, 35.4, 45.6, 46.5, 125.8,
1
(KBr discs, cm−1) 3289 (br s), 1637 (s), 1550 (m), 1491 (m); H 128.3, 128.5, 141.8, 171.3; m/z (ES+) MH+ found 218.1547,
NMR (400 MHz, CDCl3) δ = 4.65 (2H, s), 6.47 (1H, br s), C14H20NO requires 218.1545.
7.27–7.54 (8H, m), 7.80 (2H, d, J 7.0 Hz); 13C NMR (135 MHz,
4-PHENYL-1-(MORPHOLINE-1-YL)BUTANONE (9). From the reaction of
CDCl3) 44.2, 126.9, 127.6, 128.0, 128.6, 128.8, 131.6, 134.4, 4-phenylbutyric acid (164 mg, 1 mmol) and morpholine
138.2, 167.4; m/z (ES+) MH+ found 212.1070, C14H14NO (87 mg, 1 mmol) after filtration through a short pad of silica
requires 212.1075.
product 9 (202 mg, 87%) was obtained as a colourless oil; νmax
N-BENZYL-P-CHLOROBENZAMIDE (4). From the reaction of p-chloro- (thin film, cm−1) 1637 (s), 1452 (s); H NMR (400 MHz, CDCl3)
benzoic acid (156.5 mg, 1 mmol) and benzylamine (107 mg, δ = 1.98 (2H, m), 2.30 (2H, t, J 7.5 Hz), 2.68 (2H, t, J 7.0 Hz),
1 mmol) after crystallisation from EtOAc–petrol ether product 3.36 (2H, t, J 4.0 Hz), 3.62 (6H, m), 7.17–7.30 (5H, m); 13C NMR
4 (225 mg, 92%) was obtained as a white solid; m.p. (135 MHz, CDCl3) 26.6, 32.1, 35.3, 41.9, 45.9, 66.6, 66.9, 126.1,
159–161 °C; νmax (KBr discs, cm−1) 3314 (br s), 1638 (s), 1594 128.4, 128.5, 141.6, 171.5; m/z (ES+) MH+ found 234.1494,
(m), 1553 (m); 1H NMR (400 MHz, CDCl3) δ = 4.63 (2H, d, J 5.0 C14H20NO2 requires 234.1494.
1
Hz), 6.39 (1H, br s), 7.34 (5H, m), 7.39 (2H, d, J 7.5 Hz), 7.72
MORPHOLIN-4-YL-PHENYL-METHANONE (10). From the reaction of
(2H, d, J 7.5 Hz); 13C NMR (135 MHz, CDCl3) 44.3, 1277, 127.9, benzoic acid (122 mg, 1 mmol) and morpholine (87 mg,
128.4, 128.8 (2 × C), 132.7, 137.8, 137.9, 166.3; m/z (ES+) MH+ 1 mmol) after crystallisation from EtOAc–petrol ether amide 10
found 246.7125, C14H13ClNO requires 246.7119.
(181 mg, 95%) was obtained as a white solid; m.p. 115–117 °C;
N-BENZYL-P-ANISAMIDE (5). From the reaction of p-anisoic acid νmax (KBr discs, cm−1) 1629 (s) 1553 (m), 1384 (m); 1H NMR
(152 mg, 1 mmol) and benzylamine (107 mg, 1 mmol) after (400 MHz, D6-DMSO, 90 °C; νmax) δ = 3.58 (4H, m), 5.10 (4H,
crystallisation from EtOAc–petrol ether product 5 (209 mg, m), 7.41–7.97 (5H, m); 13C NMR (135 MHz, D6-DMSO) 44.0,
87%) was obtained as a white solid; m.p. 119–121 °C; νmax 65.4, 127.8, 129.1, 131.0, 1349, 169.0; m/z (ES+) MH+ found
(KBr discs, cm−1) 3267 (br m), 1632 (s), 1544 (m), 1496 (m); 1H 192.1030, C11H14NO2 requires 192.1025.
NMR (400 MHz, CDCl3) δ = 3.85 (3H, s), 4.63 (2H, d, J 5.5 Hz),
PIPERAZINE-DIBENZAMIDE (11). From the reaction of benzoic acid
6.31 (1H, br s), 6.92 (2H, d, J 8.5 Hz), 7.34 (5H, m), 7.76 (2H, d, (158.6 mg, 1.3 mmol) and piperazine (56 mg, 0.65 mmol) after
J 8.5 Hz); 13C NMR (135 MHz, CDCl3) 44.1, 55.5, 113.8, 126.7, crystallisation from EtOAc–petrol ether amide 11 (189 mg,
127.6, 127.8, 128.6, 128.8, 138.3, 162.3, 166.8; m/z (ES+) MH+ 96%) was obtained as a white solid; m.p. 125–127 °C; νmax
found 242.2937, C15H16NO2 requires 242.2931.
(KBr discs, cm−1) 1618 (s), 1432 (m), 1367 (m); 1H NMR
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(400 MHz, D6-DMSO, 90 °C) δ = 3.55 (8H, s), 7.44 (10H, m); 13
C
white solid; m.p. 96–98 °C; α2D0 = −110.7 (c = 0.3, CHCl3); νmax
1
NMR (135 MHz, D6-DMSO, 90 °C) 44.36, 126.8, 128.3, 129.4, (KBr discs, cm−1) 3257 (m br), 1693 (s), 1675 (s), 1530 (m); H
135.8, 169.5; m/z (ES+) MH+ found 295.3551, C18H19N2O4 NMR (500 MHz, D6-DMSO, 90 °C) δ = 1.40 (9H, s), 1.42 (3H, d,
requires 295.3557.
J 7.5 Hz), 1.80 (3H, m), 2.11 (1H, m), 3.37 (2H, m), 4.17 (1H,
(1′S)-4-PHENYL-N-(1′-PHENYL-ETHYL)-BUTYRAMIDE (12). From the m), 4.99 (1H, m), 7.18–7.38 (5H, m), 7.87 (1H, br s); 13C NMR
reaction of 4-phenyl butyric acid (164 mg, 1 mmol) and (S)- (135 MHz, D6-DMSO) 22.2, 23.3, 28.0, 30.9, 46.3, 474, 59.7,
α-methyl-benzylamine (121 mg, 1 mmol) after crystallisation 78.3, 125.9, 121.5, 1282, 144.6, 153.4, 171.5; m/z (ES+) MH+
from EtOAc–petrol ether product 13 (256 mg, 96%) was found 319.2023, C18H27N2O3 requires 319.2022.
obtained as a white solid; m.p. 81–83 °C; α2D0 = −48.8 (c = 0.5,
(2S,1′S)-2-(1′-PHENYL-ETHYLCARBAMOYL)-PYRROLIDINE-1-CARBOXYLIC ACID
CHCl3); νmax (KBr discs, cm−1) 3433 (m br), 1640 (s), 1545 (m); BENZYL ESTER (17). From the reaction of (N-Cbz)-(S)-proline
1H NMR (400 MHz, CDCl3) δ = 1.47 (3H, d, J 7.5 Hz), 1.96 (2H, (249 mg, 1 mmol) and (S)-α-methyl-benzylamine (121 mg,
m), 2.16 (2H, t, J 7.5 Hz), 2.63 (2H, t, J 7.0 Hz), 5.13 (1H, q, J 1 mmol) after column chromatography (3 : 1 petroleum ether–
7.5 Hz), 5.68 (1H, br s), 7.12–7.35 (5H, m); 13C NMR (135 MHz, ethyl acetate) product 18 (204 mg, 58%) was obtained as a
CDCl3) 21.7, 27.1, 35.1, 35.0, 46.7, 126.0, 126.2, 127.4, 128.4, white solid; m.p. 109–111 °C; α2D0 = −92.9 (c = 0.5, CHCl3); νmax
128.5, 128.7, 141.5, 143.3, 171.7; m/z (ES+) found MH+ (KBr discs, cm−1) 3257 (m br), 1709 (s), 1653 (s) 1671 (s), 1416
1
268.3721, C18H22NO requires 268.3734. HPLC Chiralcel AD-H (m), 1351 (m); H NMR (500 MHz, D6-DMSO, 90 °C) δ = 1.35
column, 90 : 10 hexane–iPrOH, flow 1.0 ml min−1; retention (3H, d, J 7.0 Hz), 1.82 (3H, m), 2.14 (1H, m), 3.46 (2H, m), 4.28
time for (S) enantiomer 16.13 min (racemate 16.13 and (1H, dd, J 8.0, 4.0 Hz), 4.94 (1H, q, J 7.0 Hz), 5.08 (2H, s),
21.23 min).
7.19–7.37 (10H, m), 7.96 (1H, br s); 13C NMR (135 MHz,
N-(4-HYDROXY-PHENYL)-ACETAMIDE (PARACETAMOL) (13). From the D6-DMSO) peaks for the major rotamer 22.1, 230, 31.1, 46.3,
reaction of acetic acid (60 mg, 1 mmol) and 4-aminophenol 47.6, 53.3, 65.9, 125.6, 126.5, 127.1, 127.4, 1281, 128.3, 136.8,
(109 mg, 1 mmol) after column chromatography (3 : 1 petrol 144.6, 152.8, 171.1; m/z (ES+) MH+ found 353.1851,
ether–EtOAc) product 14 (77 mg, 51%) was obtained as a white C21H25N2O3 requires 353.1865.
solid; m.p. 168–170 °C; νmax (KBr discs, cm−1) 3162 (br s), 1654
PIPERAZINE-MONOBENZAMIDE (18). From the reaction of benzoic
(s), 1610 (s), 1564 (s), 1506 (s), 1442 (s); 1H NMR (400 MHz, D6- acid (122 mg, 1 mmol) and piperazine (86 mg, 1 mmol) after
DMSO) δ = 2.01 (3H, s), 6.67 (2H, d, J 8.5 Hz), 7.33 (2H, d, J 8.5 column chromatography (2 : 1 ethyl acetate–petrol ether)
Hz), 9.12 (1H, br s), 9.63 (1H, br s); 13C NMR (135 MHz, D6- amide 18 (131 mg, 69%) was isolated as a white solid; m.p.
DMSO) 23.6, 114.9, 120.8, 131.0, 152.7, 167.5; m/z (ES+) MH+ 57–61 °C; νmax (KBr discs, cm−1) 1633 (s), 1495 (m), 1446 (m);
found 152.0708, C8H10NO2 requires 152.0712.
1H NMR (400 MHz, D6-DMSO, 90 °C) δ = 2.72 (4H, t, J 5.0 Hz),
(N-BENZYL,N′-BOC)-GLYCINAMIDE (14). From the reaction of (N- 3.42 (4H, t, J 5.0 Hz), 7.40 (5H, m); 13C NMR (135 MHz,
Boc)-glycine (175 mg, 1 mmol) and benzylamine (107 mg, D6-DMSO, 90 °C) 45.6 (2 × C), 126.7, 128.5, 129.4, 136.3, 169.4;
1 mmol) after column chromatography (3 : 1 petrol ether– m/z (ES+) MH+ found 191.2505, C11H15N2O requires 191.2497.
EtOAc) product 15 (137 mg, 52%) was obtained as a white
NON-SYMMETRIC PIPERAZINEDIAMIDE (19). From the reaction of
solid; m.p. 68–70 °C; νmax (KBr discs, cm−1) 3317 (s), 1704 (s), amide 18 (191 mg, 1 mmol) and ( )-ibuprofen (206 mg,
1658 (s), 1518 (m), 1365 (m); 1H NMR (400 MHz, CDCl3) δ = 1 mmol) after column chromatography (1 : 1 ethyl acetate–
1.41 (9H, s), 3.80 (2H, s), 4.42 (2H, s), 5.36 (1H, br s), 6.75 petrol ether) the product 19 (268 mg, 71%) was obtained as a
(1H, br s), 7.23–733 (5H, m); 13C NMR (135 MHz, CDCl3) colourless oil; νmax (KBr discs, cm−1) 1642 (s), 1618 (s),
1
28.2, 43.3, 80.2, 60.9, 127.5, 127.6, 128.6, 137.9, 156.0, 169.5; 1545 (m), 1432 (m); H NMR (400 MHz, D6-DMSO, 90 °C) 1.26
m/z (ES+) MNa+ found 287.1358, C14H20N2O3Na requires (6H, d, J 6.5 Hz), 1.73 (3H, d, J 5.5 Hz), 2.23 (1H, m), 2.83 (2H,
287.1372.
d, J 6.5 Hz), 3.84 (4H, br m), 3.96 (4H, br m), 4.44 (1H, q, J
(N-BENZYL,N′-CBZ)-GLYCINAMIDE (15). From the reaction of 5.5 Hz), 7.49 (2H, d, J 8.0 Hz), 7.57 (2H, d, J 8.0 Hz), 7.77
(N-Cbz)-glycine (209 mg, 1 mmol) and benzylamine (107 mg, (5H, m); 13C NMR (135 MHz, D6-DMSO, 90 °C) 20.9, 22.9, 30.2,
1 mmol) after column chromatography (3 : 1 petrol ether– 42.2 (2 × C benzylic ibuprofen), 45.1 (2 × C piperazine),
EtOAc) product 16 (179 mg, 60%) was obtained as a white 127.6, 127.8, 129.2, 130.0, 130.4, 138.5, 140.1, 140.3, 170.6,
solid; m.p. 110–113 °C; νmax (KBr discs, cm−1) 3321 (m), 1688 173.2; m/z (ES+) MH+ found 379.5145, C24H31N2O2 requires
(s), 1641 (s), 1532 (m), 1236 (m); 1H NMR (400 MHz, CDCl3) δ = 379.5152.
3.87 (2H, s), 4.42 (2H, s), 5.07 (2H, s), 5.49 (1H, br s), 6.42 (1H,
brs), 7.21–7.37 (5H, m); 13C NMR (135 MHz, CDCl3) 43.5, 44.7,
67.2, 127.6, 127.8, 128.1, 128.3, 128.5, 128.7, 136.0, 137.8,
156.6, 168.8; m/z (ES+) MH+ found 299.1272, C17H19N2O3
requires 299.1396.
Acknowledgements
(2S,1′S)-2-(1′-PHENYL-ETHYLCARBAMOYL)-PYRROLIDINE-1-CARBOXYLIC ACID Financial support from DEL and the European Research
TERT-BUTYL ESTER (16). From the reaction of (N-Boc)-(S)-proline Council (project 279867 – RFMiFiCS – RF-enhanced Micro-
(215 mg, 1 mmol) and (S)-α-methyl-benzylamine (121 mg, processing for Fine Chemicals Synthesis using Catalysts
1 mmol) after column chromatography (3 : 1 petroleum ether– Supported on Magnetic Nanoparticles) is gratefully
ethyl acetate) product 17 (136 mg, 43%) was obtained as a acknowledged.
Org. Biomol. Chem.
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15 R. V. Ulijn, B. Baragana, P. J. Halling and S. L. Flitsch,
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