An efficient procedure for chemoselective amidation from carboxylic acid and amine (ammonium salt) under mild conditions

Article abstract of DOI:10.1007/s11164-017-3229-4

Presented here is an efficient one-pot and catalyst-free procedure for the synthesis of amides starting from carboxylic acids and amine/ammonium salts using 2,2-dichloro-1,3-diisopropylimidazolidine-4,5-dione as the coupling agent. Reactions can proceed smoothly even with those bearing thermosensitive group(s) at ambient temperature, and the corresponding products of primary, secondary and tertiary amides can be afforded in moderate to excellent yields of up to 96%.

Full text of DOI:10.1007/s11164-017-3229-4

Res Chem Intermed
https://doi.org/10.1007/s11164-017-3229-4
An efcient procedure for chemoselective amidation
from carboxylic acid and amine (ammonium salt)
under mild conditions
Jianhui Li1,2 · Shaopo He1,2 · Haiqing Fu1,2 · Xin Chen1,2 · Min Tang1,2
·
Dela Zhang1,2 · Bo Wang1,2
Received: 3 April 2017 / Accepted: 10 December 2017
© Springer Science+Business Media B.V., part of Springer Nature 2017
Abstract Presented here is an efcient one-pot and catalyst-free procedure for
the synthesis of amides starting from carboxylic acids and amine/ammonium salts
using 2,2-dichloro-1,3-diisopropylimidazolidine-4,5-dione as the coupling agent.
Reactions can proceed smoothly even with those bearing thermosensitive group(s)
at ambient temperature, and the corresponding products of primary, secondary and
tertiary amides can be aforded in moderate to excellent yields of up to 96%.
Keywords Chemoselective · Amidation · 2,2-Dichloro-1,3-
diisopropylimidazolidine-4,5-dione · Carboxylic acid
Introduction
Amides are key building blocks in natural and synthetic compounds [1–6], and their
formation is one of the most important functional group transformations in synthetic
organic chemistry [7, 8]. Over recent decades, numerous methods have emerged
for their synthesis [9]. Apart from carboxylic acids, amides can also be synthesized
from alcohols [10–13], aldehydes [1, 14–19], esters [20, 21] and nitriles [22]. A sur-
vey conducted by the three major pharmaceutical companies indicated that 93% of
Electronic supplementary material The online version of this article (https://doi.org/10.1007/
s11164-017-3229-4) contains supplementary material, which is available to authorized users.
*
Bo Wang
wangbo@hainu.edu.cn; bo.wang@hainu.edu.cn
1
2
Key Laboratory of Advanced Materials of Tropical Island Resources (Hainan University),
Ministry of Education, No. 58 Renmin Ave., Haikou 570228, People’s Republic of China
State Key Lab of Marine Resource Utilisation in South China Sea, Hainan University, No. 58
Renmin Ave., Haikou 570228, People’s Republic of China
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J. Li et al.
N-acylations in the synthesis of 128 drug candidates are carried out by stoichio-
metric activation of carboxylic acids [2, 23, 24]. Though the formed amide bond
has favourable thermodynamic stability, the simple dehydration reaction between a
carboxylic acid and an amine is disturbed by large activation energy because of the
initial formation of stable carboxylic acid ammonium salt upon mixing [2]. Such a
problem can be solved by performing reactions at high temperatures (> 160 °C) that
are not compatible with substrates, especially those bearing thermosensitive func-
tional substituent(s) [2, 9]. Conventionally, most of the developed methods required
heavy-metal catalyst, strong acid and/or harsh reaction conditions, or to convert car-
boxylic acids into more reactive species such as acyl halides, mixed anhydrides or
active esters prior to further reaction with amines [2, 7].
Some high-efciency coupling reagents have been applied to the formation of
amides from carboxylic acids and related amines/ammonium salts. As the seminal
work in this area, Katritzky et al. employed N-acylbenzotriazoles as the coupling
agent for the synthesis of amides [25, 26]. Hardee et al. described a two-step proce-
dure using 3,3-dichloro-1,2-diisopropylcyclopropene as aromatic cation to activate
carboxylic acids via nucleophilic acyl substitution to form acid chlorides, and amides
were generated upon the introduction of amine to the system [27] (Scheme 1a).
Nguyen et al. employed 7,7-dichlorocyclohepta-1,3,5-triene as the coupling reagent
in a two-step reaction for rapid conversion of carboxylic acid to amide via the for-
mation of intermediacy of acid chloride [28, 29] (Scheme 1b). Though satisfactory
yields could be achieved, these methods still sufer from limited substrate scope,
especially those bearing thermosensitive group(s). Usually, a chemical group protec-
tion process is needed before amidation reactions, and after reaction is the deprotec-
tion process, leading to a large wastewater stream not considered environmentally
benign.
Inspired by efcient halodehydration of alcohols and chloridization using
2,2-dichloro-1,3-dicyclohexylimidazolidine-4,5-dione at room temperature (r.t.)
[30], (Scheme 1c) we envisioned a one-pot procedure using as coupling reagent
2,2-dichloro-1,3-diisopropylimidazolidine-4,5-dione (DCDD), carboxylic acids and
amines or ammonium salt for the preparation of the corresponding amides under
mild conditions. To the best of our knowledge, this presents the frst example using
DCDD for one-pot synthesis of amides, especially those bearing thermosensitive
group(s) without group protection and deprotection processes.
Experimental
General methods
Unless otherwise noted, all procedures were performed under an atmosphere of
nitrogen. Apart from DCDD, all chemicals (analytical grade) were commercially
available and purchased from Aladdin (Shanghai, China). DCDD was prepared via
reaction of N,N′-diisopropylcarbodiimide (DIC) and oxalyl chloride. The solvent
CH2Cl2 was dried by calcium hydrate to remove water and stored over molecular
sieves. 1H nuclear magnetic resonance (NMR, 400 MHz) and 13C NMR (100 MHz)
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An efcient procedure for chemoselective amidation from…
Previous work
(a)
(b)
(c)
This work
Scheme 1 One-pot synthesis of amides from carboxylic acids and amines or ammonium salt
spectra were recorded on a Bruker Avance 400 spectrometers in dimethyl sulfox-
ide (DMSO) or chloroform (CDCl3). All chemical shifts (δ) were quoted in parts
per million (ppm) and reported relative to an internal tetramethylsilane (TMS, δ
0.00) standard. The following abbreviations were used to explain the multiplicities:
s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet. Yields of prod-
ucts were measured by high-performance liquid chromatography (HPLC) analysis
using a Shimadzu instrument equipped with a Wonda Sil C18-WR column (5 µm).
High-resolution mass spectrometry (HRMS) spectra were recorded on a Shimadzu
liquid chromatography/mass spectrometry ion-trap time-of-fight (LCMS-IT-TOF)
instrument.
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J. Li et al.
General procedure for the synthesis of DCDD
A 50-mL three-necked fask was charged with DIC (1.1 mmol), CH2Cl2 (10 mL)
and a stir bar. The resulting solution was cooled to 0 °C using an ice bath, and oxalyl
chloride (1.1 mmol dissolved in 3 mL CH2Cl2) was added dropwise over 10 min-
utes. The ice bath was then removed and the reaction was stirred for another hour
at ambient temperature. DCDD was determined by HPLC analysis with a yield of
95%, and stored for later use.
General procedure for the synthesis of amides
Carboxylic acid (1 mmol), amine or ammonium chloride (1 mmol) and triethyl
amine (3 or 4 mmol) were introduced to the solution of DCDD (1.05 mmol) and
stirred at r.t. for 3 h. After reaction, the mixture was distilled under evacuation to
remove CH2Cl2. Then, 15 mL of H2O was added to the residues and a solution pH
value of 8.0 was set with potassium carbonate. Next, the mixture was extracted with
ethyl acetate (25 mL × 3), and the organic layer was isolated and combined. The
organic layer was washed with brine and dried over anhydrous MgSO4. Finally, the
solvent was removed, and the residue was chromatographed on silica gel using hex-
ane/ethyl acetate as eluent to give the corresponding pure product.
Typical procedure for treatment of the carboxylic acids with oxalyl chloride
followed by reaction with amines
Carboxylic acid (1 mmol) and oxalyl chloride (1.05 mmol) were introduced to
CH2Cl2 (10 mL) and stirred at r.t. for 0.5 h. Then, amine (1 mmol) and triethyl amine
(3 mmol) were added to CH2Cl2 (3 mL), dissolved and slowly added dropwise to the
previous solution. The resulting solution was stirred for 3 h. After complete reac-
tion, samples were taken and the yield of corresponding amides was determined by
HPLC analysis utilising a C18 column.
Morpholino(phenyl)methanone (3a) [31] White solid, m.p. 74–75 °C (lit.
1
73–75 °C) [32]. H NMR (400 MHz, CDCl3): δ = 7.28 (m, 5H), 3.30–3.97 (m,
8H); 13C NMR (100 MHz, CDCl3): δ = 170.2, 135.3, 129.7, 128.4, 127.0, 66.7,
48.1, 42.5. HRMS m/z (ESI) calculated (calcd.) for C11H14NO2 (M + H)+ 192.1019,
found 192.1097.
N,N‑Diethylbenzamide (5a) [33] Light yellow oil, m.p. 42.5–43 °C (lit.
1
42–43 °C) [34]. H NMR (400 MHz, CDCl3): δ = 7.38 (m, 5H), 3.58 (s, 2H), 3.29
(s, 2H), 1.28 (s, 3H), 1.14 (s, 3H); 13C NMR (100 MHz, CDCl3): δ = 171.3, 137.3,
129.1, 128.4, 126.3, 43.3, 39.2, 14.3, 12.9. HRMS m/z (ESI) calcd. for C11H16NO
(M + H)+ 178.1226, found 178.1226.
N,N‑Dipropylbenzamide (5b) [33] Yellow oil, m.p. 43.5–45 °C. 1H NMR
(400 MHz, CDCl3): δ = 7.32–7.54 (m, 5H), 3.45 (s, 2H), 3.14 (s, 2H), 1.67 (s, 2H),
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An efcient procedure for chemoselective amidation from…
1.51 (d, J = 4.2 Hz, 2H), 0.96 (s, 3H), 0.72 (s, 3H); 13C NMR (100 MHz, CDCl3):
δ = 171.8, 137.4, 129.0, 128.3, 126.4, 50.7, 46.3, 21.9, 20.7,11.4, 11.0. HRMS m/z
(ESI) calcd. for C13H20NO (M + H)+ 206.1539, found 206.1541.
1
N,N‑Dibutylbenzamide (5c) [33] Light yellow oil, m.p. 48.5–50.5 °C. H NMR
(400 MHz, CDCl3): δ = 7.27–7.49 (m, 5H), 3.43 (s, 2H), 3.12 (s, 2H), 1.59 (s, 2H),
1.38 (d, J = 8.9 Hz, 4H), 1.06 (d, J = 4.0 Hz, 2H), 0.91 (s, 3H), 0.70 (s, 3H); 13C
NMR (100 MHz, CDCl3): δ = 171.7, 137.4, 129.8, 129.0, 128.3, 128.1, 126.4, 48.8,
44.5, 30.8, 29.7, 19.70, 13.9, 13.6. HRMS m/z (ESI) calcd. for C15H24NO (M + H)+
234.1852, found 234.1855.
Phenyl(piperidin‑1‑yl)methanone (5d) [33] Yellow oil, m.p. 43–44 °C (lit.
1
45–47 °C) [35]. H NMR (400 MHz, CDCl3): δ = 7.36 (m, 5H), 3.68 (s, 2H),
7.31 (d, 2H), 1.64 (s, 4H), 1.48 (s, 2H); 13C NMR (100 MHz, CDCl3): δ = 170.3,
136.5, 129.3, 128.4, 126.8, 48.8, 43.1, 26.5, 25.6, 24.6. HRMS m/z (ESI) calcd. for
C12H16NO (M + H)+ 190.1226, found 190.1273.
Phenyl(pyrrolidin‑1‑yl)methanone (5e) [33] Light yellow solid, m.p. 47.5–48 °C
1
(lit. 49 °C) [4]. H NMR (400 MHz, CDCl3): δ = 7.45–7.47 (m, 2H), 7.31–7.34
(m, 3H), 3.59 (t, J = 6.0 Hz, 2H), 3.36 (t, J = 6.5 Hz, 2H), 1.87 (m, 2H), 1.80 (m,
2H); 13C NMR (100 MHz, CDCl3): δ = 169.7, 137.2, 129.7, 128.2, 127.0, 49.6,
46.1, 26.3, 24.4. HRMS m/z (ESI) calcd. for C11H14NO (M + H)+ 176.1070, found
176.1124.
(3,4‑Dihydroquinolin‑1(2H)‑yl)(phenyl)methanone (5f) [36] Light yellow
1
solid, m.p. 75–76 °C. H NMR (400 MHz, CDCl3): δ = 7.36–7.42 (m, 3H), 7.31
(t, J = 6.0 Hz, 2H), 7.19 (d, J = 8.5 Hz, 1H), 7.03 (td, J = 8.0, 1.07 Hz, 1H), 6.90
(t, J = 8.5 Hz, 1H), 6.77 (d, J = 8.8 Hz, 1H), 3.95 (t, J = 6.4 Hz, 2H), 2.89 (t,
J = 6.4 Hz, 2H), 2.08 (m, 2H); 13C NMR (100 MHz, CDCl3): δ = 165.5, 134.6,
131.6, 126.9, 125.4, 123.9, 123.7, 123.4, 121.0, 120.7, 119.9, 39.8, 22.2, 19.4.
HRMS m/z (ESI) calcd. for C16H16NO (M + H)+ 238.1226, found 238.1215.
N,N‑Dibenzylbenzamide (5g) [33] White solid, m.p. 107–108 °C (lit. 108–
1
109 °C) [32]. H NMR (400 MHz, CDCl3): δ = 7.57–7.60 (m, 2H), 7.41–7.46
(m, 8H), 7.36 (t, J = 8.8 Hz, 4H), 7.25 (d, J= 8.7 Hz, 2H), 4.79 (s, 2H), 4.47 (s,
2H); 13C NMR (100 MHz, CDCl3): δ = 172.3, 136.3, 128.9, 128.9, 128.6, 128.6,
128.5, 128.3, 128.2, 127.8, 127.7, 50.4, 46.0. HRMS m/z (ESI) calcd. for C21H20NO
(M + H)+ 302.1539, found 302.1502.
N,N‑Diphenylbenzamide (5h) [37] Light yellow solid, m.p. 181.5–182 °C (lit.
1
179–180 °C) [37]. H NMR (400 MHz, CDCl3): δ = 7.51 (d, J = 8.2 Hz, 2H),
7.31–7.36 (m, 5H), 7.20–7.28 (m, 8H); 13C NMR (100 MHz, CDCl3): δ = 170.7,
144.0, 136.2, 130.2, 129.2, 129.2, 127.9, 127.5, 126.4. HRMS m/z (ESI) calcd. for
C19H15NO (M + Na)+ 296.1046, found 296.2073.
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J. Li et al.
N‑Benzylbenzamide (5i) [33] White solid, m.p. 105–106 °C (lit. 105–107 °C)
1
[38]. H NMR (400 MHz, CDCl3): δ = 7.85 (t, J = 4.2 Hz, 2H), 7.29–7.42 (m,
9H), 4.61 (d, J = 4.3 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ = 167.7, 138.5,
134.4, 131.5, 128.7, 128.5, 127.8, 127.4, 127.2, 44.0. HRMS m/z (ESI) calcd. for
C14H12NO (M − H)- 210.0924, found 210.0887.
N‑Propylbenzamide (5j) [39] Light brown solid, m.p. 69.5–70.5 °C (lit.
1
71–72 °C) [40]. HNMR (400 MHz, CDCl3): δ = 7.81 (d, J= 4.2 Hz, 2H), 7.44 (t,
J = 7.9 Hz, 1H), 7.31–7.37 (m, 3H), 3.33–3.38 (m, 2H), 1.56–1.65 (m, 2H), 0.93
(t, J = 6.5 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ = 167.9, 134.9, 131.2, 128.4,
127.0, 41.8, 22.9, 11.4. HRMS m/z [atmospheric pressure chemical ionization
(APCI)] calcd. for C10H14NO (M + H)+ 164.1070, found 164.1090.
Morpholino(p‑tolyl)methanone (3b) [41] Light yellow oil, m.p. 75–76 °C (lit.
76.5–77.4 °C) [42]. 1H NMR (400 MHz, CDCl3): δ = 7.16–7.28 (m, 4H), 3.64(brs,
8H), 2.33 (s, 3H); 13C NMR (100 MHz, CDCl3): δ = 170.5, 140.0, 132.3, 129.1,
127.2, 66.8, 21.4. HRMS m/z (APCI) calcd. for C12H16NO2 (M + H)+ 206.1176,
found 206.1193.
Morpholino(4‑nitrophenyl)methanone (3c) [31] Light yellow solid, m.p. 101–
103 °C (lit. 101–102 °C) [15]. 1H NMR (400 MHz, CDCl3): δ = 8.26 (d, J = 8.4 Hz,
2H), 7.58 (d, J = 8.4 Hz, 2H), 3.59 (m, 8H); 13C NMR (100 MHz, CDCl3):
δ = 163.3, 143.7, 136.7, 123.4, 119.2, 62.0, 43.3, 37.8. HRMS m/z (APCI) calcd. for
C11H13N2O4 (M + H)+ 237.0870, found 237.0874.
(4‑Methoxyphenyl)(morpholino)methanone (3d) [31] White crystals, m.p.
43–44 °C (lit. 41–42 °C) [43]. 1H NMR (400 MHz, CDCl3): δ = 7.27–7.30 (m, 2H),
6.80–6.83 (m, 2H), 3.71 (d, J = 4.0 Hz, 3H), 3.55 (d, J = 4.6 Hz, 16H); 13C NMR
(100 MHz, CDCl3): δ = 170.2, 160.8, 129.1, 127.2, 113.7, 66.8, 55.3, 41.3. HRMS
m/z (ESI) calcd. for C12H16NO3 (M + H)+ 222.1125, found 222.1139.
1
Morpholino(m‑tolyl)methanone (3e) [31] White solid, m.p. 132–133 °C. H
NMR (400 MHz, DMSO-d6): δ = 7.19–7.36 (m, 4H), 3.38–3.62 (m, 8H), 2.35
(s, 3H); 13C NMR (100 MHz, DMSO-d6): δ = 169.7, 138.3, 136.1, 130.6, 128.7,
127.9, 124.5, 66.6, 41.2, 21.3. HRMS m/z (APCI) calcd. for C12H16NO2 (M + H)+
206.1176, found 206.1192.
Morpholino(o‑tolyl)methanone (3f) [31] White solid, m.p. 42–43 °C (lit.
40–41 °C) [32]. 1H NMR (400 MHz, DMSO-d6): δ = 7.17–7.34 (m, 4H), 3.64–3.69
(m, 4H), 3.50 (s, 2H), 3.13 (t, J= 4.8 Hz, 2H), 2.24 (s, 3H); 13C NMR (100 MHz,
DMSO-d6): δ = 169.1, 136.5, 134.2, 130.7, 129.2, 126.3, 126.2, 66.7, 66.6, 47.2,
41.8, 19.0. HRMS m/z (APCI) calcd. for C12H16NO2 (M + H)+ 206.1176, found
206.1185.
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An efcient procedure for chemoselective amidation from…
Morpholino(naphthalen‑1‑yl)methanone (3g) [44] Light yellow crystals, m.p.
1
109–111 °C. H NMR (400 MHz, CDCl3): δ = 7.76–7.83 (m, 3H), 7.33–7.48
(m, 4H), 3.72–3.94 (m, 4H), 3.34–3.39 (m, 2H), 3.04–3.09 (m, 2H); 13C NMR
(100 MHz, CDCl3): δ = 169.2, 133.8, 133.4, 129.5, 129.2, 128.5, 127.1, 126.5,
125.2, 124.7, 123.9, 66.9, 66.8, 47.5, 42.1. HRMS m/z (ESI) calcd. for C15H16NO2
(M + H)+ 242.1176, found 242.1169.
1‑Morpholino‑3‑phenylpropan‑1‑one (3h) [45] Light yellow oil, m.p.
1
96–98 °C. H NMR (400 MHz, CDCl3): δ = 7.14–7.27 (m, 5H), 3.55 (s, 4H), 3.44
(t, J = 4.2 Hz, 2H), 2.28 (t, J = 4.2 Hz, 2H), 2.94 (t, J = 4.2 Hz, 2H), 2.56 (t,
J = 8.3 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ = 170.8, 141.1, 128.5, 128.5,
126.2, 66.8, 66.4, 45.9, 41.9, 34.7, 31.5. HRMS m/z (ESI) calcd. for C13H17NO2
(M + Na)+ 242.1152, found 242.1156.
(4‑Chlorophenyl)(morpholino)methanone (3i) [31] White solid, m.p. 74–75 °C
(lit. 73–74 °C) [32]. 1H NMR (400 MHz, CDCl3): δ = 7.30–7.35 (m, 8H), 3.63 (brs,
4H); 13C NMR (100 MHz, CDCl3): δ = 169.2, 135.9, 133.7, 128.8, 128.7, 66.7,
48.1, 42.6. HRMS m/z (APCI) calcd. for C11H13NO2Cl (M + H)+ 226.0629, found
226.0626.
Morpholino(thiophen‑2‑yl)methanone (3j) [46] Light yellow oil, m.p. 85–87 °C.
1H NMR (400 MHz, CDCl3): δ = 7.38–7.40 (m, 1H), 7.21–7.22 (m, 1H), 6.96–
6.98 (m, 1H), 3.62–3.67 (m, 8H); 13C NMR (100 MHz, CDCl3): δ = 163.5, 136.7,
128.9, 128.9, 126.8, 66.8, 45.7. HRMS m/z (APCI) calcd. for C9H12NO2S (M + H)+
198.0583, found 198.0578.
4‑(Morpholine‑4‑carbonyl)benzaldehyde (3k) [38] Yellow solid, m.p. 48–49 °C.
1H NMR (400 MHz, CDCl3): δ = 9.99 (s, 1H), 7.89 (d, J = 8.2 Hz, 2H), 7.53 (d,
J = 8.2 Hz, 2H), 3.36–3.74 (m, 8H); 13C NMR (100 MHz, CDCl3): δ = 191.5,
169.0, 141.0, 137.0, 130.0, 127.7, 66.7, 48.0, 42.5. HRMS m/z (APCI) calcd. for
C12H14NO3 (M + H)+ 220.0968, found 220.0962.
(4‑Hydroxyphenyl)(morpholino)methanone (3l) [47] White solid, m.p.
1
63–64 °C. H NMR (400 MHz, CDCl3): δ = 9.12 (s, 1H), 7.26 (d, J = 7.9 Hz,
2H), 6.77 (d, J = 7.9 Hz, 2H), 3.72 (brs, 8H); 13C NMR (100 MHz, CDCl3):
δ = 171.6, 159.1, 129.3, 125.2, 115.6, 66.9, 48.8, 43.1. HRMS m/z (APCI) calcd. for
C11H12NO3 (M − H)- 206.0823, found 206.0843.
(E)‑1‑Morpholino‑3‑phenylprop‑2‑en‑1‑one (3m) [32] White solid, m.p.
73–75 °C (lit. 71–73 °C) [32]. 1H NMR (400 MHz, CDCl3): δ = 7.70 (d, J = 7.9 Hz,
1H), 7.52 (dd, J = 3.8 Hz, 2H), 7.35–7.37 (m, 3H), δ = 6.86 (d, J = 5.8 Hz, 1H),3.66–
3.71 (m, 8H); 13C NMR (100 MHz, CDCl3): δ = 165.6, 143.2, 135.1, 129.8, 128.8,
127.8, 116.6, 66.8, 46.2, 41.8. HRMS m/z (APCI) calcd. for C13H16NO2 (M + H)+
218.1176, found 218.1167.
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J. Li et al.
Cyclohexyl(morpholino)methanone (3n) [45] Colorless oil, m.p. 53.5–54.5 °C
(lit. 54–55 °C) [48]. 1H NMR (400 MHz, CDCl3): δ = 3.42–3.60 (m, 8H), 2.33–2.40
(m, 1H), 1.72–1.75 (m, 2H), 1.63–1.66 (m, 3H), 1.44–1.51 (m, 2H), 1.15–1.22 (m,
3H); 13C NMR (100 MHz, CDCl3): δ = 173.8, 66.0, 65.9, 44.9, 40.9, 39.2, 28.3,
24.8. HRMS m/z (ESI) calcd. for C11H20NO2 (M + H)+ 198.1489, found 198.1472.
1‑Morpholinopentan‑1‑one (3o) White oil, m.p. 46.5–47.5 °C. 1H NMR
(400 MHz, CDCl3): δ = 3.39–3.61 (m, 8H), 2.25 (t, J = 7.9 Hz, 2H), 1.51–1.58 (m,
2H), 1.25–1.35 (m, 2H), 0.86 (t, J = 8.1 Hz, 3H); 13C NMR (100 MHz, CDCl3):
δ = 171.9, 66.9, 66.7, 46.0, 41.8, 32.8, 22.5, 13.8. HRMS m/z (ESI) calcd. for
C9H18NO2 (M + H)+ 172.1332, found 172.1341.
Benzamide (7a) [49] Of-white solid, m.p. 127–128 °C (lit. 129–130 °C) [50].
1H NMR (400 MHz, DMSO-d6): δ = 8.24–8.27 (m, 2H), 7.56–7.59 (m, 3H), 6.09
(brs, 2H); 13C NMR (100 MHz, DMSO-d6): δ = 173.2, 139.5, 136.5, 133.4, 132.7.
HRMS m/z (APCI) calcd. for C7H8NO (M + H)+ 122.0600, found 122.0585.
4‑Methylbenzamide (7b) [49] White solid, m.p. 128–129 °C (lit. 129–130 °C)
1
[50]. H NMR (400 MHz, DMSO-d6): δ = 7.80 (d, J = 7.9 Hz, 2H), 7.25 (d,
J = 8.3 Hz, 2H), 6.04 (brs, 2H), 2.35 (brs, 3H); 13C NMR (100 MHz, DMSO-d6):
δ = 168.3, 141.5, 131.9, 129.2, 128.0, 21.4. HRMS m/z (APCI) calcd. for C8H10NO
(M + H)+ 136.0757, found 136.0737.
4‑Methoxybenzamide (7d) [51] White solid, m.p. 164–165 °C (lit. 163–164 °C)
1
[52]. H NMR (400 MHz, DMSO-d6): δ = 7.86 (d, J = 8.8 Hz, 2H), 6.98 (d,
J = 8.8 Hz, 2H), 5.91 (brs, 2H), 3.81 (s, 3H); 13C NMR (100 MHz, DMSO-d6):
δ = 167.9, 162.0, 129.8, 127.0, 113.8, 55.8. HRMS m/z (ESI) calcd. for C8H10NO2
(M + H)+ 152.0706, found 152.0718.
1‑Naphthamide (7g) [51] White solid, m.p. 198–200 °C (lit. 196–199 °C) [51].
1H NMR (400 MHz, DMSO-d6): δ = 8.33 (d, J = 8.9 Hz, 1H), 8.01 (d, J = 8.9 Hz,
1H), 7.98 (d, J = 7.8 Hz, 1H), 7.66 (d, J = 8.8 Hz, 1H), 7.56–7.59 (m, 2H), 7.54 (d,
J = 4.9 Hz, 1H), 6.01 (brs, 2H); 13C NMR (100 MHz, DMSO-d6): δ = 171.1, 135.1,
133.7, 130.2, 130.2, 128.6, 127.1, 126.6, 126.1, 125.6, 125.4. HRMS m/z (APCI)
calcd. for C11H10NO (M + H)+ 172.0757, found 172.0716.
Thiophene‑2‑carboxamide (7j) [51] White solid, m.p. 196–177 °C (lit. 177–
179 °C) [50]. 1H NMR (400 MHz, DMSO-d6): δ = 7.99 (s, 1H), 7.74–7.76 (m, 2H),
7.40 (s, 1H), 7.13–7.15 (m, 1H); 13C NMR (100 MHz, DMSO-d6): δ = 163.4, 140.8,
131.5, 129.2, 128.4. HRMS m/z (APCI) calcd. for C5H6NOS (M + H)+ 128.0165,
found 128.0166.
1,3‑Diisopropylimidazolidine‑2,4,5‑trione (8) [53] White crystals, m.p.
1
84–85 °C (lit. 83–85 °C) [53]. H NMR (400 MHz, CDCl3): δ = 4.38–4.45 (m,
2H), 1.44 (d, J = 7.9 Hz, 12H); 13C NMR (100 MHz, CDCl3): δ = 156.4, 153.2,
1 3

An efcient procedure for chemoselective amidation from…
44.8, 19.8. HRMS m/z (APCI) calcd. for C9H14N2O3 (M + H)+ 199.1077, found
199.1141.
Results and discussion
Initial investigations for suitable reaction conditions for the catalyst-free one-pot
procedure for amide formation using benzoic acid and morpholine as the model
substrates were performed. Reactions were conducted with varied temperatures,
bases, solvents [dichloromethane (DCM), CH3CN, tetrahydrofuran (THF), toluene,
methanol] and the loadings of DCDD were evaluated; the results are summarized in
Table 1. The best yields were obtained at r.t. with DCM as the solvent and triethyl-
amine as the base at the ratio of 3:1 (base-to-reactants).
Table 1 Optimization of reaction conditions
Entry
Ratio (mol)
Solvent
Base (loading)
Temp. (°C)
Yielda (%)
1
2
3
4
5
6
7
8
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1.05
1:1.45
DCM
CH3CN
THF
Toluene
CH3OH
DCM
DCM
DCM
DCM
DCM
DCM
DCM
Toluene
Toluene
DCM
TEA (2:1)
TEA (2:1)
TEA (2:1)
TEA (2:1)
TEA (2:1)
K2CO3 (2:1)
K3PO4 (2:1)
Cs2CO3 (2:1)
EtONa (2:1)
–
TEA (3:1)
TEA (4:1)
TEA (3:1)
TEA (3:1)
TEA (3:1)
TEA (3:1)
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
50
75
r.t.
r.t.
90
56
35
71
12
56
70
76
39
18
91
89
55
Trace
94
94
9
10
11
12
13
14
15
16
DCM
Conditions: reactions were carried out on a millimolar scale; benzoic acid 1a, 1.0 mmol, morpholine 2a,
1.0 mmol and base dissolved in 13 mL of CH2Cl2; the ratios of substrate benzoic acid over DCDD are
listed in Table 1; reaction time 3 h
aYields were determined by HPLC analysis based on the benzoic acid
1 3

J. Li et al.
Table 2 The scope of carboxylic acids in synthesis of amides
Conditions: reactions were performed on a millimolar scale, carboxylic acid, 1.0 mmol, morpholine,
1.0 mmol, DCDD, 1.05 mmol and triethyl amine 3.0 mmol dissolved in 13 mL CH2Cl2, reaction time,
3 h. Yields were determined by HPLC analysis equipped with a C18 column
With optimized conditions in hand, extending the scope of substrate carboxylic
acid was conducted by using morpholine (secondary amine) as the amine moiety,
and the results are summarized in Table 2. All reactions proceeded well and all
products were provided with good to excellent yields of up to 96%. As indicated,
substituents at diferent positions on the aromatic ring seem to have conspicuous
impacts on the yield of product. For instance, 4-methylbenzoic acid and 3-methylb-
enzoic acid, with an electron-donating group at the para position and meta position
on an aromatic ring, aforded their corresponding products 3b and 3e in yields of
95% and 92%, respectively; however, with the same group at the ortho position, a
poorer yield of product 3f was provided. Electronic factors, including p-OH, p-Me,
p-Cl, p-MeO and p-NO2 in the substituents of the aromatic acids or heterocyclic
acids (e.g., 1j), made little diference in the yields obtained. Also, this procedure
is applicable to unsaturated acid, and alicyclic and cyclic acids; the corresponding
product 3m was obtained with a yield of 81%, products 3n and 3o were aforded in
yields of 70% and 86%, respectively.
To further extend the scope of amines, an array of primary and secondary amines
listed in Table 3 were subjected using benzoic acid as the carboxylic acid moiety,
1 3

An efcient procedure for chemoselective amidation from…
Table 3 Synthesis of amides from benzoic acid and primary amines or secondary amines
Conditions: reactions were performed on a millimolar scale, benzoic acid, 1.0 mmol, amine, 1.0 mmol,
DCDD, 1.05 mmol and triethyl amine 3.0 mmol dissolved in 13 mL CH2Cl2, reaction time, 3 h. Yields
were determined by HPLC analysis equipped with a C18 column
and the results are summarized in Table 3. As expected, most of the reactions pro-
ceeded smoothly and the corresponding products were obtained with yields varying
from 56% to 96%. Compared with cyclic alkylamines (secondary amine), dialkyl/
dibenzyl amines could provide lower yields (3a, 5a–j, Table 3); in the same con-
ditions with primary amines, the corresponding products were obtained in poorer
yields (5i, 5j, Table 3). We wonder whether there were similar situations when using
ammonium as the amine moiety, which encouraged us to further explore its substrate
scope by using ammonium (amines with no substituent) salt as the amine moiety.
Reactions with fve aromatic carboxylic acids and ammonium chloride were then
applied, and the results are summarized in Table 4. Most of the reactions could
aford their corresponding products with yields of up to 84% (entries 2–4, Table 4).
One exception occurred when using p-nitrobenzoic acid; by using a substrate with
an electron-withdrawing group on the aromatic ring, no product was detected, indi-
cating that with ammonia, the p-nitrobenzoyl group attack by NH3 at the C–Cl bond
is probably preferred stereochemically with release of the p-nitrobenzoate ion.
To test whether carboxylic acids can react with oxalyl chloride to yield chloride
intermediate, which can further react with amine to provide the desired amide, car-
boxylic acid was treated directly with oxalyl chloride, followed by reaction with
1 3

J. Li et al.
Table 4 Synthesis of amides from carboxylic acids and ammonium chloride
Entry
1
Acids
Product
Yield a(%)
55
Code
7a
2
3
66
79
7b
7d
4
5
6
84
82
7g
7j
Trace
7c
Conditions: reactions were performed on a millimolar scale, carboxylic acid, 1.0 mmol, ammonium chlo-
ride, 1.0 mmol, DCDD, 1.05 mmol and triethyl amine 4.0 mmol dissolved in 13 mL CH2Cl2, reaction
time, 3 h
aYields were determined by HPLC analysis equipped with a C18 column
Scheme 2 Control experiments using carboxylic acid to react with oxalyl chloride, and followed by
reaction with amines
amines, and the results are summarized in Scheme 2. To our disappointment, the
yield of the corresponding amide was very poor. Benzoic acid, 4-methoxybenzoic
1 3

An efcient procedure for chemoselective amidation from…
acid with an electron-donating group, and 4-nitrobenzoic acid with an electron-
withdrawn group on the aromatic ring were tested with morpholine as the amine
moiety. However, only substrate 4-methoxybenzoic acid could provide the corre-
sponding product 3d with the yield of 12%. When using benzoic acid to react with
oxalyl chloride, followed by reaction with another second amine (diethylamine), the
corresponding product 5a was not detected by HPLC analysis.
Based on the results and referencing some relevant publications [1, 30, 39], a pos-
sible mechanism is proposed in Fig. 1. Aided by two amide nitrogen atoms in the
molecular of DCDD, the initial step is the heterolytic cleavage of a C–Cl bond to
form an intermediate A. Subsequently, the generated carbocation A was attacked by
a carboxylic acid to form the intermediate B. Followed by the attack of amine to
intermediate B at the carbonyl carbon to simultaneously form the amide bond with
liberation of HCl and the urea 8 [53–55].
Fig. 1 Possible reaction pathway
1 3

J. Li et al.
Conclusion
In summary, we have developed an efcient one-pot and catalyst-free procedure for
the synthesis of an array of amides with good to excellent yields of up to 96% under
mild conditions using DCDD as the coupling agent at 1.05 equivalents; primary or
secondary amines or ammonium salt were used as the amine moieties. A possible
mechanism for this procedure is also proposed. To the best of our knowledge, this
represents the frst example using DCDD to successfully synthesize amides, espe-
cially those bearing thermosensitive group(s) with no group protection process prior
to amide formation reactions. Furthermore, this procedure is believed to have poten-
tial for sustainable industrial applications.
Acknowledgements Financial support from the National Natural Science Foundation of China
(21502036), Innovative Research Team Project of Hainan Natural Science Foundation (2016CXTD006),
and Hainan University (kyqd1408) are gratefully acknowledged.
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