Convenient preparation of primary amides via activation of carboxylic acids with ethyl chloroformate and triethylamine under mild conditions

Article abstract of DOI:10.1246/cl.130096

Primary amides were easily prepared in 22-99% yields from the corresponding carboxylic acids 1 or 5 with NH₄Cl via activation with ClCO ₂Et and Et₃N. The enantiomers of the corresponding primary amides of Cbz-, Boc-, or Fmoc-α-amino acids can be separated by using a chiral column.

Full text of DOI:10.1246/cl.130096

doi:10.1246/cl.130096
580
Published on the web April 24, 2013
Convenient Preparation of Primary Amides via Activation of Carboxylic Acids
with Ethyl Chloroformate and Triethylamine under Mild Conditions
Takuya Noguchi, Masahiro Sekine, Yuki Yokoo, Seunghee Jung, and Nobuyuki Imai*
Faculty of Pharmacy, Chiba Institute of Science, 15-8 Shiomi-cho, Choshi, Chiba 288-0025
(Received February 5, 2013; CL-130096; E-mail: nimai@cis.ac.jp)
ClCO2Et
Primary amides were easily prepared in 22-99% yields from
O
O
R
O
R
O
Et3N
ammonia
source
R
*
*
the corresponding carboxylic acids 1 or 5 with NH4Cl via
activation with ClCO2Et and Et3N. The enantiomers of the
corresponding primary amides of Cbz-, Boc-, or Fmoc-¡-amino
acids can be separated by using a chiral column.
*
O
OEt
P-HN
OH
P-HN
NH2
THF
P-HN
P = protecting group
Scheme 1.
Table 1. Primary amidation of 3-phenylpropanoic acid (1a)a
The classical methods for amide synthesis are the reactions
of amines with activated carboxylic acids such as acyl halides,
acyl azides, acyl imidazoles, esters, anhydrides, or carbonic
carboxylic anhydrides.1 However, the syntheses of primary
amides from these intermediates with ammonia have been
limited because the nucleophilicity of ammonia is lower than
those of primary and secondary amines. The reaction must be
carried out at a high pressure and/or low temperature because
ammonia boils at ¹33 °C under a pressure of 1 atm. In these
cases, the solubility of the starting materials in water is also
important. Recently, the preparation of primary amides using
NH4OH via the activation of carboxylic acids with 1-(meth-
anesulfonyl)benzotriazole and Et3N2 or with 1-hydroxybenzo-
triazole (HOBt) and N,N¤-dicyclohexylcarbodiimide (DCC)3 has
been reported. Kunishima has reported a simple and practical
method for the preparation of primary amides, in which NH4Cl,
Et3N, and a typical coupling reagent for peptide synthesis, 4-
(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chlo-
ride (DMT-MM), were used.4 We have just shown that the
amidation of N-protected ¡-amino acids with unprotected
¡-amino acids via the mixed carbonic carboxylic anhydrides
provides the corresponding dipeptides without C-protection in
good to excellent yields.5
Herein, we describe the preparation of primary amides from
the corresponding carboxylic acids with an ammonia source via
activation with ClCO2Et and Et3N (Scheme 1). It was found that
the enantiomers of the corresponding primary amides of Cbz-,
Boc-, and Fmoc-phenylalanines or Cbz-¡-amino acids are
separable by high-pressure liquid chromatography (HPLC)
using Chiralcel AD, OD, or OJ.
In a preliminary investigation, the reaction of 3-phenyl-
propanoic acid (1a) with 1.5 equivalents of an ammonia source
(NH3, NH4OH, NH4Cl, or MeCO2NH4) in the presence of 1.4
equivalents of ClCO2Et and 3.0 equivalents of Et3N in
tetrahydrofuran (THF) afforded 3-phenylpropanamide (2a) in
excellent yields, as indicated in Table 1. The best yield (99%,
Entry 3) was obtained using NH4Cl, which is very easy to
handle.
O
O
1) ClCO2Et, Et3N, THF, 0 °C, 30 min
Ph
NH2
Ph
OH
2) ammonia source, 0 °C, 30 min
1a
2a
Entry
Ammonia source
Yielde/%
1
2
3
4
NH3/MeOHb
97
97
99
93
NH4OH/H2Oc
NH4Cl/H2Od
MeCO2NH4/H2Od
aAll reactions were carried out with 1.0 mmol of 1a, 1.4 mmol
of ClCO2Et, and 3.0 mmol of Et3N in 20 mL of THF. After
stirring for 30 min at 0 °C, 1.5 mmol of ammonia source was
b
¹1
added at 0 °C to the reaction mixture. 2.0 mol L methanol
solution was used. c28% aqueous solution was used. d1.0
¹1
e
mol L aqueous solution was used. Isolated yield.
and 3). Even with the sterically hindered pivalic acid (1d), the
reaction proceeded easily to afford the corresponding primary
amide 2d in excellent yield (Entry 4), which was similar to the
case of 2a. 4-Methoxybenzoic acid (1i) containing an electron-
donating group reacted to afford 4-methoxybenzamide (2i) in
22% yield (Entry 9), although benzoic acid (1e), 4-nitrobenzoic
acid (1f), and acetylsalicylic acid (1g) containing electron-
withdrawing groups were converted to benzamide (2e), 4-
nitrobenzamide (2f), and acetylsalicylamide (2g) in 67%, 85%,
and 65% yields, respectively (Entries 5-7). Salicylic acid (1h)
reacted with NH4Cl using 2.8 equivalents of ClCO2Et to afford
2-ethoxycarbonyloxybenzamide in 52% yield (Entry 8). Un-
fortunately, the reaction of 4-methoxybenzoic acid (1i) gave a
low yield because the presence of a strong electron-donating
group on the aromatic ring deactivates the carbonyl carbon (A)
through the resonance effect (Entry 9). Then, the amidation of 1i
with NH4Cl via activation with ClCO2i-Bu was carried out to
afford the corresponding amide 2i in 19% yield (Entry 10).
For example, the reaction of the mixed carbonic carboxylic
anhydride of 1i with benzylamine afforded the corresponding
N-benzyl-4-methoxybenzamide (3i) in 31% yield with 50%
yield (based on benzylamine) of the by-product 4i and 40%
yield of 1i, as shown in Scheme 2.
The results of the primary amidation of several kinds of
carboxylic acids 1a-1i using NH4Cl via the corresponding
mixed carbonic carboxylic anhydride are collected in Table 2.
The reactions of cinnamic acid (1b) and the derivative 1c as a
conjugated carboxylic acid afforded the corresponding primary
amides 2b and 2c in 77% and 70% yields, respectively (Entries 2
Furthermore, the primary amidation of Cbz-L-Phe-OH 5a
with NH3/MeOH, NH4OH/H2O, MeCO2NH4/H2O, or NH4Cl/
H2O as the ammonia source using ClCO2Et and Et3N afforded
Cbz-L-Phe-NH2 6a in 83%, 90%, 88%, and 92% yields,
Chem. Lett. 2013, 42, 580-582
© 2013 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

581
Table 2. Primary amidation of carboxylic acids
ammonium chloridea
1
with
Table 3. Preparation of primary amides derived from N-
protected ¡-amino acids 5a
O
R
O
R
O
1) ClCO2Et, Et3N, THF, 0 °C, 30 min
O
1) ClCO2Et, Et3N, THF, 0 °C, 30 min
*
*
R
NH2
P-HN
OH
P-HN
NH2
R
OH
2) NH4Cl, H2O, 0 °C, 30 min
2) NH4Cl, H2O, 0 °C, 30 min
5
6
1
2
Yieldc
Eluent Retention time
%eed Chiralcel
/%
Entry
R
2
Yieldb/%
Entry Product 6
/%
/min
1
2
3c
4
5
6
C6H5CH2CH2
2a
2b
2c
2d
2e
2f
2g
2h
2i
99
77
70
94
67
85
65
0e
1
2
Cbz-L-Phe-NH2 6a
Cbz-D-Phe-NH2 6a¤
92 >99
92 >99
87 >99
AD
AD
OJ
OJ
OJ
10
10
10
10
2
2
8
8
5
23.6
19.2
20.9
40.0
45.6
29.0
31.5
38.5
31.8
37.6
21.7
26.8
50.2
43.0
C6H5CH=CH
4-MeOC6H5CH=CH
t-Bu
3b Fmoc-L-Phe-NH2 6b
4b Fmoc-D-Phe-NH2 6b¤ 90 >99
5
Boc-L-Phe-NH2 6c
90 >99
96 >99
91 >99
91 >99
96 >99
91 >99
90 >99
94 >99
69 >99e
74 >99e
C6H5
6b Boc-D-Phe-NH2 6c¤
OJ
4-NO2C6H4
2-AcOC6H4
2-HOC6H4
4-MeOC6H4
4-MeOC6H4
7
8
9
Cbz-L-Ala-NH2 6d
Cbz-D-Ala-NH2 6d¤
Cbz-L-Val-NH2 6e
OD
OD
OD
OD
AD
AD
AD
AD
7
8d
9
22
19
10 Cbz-D-Val-NH2 6e¤
11 Cbz-L-Met-NH2 6f
12 Cbz-D-Met-NH2 6f¤
13 Cbz-L-Gln-NH2 6g
14 Cbz-D-Gln-NH2 6g¤
5
10f
2i
10
10
10
10
aAll reactions were carried out with 1.0 mmol of 1, 1.4 mmol
of ClCO2Et, and 3.0 mmol of Et3N in 20 mL of THF. After
stirring for 30 min at 0 °C, 1.5 mmol of a 1.0 mol L aqueous
solution of NH4Cl was added at 0 °C to the reaction mixture.
bIsolated yield. cThis reaction was carried out with 0.5 mmol of
1c, 0.7 mmol of ClCO2Et, and 1.5 mmol of Et3N in 10 mL of
THF. After stirring for 30 min at 0 °C, 0.75 mmol of a
¹1
aAll reactions were carried out with 0.5 mmol of 5, 0.7 mmol
of ClCO2Et, and 1.5 mmol of Et3N in 10 mL of THF. After
stirring for 30 min at 0 °C, 0.75 mmol of a 1.0 mol L¹1 aqueous
solution of NH4Cl was added at 0 °C to the reaction mixture.
bThese reactions were carried out with 0.2 mmol of 5,
0.28 mmol of ClCO2Et, and 0.6 mmol of Et3N in 4 mL of
THF. After stirring for 30 min at 0 °C, 0.3 mmol of a
1.0 mol L aqueous solution of NH4Cl was added at 0 °C to
the reaction mixture. Isolated yield. dDetermined by HPLC
analysis with a mixture of hexane-isopropanol as an eluent
using Chiralcel AD, OD, or OJ (1.0 mL min¹1). Determined
¹1
1.0 mol L aqueous solution of NH4Cl was added at 0 °C to
the reaction mixture. dThis reaction was carried out with
1.0 mmol of 1h, 2.8 mmol of ClCO2Et, and 3.0 mmol of Et3N
in 20 mL of THF. After stirring for 30 min at 0 °C, 1.5 mmol of
a 1.0 mol L¹1 aqueous solution of NH4Cl was added at 0 °C to
¹1
c
e
the reaction mixture. This reaction afforded 2-ethoxycarbon-
yloxybenzamide in 52% yield. fClCO2i-Bu was used instead of
ClCO2Et.
e
by HPLC analysis with a 90:10:0.1 mixture of hexane-
isopropanol-Et2NH as an eluent using Chiralcel AD (1.0
mL min¹1).
O
O
O
O
O
BnNH2
NHBn
OH
(1.0 mmol)
O
OEt
+
BnHN OEt
+
A
B
THF
MeO
3i (31% yield)
MeO
1i (40% yield)
MeO
(1.0 mmol)
4i (50% yield)
¡-amino acids 5 by using NH4Cl under mild conditions, and that
racemization does not occur in our developed method. Further
investigations on this type of reaction are underway in our
group.
Scheme 2. Reaction of the mixed carbonic carboxylic anhy-
dride of 1i with benzylamine.
respectively, as a single enantiomer through HPLC analysis
using Chiralcel AD in these cases.6 The best result (92% yield)
was obtained using NH4Cl, as indicated in Entry 1 of Table 3.
The reactions of N-protected ¡-amino acids 5a-5g with NH4Cl
as an ammonia source were carried out, and the results are
collected in Table 3. Cbz-D-Phe-OH 5a¤ reacted with NH4Cl
under similar conditions to Entry 1 to afford Cbz-D-Phe-NH2 6a¤
in 92% yield as the D-form enantiomer (Entry 2). The reactions
of L- and D-phenylalanine derivatives 5b, 5c and 5b¤, 5c¤
protected with other conventional groups such as 9-fluorenyl-
methoxycarbonyl (Fmoc) and tert-butoxycarbonyl (Boc) afford-
ed the corresponding primary amides 6b, 6c and 6b¤, 6c¤ through
HPLC analysis using Chiralcel OJ in 87-96% yields, and no
racemization was observed (Entries 3-6). Finally, the reactions
of several kinds of Cbz-L- and D-¡-amino acids 5d-5g and 5d¤-
5g¤ with NH4Cl under mild conditions gave the corresponding
primary amides 6d-6g and 6d¤-6g¤ through HPLC analysis
using Chiralcel AD or OD in 69-96% yields with >99% ee
(Entries 7-14).
References and Notes
1
a) M. A. Blaskovich, Handbook on Syntheses of Amino
Acids: General Routes for the Syntheses of Amino Acids,
Oxford University Press, New York, 2010. b) C. T. Hoang, F.
Bouillère, S. Johannesen, A. Zulauf, C. Panel, A. Pouilhès,
D. Gori, V. Alezra, C. Kouklovsky, J. Org. Chem. 2009, 74,
4177. c) T. Mori, S. Higashibayashi, T. Goto, M. Kohno, Y.
Satouchi, K. Shinko, K. Suzuki, S. Suzuki, H. Tohmiya, K.
Hashimoto, M. Nakata, Chem.®Asian J. 2008, 3, 984. d)
C. A. G. N. Montalbetti, V. Falque, Tetrahedron 2005, 61,
10827. e) T. Wieland, M. Bodanszky, The World of Peptides:
A Brief History of Peptide Chemistry, Springer-Verlag, New
York, 1991, pp. 77-102. doi:10.1007/978-3-642-75850-8_4.
A. R. Katritzky, H.-Y. He, K. Suzuki, J. Org. Chem. 2000,
65, 8210.
2
3
4
S.-T. Chen, S.-H. Wu, K.-T. Wang, Synthesis 1989, 37.
T. Mizuhara, K. Hioki, M. Yamada, H. Sasaki, D. Morisaki,
M. Kunishima, Chem. Lett. 2008, 37, 1190.
In conclusion, we have found that primary amides 6 are
prepared in 69-96% yields from the corresponding N-protected
5
a) T. Noguchi, S. Jung, N. Imai, Chem. Lett. 2012, 41, 577.
b) T. Noguchi, N. Tehara, Y. Uesugi, S. Jung, N. Imai, Chem.
Chem. Lett. 2013, 42, 580-582
© 2013 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

582
Lett. 2012, 41, 42.
was added at 0 °C to the mixure. The resulted colorless clear
solution was extracted with 100 mL of EtOAc, washed with
10 mL of brine, and dried over anhydrous MgSO4. The crude
product was recrystallized from 60 mL of a 1:9 mixture of
chloroform and hexane to afford 137 mg (92% yield) of 6a
6
A typical procedure of the primary amidation of 5a using
ClCO2Et is as follows. To a solution of 150 mg (0.5 mmol)
of Cbz-L-Phe-OH 5a in 10 mL of THF, 67 ¯L (0.7 mmol,
1.4 equiv) of ClCO2Et and 208 ¯L (1.5 mmol, 3.0 equiv) of
Et3N were added at 0 °C. After stirring for 30 min at 0 °C,
0.75 mL of a 1.0 M aqueous solution of NH4Cl (0.75 mmol,
1.5 equiv) was added at 0 °C to the colorless suspension. The
mixture was stirred for 30 min at 0 °C, and 10 mL of water
1
(Cbz-L-Phe-NH2). 6a: colorless powder; H NMR (CDCl3):
¤ 3.02-3.15 (2H, m, CH2), 4.42-4.45 (1H, m, CH), 5.08 (2H,
s, CH2), 5.34 (1H, d, J = 7.5 Hz, NH), 5.49 (1H, brs, NH),
5.74 (1H, brs, NH), 7.20-7.38 (10H, m, C6H5 © 2).
Chem. Lett. 2013, 42, 580-582
© 2013 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/