RSC Advances: Paper
RSC Advances: Paper
A one-pot synthesis of secondary and tertiary amides from carboxylic acids and amines by using SOCl2 has
been developed. Also when sterically hindered amines were used as the starting materials, excellent yields
Received 19th November 2015
Accepted 29th March 2016
of the corresponding amides were obtained. The amidation of N-protected a-amino acids with secondary
amines proceeds effectively with good yields. The process works well also in the presence of acid sensitive
DOI: 10.1039/c5ra24527c
groups and occurs with almost complete retention of stereochemical integrity of chiral substrates. This
www.rsc.org/advances protocol could be extended to industrial large-scale production processes.
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Table 1 Comparison between different one-pot thionyl chloride injection port was heated to 250 C. The oven temperature
methods for amide synthesis program was initially set at 50 C ramped to 200 C at 0.5 C
min1 with a hold of 20 min.
ESI-QTOF mass spectra were recorded on a Quadrupole Time
of Flight (QTOF) mass spectrometer tted with an electrospray
ionization source (ESI) operating in positive ion mode.
Analytical RP-HPLC analyses were carried out using a C18
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N,N-Diethylcinnamamide (4). Viscous colorless oil, 86%, rel.): 239 [M+c] (55), 238 (40), 210 (10), 148 (5), 134 (6), 105 (100),
TLC (eluent: diethyl ether/P.E. 70 : 30 v/v): Rf ¼ 0.55; 1H NMR 91 (20), 77 (35). Anal. calcd for C16H17NO: C, 80.30; H, 7.16; N,
(300 MHz, CDCl3) d: 7.73 (d, J ¼ 15.3 Hz, 1H, CH vinyl), 7.61– 5.85. Found: C, 80.41; H, 7.17; N, 5.86.
7.50 (m, 2H, ArH), 7.40–7.34 (m. 3H, ArH), 6.84 (d, J ¼ 15.3 Hz, N-Propylbenzamide (10). Viscous colorless oil, 92%, TLC
1H, CH vinyl), 3.60–3.40 (m, 4H, NCH2), 1.33–1.15 (m, 6H, (eluent: diethyl ether/P.E. 70 : 30 v/v): Rf ¼ 0.38, 1H NMR (300
CH2CH3) ppm; 13C NMR (75 MHz, CDCl3) d: 165.7, 142.3, 135.5, MHz, CDCl3) d: 7.95–7.70 (m, 2H, ArH), 7.51–7.28 (m, 3H, ArH),
129.4, 128.7, 127.7, 117.7, 42.3, 41.1, 15.1, 13.2 ppm; MS (EI, 70 3.36 (t, J ¼ 7.2 Hz, 2H, NHCH2), 1.72–1.54 (m, 2H, NHCH2CH2),
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eV) m/z (% rel.): 203 [M+c] (31), 188 (20), 131 (100), 103 (40), 77 0.90 (t, J ¼ 7.2, Hz, 3H, CH3CH2); 13C NMR (75 MHz, CDCl3) d:
(23). Anal. calcd for C13H17NO: C, 76.81; H, 8.43; N, 6.89. Found: 168.9, 131.9, 129.9, 128.5, 127.4, 42.3, 22.5, 11.3; MS (EI, 70 eV)
C, 76.76; H, 8.41; N, 6.90. m/z (% rel.): 163 [M+c] (40), 148 (5), 134 (10), 105 (100), 77 (40).
N,N-Diethylpalmitamide (5). Viscous colorless oil, 90%, TLC Anal. calcd for C10H13NO: C, 73.59; H, 8.03; N, 8.58. Found: C,
(eluent: diethyl ether/P.E. 70 : 30 v/v): Rf ¼ 0.68; 1H NMR (300 73.69; H, 8.04; N, 8.59.
MHz, CDCl3) d: 3.42–3.20 (m, 4H, NCH2), 2.35 (t, J ¼ 7.2 Hz, 2H, N-Phenylbenzamide (11). Viscous colorless oil, 89%, TLC
CH2CO), 1.67–1.50 (m, 2H, CH2CH2CO), 1.34–1.10 (m, 30H, (eluent: diethyl ether/P.E. 70 : 30 v/v): Rf ¼ 0.58, 1H NMR (300
CH3(CH2)12CH2CH2CO and (CH3CH2)2N), 0.81 (t, J ¼ 6.6 Hz, 3H, MHz, CDCl3) d: 8.35–7.05 (m, 11H, ArH and NH), 13C NMR (75
(CH2)14CH3); 13C NMR (75 MHz, CDCl3) d: 173.8, 34.2, 32.5, 31.8, MHz, CDCl3) d: 165.9, 137.9, 133.2, 130.1, 129.0, 128.7, 127.1,
29.6, 29.4, 29.3, 29.2, 25.7, 24.8, 22.6, 14.0; MS (EI, 70 eV) m/z (% 124.3, 120.3 MS (EI, 70 eV) m/z (% rel.): 197 [M+c] (60), 105 (100),
rel.): 311 [M+c] (12), 128 (25), 115 (100), 100 (28), 72 (16). Anal. 77 (50). Anal. calcd for C13H11NO: C, 79.16; H, 5.62; N, 7.10.
calcd for C20H41NO: C, 77.10; H, 13.26; N, 4.50. Found: C, 77.18; Found: C, 79.27; H, 5.63; N, 7.11.
H, 13.29; N, 4.48. N,N-Diethyl-(S)-2-(4-nitrophenylsulfonamido)-3-phenylpro-
N,N-Diethylmyristamide (6). Viscous colorless oil, 88%, TLC panamide (12). Pale yellow oil, 81%, TLC (eluent: chloroform/
(eluent: diethyl ether/P.E. 70 : 30 v/v): Rf ¼ 0.67, 1H NMR (300 methanol 90 : 10 v/v): Rf ¼ 0.62; 1H NMR (300 MHz, CDCl3) d:
MHz, CDCl3) d: 3.38 (q, J ¼ 7.2 Hz, 2H, NCH2), 3.31 (q, J ¼ 7.2 8.22 (d, J ¼ 9.0 Hz, 2H), 7.88 (d, J ¼ 9.0 Hz, 2H, ArH), 7.25–7.15
Hz, 2H, NCH2), 2.29 (t, J ¼ 7.2 Hz, 2H, CH2CO), 1.70–1.59 (m, (m, 3H, ArH), 7.14–7.04 (m, 2H, ArH), 6.24 (d, J ¼ 8.1 Hz, 1H,
4H, (CH2)2CH2CO), 1.38–1.23 (m, 18H, CH3(CH2)9(CH2)2- NH), 4.48–4.32 (m, 1H, CHCO), 3.39–3.23 (m, 1H, CH2CH3),
CH2CO), 1.18 (t, J ¼ 7.2 Hz, 3H, CH2CH3), 1.12 (t, J ¼ 7.2 Hz, 3H, 3.09–2.83 (m, 5H, CH2Ph and NCH2), 0.99–0.80 (m, 6H,
NCH2CH3), 0.89 (t, J ¼ 6.6 Hz, 3H, CH3(CH2)12CO); 13C NMR (75 CH2CH3); 13C NMR (75 MHz, CDCl3) d: 169.3, 149.8, 146.3,
MHz, CDCl3) d: 172.2, 41.9, 39.9, 33.1, 31.9, 29.6, 29.5, 29.4, 29.3, 135.4, 129.5, 128.6, 128.2, 127.3, 123.9, 54.5, 41.5, 40.7, 13.9,
25.5, 22.6, 14.4, 14.1, 13.1; MS (EI, 70 eV) m/z (% rel.): 283 [M+c] 12.5; MS (EI, 70 eV) m/z (% rel.): 405 [M+c] (2), 314 (51), 305
(12), 128 (25), 115 (100), 100 (28), 72 (16). Anal. calcd for (100), 203 (44), 100 (55), 72 (61). Anal. calcd for C19H23N3O5S:
C18H37NO: C, 76.26; H, 13.16; N, 4.94. Found: C, 76.37; H, 13.27; C, 56.28; H, 5.72; N, 10.36; S, 7.91. Found: C, 56.43; H, 5.74; N,
N, 4.95. 10.33; S, 7.88.
N-Ethyl-N-isopropylbenzamide (7). Viscous colorless oil, N,N-Diethyl-(S)-2-(4-nitrophenylsulfonamido)-propanamide
86%, TLC (eluent: diethyl ether/P.E. 70/30 v/v): Rf ¼ 0.71; 1H (13). Pale yellow oil, 83%, TLC (eluent: chloroform/methanol
NMR (300 MHz, CDCl3) d: 7.50–7.20 (m, 5H, ArH), 4.10–3.80 (m, 90 : 10 v/v): Rf ¼ 0.72; 1H NMR (300 MHz, CDCl3) d: 8.32 (d, J
1H, NCH), 3.52–3.25 (m, 2H, NCH2), 1.39–0.95 (m, 9H, ¼ 8.1 Hz, 2H, ArH), 8.04 (d, J ¼ 8.1 Hz, 2H, ArH), 6.24 (d, J ¼ 8.7
CH(CH3)2 and CH2CH3); 13C NMR (75 MHz, CDCl3) d: 171.1, Hz, 1H, NH), 4.32–4.18 (m, 1H, CHCO), 3.30–3.05 (m, 4H,
129.9, 128.9, 128.4, 125.9, 50.2, 35.2, 21.1, 14.8; m/z (% rel.): NCH2), 1.33 (d, J ¼ 6.9 Hz, 3H, CHCH3), 1.09 (t, J ¼ Hz, 3H,
[M+c] 191 (22), 190 (25), 176 (5), 162 (10), 148 (5), 105 (100), 77 CH2CH3), 0.92 (t, J ¼ Hz, 3H, CH2CH3); 13C NMR (75 MHz,
(35). Anal. calcd for C12H17NO: C, 75.35; H, 8.96; N, 7.32. Found: CDCl3) d: 170.1, 149.9, 146.3, 128.4, 124.1, 49.2, 41.6, 40.6, 20.5,
C, 75.48; H, 8.94; N, 7.31. 14.3, 12.6; MS (EI, 70 eV) m/z (% rel.): 229 (69), 186 (15), 122
N-Benzoylpiperidine (8). Viscous colorless oil, 88%, TLC (10), 100 (95), 72 (100). Anal. calcd for C13H19N3O5S: C, 47.41;
(eluent: diethyl ether/P.E. 70 : 30 v/v): Rf ¼ 0.50; 1H NMR (300 H, 5.81; N, 12.76; S, 9.74. Found: C, 47.55; H, 5.82; N, 12.80; S,
MHz, CDCl3) d: 7.29–7.15 (m, 5H, ArH), 3.65–3.45 (m, 2H, 9.76.
NCH2), 3.28–3.10 (m, 2H, NCH2), 1.58–1.27 (m, 6H, 4-Acetamidophenylacetate (14). Viscous colorless oil, 48%,
NCH2(CH2)3); 13C NMR (75 MHz, CDCl3) d: 170.1, 136.3, 129.2, TLC (eluent: diethyl ether/P.E. 70 : 30 v/v): Rf ¼ 0.88; 1H NMR
128.2, 126.6, 48.5, 42.9, 26.3, 25.5, 24.4; MS (EI, 70 eV) m/z (% (300 MHz, CDCl3) d: 7.91 (s, 1H, NH), 7.55 (d, J ¼ 9.0 Hz, 2H,
rel.): 189 [M+c] (35), 188 (100), 105 (75), 77 (41). Anal. calcd for ArH), 7.01 (d, J ¼ 9.0 Hz, 2H, ArH), 2.29 (s, 3H, CH3CO), 2.17 (s,
C12H15NO: C, 76.16; H, 7.99; N, 7.40. Found: C, 76.29; H, 8.01; N, 3H, CH3CO), 13C NMR (75 MHz, CDCl3) d 169.8, 168.6, 147.0,
7.41. 135.9, 121.8, 120.8, 24.4, 21.1; MS (EI, 70 eV) m/z (% rel.): 193
N-Benzyl-N-ethylbenzamide (9). Viscous colorless oil, 85%, [M+c] (10), 151 (55), 109 (100), 80 (10). Anal. calcd for C10H11NO3:
TLC (eluent: diethyl ether/P.E. 70 : 30 v/v): Rf ¼ 0.59; 1H NMR C, 62.17; H, 5.74; N, 7.25. Found: C, 62.26; H, 5.75; N, 7.26.
(300 MHz, CDCl3) d: 7.60–6.90 (m, 10H, ArH), 4.90–4.42 (m, 2H, N,N-Diethyl-(S)-2-(tert-butoxycarbonyl)-amino-3-phenylpro-
NCH2Ph), 3.78–3.05 (m, 2H, NCH2), 1.38–1.02 (m, 3H, CH2CH3); panamide (15). Pale yellow oil, 78%, TLC (eluent: diethyl ether/
13
C NMR (75 MHz, CDCl3) d:170.8, 133.4, 130.1, 129.8, 128.9, P.E. 70 : 30 v/v): Rf ¼ 0.81; 1H NMR (300 MHz, CDCl3) d: 7.26–
128.5, 128.3, 127.6, 126.6, 53.9, 42.9, 13.9; MS (EI, 70 eV) m/z (% 7.10 (m, 5H, ArH), 5.39 (d, J ¼ 9 Hz, 1H, NH), 4.74–4.64 (m, 1H,
CHCO), 3.53–3.41 (m, 1H, CH2CH3); 3.11–2.80 (m, 5H CH2Ph,
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CH2CH3), 1.37 (s, 9H, tBu), 0.99 (t, J ¼ 7.2 Hz, 3H, CH3CH2N), eV) m/z (% rel.): 270 [M+c] (1), 197 (19), 170 (40), 114 (94), 100
0.92 (t, J ¼ 7.2 Hz, 3H, CH3CH2N), 13C NMR (75 MHz, CDCl3) (30), 70 (100), 57 (45). Anal. calcd for C14H26N2O3: C, 62.19; H,
d 170.8, 154.9, 136.5, 129.5, 128.3, 126.7, 79.5, 51.3, 41.5, 40.4, 9.69; N, 10.36. Found: C, 62.23; H, 9.63; N, 10.31.
28.2, 14.0; MS (EI, 70 eV) m/z (% rel.): 320 [M+c] (2), 229 (6), 220
(20), 164 (45), 129 (40), 120 (100), 100 (35), 91 (20), 72 (40), 57
Synthesis of dipeptide methyl 3-methyl-2-(S)-(2-(R)-(4-
(70). Anal. calcd for C18H28N2O3: C, 67.47; H, 8.81; N, 8.74.
nitrophenylsulfonamido)-propanamido)butanoate (20)
Found: C, 67.51; H, 8.87; N, 8.75.
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Table 2 Results of one pot synthesis of amides under the reaction Table 2 (Contd. )
conditions reported in Scheme 1
Product Reaction time (min) Yielda (%)
Product Reaction time (min) Yielda (%)
20 40 65
1 5 86
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a
Yields based on starting amount of carboxylic acid.
2 5 88
3 5 91
work up, provided the corresponding N,N-diethylbenzamide (1)
in 86% overall yield (Table 2).
The molecular structure of 1 was assigned by 1H and 13C
4 5 86 NMR spectroscopy and GC/MS analysis.
An additional experiment was performed to investigate the
reaction progress in absence of the tertiary amine Et3N. To this
5 5 90 aim 1 mmol of SOCl2 was added to 1 mmol of benzoic acid and 1
mmol of diethylamine (Et2NH) in dichloromethane at room
temperature. Aer 20 minutes the reaction was not yet complete
6 5 88 and a mixture of benzoic acid (65% yield) and N,N-dieth-
ylbenzamide (31% yield) was recovered.
The use of stoichiometric amounts of diethylamine, in
7 5 86 absence of Et3N, leads to a lower conversion to amides since the
diethylamine works also as a base to neutralize the hydrochloric
acid that is generated during the reaction. This result demon-
8 5 88
strated that the presence of the tertiary amine is essential to
obtain the amide in high yields.
We also experienced that the outcome of the reaction is
9 5 85
strongly dependent on the order of reagent addition. In fact, if
benzoic acid is preliminarily added to thionyl chloride and
10 5 92 Et2NH and Et3N are added subsequently, the reaction yield is
lowered and aer 5 minutes, the reaction is not yet complete.
The obtained reaction product contained also the benzoyl
11 5 89
chloride with a percentage of 35% as detected by GC/MS
analysis.
12 20 81 Furthermore, it was veried that SOCl2 does not react with
the amine. In fact, the N-benzyl-N-ethylamine was recovered
unchanged aer it was treated with SOCl2 at room temperature
13 20 83 for 1 hour.
With the aim of investigating the reaction mechanism, we
14 15 48 designed 13C NMR experiments by performing and monitoring
the reactions directly into the NMR tube using CDCl3 as solvent
and observing the chemical shis of the carbonyl groups of the
15 15 78
products present in the reaction mixture.
The purpose of these experiments was to identify the reactive
16 20 75 intermediate generated during the one pot amide formation
reaction. Therefore, we recorded preliminarily the 13C NMR
spectra of benzoic acid and benzoyl chloride that exhibit
17 20 68
carbonyl resonance signals respectively at 172.51 ppm and
168.38 ppm.
18 16 75 Subsequently in a NMR tube, benzoic acid (1 mmol) was
treated with thionyl chloride (1 mmol) at room temperature in
CDCl3 as solvent. The progress of the reaction was followed by
19 15 73 recording the 13C NMR spectrum of the reaction mixture. Aer
more than 2 hours 13C NMR spectrum showed the presence of
the signal at (172.44 ppm) corresponding to the carbonyl group
of benzoic acid and a signal of very low intensity, that can be
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just appreciated, relating to acyl chloride carbonyl group are similar to those of the reaction with diethylamine (Table 2,
(168.52 ppm) This demonstrated that benzoyl chloride is 7–9).
formed hardly under these reaction conditions. Then, with the purpose to investigate the steric hindrance
In an additional experiment, the same reaction was per- present on the carboxylic acid, the developed procedure was
formed at room temperature by adding thionyl chloride (1 applied to two N-protected a-amino acids, N-nosyl-L-phenylala-
mmol) to a mixture of benzoic acid (1 mmol) and triethylamine nine and N-nosyl-L-alanine.
(3 mmol) dissolved in CDCl3. In this case the reaction proceeds N-Nosyl-L-phenylalanine and N-nosyl-L-alanine were con-
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rapidly and in the 13C NMR spectrum it was observed imme- verted into the corresponding N,N-diethylamides (Table 2, 12,
diately the disappearance of the signal relating to the resonance 13) in 20 minutes and with yields slightly lower.
of benzoic acid carbonyl group and the appearance at 168.13 Based on these results it can be argued that steric hindrance
ppm of the signal generated by benzoyl chloride carbonyl group. offered by the groups on the nitrogen atom of the amine does
Finally, we reproduced, the one pot formation of N,N-dieth- not affect the reaction progress while the reaction times are
ylbenzamide (1) in a NMR tube, under the described conditions longer and the reaction yields are a little lower when sterically
for the synthesis of amides 1–17, and immediately recorded the hindered carboxylic acids are used.
13
C NMR spectrum. In the obtained 13C NMR spectrum at once The adopted procedure for obtaining N,N-diethylamides was
the presence of two resonances attributable to the carbonyl also applied successfully to N-Boc-L-phenylalanine, a substrate
groups of N,N-diethylbenzamide at 171.36 ppm and of benzoyl bearing the acid labile group tert-butoxycarbonyl (Boc). The
chloride at 168.32 ppm was observed. Aer about 10 minutes, corresponding N,N-diethylamide (15) was obtained in 78% yield
the re-recorded 13C NMR spectrum of the reaction mixture keeping unchanged the acid-sensitive Boc group (Table 2). On
revealed only the presence of the resonance corresponding to the contrary the application of the two-step amide synthesis,
the amidic carbonyl group. through the formation of acyl chloride, to N-Boc-L-phenylala-
These results could be justied by the action of tertiary nine does not work well due to the instability of the corre-
amine that causes the formation of the carboxylate, which sponding acyl chloride that, when isolated in the absence of the
reacts quickly at room temperature with thionyl chloride to nucleophile, decomposes readily.
form the acid chloride that immediately reacts with the N,N- The described protocol was also employed to obtain
diethylamine to give the corresponding amide. secondary amides by using primary amines as nucleophilic
This experimental evidence suggests that benzoyl chloride is reagents. To this aim, N-propylamine and aniline were selected
the reactive intermediate of the adopted one pot procedure as nucleophiles. The reactions afforded the corresponding
(Scheme 2). amides in short times and high yields (Table 2, 10, 11) by
The reaction was subsequently extended to other aromatic demonstrating that the adopted one-pot procedure is also
substrates, in all experimented cases the reaction is complete applicable successfully for obtaining secondary amides.
within 5 minutes and has provided excellent yields (86–91%) We also investigated the stereochemical aspects of the
(Table 2, 2–4). reaction by extending the developed procedure to the formation
The methodology was then applied to two long chain of a couple of diastereoisomeric amides. To this aim N-((R)-1-
aliphatic carboxylic acids, palmitic and myristic acid. Also with phenylethyl)-2-(S)-(4-nitrophenylsulfonamido)-propanamide
these systems no changes were observed during the reaction, in (16) and N-((S)-1-phenylethyl)-2-(S)-(4-nitrophenylsulfonamido)
fact the amide formation occurs even in short times and high propanamide (17) were synthesized by treating N-(4-nitro-
yields (88–90%) (Table 2, 5, 6). benzenesulfonyl)-L-alanine with (R)-1-phenylethylamine and (S)-
In order to evaluate the possible effects due to the steric 1-phenylethylamine respectively according the adopted condi-
hindrance of the amine, N-ethyl-N-isopropylamine, piperidine tions. The corresponding amides 16 and 17 were obtained in
and N-benzyl-N-ethylamine were treated with benzoic acid 68–75% yields aer 20 minutes (Table 2). The 1H NMR and 13C
under the described reaction conditions. NMR spectroscopic data of crude amides 16 and 17 did not
Signicant effects due to steric hindrance of the amines were show any signals from possible epimers resulting from an
not detected. Both the reaction kinetics that the reaction yields inversion of the conguration at the a-carbon atom of the
alanine.
The absence of epimerization was also monitored by HPLC
analysis of the crude amides 16 and 17 and of a suitably
prepared mixture of the two diastereoisomers 16 and 17
(approx. 30% : 70%). The two diastereoisomers were readily
resolved by HPLC: the presence of two chromatographic peaks
with retention times of 15.558 and 16.867 minutes was observed
in the HPLC analysis of the mixture (Fig. 1B). Chromatograms
of the single amide 16 (Fig. 1A) and 17 (Fig. 1C) showed the
presence of a unique peak with retention times of 16.908 and
15.433 minutes respectively.
HPLC analysis in combination with NMR data of the two
Scheme 2 Proposed mechanism of the one pot amide synthesis. diastereomeric amides 16 and 17, demonstrated the absence of
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Conclusions
Fig. 1 HPLC analyses of crude amides 16 and 17: (A) N-((R)-1-phe- Thionyl chloride works as coupling reagent and allows obtain-
nylethyl)-2-(S)-(4-nitrophenylsulfonamido)-propanamide (16); (B) ing, at room temperature and in short times, secondary and
a mixture of 16 and 17 (approx. 30% : 70%); (C) N-((S)-1-phenylethyl)-
tertiary amides in high yields without need of further purica-
2-(S)-(4-nitrophenylsulfonamido)-propanamide (17).
tion. Furthermore, the adopted conditions did not cause any
signicant loss of the optical integrity at the chiral centres of the
precursors as conrmed by HPLC and NMR analysis of a couple
epimerization products excluding any detectable epimerization
of synthesized diastereoisomeric amides and by the high
throughout the synthetic process.
enantiomeric excess estimated for N,N-diethylamides of N-Boc-
Furthermore, in order to evaluate the enantiomeric purity of
D-proline.
N,N-diethylamides of N-Boc protected a-amino acids, two N,N-
The reaction progress is affected by steric hindrance only
diethylamides of N-Boc-L-proline (18) and its enantiomer N-Boc-
when bulky groups are present on the carboxylic acid molecule.
D-proline (19) were synthesized using the developed protocol
The synthesis of amides is performed in an efficient one-pot
(Table 2) and characterized by chiral GC/MS analysis.
procedure under mild reaction conditions; the order of
The separation of L-amide 18 and D-amide 19 was achieved by
reagent addition is predetermined for obtaining the amides in
chiral GC/MS analysis of a mixture of the two enantiomers 18
high yields.
and 19 (approx. 70% : 30%): the corresponding chromatogram
The reaction mechanism was investigated by performing 13C
showed the presence of two peaks with retention times of
NMR experiments, which showed, as the reactive intermediate
114.08 and 114.73 minutes related to 18 and 19 respectively.
is the acyl chloride. This is formed easily from the carboxylate
The chiral GC/MS analysis of the single amide 18 showed
generated in situ from the corresponding carboxylic acid in the
a unique peak at 113.97 min. While that of the single amide 19
presence of the tertiary amine.
showed two peaks at 113.88 and 114.75 minutes which corre-
Our approach was successfully extended to a-amino acids
sponded to identical mass spectra. The estimated enantiomeric
bearing acid-sensitive groups and to the synthesis of a dipeptide
excess of D-amide 19 was 99.2%. The resulting ee was really
system; these results prove the applicative validity of the
satisfactory.
developed procedure also in the peptide synthesis.
For completeness, since the amidation is mainly used in
Finally, the reaction can be also applied for large-scale
peptide synthesis, the developed protocol was also experi-
synthesis of amides demonstrating its applicability for amide
mented for the synthesis of a small peptide. For this purpose
syntheses of preparative and semi-industrial interest.
the dipeptide system methyl 3-methyl-2-(S)-(2-(R)-(4-
nitrophenylsulfonamido)-propanamido)butanoate (20) was
prepared by treating N-4-nitrophenylsulfonyl-D-alanine (1 Acknowledgements
mmol) with L-valine methyl ester hydrochloride (1 mmol) under
This work was supported by grants from MIUR (Ministero Ital-
the adopted reaction conditions using 5 equivalents of Et3N.
iano dell'Università e della Ricerca, ex-60% funds).
The methodology was successful in giving, aer 40 minutes, the
desired dipeptide derivative 20, which was isolated in good
yields (65%, Table 2). References
A last experiment was performed to verify the preparation of
1 (a) L. Stryer, Biochemistry, ed. W. H. Freeman, New York, 4th
the amides in large scale. 10 grams of benzoic acid were treated
edn, 1995, p. 17; (b) V. A. K. Ghose, N. Viswanadhan and
with Et2NH (8.5 mL) and Et3N (34.5 mL) in dichloromethane,
J. J. Wendoloski, Comb. Chem., 1999, 1, 55; (c) E. Valeur
then SOCl2 (8.5 mL) was added to the reaction mixture at room
and M. Bradley, Chem. Soc. Rev., 2009, 38, 606–631; (d)
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View Article Online
V. R. Pattabiraman and J. W. Bode, Nature, 2011, 480, 471– 12 G. Blotny, Tetrahedron, 2006, 62, 9507–9522.
479; (e) J. K. Park, W. K. Shin and D. K. An, Bull. Korean 13 C. E. Garrett, X. Jiang, K. Prasad and O. Repič, Tetrahedron
Chem. Soc., 2013, 34, 1592–1594; (f) X. Yu and D. Sun, Lett., 2002, 43, 4161–4165.
Molecules, 2013, 18, 6230–6268; (g) J. D. Goodreid, 14 A. Devos, J. Remion, A.-M. Frisque-Hesbain, A. Colens and
P. A. Duspara, C. Bosch and R. A. Batey, J. Org. Chem., L. J. Ghosez, J. Chem. Soc., Chem. Commun., 1979, 1180–1181.
2014, 79, 943–954. 15 E. Falb, T. Yechezkel, Y. Salitra and C. Gilon, J. Pept. Res.,
2 (a) L. Zhang, X. Wang, J. Wang, N. Grinberg, 1999, 53, 507–517.
Published on 01 April 2016. Downloaded by University of California - Santa Barbara on 25/03/2018 09:03:07.
D. K. Krishnamurthy and C. H. Senanayake, Tetrahedron 16 (a) J. P. E. Human and J. A. Mills, Nature, 1946, 158, 877; (b)
Lett., 2009, 50, 2964–2966; (b) R. M. Lanigan and F. Matsuda, M. Yanaqiya and T. Matsumoto, Tetrahedron
T. D. Sheppard, Eur. J. Org. Chem., 2013, 7453–7465; (c) Lett., 1982, 23, 4043–4046.
K. B. Zambro, S. R. Dubbaka, D. Markovic, E. Moreno- 17 F. Matsuda, S. Itoh, N. Hattori, M. Yanagiya and
Clavijo and P. Vogel, Org. Lett., 2013, 15, 2550–2553; (d) T. Matsumoto, Tetrahedron, 1985, 41, 3625–3631.
K. Nakamura, T. Nakajima, T. Aoyama, S. Okitsu and 18 R. J. Cvetovich and L. DiMichele, Org. Process Res. Dev., 2006,
M. Koyama, Tetrahedron, 2014, 70, 8097–8107. 10, 944–946.
3 G. Johansson, Kirk-Othmer Encyclopedia of Chemical 19 J. Y. L. Chung, R. J. Cvetovich, M. McLaughlin, J. Amato,
Technology, John Wiley & Sons, New York, 2004, vol. 2, pp. F.-R. Tsay, M. Jensen, S. Weissman and D. Zewge, J. Org.
442–463. Chem., 2006, 71, 8602–8609.
4 (a) L. Amarnath, I. Andrews, R. Bandichhor, A. Bhattacharya, 20 O. Jacobson, Y. Bechor, A. Icar, N. Novak, A. Birman,
P. Dunn, J. Hayler, W. Hinkley, N. Holub, D. Hughes, H. Marom, L. Fadeeva, E. Golan, I. Leibovitch, M. Gutman,
L. Humphreys, B. Kaptein, H. Krishnen, K. Lorenz, E. Even-Sapir, R. Chisin, M. Gozin and E. Mishani, Bioorg.
S. Mathew, G. Nagaraju, T. Rammeloo, P. Richardson, Med. Chem., 2005, 13, 6195–6205.
L. Wang, A. Wells and T. White, Org. Process Res. Dev., 21 J. J. Morris, L. R. Hughes, A. T. Glen and P. J. Taylor, J. Med.
2012, 16, 535–544; (b) R. Bandichhor, A. Bhattacharya, Chem., 1991, 34, 447–455.
L. Diorazio, P. Dunn, K. Fraunhoffer, F. Gallou, J. Hayler, 22 Y. Ito, I. Washio and M. Ueda, Macromolecules, 2008, 41,
M. Hickey, W. Hinkley, D. Hughes, L. Humphreys, 2778–3278.
B. Kaptein, S. Mathew, T. Rammeloo, P. Richardson and 23 S. Tortoioli, D. Marchal, M. Kesselgruber, T. Pabst,
T. White, Org. Process Res. Dev., 2013, 17, 615–626. W. Skranc and S. Abele, Org. Process Res. Dev., 2014, 18,
5 D. J. C. Constable, P. J. Dunn, J. D. Hayler, G. R. Humphrey, 1759–1762.
J. L. Leazer Jr, R. J. Linderman, K. Lorenz, J. Manley, 24 T. Kumagai, T. Anki, T. Ebi, A. Konishi, K. Matsumoto,
B. A. Pearlman, A. Wells, A. Zaks and T. Y. Zhang, Green H. Kurata, T. Kubo, K. Katsumoto, C. Kitamura and
Chem., 2007, 9, 411–420. T. Kawase, Tetrahedron, 2010, 66, 8968–8973.
6 C. A. G. N. Montalbetti and V. Falque, Tetrahedron, 2005, 61, 25 S. Pass, B. Amit and A. Patchornik, J. Am. Chem. Soc., 1981,
10827–10852. 103, 7675–7676.
7 I. Weisz, J. Roboz and G. Bekesi, Tetrahedron Lett., 1996, 37, 26 (a) M. M. Joullié and K. M. Lassen, ARKIVOC, 2010, 189–250;
563–566. (b) C. Najera, Synlett, 2002, 1388–1403.
8 L. A. Rozov, P. W. Rafalko, S. M. Evans, L. Brockunier and 27 (a) M. L. Di Gioia, A. Barattucci, P. Bonaccorsi, A. Leggio,
K. J. Ramig, J. Org. Chem., 1995, 60, 1319–1325. L. Minuti, E. Romio, A. Temperini and C. Siciliano, RSC
9 L. A. Carpino, B. J. Cohen Jr, K. E. Stephens, Y. Sadat-Aalaee, Adv., 2014, 4, 2678–2686; (b) O. Marder and F. Albericio,
J.-H. Tien and D. C. Langridge, J. Org. Chem., 1986, 51, 3732. Chim. Oggi, 2003, 21, 35–40.
10 A. Wissner and C. V. J. Grudzinskas, J. Org. Chem., 1978, 43, 28 R. De Marco, M. L. Di Gioia, A. Leggio, A. Liguori, F. Perri,
3972–3974. C. Siciliano and M. C. Viscomi, Amino Acids, 2010, 38, 691–
11 G. Prabhu, H. Basavaprabhu, N. Narendra, 700.
T. M. Vishwanatha and V. V. Sureshbabu, Tetrahedron, 29 A. Leggio, M. L. Di Gioia, F. Perri and A. Liguori, Tetrahedron,
2015, 71, 2785–2832. 2007, 63, 8164–8173.
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