A convenient synthesis of amino acid arylamides utilizing methanesulfonyl chloride and N-methylimidazole

Article abstract of DOI:10.1055/s-0030-1259099

N-Cbz-protected amino acids reacted with various aryl-amines in the presence of methanesulfonyl chloride and N-methylimidazole in dichloromethane to give the corresponding arylamides in high yields. No obvious racemization was observed under the mild conditions. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1259099

LETTER
129
A Convenient Synthesis of Amino Acid Arylamides Utilizing Methanesulfonyl
Chloride and N-Methylimidazole
C
onvenientSyn
i
thesis
o
g
f
A
minoA
c
u
idArylamid
a
es ng Mao,a Zhenyu Wang,a Yongjia Li,a Xiqian Han,b Weicheng Zhou*a
a
State Key Lab of New Drug & Pharmaceutical Process, Shanghai Institute of Pharmaceutical Industry,
1111 Zhongshanbeiyi Road, Shanghai 200437, P. R. of China
Fax +86(21)35052484; E-mail: zhouwc@sipi.com.cn
Pharmaceutical College, Shandong University, 44 West Wenhua Road, Jinan, Shandong 250012, P. R. of China
b
Received 17 August 2010
cine (N-Cbz-Ile) and phenylalanine (N-Cbz-Phe) as the
building blocks. Our initial experiment to convert N-Cbz-
phenylalanine (1a) with p-methylaniline (2a) into 3a
using several procedures gave disappointing results
Abstract: N-Cbz-protected amino acids reacted with various aryl-
amines in the presence of methanesulfonyl chloride and N-meth-
ylimidazole in dichloromethane to give the corresponding
arylamides in high yields. No obvious racemization was observed
under the mild conditions.
Key words: amino acid arylamides, N-Cbz-protected amino acids,
condensation, steric hindrance, enantioretention
Table 1 Optimization of Reaction Conditions
Amino acid arylamides are compounds of great interest
and are widely used in polymers, dendrimers, peptidomi-
metics, and pharmaceuticals.1 For example, amino acid p-
nitroanilides are often used as chromogenic substrates for
the determination of the activity of proteolytic enzymes
present in body fluids.2 However, the preparative methods
appeared to be rather troublesome since free arylamines
used in the reactions are very weak nucleophiles. As a
consequence, much effort has been invested in the devel-
opment of efficient synthesis.
Cbz
H2N
OH
N
H
O
1a
conditions
H
Cbz
N
+
N
H
O
3a
2a
Entry Conditions
Solvent Time Yield (%)a
(h)
In general, amino acid arylamides are prepared from the
amino acids and arylamines in the presence of the cou-
pling agents. The commonly used coupling agents, e.g.,
DCC,3 DCC–HOBt4 and the mixed anhydride,5 rarely re-
sult in satisfactory yields. Other methods based on reac-
tive condensing agents, e.g., phosphorous or boron
derivatives, often lead to significant racemization.6 Acid
chlorides7 and thermal activation8 have been recommend-
ed to cope with the reaction using the arylamine with low
nucleophilicity, but they also afford products of question-
able optical purity. Recently, a three-step protocol for the
preparation of amino acid and peptide C-terminal elec-
tron-deficient arylamides was described, based on the re-
action of an azide with selenocarboxylates. Although high
yields were obtained, some racemization proved to be in-
evitable.9 In conclusion, each of the known methods for
the preparation of amino acid arylamides suffers from
some drawbacks such as low yields, racemization, hazard-
ous and expensive condensing reagents.
1
2
3
4
5
DCC–Et3N (3.0 equiv)
DCC–Et3N (3.0 equiv)
EDCI–Et3N (3.0 equiv)
EDCI–Et3N (3.0 equiv)
THF
7
7
6
6
2
47
CH2Cl2
THF
41
61
THF
51
isobutyl chloroformate–Et3N
(3.0 equiv)
CH2Cl2
complex
6b MsCl–pyridine (3.0 equiv)
7b MsCl–Et3N (3.0 equiv)
8c MsCl–Et3N (3.0 equiv)
9b MsCl–MeIm (3.0 equiv)
10b MsCl–MeIm (3.0 equiv)
11b MsCl–MeIm (2.5 equiv)
12b MsCl–MeIm (2.0 equiv)
13b MsCl–MeIm (1.5 equiv)
14b MsCl–MeIm (2.5 equiv)
a Isolated yield based on 2a.
THF
2
2
2
2
2
2
2
2
3
complex
36
THF
THF
46
THF
70
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
89
89
80
In the context of developing peptidomimetic inhibitors in
our ongoing research, we needed some C-terminal aryl-
amides of N-Cbz-protected leucine (N-Cbz-Leu), isoleu-
63
87
b To a solution of 1a (1 equiv) and base in the given solvent was added
MsCl (1 equiv) below –5 °C. After stirring for 20 min, 2a (0.9 equiv)
was added and the solution was stirred at r.t.
SYNLETT 2011, No. 1, pp 0129–0133
x
x.
x
x.
2
0
1
0
Advanced online publication: 10.12.2010
DOI: 10.1055/s-0030-1259099; Art ID: W13010ST
© Georg Thieme Verlag Stuttgart · New York

130
L. Mao et al.
LETTER
(Table 1, entries 1–5). This seemingly trivial transforma-
tion to produce 3a was plagued with poor isolated yields.
H2N Ar (2)
R
R
H
MsCl
Cbz
OH
Cbz
N
N
N
Ar
H
H
We speculated that the poor yield resulted from not only
the weak nucleophilicity of p-methylaniline, but also the
steric encumbrance around the carboxyl group. Nicolaou
had published a method for the formation of hindered a-
diazoketones that was presumed to proceed through a
mixed anhydride of carboxylic acid with methanesulfonyl
chloride (MsCl).10 Later, Woo adopted this method in his
preparation of Weinreb amides from hindered carboxylic
acids.11 Both Nicolaou and Woo obtained their target
compounds in reasonable yields. This method, using
methanesulfonic acid as a counter acid moiety is a prom-
ising candidate for an efficient arylamidation (Scheme 1)
from sterically hindered amino acid. In this paper, we re-
port a convenient synthesis of amino acid arylamides from
N-Cbz-protected amino acids and arylamines utilizing
methanesulfonyl chloride and N-methylimidazole
(MeIm).
O
O
1
3
Scheme 1 Synthesis of arylamides from N-Cbz-protected amino
creasing the ratio of 1a:2a to 1:3 from 1:0.9 only gave a
slight improvement of the yield (Table 1, entry 8). To im-
prove the conversion of 1a into 3a, we decided to use N-
methylimidazole (MeIm) as the base, which was shown to
be an efficient promoter in sulfonate formation.12 To our
delight, a noticeable increase in yield was observed
(Table 1, entry 9). Furthermore, using dichloromethane as
the solvent gave the better result (Table 1, entry 10). In a
successive series of experiments, decreasing the amount
of MeIm to 2.5 equivalents maintained the yield but a fur-
ther decrease led to a significant loss of the product
(Table 1, entries 11–13). Prolonging the reaction time
from two hours to three hours had little effect on the yield
(Table 1, entry 14).
We investigated the effect of different bases and solvents
on the arylamidation with the model reaction between 1a
and 2a using MsCl. Preliminary experiments using trieth-
ylamine or pyridine as the base gave rather disappointing
results (Table 1, entries 6 and 7). Further attempt by in-
Encouraged by these results, the conditions used in
Table 1, entry 11 were applied to prepare other building
blocks in our research of developing peptidomimetic in-
hibitors. The results are presented in Table 2.13
Table 2 Synthesis of Arylamides from N-Cbz-Protected Amino Acids and Arylamines with MsCl and MeIma
Entry
Amino acid
Arylamine
Product
Yield (%)b
89
H
N
H2N
Cbz
Phe
1
N-Cbz-Phe (1a)
2a
3a
H
N
H2N
Cbz
Phe
Phe
Phe
2
3
1a
1a
90
87
2b
3b
H
N
H2N
Cbz
F
F
2c
3c
H
N
H2N
Cbz
4
5
1a
1a
90
87
N
N
N
N
2d
3d
H
N
H2N
Cbz
Phe
N
N
O
O
2e
3e
Synlett 2011, No. 1, 129–133 © Thieme Stuttgart · New York

LETTER
Convenient Synthesis of Amino Acid Arylamides
131
Table 2 Synthesis of Arylamides from N-Cbz-Protected Amino Acids and Arylamines with MsCl and MeIma (continued)
Entry
6
Amino acid
Arylamine
Product
Yield (%)b
H
N
H2N
F
F
F
F
Cbz
Phe
1a
77
2f
3f
H
N
H2N
Cbz
Phe
7
8
1a
80
89
88
83
89
NO2
NO2
2g
3g
H
H2N
Cbz Leu
N
N-Cbz-Leu (1b)
2a
3h
H
H2N
Cbz
Leu
N
9
1b
1b
1b
OMe
OMe
2i
3i
H
H2N
N
Leu
Leu
Cbz
10
11
2b
3j
H
H2N
N
Cbz
F
F
2c
3k
H
H2N
N
Cbz
Leu
12
13
14
1b
1b
1b
81
83
82
N
N
N
N
2d
3l
H
N
H2N
F
F
Leu
Leu
F
F
Cbz
2f
3m
H
N
H2N
Cbz
N
N
N
2g
3n
H
N
H2N
Cbz
Leu
15
1b
89
N
2h
3o
H
H2N
Cbz
Ile
Ile
N
16
17
N-Cbz-Ile (1c)
86
83
2a
3p
H
H2N
N
Cbz
1c
F
F
2c
3q
Synlett 2011, No. 1, 129–133 © Thieme Stuttgart · New York

132
L. Mao et al.
LETTER
Table 2 Synthesis of Arylamides from N-Cbz-Protected Amino Acids and Arylamines with MsCl and MeIma (continued)
Entry
18
Amino acid
Arylamine
Product
Yield (%)b
H
H2N
Cbz
N
Ile
1c
86
N
N
2i
3r
H
H2N
F
F
Cbz
N
F
F
Ile
Ile
19
20
1c
1c
84
87
2f
3s
H
N
H2N
Cbz
N
N
N
N
2d
3t
H
H2N
Cbz
Ile
Ile
N
21
22
1c
1c
87
89
N
N
2g
3u
H
H2N
N
Cbz
N
N
2h
3v
a To a solution of N-Cbz-protected amino acid (1.0 equiv) and MeIm (2.5equiv) in CH2Cl2 (5 mL/g) was added MsCl (1.0 equiv) below –5 °C
and stirred for additional 20 min, then the arylamine (0.9 equiv) was added to this mixture and stirred for 2 h at r.t.
b Isolated yield based on arylamines.
Arylamides generated from N-Cbz-protected amino acids observed. These results indicate that there is no significant
and arylamines were obtained in reasonable yields using racemization in the synthesis.
MsCl and MeIm in dichloromethane (Table 2). A range of
In summary, we have demonstrated that N-terminal-
4-methyl-, 4-methoxy-, 4-fluoro-, 3,4-difluoro-, 4-pyra-
protected amino acids could be readily converted in high
zolyl-, 4-pyrrolyl-, 4-pyrrolidinyl-, 4-morpholinyl-, 4-
yields into various C-arylamides utilizing methanesulfo-
nyl chloride and N-methylimidazole in dichloromethane
even if the arlyamines have extremely low nucleophilicity
piperidyl- and 4-nitro-substituted anilines were readily
condensed with N-Cbz-protected amino acids (N-Cbz-
protected Phe, Leu and Ile) under the mild conditions.
and the amino acids are sterically hindered. It is also note-
Both electron-donating and electron-withdrawing aryl-
worthy that under the mild conditions, no significant race-
amines worked well. It was noted that the weakly nucleo-
philic p-nitroaniline (p-NA) (pKa 1.0 vs pKa 5.2 for
aniline) and 3,4-difluoroaniline (pKa 1.4) also gave satis-
fying yields under the reaction conditions (Table 2, en-
tries 6, 7, 13 and 19).
To determine whether the reaction conditions caused ra-
cemization in this procedure, the enantiomeric excess (ee)
of both 3b and 3g were measured by chiral HPLC. As
shown in Figure 1 (3b, for example), racemates of Cbz-
Phe-anilide were baseline separated with retention time of
31.2 min and 38.9 min, respectively, in the chiral HPLC
system (chromatogram A, Figure 1). Using this analytical
method, we determined that ee of 3b was more than
99.5% (chromatogram B, Figure 1). The same method
was applied to 3g and the ee of more than 99.5% was also
Figure 1 Enantiomeric excess determination of L-Cbz-Phe-anilide
(3b) by chiral HPLC. The chromatograms shown are (A) recemate of
Cbz-Phe-anilide, and (B) L-Cbz-Phe-anilide (3b). Chromatographic
condition: CHIRAL, AD-H column (250 × 4.6 mm, 5mm); hexane–
i-PrOH–TFA (90:10:0.1); 0.8 mL/min; 30 °C
Synlett 2011, No. 1, 129–133 © Thieme Stuttgart · New York

LETTER
Convenient Synthesis of Amino Acid Arylamides
133
(5) (a) Nedev, H.; Nabarisoa, H.; Haertle, T. Tetrahedron Lett.
1993, 34, 4201. (b) Pozdnev, V. Int. J. Peptide Protein Res.
1994, 44, 36. (c) Schutkowski, M.; Mrestani-Klaus, C.;
Neubert, K. Int. J. Peptide Protein Res. 1995, 45, 257.
(d) Beniton, N.; Lee, Y.; Steinaur, R.; Chen, F. Int. J. Peptide
Protein Res. 1992, 40, 559.
mization occurred at the C-terminal position. Thus, this
method is a promising way for the synthesis of this impor-
tant class of compounds.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
(6) Kato, T.; Nagatsu, T.; Kimura, T.; Sakakibara, S.
Experientia 1978, 19, 351.
(7) (a) Zimmerman, M.; Ashe, B.; Yurewicz, E.; Patel, G. Anal.
Biochem. 1977, 78, 47. (b) Teno, N.; Wanaka, K.; Okada,
Y.; Tsuda, Y.; Okamoto, U.; Hijikata-Okunomiya, A.;
Naito, T.; Okamoto, S. Chem. Pharm. Bull. 1991, 39, 2340.
(8) (a) Haverback, B.; Dyce, B.; Bundy, H.; Edmondson, H. Am.
J. Med. 1960, 29, 424. (b) Bundy, H. Arch. Biochem.
Biophys. 1963, 102, 416.
Acknowledgment
The work was supported by ‘New Drug Innovation
2009X09301007’ from the Ministry of Science and Technology of
China and ‘Shanghai Nature Science foundation 10ZR149300’
from the Shanghai Committee of Science and Technology.
(9) Wu, X.; Hu, L. J. Org. Chem. 2007, 72, 765.
(10) Nicolaou, K.; Baran, P.; Zhong, Y.; Choi, H.; Fong, K.; He,
Y.; Yoon, W. Org. Lett. 1999, 1, 883.
References and Notes
(11) Woo, J.; Fenster, E.; Dake, G. J. Org. Chem. 2004, 69, 8984.
(12) (a) Wakasugi, K.; Iida, A.; Misaki, T.; Nishii, Y.; Tanabe, Y.
Adv. Synth. Catal. 2003, 345, 1209. (b) Nakatsuji, H.;
Ueno, K.; Misaki, T.; Tanabe, Y. Org. Lett. 2008, 10, 2131.
(13) Typical Procedure for the Preparation of Amino Acid
Arylamides: MeIm (25.0 mmol) was added to a stirred
solution of Cbz-Phe (10.0 mmol) in CH2Cl2 (15 mL) at 0–5
°C, and the mixture was stirred for 10 min. MsCl (10.0
mmol) in CH2Cl2 (1.0 mL) was added to the mixture under
–5 °C. After the mixture was stirred under that temperature
for 20 min, aniline (9.0 mmol) was added. Then the mixture
was stirred at r.t. for 2 h. H2O (100 mL) was added to the
mixture, which was extracted with additional CH2Cl2 (100
mL). The organic layer was washed with sat. NaCl solution
(3 × 50 mL) and dried with anhyd Na2SO4. The solvent was
removed by evaporation under reduced pressure.
(1) (a) Yin, H.; Frederick, K.; Liu, D.; Wand, A.; DeGrado, W.
Org. Lett. 2006, 8, 223. (b) Vinogradov, S. Org. Lett. 2005,
7, 1761. (c) Yin, H.; Gerlach, L.; Miller, M.; Moore, D.; Liu,
D.; Vilaire, G.; Bennett, J.; DeGrado, W. Bioorg. Med.
Chem. Lett. 2006, 16, 3380. (d) Kirkland, T.; Adler, M.;
Bauman, J.; Chen, M.; Haeggstrm, J.; King, B.; Kochanny,
M.; Liang, A.; Mendoza, L.; Phillips, G. Bioorg. Med. Chem.
2008, 16, 4963. (e) Foss, J. F.; Mathews, T.; Kharel, Y.;
Kennedy, P.; Snyder, A.; Davis, M.; Lynch, K.; Macdonald,
T. Bioorg. Med. Chem. 2007, 15, 663.
(2) Svendsen, L.; Blomback, B.; Blomback, M.; Olsson, P.
Thromb. Res. 1972, 1, 267.
(3) (a) Zimmerman, M.; Yurewicz, E.; Patel, G. Anal. Biochem.
1976, 70, 258. (b) Fujiwara, K.; Tsuru, D. J. Biochem. 1978,
83, 1145. (c) Sharma, S.; Castellino, F. Thromb. Res. 1990,
57, 127.
Purification by chromatography on silica gel (CH2Cl2–
MeOH) gave 3b as a white solid; mp 169–170 °C; [a]D
(4) Okada, Y.; Tsuda, Y.; Hirata, A.; Nagamatsu, Y.; Okamoto,
U. Chem. Pharm. Bull. 1982, 30, 4060.
25
46.0 (c = 0.2, DMSO); ee >99.5%. 1H NMR (400 MHz,
DMSO): d = 2.88 (dd, 1 H), 3.03 (dd, 1 H), 4.43 (m, 1 H),
4.99 (s, 2 H), 5.43 (br s, 1 H), 7.00–7.60 (m, 15 H), 10.04 (br
s, 1 H). HRMS (ESI+): m/z [M + Na+] calcd for C23H22N2O3:
397.1528; found: 397.1530.
Synlett 2011, No. 1, 129–133 © Thieme Stuttgart · New York