Solvent-free iron(III) chloride-catalyzed direct amidation of esters

Article abstract of DOI:10.3390/molecules25051040

Amide functional groups are prominent in a broad range of organic compounds with diverse beneficial applications. In this work, we report the synthesis of these functional groups via an iron(iii) chloride-catalyzed direct amidation of esters. The reactions are conducted under solvent-free conditions and found to be compatible with a range of amine and ester substrates generating the desired amides in short reaction times and good to excellent yields at a catalyst loading of 15 mol%.

Full text of DOI:10.3390/molecules25051040

ASroticllevent‐Free Iron(III) Chloride‐Catalyzed Direct
Amidation of Esters
1
1
1
2
Blessing D.Mkhonazi , Malibongwe Shandu , Ronewa Tshinavhe , Sandile B. Simelane and
1,
Paseka T. Moshapo *
1
Research Centre in Synthesis and Catalysis, Department of Chemical Science, University of Johannesburg,
PO Box 524, Auckland Park 2006, South Africa; 201585722@student.uj.ac.za (B.D.M.);
201305188@student.uj.ac.za (M.S.); 201424658@student.uj.ac.za (R.T.)
Department of Chemistry, University of Eswatini, Private Bag 4, Kwaluseni M201, Eswatini;
2
bssimelane@uniswa.sz
* Correspondence: pasekam@uj.ac.za; Tel.: +27‐11‐559‐2372
Academic Editor: Hans‐Joachim Knölker
Received: 10 January 2020; Accepted: 21 February 2020; Published: 26 February 2020
Abstract: Amide functional groups are prominent in a broad range of organic compounds with
diverse beneficial applications. In this work, we report the synthesis of these functional groups via
an iron(iii) chloride‐catalyzed direct amidation of esters. The reactions are conducted under
solvent‐free conditions and found to be compatible with a range of amine and ester substrates
generating the desired amides in short reaction times and good to excellent yields at a catalyst
loading of 15 mol%.
Keywords: amidation; iron(III) chloride; amides; esters; solvent‐free
1. Introduction
Amide functional groups are present in a plethora of natural and organic molecules with
beneficial applications in the pharmaceutical, agrochemical, and textile industries. Examples include
proteins; medicinal drugs such as apixaban, lenalidomide, and enzalutamide; as well as pesticides
®
such as Boscalid [1–5]. In 2018, amide functional groups were present in 68% of new small molecule
drugs approved by the FDA [6]. In general, amides are synthesized by a reaction between carboxylic
acids and amines using activating reagents such as HATU, PPh , and DCC in excess amounts [7].
3
Alternatively, carboxylic acids can be converted to their acid chloride or anhydride derivatives that
readily react with amines to form the desired amide bonds. These reactions are often not catalytic
and generate large quantities of undesired co‐products. The synthesis of amides using greener and
more atom economic reaction conditions is therefore an attractive approach to curb this problem
[8,9]. Alternative amidation methodologies have been reported and some of these methods include
the use of boron‐based catalysts for efficient coupling of carboxylic acids at mild reaction
temperatures; however, these reactions generate boronic acid side products [10–12]. Transition metal
catalysts have also been used to couple amines and azides with a variety of substrates such as
carboxylic acids, aldehydes, alcohols, alkynes and aryl halides [13–15]. Esters are key features in
several organic synthesis substrates and have also been reported as useful substrates for amide
coupling under acidic or basic conditions [16–20]. Some of the recent reports in direct ester
amidation reactions include the use of lanthanum trifluoromethanesulfonate (Ln(Otf) ) in low
3
catalyst loading as reported by Ohshima and co‐workers [21]. Hu and co‐workers reported the use
of a nickel catalyst for reductive amidation of esters using nitroarenes [22]. Similar reductive
coupling reactions using chromium catalysts have also been recently reported by Zeng and
co‐workers [23]. Nickel has also been employed by Newman and co‐workers for direct amidation of
Molecules 2020, 25, 1040; doi:10.3390/molecules25051040
www.mdpi.com/journal/molecules

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methyl esters at high reaction temperatures [24]. Therefore, there is a growing interest in the use of
esters as substrates for direct amidation reactions. This interest provides an opportunity for the
investigation of more catalysts as well as different amino substrates that can be used to promote
ester amidation [25,26]. In this study, we report the direct amidation of esters using relatively cheap
and readily available FeCl
3
catalyst [27–29] under solvent‐free reaction conditions.
2. Results and Discussion
To establish the optimal reaction conditions for amidation of esters, readily available ethyl
acetate and benzyl amine were selected as the ester and amine of choice, respectively (Scheme 1).
Iron catalysts, namely, FeCl
amidation of 1a and 2a under solvent‐free conditions at 50 °C. These catalysts were also compared to
other readily available catalysts such as AlCl and BiCl and as can be seen in Figure 1, FeCl was
3
, FeCl
2
, and FeBr
3
, were evaluated as suitable promoters for the direct
3
3
3
found to be the most active catalyst as it afforded a higher yield of the desired product 3a. A control
experiment conducted at 50 °C in the absence of a catalyst did not form any product after 24 h. Thus,
FeCl
3
was selected as the preferred catalyst for further reaction optimization and evaluation.
O
O
NH2
Catalyst (10 mol %)
N
H
+
O
50 oC, 24 hrs
1a
1.1 mmol
3a
2a
1 mmol
Scheme 1. Catalyst = AlCl
3
, FeCl
3
, FeCl
2
, FeBr
3
or BiCl .
3
Figure 1. Reaction optimization. N.D. = Not Detected.
We then investigated the optimal reaction temperature and FeCl catalyst loading (Figure 1).
3
Eighty degrees Celsius was the most favorable reaction temperature as the reaction went to
completion within 5 h at 10 mol% catalyst loading. Increasing the reaction temperature to 100 °C did
not effect a notable change in the rate of the reaction. Furthermore, increasing the catalyst loading to
15 mol% improved the rate of the reaction as TLC indicated completion of the reaction within 90
min. As a result, 15 mol% catalyst loading and 80 °C were selected as our optimal reaction
conditions. In anticipation of reaction conditions that may require solvents (i.e., cases where both
ester and amine substrates are solids or reactions that solidify upon mixing of substrates), we also
investigated suitable solvents for FeCl catalyzed direct amidation of esters. We randomly selected
3
four common organic solvents for investigation and the reactions between ester 1a and amine 2a
(Scheme 1) were left to proceed for 90 min upon which TLC analysis indicated reaction completion
for reactions conducted in acetonitrile and 1,2 dichloroethane (Table 1). Starting amine 2a was
observed in the tetrahydrofuran and toluene reactions after 90 min. Therefore, acetonitrile was

Molecules 2020, 25, 1040
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found to be the most favorable solvent as it is relatively greener in comparison to 1,2 dichloroethane
and it also afforded the product in high yield. The steric effect of alkoxy groups around the ester
carbonyl carbon was also investigated (Scheme 2). An increase in steric bulk (isopropoxy) and chain
length of the alkoxy group (n‐butoxy) resulted in a decrease in ester reactivity and the reactions
required longer reaction times to reach completion. However, there was no significant difference
between esters with methoxy and ethoxy groups.
Table 1. Solvent evaluation.
Entry
Solvent
Product Yield
84% a
1
2
3
4
5
Toluene
Acetonitrile
Tetrahydrofuran
1,2 Dichloroethane
No Solvent
96%
85% a
94%
99%
Reaction conditions: ester 1a (1.1 mmol), amine 2a (1 mmol), 15 mol% FeCl3, 80 oC. a Reaction did not
reach completion within 90 min.
Scheme 2. a Reaction mixture solidified and 0.5 mL CH3CN was added.
Having established the optimal reaction conditions, we then investigated the catalyst’s reaction
scope by varying both ester 1 and amine 2 substrates according to Scheme 3. Reactions were
monitored by TLC. Aqueous work‐up and flash column chromatography afforded the various
amide products shown in Scheme 3. Aryl esters containing electron withdrawing groups were more
active towards amidation than those with electron donating groups (product 3d vs. 3e). Both
primary and secondary amines reacted to form amide products 3 in good yields. No reaction was
observed between aryl ester 1b (R
=
Et) and aniline. Interestingly, amidation of
2‐pyridinecarboxylates with aryl amines was successful and afforded 2‐pyridinecarboxamide
products (3f to 3o) in high yields. The formation of these pyridinecarboxamide products can be
attributed to the possible coordination of the carbonyl oxygen and pyridine nitrogen to iron, thus,
forming a stabilized intermediate complex that can undergo the observed amidation.

Molecules 2020, 25, 1040
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O
O
O
O
N
N
H
N
H
N
H
O2N
3b
, 97%
3d
, 92%
3e
, 47%
3c
, 89%
OCH3
O
O
O
O
N
N
H
N
H
N
H
H
N
N
N
N
3g
, 92%
3f
, 86%
3h
, 69%
3i
, 52%
Cl
O
O
O
O
O
N
H
N
N
N
N
H
N
N
N
N
N
O
3k
, 99%
3j
, 82%
3l
,92%
3m
3n
, 40%
, 77%
O
O
O
O
O
N
N
O
O
O
N
H
N
N
H
H
N
3o
, 71%
a
3p
, 89%
3r
, 73%
3q
, 87%
O
O
O
O
H
O
N
O
N
N
N
N
H
O
a
a
3v
, 64%
3s
3t
, 78%
, 70%
3u
, 73%
Scheme 3. General reaction scheme for FeCl3 substrate scope evaluation. a Reaction mixture solidified
and 0.5 mL of CH3CN was added.
To test the proposed nitrogen and oxygen iron coordination hypothesis, 3‐pyridinecarboxylate
was reacted with aniline and as expected, the reaction failed to afford the desired product. Reactions
with 2‐pyridinecarboxamide were successful with aryl amines possessing both electron donating
and electron withdrawing groups as well as alkyl amines. No product formation was observed when
4‐nitroaniline was used as a substrate and the starting materials were recovered. Phenyloxy esters
were also found to be suitable substrates for direct amidation and afforded the desired amides in
good yields ranging from 70% to 89% (3p to 3s).
We further investigated the direct amidation of esters possessing alkyl bromide functional
groups according to Scheme 4. Amidation of 4‐bromobutanoate 4a with benzyl amine 2a afforded
lactam 3t. We then envisaged that increasing the alkyl chain length in Scheme 4 would enable us to
synthesize lactams with varying ring sizes. 5‐bromobutanoate 4b afforded lactam 3u in 73%;
however, the reaction could not be replicated with 6‐bromobutanoate as it formed several side
products. Amidation using aniline afforded the substitution product 3v which failed to undergo an
intramolecular cyclization to form the desired lactam product.

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Scheme 4. Lactam synthesis.
Finally, and having succeeded in the amidation of 2‐pyridinecarboxylates, we then utilized the
developed methodology in the synthesis of pyrimidine carboxamides 7. Although their mode of
action is unknown, these molecules are worth investigating due to their reported potent
anti‐tubercular activities against clinical Mycobacterium tuberculosis (Mtb) strains [30]. Direct
amidation of the corresponding ester 6 synthesized from commercially available dichloropyrimidine
5 afforded the amide 7 in good isolated yields (Scheme 5).
Scheme 5. Application of the developed protocol in the synthesis of anti‐TB pyrimidine
carboxamides.
In conclusion, we have successfully demonstrated a solvent‐free direct amidation of esters
using FeCl3 as a Lewis acid catalyst at 80 °C. Amidation was effective with both primary and
secondary amines and most of the reactions were complete in short reaction times (1.5–12 h) and
good yields (47–99%). Linear and branched alkoxy groups on the corresponding esters could be
displaced with ease to afford the desired amides. We have also demonstrated the synthesis of
lactams with varying ring sizes from reactions between primary alkyl amines and 4‐bromo or
5‐bromoalkyl esters. The successful amidation of 2‐pyridine carboxylates is currently being used in
the synthesis of a library of novel aminopyrimidine carboxamides that will be screened for anti‐TB
activity.
4. Materials and Methods
All the solvents used were freshly distilled and dried by appropriate techniques. All reagents
were purchased from Sigma Aldrich FeCl3 reagent grade 97% was used as the catalyst. All reactions
were monitored by thin layer chromatography (TLC) on aluminum‐backed Merck silica gel 60 F254
plates using an ascending technique. The plates were visualized under UV light at 254 nm. Gravity
column chromatography was done on Merck silica gel 60 (70–230 mesh). All proton nuclear
1
magnetic resonance ( H NMR) spectra were recorded using deuterated chloroform solutions on a
13
Bruker Ultrashield (400 or 500 MHz) spectrometer. Carbon‐13 nuclear magnetic resonance ( C
NMR) spectra were recorded on the same instruments at 100 MHz. All chemical shifts are reported
in ppm. The chemical structures of the synthesized compounds were confirmed by comparison of
1
13
their NMR data to literature reported data. Optimization reactions, H and C NMR data of all the
compounds are available online as a supplementary material.
Typical Experimental Procedure for FeCl3‐Catalyzed Direct Amidation of Esters. An oven‐dried pressure
tube equipped with a magnetic stirrer was evacuated with nitrogen. To this was added of ester 1a
(492 uL, 5.04 mmol), followed by amine 2a (0.5 mL, 4.58 mmol), and finally FeCl3 (111 mg, 0.684
mmol). The mixture was then sealed and stirred at 80 °C (0.5 mL of CH3CN was added if the reaction
mixture solidified). The reaction was monitored by TLC until completion upon which it was diluted
with EtOAc and washed once with saturated NaHCO3 and once with distilled H2O. The combined
aqueous layers were extracted once with ethyl acetate. The combined organic layers were then dried

Molecules 2020, 25, 1040
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over MgSO4, filtered and solvents removed under reduced pressure. The crude product was purified
by silica gel flash column chromatography using a combination of hexane and ethyl acetate (3:2).
1
N‐Benzylacetamide (3a). Yield: 99%; H NMR (400 MHz, CDCl3) δ 7.30–7.15 (m, 5H), 6.44 (br, 1H), 4.34
13
(d, J = 5.6 Hz, 2H), 1.94, (s, 3H); C NMR (100 MHz, CDCl3) δ 170.0, 138.2, 128.5, 127.6, 127.3, 43.5,
23.0. (The obtained NMR data agreed with the literature data for this compound.) [31]
1
N‐Benzylbenzamide (3b). Yield: 97%; H NMR (400 MHz, CDCl3) δ 7.36 (d, J = 7.2 Hz, 2H), 7.55–7.20
13
(m, 8H), 6.49 (s, 1H), 4.62 (d, J = 5.6 Hz, 2H); C NMR (100 MHz, CDCl3) δ 167.3, 138.2, 134.4, 131.5,
128.8, 128.6, 127.9, 127.6, 126.9, 44.1. (The obtained NMR data agreed with the literature data for this
compound.) [32]
1
Phenyl(piperidin‐1‐yl)methanone (3c). Yield: 89%; H NMR (400 MHz, CDCl3) δ7.36 (br, 5H), 3.68 (br,
2H), 3.30 (br, 2H), 1.70–1.40 (m, 6H). (The obtained NMR data agreed with the literature data for this
compound.) [33]
1
N‐(4‐Nitrobenzyl)benzamide (3d). Yield: 92%; H NMR (500 MHz, CDCl3) δ 8.20 (d, J = 8.5 Hz, 2H), 7.91
13
(d, J = 8.5 Hz, 2H), 7.40–7.23 (m, 5H), 6.83 (br, 1H), 4.60 (d, J = 5.5 Hz, 2H); C NMR (125 MHz,
CDCl3) δ 165.4, 149.6, 139.9, 137.5, 128.9, 128.2, 127.9, 127.8, 123.7, 44.4. (The obtained NMR data
agreed with the literature data for this compound.) [32]
1
N‐(4‐Methylbenzyl)benzamide (3e). Yield: 47%; H NMR (500 MHz, CDCl3) δ 7.67 (d, J = 7.5 Hz, 2H),
13
7.40–7.18 (m, 7H), 6.51 (br, 1H), 4.60 (d, J = 5.0 Hz, 2H), 2.37 (s, 3H); C NMR (125 MHz, CDCl3) δ
167.3, 141.9, 138.4, 131.6, 129.2, 128.7, 127.9, 127.5, 127.0, 44.1, 21.4. (The obtained NMR data agreed
with the literature data for this compound.) [32]
1
N‐Phenylpicolinamide (3f) . Yield: 86%; H NMR (500 MHz, CDCl3) δ 10.1 (br, 1H), 8.59 (d, J = 3.2 Hz,
1H), 8.28 (d, J = 6.4 Hz, 1H), 7.92 – 7.83 (m, 1H), 7.77 (d, J = 6.0 Hz, 1H), 7.50 – 7.31 (m, 3H), 7.13 (t. J =
13
5.8 Hz, 1H); C NMR (100 MHz, CDCl3) δ 161.9, 149.8, 147.9, 137.7, 137.6, 129.0, 126.3, 124.2, 122.3,
119.6. (The obtained NMR data agreed with the literature data for this compound.) [34]
1
N‐(4‐(tert‐Butyl)phenyl)picolinamide (3g). Yield: 92%; H NMR (500 MHz, CDCl3) δ 9.97 (br, 1H), 8.57
(d, J = 4.0 Hz, 1H), 8.28 (d, J = 8.0 Hz, 1H), 7.84 (t, J = 7.8 Hz, 1H), 7.70 (d, J = 8.5 Hz, 2H), 7.48 – 7.36 (m,
13
3H), 1.32 (s, 9H); C NMR (125 MHz, CDCl3) δ 161.8, 149.9, 147.8, 147.1, 137.5, 135.1, 126.2, 125.9,
125.8, 122.2, 119.4, 34.6, 31.3. (The obtained NMR data agreed with the literature data for this
[
compound.) 34]
1
(N‐(2‐Isopropylphenyl)picolinamide (3h). Yield: 69%; H NMR (500 MHz, CDCl3) δ 10.2 (br, 1H), 8.62 (d,
J = 4.0 Hz, 1H), 8.32 (d, J = 8.0 Hz, 1H), 8.22 (d, J = 8.0 Hz, 1H), 7.88 (t, J = 8.0 Hz, 1H), 7.51–7.12 (m,
13
4H), 3.34 – 3.20 (m, 1H), 1.34 (d, J = 7.0 Hz, 6H); C NMR (100 MHz, CDCl3) δ 162.1, 150.3, 148.1,
139,0, 137.5, 134.5, 126.5, 126.4, 125.6, 125.2, 122.4, 118.9, 28.2, 22.9. (The obtained NMR data agreed
with the literature data for this compound.) [34]
1
N‐(4‐Methoxyphenyl)picolinamide (3i). Yield: 52%; H NMR (500 MHz, CDCl3) δ 9.89 (br, 1H), 8.57 (d, J
= 4.0 Hz, 1H), 7.86 (t, J = 8.0 Hz, 1H), 7.78 – 7.62 (m, 2H), 7.48–7.40 (m, 1H), 6.90 (d, J = 8.5 Hz, 2H),
13
3.78 (s, 3H); C NMR (125 MHz, CDCl3) δ 161.7, 156.4, 150.0, 147.9, 137.6, 131.0, 126.2, 122.2, 121.2,
114.2, 55.4. (The obtained NMR data agreed with the literature data for this compound.) [34]
1
N‐(4‐Chlorophenyl)picolinamide (3j). Yield: 82%; H NMR (500 MHz, CDCl3) δ 9.98 (br, 1H), 8.52 (d, J =
3.5 Hz, 1H), 8.20 (d, J = 7.5 Hz, 1H), 7.82 (t, J = 7.5 Hz, 1H), 7.68 (d, J = 8.5 Hz, 2H), 7.40 (t, J = 5.6 Hz,
13
1H), 7.27 (d, J = 8.5 Hz, 2H); C NMR (100 MHz, CDCl3) δ 161.8, 149.4, 147.8, 137.5, 136.3, 129.0, 128.9,
126.4, 122.2, 120.8. (The obtained NMR data agreed with the literature data for this compound.) [34]
1
N‐Benzylpicolinamide (3k). Yield: 99%; H NMR (500 MHz, CDCl3) δ 8.52–8.38 (m, 2H), 8.20 (d, J = 8.0
13
Hz, 1H), 7.77 (t, J = 8.0 Hz, 1H), 7.45–7.20 (m, 6H), 4.63 (d, J = 6.0 Hz, 2H); C NMR (100 MHz, CDCl3)
δ 164.0, 149.7, 147.8, 138.1, 137.1, 128.4, 127.6, 127.2, 125.9,122.1, 43.2. (The obtained NMR data agreed
with the literature data for this compound.) [34]

Molecules 2020, 25, 1040
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1
N‐Benzyl‐N‐methylpicolinamide (3l). Yield: 92%; mixture of rotamers, H NMR (400 MHz, CDCl3) δ
8.52 (dd, J = 4.4 amd 14.0 Hz, 2H), 7.80 –7.58 (m, 4H), 7.35–7.10 (m, 12H), 4.72 (s, 2H), 4.62 (s. 2H), 2.97
13
(s, 3H), 2.91 (s, 3H); C NMR (100 MHz, CDCl3) δ 169.1, 168.8, 154.4, 154.3, 148.1, 136.8, 136.6, 128.5,
128.4, 128.0, 127.4, 127.3, 124.2, 123.5, 123.4, 54.4, 51.0, 36.3, 33.1. (The obtained NMR data agreed
with the literature data for this compound.) [34]
1
Piperidin‐1‐yl(pyridin‐2‐yl)methanone (3m). Yield: 77%; H NMR (500 MHz, CDCl3) δ 8.51 (d, J = 4.0 Hz,
1H), 7.70 (t, J = 7.8 Hz, 1H), 7.49 (d, J = 7.5 Hz, 1H), 7.30–7.15 (m, 1H), 3.81–3.65 (m, 2H), 3.31–3.48 (m,
13
2H), 1.72–1.43 (m, 6H); C NMR (100 MHz, CDCl3) δ 167.5, 154.7, 148.3, 136.8, 124.0, 123.1, 48.1, 43.2,
26.4, 25.4, 24.4. (The obtained NMR data agreed with the literature data for this compound.)[35]
1
Morpholino(pyridin‐2‐yl)methanone (3n). Yield: 40%; H NMR (500 MHz, CDCl3) δ 8.50 (d, J = 4.0 Hz,
13
1H), 7.23 (t, J = 7.8 Hz, 1H), 7.60 (d, J = 7.5 Hz, 1H), 7.27 (t, J = 6.0 Hz, 1H), 3.88–3.50 (m, 8H); C NMR
(125 MHz, CDCl3) δ 167.3, 153.6, 148.1, 137.0, 124.5, 124.0, 66.9, 66.6, 47.6, 42.7. (The obtained NMR
data agreed with the literature data for this compound.) [36]
1
N‐(2‐morpholinoethyl)picolinamide (3o). Yield: 71%; H NMR (500 MHz, CDCl3) δ 8.46 (d, J = 4.0 Hz,
1H), 8.25 (br, 1H), 8.08 (d, J = 8.0 Hz, 1H), 7.73 (t, J = 8.0 Hz, 1H), 7.31 (t, J = 6.0 Hz, 1H), 3.70–3.41 (m,
13
6H), 2.61–2.31 (m, 6H); C NMR (100 MHz, CDCl3) δ 164.2, 149.9, 147.9, 127.0, 125.8, 122.0, 66.8, 57.2,
53.3, 35.8. (The obtained NMR data agreed with the literature data for this compound.)[37]
1
N‐Benzyl‐2‐phenoxyacetamide (3p). Yield: 89%; H NMR (500 MHz, CDCl3) δ 7.48–7.21 (m, 7H), 7.10–
13
6.87 (m, 4H); C NMR (100 MHz, CDCl3) δ 168.1, 157.1, 137.7, 129.7, 128.6, 127.6, 127.5, 122.1, 114.6,
67.3, 42.9. (The obtained NMR data agreed with the literature data for this compound.)[38]
1
2‐Phenoxy‐N‐phenylacetamide (3q). Yield: 87%; H NMR (500 MHz, CDCl3) δ 8.32 (bs, 1H), 7.59 (d, J =
13
8.0 Hz, 2H), 7.42–7.29 (m, 4H), 7.25–6.92 (m, 4H); C NMR (100 MHz, CDCl3) δ 166.2, 157.0, 136.8,
129.8, 129.0, 124.7, 122.3, 120.1, 114.8, 67.6. (The obtained NMR data agreed with the literature data
for this compound.)[39]
1
2‐Phenoxy‐1‐(piperidin‐1‐yl)ethanone (3r). Yield: 70%; H NMR (500 MHz, CDCl3) δ 7.38–7.20 (m, 2H),
13
7.12–6.87 (m, 3H), 4.63 (s, 2H), 3.60–3.42 (m, 4H), 1.69–1.48 (m, 6H); C NMR (100 MHz, CDCl3) δ
166.0, 157.9, 129.4, 121.3, 114.5, 67.6, 46.3, 43.0, 26.3, 25.4, 24.3.
1
N‐(2‐Morpholinoethyl)‐2‐phenoxyacetamide (3s). Yield: 70%; H NMR (500 MHz, CDCl3) δ 7.37–7.25 (m,
2H), 7.09 (br, 1H), 7.09–6.70 (m, 3H), 4.45 (s, 2H), 3.65–3.47 (m, 4H), 3.44–3.35 (m, 2H), 2.52–2.27 (m,
13
6H); C NMR (100 MHz, CDCl3) δ 168.0, 157.2, 129.6, 121.9, 67.2, 66.8, 56.5, 53.0, 35.1.
1
1‐Benzylpyrrolidin‐2‐one (3t). Yield: 78%; H NMR (400 MHz, CDCl3) δ 7.24–7.71 (m, 5H), 4.35 (s, 2H),
13
3.15 (t, J = 6.8 Hz, 3H), 2.33 (t, J = 8.0 Hz, 2H), 1.91–1.83 (m, 2H); C NMR (100 MHz, CDCl3) δ 174.1,
135.9, 127.9, 127.3, 126.7, 45.8, 45.7, 30.1, 16.9. (The obtained NMR data agreed with the literature
data for this compound.) [39]
1
1‐Benzylpiperidin‐2‐one (3u). Yield: 73%; H NMR (500 MHz, CDCl3) δ 7.35–7.18 (m, 5H), 4.53 (s, 2H),
13
3.13 (t, J = 5.0 Hz, 2H), 2.59–2.31 (m, 2H), 1.81–1.67 (m, 4H); C NMR (125 MHz, CDCl3) δ 169.7,
137.11, 128.4, 127.8, 127.1, 49.9, 47.1, 32.2, 23.0, 21.2. (The obtained NMR data agreed with the
literature data for this compound.) [39]
1
Methyl 5‐(phenylamino)pentanoate (3v). Yield: 64%; H NMR (500 MHz, CDCl3) δ 7.16 (t, J = 7.8 Hz,
2H), 6.68 (t, J = 7.0 Hz, 1H), 6.59 (d, J = 7.5 Hz, 2H), 3.66 (s, 3H), 3.27 (t, J = 6.8 Hz, 1H), 3.12 (t, J = 7.0
13
Hz, 1H), 2.45–2.30 (m, 2H), 1.82–1.59 (m, 4H); C NMR (100 MHz, CDCl3) δ 173.7, 148.1, 129.2, 129.1,
117.2, 112.7, 51.4, 43.4, 33.7, 33.6, 28.8, 26.5, 22.4. (The obtained NMR data agreed with the literature
data for this compound.) [40]
1
6‐((4‐Fluorobenzyl)(methyl)amino)‐N‐phenylpyrimidine‐4‐carboxamide (7). Yield: 66%; Clear oil; H NMR
(400 MHz, CDCl3) δ 9.94 (s, 1H), 8.62 (s, 1H), 7.74 (d, J = 8.0 Hz, 2H), 7.31–7.43 (m, 3H), 7.10–7.28 (m,
13
3H), 6.90–7.08 (m, 2H), 4.86 (br, 2H), 3.11 (br, 3H). C NMR (100 MHz, CDCl3) δ 163.2, 161.4, 157.1,
19
155.2, 137.4, 129.1, 124.6, 119.7, 115.8, 115.6, 100.3, 33.40. F NMR (376 MHz, CDCl3) δ ‐114.8 (The
obtained NMR data agreed with the literature data for this compound.) [30]

Molecules 2020, 25, 1040
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Supplementary Materials: The following are available online. Materials and methods, results of optimization
conditions as well as NMR spectra of products.
Author Contributions: Conceptualization, P.T.M.; methodology, B.D.M., M.S. and R.T.; formal analysis, P.T.M.,
S.B.S., B.D.M., M.S. and R.T.; writing—original draft preparation, P.T.M.; writing—review and editing, P.T.M.,
S.B.S. All authors have read and agreed to the published version of the manuscript.
Funding: This research was funded by the National Research Foundation of South Africa, Grant number 118082
and the article processing charge (APC) was funded by Prof. H.‐J. Knölker.
Acknowledgments: We thank the University of Johannesburg and Chemical Science Department for providing
the research infrastructure. We also express gratitude to our NMR technician Mr Mutshinyalo Nwamadi for
assisting us in acquiring the NMR data.
Conflicts of Interest: The authors declare no conflict of interest.
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