Facile direct synthesis of amides from trichloroethyl esters using catalytic DBU

Article abstract of DOI:10.1139/cjc-2018-0234

A practical method for the direct synthesis of amide compounds is described. Using small quantities of DBU as a catalyst, the direct conversion of 2,2,2-trichloroethyl esters to their corresponding amides was readily achieved. Based on this protocol, various amide compounds were successfully synthesized in high yield, suggesting a promising approach for the practical one-pot aminolysis from 2,2,2-trichloroethyl protected esters.

Full text of DOI:10.1139/cjc-2018-0234

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Facile Direct Synthesis of Amides from Trichloroethyl
Esters Using Catalytic DBU
Minh Thanh La,a,b, and Hee-Kwon Kima,b,
*
aDepartment of Nuclear Medicine, Molecular Imaging & Therapeutic Medicine Research Center,
Chonbuk National University Medical School and Hospital, Jeonju, 54907, Republic of Korea
bResearch Institute of Clinical Medicine of Chonbuk National University-Biomedical Research
Institute of Chonbuk National University Hospital, Jeonju, 54907, Republic of Korea
Corresponding author: Hee-Kwon Kim. E-mail: hkkim717@jbnu.ac.kr; Tel.: +82 63 250 2768;
Fax: +82 63 255 1172.
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Abstract: A practical method for the direct synthesis of amide compounds is described. Using
small quantities of DBU as a catalyst, the direct conversion of 2,2,2-trichloroethyl esters to their
corresponding amides was readily achieved. Based on this protocol, various amide compounds
were successfully synthesized in high yield, suggesting a promising approach for the practical
one-pot aminolysis from 2,2,2-trichloroethyl protected esters.
Keywords: Amide, DBU, Trichloroethyl ester, Organocatalyst.
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Introduction
Amides are one of the most common functional groups and play a crucial role in living
systems as amino acid linkage sites in protein.1,2 Amide bond formation via the acylation of
amines is one of the most important organic reactions, and is frequently employed in the
synthesis of bioactive molecules. Exemplary amide-containing pharmaceuticals include
antibiotics, anticancer agents, local anesthetics, and angiotensin-converting enzyme inhibitors.3-7
Additionally, many biologically active compounds contain amide bonds within their structures.8-
12
Strategies for the synthesis of amides have been developed for many years, yielding a
variety of synthetic protocols for the formation of amide bonds.13-15 Coupling reactions or two-
step processes including the activation of a carboxylic acid and the reaction of an amine are
commonly used methods to synthesize amides.16,17 The acylation of amines using acid chlorides
is a popular method to synthesize amides; however, formation of ketenes via reaction of an acyl
chloride containing a proton at an α-stereocenter will erode the stereochemistry of the
substrate.18-21 Acyl azides and anhydrides have also been used to generate amide bonds.22
However, these methods have not been universally applicable across various multi-step synthesis
reactions. The development of a simple, safe, and widely applicable amidation protocol is thus
important to organic synthesis.
Carboxylic acids are commonly employed in their protected form as esters during many
chemical syntheses. Methyl esters are generally employed to synthesis amide with various
catalysts.23-25 Nevertheless, these reactions require high temperatures and long reaction times to
obtain the products. Among several protecting groups, the 2,2,2-trichloroethyl group is known to
be an efficient carboxylic acid protecting group and is also easily deprotected via reductive
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methods.26-28 Usually, two separate steps are required to prepare amides from 2,2,2-trichloroethyl
esters: removal of the ester group and production of new amides via treatment with amines.
An alternative approach is the direct aminolysis of 2,2,2-trichloroethyl esters with primary
and secondary amines as it could lead to a reduction in cost, time, and waste. However, the direct
synthesis of amides using 2,2,2-trihaloethyl esters is rarely reported. Burke et al. employed
phosphorus(III) compounds to achieve the conversion of a 2,2,2-trihaloethyl ester to an amide
(Scheme 1).29 However, the drawback of producing halogenic acids may affect compounds
bearing acid-sensitive functional groups; the method also did not use a catalytic amount of
reagent.
The development of a new synthetic methodology employing a small quantity of catalyst is
useful for organic synthesis by offering a new synthetic approach within the chemist’s toolbox.
The direct aminolysis of 2,2,2-trichloroethyl esters in the presence of a catalytic amount of base
is an attractive approach to the synthesis of amides. To the best of our knowledge, this route to
amides has not been reported. Herein, we describe the synthesis of amides from 2,2,2-
trichloroethyl esters by aminolysis using primary and secondary amines and a catalytic amount
of DBU.
Scheme 1
Results and discussion
2,2,2-Trichloroethyl benzoate and n-butylamine were employed as model substrates to
determine the organic catalytic reagents needed for the amidation reaction. Reactions were
performed using 1.0 equiv. of 2,2,2-trichloroethyl benzoate and 1.4 equiv. of n-butylamine in the
presence of a catalytic amount of base. Also, the control reaction without any catalysts was
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carried out. First, we screened a series of commercially available organic reagents including 1,8-
diazabicyclo[5.4.0]undec-7-ene
(DBU),
pyridine,
triethylamine
(Et3N),
N,N-
diisopropylethylamine (DIPEA),
4-dimethylaminopyridine
(DMAP),
1,5-
diazabicyclo[4.3.0]non-5-ene (DBN) and 1,4-diazabicyclo[2.2.2]octane (DABCO) as well as
inorganic bases (NaHCO3, K2CO3) to determine the best catalyst. 0.2 equiv. of each catalyst was
tested to determine the best reagent for conversion of the desired amide after reacting for 12 h.
As can be seen in Table 1, the yields were affected by the different catalysts. Without any
catalyst, low yield of product was observed. The inorganic catalyst bases (NaHCO3, K2CO3)
displayed a moderate activity, while the organic reagents exhibited various levels of activity. The
catalytic activities of pyridine, DIPEA, DABCO, DMAP, and Et3N were considered moderate,
while DBN and DBU exhibited high activity over a reaction period of 12 h. In particular, when
DBU was employed for the amidation reaction, the yield increased to 95%. There was also no
significant difference in yield (>90%, Table 1, entry 7-8) when 0.2 equiv. or 0.5 equiv. of DBU
was used for the reaction after a period of 12 h. Based on the yields, DBU was chosen as the
catalyst for further studies.
Figure 1
Table 1
Different solvents were subsequently tested in this reaction to find optimized condition.
Reactions performed in toluene resulted in a moderate amide yield, whereas THF, 1,4-dioxane,
PhCF3, and CH3CN were shown to be effective solvents with regard to producing the desired
amide (Table 2 entries 1,3,4, and 5: 82% for THF, 87% for 1,4-dioxane, 83% for PhCF3, and 95%
for CH3CN). Based on these results, CH3CN was determined to be the best solvent among others
for the amidation reaction.
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We next investigated the effects of temperature on the synthesis of amides. Using 20 mol%
of DBU and CH3CN solvent, reactions were performed at various temperatures (room
temperature, 40 °C, 60 °C, and 80 °C). The reaction temperature significantly affected the
conversion yield of the corresponding amide. Not surprisingly, the yield of the reaction after 12 h
increases with increasing temperature (Table 2, entries 5-8).
Table 2
With optimized experimental conditions, the scope of the methodology was examined
using various 2,2,2-trichloroethyl esters and primary and secondary amines (Table 3, Chart 1).
First, aromatic compounds were investigated as substrates. 2,2,2-Trichloroethyl benzoate. Aryl
esters were converted to the corresponding amides in high yield (entries 1-10, table 3). The effect
of electron-donating and electron-withdrawing groups on the rate of conversion to aryl esters to
product was determined. As expected, an electron withdrawing p-NO2 group on the ester
increased the rate of conversion to product (Figure 2a) as almost complete conversion to product
was achieved within one hour. In contrast, an electron donating p-Me group on the ester
decreased the rate (Figure 2c) as 12 h was required to achieve 80 % conversion to product with
this ester. Again, DBU was the most effective catalyst for both of these reactions (Figures 2a and
c).
Figure 2
We also extended the synthetic method for the utilization of secondary amines. The
reaction proceeds well with both primary and secondary amines (entries 4, 5, 7, 9, 10, Table 3).
Aliphatic esters were also effective substrates (entries 11-22, Table 3). Even 2,2,2-
trichloroethyldiphenylacetate, which contains a bulky diphenylmethyl moiety, was converted to
the corresponding amide in high yield (Table 3, entries 21 and 22). In additions, the reaction of
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the TCE ester of N-Boc-D-phenylalanine (1k), a substrate with stereocenter adjacent to the ester
group, with benzyl amine produced the corresponding amide 3w with considerable epimerization
at the α-stereocentre. The product 3w was isolated in only 23% enantiomeric excess at the end of
the reaction.
Table 3
Next, a scale-up amidation reaction from 2,2,2-trichloroethyl esters was performed
(Scheme 2). The reaction to prepare amide was proven to be scalable and practical because the
gram-scale reaction was also efficiently carried out. The reaction of 2,2,2-trichloroethyl benzoate
1a (20.0 mmol, 1.0 equiv., 5.04 g) and n-butylamine 2a (30.0 mmol, 1.5 equiv.) produced the
corresponding amide 3a in 92% yield under optimized reaction conditions.
Scheme 2
We propose a reaction pathway based on a previous report31 that used DBU as a nucleophilic
catalyst for preparing amides from acyl imidazoles. As shown in Figure 3, DBU attacks the
carbonyl group of the ester to form intermediate B. Intermediate B then reacts with the amine to
generate the amide.
Figure 3
Chart 1
Conclusion
In summary, we described a practical one-pot method for the preparation of various amide
compounds. DBU was shown to be an efficient catalyst for the synthesis of a variety of target
amide structures. Our results suggest that the direct one-pot synthesis of amide compounds from
2,2,2-trichloroethyl esters in the presence of DBU catalyst in MeCN is a highly effective method.
Experimental section
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General
Solvents used as reaction media were dried over pre-dried molecular sieves (4 Å) in a microwave
oven. Solvents for extraction and chromatography were reagent grade and used as received.
Reagents were purified prior to use unless otherwise stated following the guidelines of Perrin and
Armarego.30 Column chromatography was performed with silica gel 60 (70−230 mesh) using a
1
13
mixture of ethylacetate/hexane as eluent. H and C NMR spectra were, respectively, recorded
on a 600 MHz or 400 MHz (1H NMR), 150 MHz or 100 MHz (13C NMR) spectrometer in
deuterated chloroform (CDCl3) with tetramethylsilane(TMS) as an internal reference. Data are
reported as (ap = apparent, s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br =
broad; coupling constant(s) in Hz, integration). High-resolution mass spectroscopy was
performed using 6200 series TOF/6500 series Q-TOF B.08.00 (B8058.0). The identity of the
1
13
known compounds was established by the comparison of their H and C NMR peaks with the
authentic values.
General procedure for the preparation of amide compounds (3a-3v)
To a stirred solution of 2,2,2-trichloroethyl benzoate (1a, 0.260 g, 1.03 mmol) in MeCN (2 mL)
at room temperature was added n-butylamine (0.105 g, 1.44 mmol) and DBU (0.31 g, 0.20
mmol). The mixture was stirred for 12 h at 80 °C, allowed to cool to room temperature and
extracted with CH2Cl2 (2 x 20 mL). The organic layer was dried over sodium sulfate and
concentrated under reduced pressure. The resulting residue was then purified by flash column
chromatography on silica gel with hexane-EtOAc as eluent to afford the desired product 3a
(0.173 g, 95%).
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N-butylbenzamide (3a)
Light yellow oil; 1H NMR (600 MHz, CDCl3) δ 7.74 (d, J = 6.6 Hz, 2H), 7.45 (t, J = 7.8 Hz, 1H),
7.39 (t, J = 7.2 Hz, 2H), 6.30 (s, 1H), 3.41 (q, J = 7.2 Hz, 2H), 1.57 (quint, J = 7.2 Hz, 2H), 1.38
13
(sextet, J = 7.8 Hz, 2H), 0.92 (t, J = 7.8 Hz, 3H); C NMR (150 MHz, CDCl3) δ 167.7, 134.9,
131.4, 128.6 (2C), 127.0 (2C), 39.9, 31.8, 20.2, 13.9; HRMS (ESI) m/z (M+H)+ calcd for
C11H16NO = 178.1232; found 178.1226.
N-benzylbenzamide (3b)
White solid. m.p. 107-109 °C; 1H NMR (400 MHz, CDCl3) δ 7.90 (dd, J = 8.4, 1.6 Hz, 2H), 7.51
(tt, J = 7.2, 2.0 Hz, 1H), 7.43 (t, J = 7.6 Hz, 2H), 7.39-7.29 (m, 5H), 6.71 (s, 1H), 4.64 (d, J = 6.4
Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 167.4, 138.3, 134.3, 131.5, 128.7 (2C), 128.6 (2C),
127.9 (2C), 127.6, 127.0 (2C), 40.1; HRMS (ESI) m/z (M+H)+ calcd for C14H14NO = 212.1075;
found 212.1070.
4-methyl-N-phenethylbenzamide (3c)
White solid; m.p. 83-85°C; 1H NMR (600 MHz, CDCl3) δ 7.58 (d, J = 8.4 Hz, 2H), 7.31 (t, J =
7.8 Hz, 2H), 7.21-7.21 (m, 3H), 7.18 (d, J = 7.2 Hz, 2H), 6.19 (s, 1H), 3.69 (q, J = 6.6 Hz, 2H),
2.91 (t, J = 7.2 Hz, 2H), 2.37 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 167.5, 141.9, 139.1, 131.8,
129.3 (2C), 128.9 (2C), 128.8 (2C), 126.9 (2C), 126.6, 41.2, 35.8, 21.5; HRMS (ESI) m/z
(M+H)+ calcd for C16H18NO = 240.1388; found 240.1383.
Pyrrolidin-1-yl(p-tolyl)methanone (3d)
White solid; m.p. 81-83°C; 1H NMR (600 MHz, CDCl3) δ 7.40 (d, J = 8.4 Hz, 2H), 7.17 (d, J =
13
8.4 Hz, 2H), 3.70-3.30 (m, 4H), 2.35 (s, 3H), 1.89 (br s, 4H); C NMR (150 MHz, CDCl3) δ
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169.8, 139.8, 134.3, 128.8 (2C), 127.2 (2C), 49.6, 46.2, 26.4, 24.5, 21.4; HRMS (ESI) m/z
(M+H)+ calcd for C12H16NO = 190.1232; found 190.1226.
(4-methoxyphenyl)(pyrrolidin-1-yl)methanone (3e)
White solid; m.p. 78-80 °C; 1H NMR (600 MHz, CDCl3) δ 7.48 (d, J = 9.0 Hz, 2H), 6.87 (d, J =
9.0 Hz, 2H), 3.80 (s, 3H), 3.53 (br s, 4H), 1.88 (br s, 4H); 13C NMR (150 MHz, CDCl3) δ 169.4,
160.7, 129.4, 129.1 (2C), 113.4 (2C), 55.3, 49.8, 46.3, 26.5, 24.4; HRMS (ESI) m/z (M+H)+
calcd for C12H16NO2 = 206.1181; found 206.1176.
N-butyl-4-chlorobenzamide (3f)
White solid; m.p. 79-81 °C; 1H NMR (600 MHz, CDCl3) δ 7.68 (d, J = 7.8 Hz, 2H), 7.36 (d, J =
8.4 Hz, 2H), 6.29 (s, 1H), 3.41 (q, J = 7.8 Hz, 2H), 1.56 (quint, J = 6.6 Hz, 2H), 1.38 (sextet, J =
7.8 Hz, 2H), 0.92 (t, J = 7.8 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 166.6, 137.6, 133.2, 128.8
(2C), 128.4 (2C), 40.0, 31.8, 20.2, 13.9; HRMS (ESI) m/z (M+H)+ calcd for C11H15ClNO =
212.0842; found 212.0837.
(4-chlorophenyl)(pyrrolidin-1-yl)methanone (3g)
White solid; m.p. 73-75 °C; 1H NMR (600 MHz, CDCl3) δ 7.44 (d, J = 9.0 Hz, 2H), 7.34 (d, J =
13
8.4 Hz, 2H), 3.70-3.30 (m, 4H), 1.90 (br s, 4H); C NMR (150 MHz, CDCl3) δ 168.5, 135.8,
135.5, 128.7 (2C), 128.5 (2C), 49.6, 46.3, 26.4, 24.4; HRMS (ESI) m/z (M+H)+ calcd for
C11H13ClNO = 210.0686; found 210.0680.
N-butyl-4-nitrobenzamide (3h)
White solid; m.p. 102-104 °C; 1H NMR (600 MHz, CDCl3) δ 8.25 (d, J = 9.0 Hz, 2H), 7.90 (d, J
= 9.0 Hz, 2H), 6.33 (s, 1H), 3.46 (q, J = 6.6 Hz, 2H), 1.60 (quint, J = 6.6 Hz, 2H), 1.40 (sextet, J
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13
= 7.2 Hz, 2H), 0.94 (t, J = 7.8 Hz, 3H); C NMR (150 MHz, CDCl3) δ 165.6, 149.5, 140.5,
128.1 (2C), 123.9 (2C), 40.2, 31.6, 20.2, 13.8; HRMS (ESI) m/z (M+H)+ calcd for C11H15N2O3 =
223.1083; found 223.1077.
(4-nitrophenyl)(pyrrolidin-1-yl)methanone (3i)
White solid; m.p. 92-94 °C; 1H NMR (600 MHz, CDCl3) δ 8.24 (d, J = 8.4 Hz, 2H), 7.65 (d, J =
9.0 Hz, 2H), 3.63 (t, J = 6.6 Hz, 2H), 3.35 (t, J = 6.6 Hz, 2H), 1.98 (quint, J = 6.6 Hz, 2H), 1.89
13
(quint, J = 6.6 Hz, 2H); C NMR (150 MHz, CDCl3) δ 167.4, 148.4, 143.2, 128.2 (2C), 123.8
(2C), 49.5, 46.4, 26.5, 24.4; HRMS (ESI) m/z (M+H)+ calcd for C11H13N2O3 = 221.0926; found
221.0921.
Morpholino(4-nitrophenyl)methanone (3j)
White solid; m.p. 104-106 °C; 1H NMR (600 MHz, CDCl3) δ 8.24 (d, J = 8.4 Hz, 2H), 7.55 (d, J
13
= 9.0 Hz, 2H), 3.77 (s, 4H), 3.60 (s, 2H), 3.58 (s, 2H); C NMR (150 MHz, CDCl3) δ 168.1,
148.5, 141.5, 128.2 (2C), 124.0 (2C), 66.8 (2C), 48.1, 42.6; HRMS (ESI) m/z (M+H)+ calcd for
C11H13N2O3 = 237.0875; found 237.0870.
N-(4-methylbenzyl)butyramide (3k)
White solid; m.p. 75-77 °C; 1H NMR (600 MHz, CDCl3) δ 7.15 (d, J = 8.4 Hz, 2H), 7.12 (d, J =
8.4 Hz, 2H), 5.77 (s, 1H), 4.37 (d, J = 6.0 Hz, 2H), 2.32 (s, 3H), 2.16 (t, J = 7.2 Hz, 2H), 1.67
(sextet, J = 7.8 Hz, 2H), 0.93 (t, J = 7.8 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 172.9, 137.3,
135.5, 129.4 (2C), 127.9 (2C), 43.4, 38.8, 21.2, 19.3, 13.9; HRMS (ESI) m/z (M+H)+ calcd for
C12H18NO = 192.1388; found 192.1383.
N-phenethylbutyramide (3l)
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White solid; m.p. 49-51 °C; 1H NMR (600 MHz, CDCl3) δ 7.29 (t, J = 7.2 Hz, 2H), 7.21 (t, J =
7.2 Hz, 1H), 7.17 (d, J = 6.6 Hz, 2H), 5.59 (s, 1H), 3.50 (q, J = 7.2 Hz, 2H), 2.80 (t, J = 6.6 Hz,
13
2H), 2.08 (t, J = 7.8 Hz, 2H), 1.61 (sextet, J = 7.8 Hz, 2H), 0.90 (t, J = 7.2 Hz, 3H); C NMR
(150 MHz, CDCl3) δ 173.1, 139.0, 128.8 (2C), 128.7 (2C), 126.6, 40.6, 38.8, 35.8, 19.2, 13.9;
HRMS (ESI) m/z (M+H)+ calcd for C12H18NO = 192.1388; found 192.1383.
3-methyl-N-phenethylbutanamide (3m)
White solid; m.p. 75-77 °C; 1H NMR (600 MHz, CDCl3) δ 7.29 (t, J = 7.8 Hz, 2H), 7.21 (t, J =
7.8 Hz, 1H), 7.17 (d, J =7.2 Hz, 2H), 5.57 (s, 1H), 3.50 (q, J = 7.2 Hz, 2H), 2.80 (t, J = 6.6 Hz,
13
2H), 2.06 (nonet, J = 6.0 Hz, 1H), 1.96 (d, J = 7.2 Hz, 2H), 0.90 (d, J = 7.2 Hz, 6H); C NMR
(150 MHz, CDCl3) δ 172.6, 139.0, 128.8 (2C), 128.7 (2C), 126.6, 46.2, 40.7, 35.9, 26.2, 22.5
(2C); HRMS (ESI) m/z (M+H)+ calcd for C13H20NO = 206.1545; found 206.1539.
N-(furan-2-ylmethyl)-3-methylbutanamide (3n)
Light yellow oil; 1H NMR (600 MHz, CDCl3) δ 7.31 (s, 1H), 6.28 (dd, J = 2.4, 1.2 Hz, 1H), 6.19
(d, J = 3.6 Hz, 1H), 5.93 (s, 1H), 4.39 (d, J = 6.6 Hz, 2H), 2.10 (nonet, J = 7.2 Hz, 1H), 2.03 (d, J
13
= 6.6 Hz, 2H), 0.91 (d, J = 6.0 Hz, 6H); C NMR (150 MHz, CDCl3) δ 172.4, 151.5, 142.2,
110.5, 107.4, 46.0, 36.4, 26.2, 22.5 (2C); HRMS (ESI) m/z (M+H)+ calcd for C10H16NO2 =
182.1181; found 182.1176.
N-benzylcyclohexanecarboxamide (3o)
White solid; m.p. 112-114 °C; 1H NMR (600 MHz, CDCl3) δ 7.31 (t, J = 6.6 Hz, 2H), 7.27-7.22
(m, 3H), 5.85 (s, 1H), 4.40 (d, J = 6.6 Hz, 2H), 2.10 (tt, J = 12.0, 3.0 Hz, 1H), 1.86 (dd, J = 13.8,
1.8 Hz, 2H), 1.81-1.72 (m, 2H), 1.69-1.62 (m, 1H), 1.45 (ddd, J = 24.6, 12.0, 2.4 Hz, 2H), 1.29-
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1.17 (m, 3H); 13C NMR (150 MHz, CDCl3) δ 176.1, 138.6, 128.8 (2C), 127.8 (2C), 127.5, 45.6,
43.4, 29.8 (2C), 25.8 (3C); HRMS (ESI) m/z (M+H)+ calcd for C14H20NO = 218.1545; found
218.1539.
N-phenethylcyclohexanecarboxamide (3p)
White solid; m.p. 95-97 °C; 1H NMR (600 MHz, CDCl3) δ 7.29 (t, J = 7.8 Hz, 2H), 7.22 (t, J =
7.8 Hz, 1H), 7.17 (d, J = 7.8 Hz, 2H), 5.49 (s, 1H), 3.49 (q, J = 6.6 Hz, 2H), 2.79 (t, J = 6.6 Hz,
2H), 2.00 (tt, J = 11.4, 3.0 Hz, 1H), 1.85-1.70 (m, 4H), 1.69-1.59 (m, 1H), 1.45-1.31 (m, 2H),
13
1.27-1.14 (m, 3H); C NMR (150 MHz, CDCl3) δ 176.2, 139.1, 128.9 (2C), 128.7 (2C), 126.6,
45.6, 40.4, 35.8, 29.7 (2C), 25.8 (3C); HRMS (ESI) m/z (M+H)+ calcd for C15H22NO = 232.1701;
found 232.1696.
N-benzyl-3-phenylpropanamide (3q)
White solid; m.p. 85-87 °C; 1H NMR (600 MHz, CDCl3) δ 7.30-7.22 (m, 5H), 7.22-7.16 (m, 3H),
7.13 (d, J = 7.2 Hz, 2H), 5.73 (s, 1H), 4.37 (d, J = 6.6 Hz, 2H), 2.91 (t, J = 7.8 Hz, 2H), 2.50 (t, J
= 8.4 Hz, 2H); 13C NMR (150 MHz, CDCl3) δ 172.0, 140.8, 138.2, 128.7 (2C), 128.6 (2C), 128.5
(2C), 127.8 (2C), 127.5, 126.3, 43.6, 38.6, 31.8; HRMS (ESI) m/z (M+H)+ calcd for C16H18NO =
240.1388; found 240.1383.
N-butyl-3-phenylpropanamide (3r)
White solid; m.p. 34-36 °C; 1H NMR (600 MHz, CDCl3) δ 7.25 (t, J = 7.8 Hz, 2H), 7.19-7.15 (m,
3H), 5.53 (s, 1H), 3.18 (q, J = 7.2 Hz, 2H), 2.93 (t, J = 7.8 Hz, 2H), 2.44 (t, J = 8.4 Hz, 2H), 1.38
13
(quint, J = 7.8 Hz, 2H), 1.24 (sextet, J = 7.2 Hz, 2H), 0.86 (t, J = 6.6 Hz, 3H); C NMR (150
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MHz, CDCl3) δ 172.1, 141.0, 128.6 (2C), 128.4 (2C), 126.3, 39.3, 38.6, 31.9, 31.7, 20.1, 13.8;
HRMS (ESI) m/z (M+H)+ calcd for C13H20NO = 206.1545; found 206.1539.
N-isobutyl-3-phenylpropanamide (3s)
White solid; m.p. 59-61 °C; 1H NMR (600 MHz, CDCl3) δ 7.26 (t, J = 7.8 Hz, 2H), 7.21-7.16 (m,
3H), 5.46 (s, 1H), 3.02 (t, J = 6.6 Hz, 2H), 2.95 (t, J = 7.2 Hz, 2H), 2.47 (t, J = 8.4 Hz, 2H), 1.66
13
(nonet, J = 6.6 Hz, 1H), 0.80 (d, J = 7.2 Hz, 6H); C NMR (150 MHz, CDCl3) δ 172.1, 141.0,
128.6 (2C), 128.4 (2C), 126.3, 46.9, 38.7, 31.9, 28.5, 20.1 (2C); HRMS (ESI) m/z (M+Na)+ calcd
for C13H19NONa = 228.1364; found 228.1359.
N-(furan-2-ylmethyl)-3-phenylpropanamide (3t)
White solid; m.p. 60-62 °C; 1H NMR (600 MHz, CDCl3) δ 7.31 (d, J = 2.4 Hz, 1H), 7.25 (t, J =
7.2 Hz, 2H), 7.20-7.14 (m, 3H), 6.28 (dd, J = 3.0, 1.8 Hz, 1H), 6.13 (d, J = 3.0 Hz, 1H), 5.82 (s,
1H), 4.37 (d, J = 5.4 Hz, 2H), 2.95 (d, J = 7.8 Hz, 2H), 2.47 (d, J = 7.8 Hz, 2H); 13C NMR (150
MHz, CDCl3) δ 172.0, 151.3, 142.2, 140.8, 128.6 (2C), 128.4 (2C), 126.3, 110.5, 107.5, 38.4,
36.5, 31.7; HRMS (ESI) m/z (M+H)+ calcd for C14H15NO2 = 230.1181; found 230.1176.
N-hexyl-2,2-diphenylacetamide (3u)
White solid; m.p. 74-76 °C; 1H NMR (400 MHz, CDCl3) δ 7.40-7.32 (m, 4H), 7.32-7.25 (m, 6H),
5.65 (s, 1H), 4.95 (s, 1H), 3.29 (q, J = 7.2 Hz, 2H), 1.50 (quint, J = 7.2 Hz, 2H), 1.36-1.20 (m,
13
6H), 0.89 (d, J = 6.8 Hz, 3H); C NMR (150 MHz, CDCl3) δ 171.8, 139.5 (2C), 128.9 (4C),
128.8 (4C), 127.2 (2C), 59.3, 39.9, 31.4, 29.4, 26.5, 22.5, 14.0; HRMS (ESI) m/z (M+H)+ calcd
for C20H26NO = 296.2014; found 296.2009.
N-phenethyl-2,2-diphenylacetamide (3v)
14

Page 15 of 29
White solid; m.p. 111-113 °C; 1H NMR (600 MHz, CDCl3) δ 7.28 (t, J = 7.2 Hz, 4H), 7.27-7.18
(m, 5H), 7.15 (d, J = 7.8 Hz, 4H), 7.02 (d, J = 6.6 Hz, 2H), 5.61 (s, 1H), 4.87 (s, 1H), 3.54 (q, J =
13
7.2 Hz, 2H), 2.76 (t, J = 6.6 Hz, 2H); C NMR (150 MHz, CDCl3) δ 171.9, 139.4 (2C), 138.7,
129.0 (4C), 128.9 (6C), 128.7 (2C), 127.3 (2C), 126.6, 59.3, 40.9, 35.6; HRMS (ESI) m/z
(M+H)+ calcd for C22H22NO = 316.1701; found 316.1696.
(R)-tert-butyl 1-(benzylamino)-1-oxo-3-phenylpropan-2-ylcarbamate (3w)
1
White solid; m.p. 147-149 °C; H NMR (400 MHz, CDCl3) δ 7.33-7.24 (m, 6H), 7.23-7.18 (m,
2H), 7.18-7.06 (m, 2H), 6.20 ( br s, 1H), 5.13 ( br s, 1H), 4.45-4.30 (m, 3H), 3.15-3.03 (m, 2H),
1.40 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 171.0, 155.4, 137.7, 136.7, 129.3 (2C), 128.7 (2C),
128.6 (2C), 127.6 (2C), 127.4, 126.9, 80.2, 56.0, 43.4, 38.6, 28.2 (3C); HRMS (ESI) m/z (M+H)+
calcd for C21H27N2O3 = 355.2022; found 355.2016. [α ]16 -2.6 (c 1.00, CHCl3); HPLC
D
conditions: DAICEL CHIRALCEL AS-H, eluent: Hexane/2-Propanol = 9.0:1.0, flow: 1.0
mL/min, detection: 220 nm, tR: 12.74 min (major), 7.93 min (minor).
Acknowledgements
This research was supported by Basic Science Research Program through the National Research
Foundation of Korea (NRF) funded by the Ministry of Education (2018R1D1A1B07047572).
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Page 19 of 29
Table 1. Screening of catalytic agents for the synthesis of amide structures
O
O
Organic Cat.
MeCN
+
CCl3
H2N
O
N
H
1a
2a
3a
Entry Catalyst (equiv.) Time (h) Yield (%)b
1
2
3
4
5
6
7
8
9
10
Pyridine (0.2)
DABCO (0.2)
Et3N (0.2)
12
12
12
12
12
12
12
12
12
12
12
71
53
69
52
65
78
95
95
73
64
25
DIPEA (0.2)
DMAP (0.2)
DBN (0.2)
DBU (0.2)
DBU (0.5)
K2CO3 (0.2)
NaHCO3 (0.2)
None
11
a
Reaction conditions: 1a 2,2,2-trichloroethyl benzoate (1.0 mmol), amine (1.4 mmol), MeCN,
80 oC.
b Isolated yield after column purification.
19

Page 20 of 29
Table 2. Screening of reaction conditions for the preparation amide structures a
O
O
Organic Cat.
solvent, 12h
+
CCl3
H2N
O
N
H
1a
2a
3a
Entry Solvent
Temp
Yield (%)b
1
2
3
4
5
6
7
8
THF
80 oC
80 oC
80 oC
80 oC
80 oC
r.t.
82
56
87
83
95
41
53
64
Toluene
1,4-dioxane
PhCF3
CH3CN
CH3CN
CH3CN
CH3CN
40 oC
60 oC
a Reaction conditions: 1a 2,2,2-trichloroethyl benzoate (1.0 mmol), amine (1.4 mmol), 12h.
b Isolated yield after column purification.
20

Page 21 of 29
Table 3. Scope of amidation from 2,2,2-trichloroethyl estersa
O
O
R3
20 mol % DBU
R1
R3
R1
NH
CCl3 +
N
O
1
R4
2
MeCN
80 oC, 12h
R2
R4
R2
3
Entry Trichloroethyl ester Product
Yield(%)b Entry Trichloroethyl ester Product Yield(%)b
1
2
1a
1a
1b
1b
1c
1d
1d
1e
1e
1e
1f
3a
3b
3c
3d
3e
3f
96
94
88
90
87
93
94
90
87
93
93
94
13
14
15
16
17
18
19
20
21
22
23
1g
1g
1h
1h
1i
3m
3n
3o
3p
3q
3r
93
88
94
94
93
92
92
89
94
91
87
3
4
5
6
1i
7
3g
3h
3i
1i
3s
8
1i
3t
9
1j
3u
3v
3w
10
11
12
3j
1j
3k
3l
1k
1f
a Reaction conditions: 2,2,2-trichloroethyl ester (1.0 mmol), amine (1.4 mmol), DBU (0.2 mmol),
MeCN, 80 oC for 12 h,
b Isolated yields after column purification.
21

Page 22 of 29
Scheme and Figure Captions
Scheme 1. Synthesis of amide via 2,2,2-trichloroethyl esters
Scheme 2. The gram-scale reaction of 2,2,2-trichloroethyl benzoate 1a with n-butylamine 2a
Figure 1. Structures of basic organic reagents used for screening
Figure 2. The effects of aromatic substituents on the rate of amidation reaction
Figure 3. The proposed mechanism of aminolysis reaction
Chart 1. The structures of 2,2,2-trichloroethyl esters and amides
22

Page 23 of 29
Scheme 1. Synthesis of amide via 2,2,2-trichloroethyl esters
222x97mm (150 x 150 DPI)

Page 24 of 29
Scheme 2. The gram-scale reaction of 2,2,2-trichloroethyl benzoate 1a with n-butylamine 2a
150x35mm (150 x 150 DPI)

Page 25 of 29
Figure 1. Structures of basic organic reagents used for screening
115x62mm (150 x 150 DPI)

Page 26 of 29
100
90
80
70
60
50
40
30
20
10
0
DBU
O
Cl
Cl
Cl
DMAP
Pyridine
Et3N
O
O2N
0
2
4
6
8
10
12
Time (h)
A
100
90
80
70
60
50
40
30
20
10
0
DBU
DMAP
Pyridine
Et3N
O
Cl
Cl
O
Cl
0
2
4
6
8
10
12
B
Time (h)
100
90
80
70
60
50
40
30
20
10
0
O
Cl
Cl
O
Cl
H3C
DBU
DMAP
Pyridine
Et3N
0
2
4
6
8
10
12
Time (h)
C

Page 27 of 29
Figure 3. The proposed mechanism of aminolysis reaction
98x95mm (150 x 150 DPI)

Page 28 of 29
Chart 1. The structures of 2,2,2-trichloroethyl esters and amides
192x287mm (150 x 150 DPI)

Page 29 of 29
214x78mm (150 x 150 DPI)