A novel and efficient amidation of 2-aminothiazole

Article abstract of DOI:10.1016/j.tetlet.2014.10.031

A facile and efficient method has been developed for the synthesis of novel thiazolyl carboxamide derivatives by direct reaction of the corresponding esters and 2-aminothiazole. Treatment of 2-aminothiozole with various carboxylic esters in the presence of t-butylmagnesium chloride provides the biologically significant thiazolyl carboxamide derivatives in good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2014.10.031

Accepted Manuscript
A novel and efficient amidation of 2-aminothiazole
Minho Choi, Sun-Woo Won, Hyeju Jo, Mayavan Viji, Seung-Yong Seo, Yeon-
Ju Lee, Hyi-Seung Lee, Heesoon Lee, Jin Tae Hong, Young-Shin Kwak, Jae-
Kyung Jung
PII:
S0040-4039(14)01714-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.10.031
TETL 45260
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
26 August 2014
1 October 2014
7 October 2014
Please cite this article as: Choi, M., Won, S-W., Jo, H., Viji, M., Seo, S-Y., Lee, Y-J., Lee, H-S., Lee, H., Hong,
J.T., Kwak, Y-S., Jung, J-K., A novel and efficient amidation of 2-aminothiazole, Tetrahedron Letters (2014), doi:
http://dx.doi.org/10.1016/j.tetlet.2014.10.031
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Graphical Abstract
A novel and efficient amidation of 2-
aminothiazole
Leave this area blank for abstract info.
Minho Choia, Sun-Woo Wonb, Hyeju Joa, Mayavan Vijia, Seung-Yong Seoc, Yeon-Ju Leed, Hyi-Seung Leed,
Heesoon Leea, Jin Tae Honga, Young-Shin Kwakb,∗, Jae-Kyung Junga,∗
O
S
S
O
t-BuMgCl
+
R'
N
R
N
N
H2N
R
O
THF, 0 oC- rt , 2 h
H

1
Tetrahedron Letters
journal homepage: www.els evier.com
A novel and efficient amidation of 2-aminothiazole
Minho Choia, Sun-Woo Wonb, Hyeju Joa, Mayavan Vijia, Seung-Yong Seoc, Yeon-Ju Leed, Hyi-Seung Leed,
Heesoon Leea, Jin Tae Honga, Young-Shin Kwakb,∗, Jae-Kyung Junga,∗
a College of Pharmacy and Medicinal Research Center (MRC), Chungbuk National University, Cheongju 362M-763, Republic of Korea
b College of Pharmacy, Korea University, Sejong 339-700, Republic of Korea
c College of Pharmacy and Gachon Institute of Pharmaceutical Sciences, Gachon University, Incheon 406-779, Republic of Korea
d Korea Ocean Res & Dev Inst, Ansan 426-44, South Korea
ARTICLE INFO
ABSTRACT
Article history:
Received
A facile and efficient method has been developed for the synthesis of novel
thiazolylcarboxamide derivatives by direct reaction of corresponding esters and 2-
aminothiazole. Treatment of 2-aminothiozole with various carboxylic esters in the presence of t-
butylmagnesium chloride provides the biologically significant thiazolylcarboxamide derivatives
in good to excellent yields.
Received in revised form
Accepted
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved.
Amide
2-Aminothiazole
Carboxamide
Transamidation
t-Butylmagnesiumchloride
Amidation is a highly useful synthetic strategy used by nature
as exemplified by proteins, peptides and many other naturally
occurring substances1. The reaction also occupies a prominent
position in many fields of chemical industry including material
science and drug development.2 It is noteworthy that more than
25% of known drug molecules possess amide groups.3 Numerous
amidation protocols have been extensively explored and
developed1-3 and in principle most amides are synthesized by the
called as non-steroidal, anti-inflammatory drug (NSAID)5 and
Thiazotropsin A is binding to the minor groove of duplex DNA6
(Figure 1). Despite significant progress made in peptide coupling
strategies, however, chemists still are seeking after an optimized
synthetic protocol for thiazolyl carboxamides since most of the
known methods require activation of carboxylic acids by using
stoichiometric amount of coupling reagent and often tedious
workup procedures.7 Moreover, due to the weak nucleophilicity
of the amino group in 2-aminothiazole, the reaction suffers from
undesirably long reaction time and low yields. Thus, facile
formation of thiazolyl carboxamides has remained as a major
hurdle in medicinal chemist’s compound design. We herein
report a novel and direct coupling method between 2-
aminothiazole and unactivated esters that yields thiazolyl
carboxamides atom-economically and in high yields.
reaction between amines with activated
derivatives.4
carboxylic acid
Figure 1. Representative drugs possessing a thiazole amide.
Thiazolyl carboxamides, the amides of 2-aminothiazoles are
very important structural motifs used by drug discovery chemists
and found in many important disease-intervening substances. For
example, Meloxicam is a selective cyclooxygenase-2 inhibitor
Scheme 1. Direct amidation strategy
———
∗ Corresponding author. Tel.: +82 43 261 2635; fax: +82 43 268 2732 (J.-K.J.); tel.; +82 44 860 1622 (Y.-S.K.)
E-mail address: orgjkjung@chungbuk.ac.kr (J.-K. Jung), youngshin@korea.ac.kr (Y.-S. Kwak).

2
Tetrahedron Letters
Table 2. Transamidation of 2-aminothiazole with various
estersa
Table 1. Optimization of the transamidation reactiona
O
S
S
Base
O
Yieldc (%)c
+
BocHN
Entry
Substrate
Product
BocHN
R'
N
N
H
THF, 0 oC-rt, 2 h
N
H2N
O
1a
2
3a
81.0
1
2-
Entry
Aminothiazole
(equiv.)
Base (equiv.)
Yieldb (%)b
1
1.0
2.0
2.0
3.0
2.0
2.0
t-BuMgCl (1.0)
t-BuMgCl (1.0)
t-BuMgCl (2.0)
t-BuMgCl (1.0)
i-PrMgCl (2.0)
i-PrMgCl (1.0)
38
43
81
50
64
31
2
3
4
5
6
69.4
70.8
2
3
a Unless otherwise stated, all the reaction were conducted in 1.0
equiv of ester 1a, 2-aminothiazole 2, and the base (as mentioned
above equivalence) were stirred at 0 ºC then rt for 2 h. b isolated
yields.
4
5
73.6
69.6
65.7
71.3
83.2
Issues arise in the general amidation reactions owing to the
onerous formation of activated esters (electrophiles) and low
reactivity of 2-aminothiazole (nucleophile). In order to overcome
the issues, we turned our attention to generating an activated
nucleophile instead. Inspired by the Merck’s procedure
developed for the synthesis of Weinreb amides,8 we were
prompted at using the magnesium amidate of 2-aminothiazole.
As a touchstone for the utility of the magnesium amidate in
amidation, we designed a highly challenged coupling reaction as
an initial study. The study was performed with the ester 1a (1.0
equiv) and 2-aminothiazole 2 (1.0 equiv) in the presence of the
base t-butylmagnesiumchloride (t-BuMgCl, 1.0 equiv) in THF at
0 ºC. The highly sterically-challenged neopentyl position of 1a
was successfully elaborated by the amidate and afforded the
desired thiazolyl amide 3a in 38% yield as shown in Table
1.(entry 1) Encouraged by this result, we screened several
reaction conditions to optimize the amidation. We were pleased
to find that the desired product 3a was obtained in 81% yield
when the reaction was performed with 2 euiv. of 2 and 2 euiv. of
the base (Table 1, entry 3). When i-PrMgCl was used as base,
relatively low yields of the desired product were obtained. (entry
5 and 6). 9 It is worth to note that the amide coupling with the
corresponding acid of 1a under the conventional protocols
utilizing EDC, HATU, and HOBt afforded the desired product 3a
in less than 30% yield. 10
6
7
O
8b
O
1h
9b
79.0
74.2
10b
The scope of this application was investigated by using 2-
aminothiazole and different carboxylic ester derivatives, which
proved to be widely applicable. Smooth conversion to the
corresponding amidation products was observed all through the
tested reactions in good to excellent yields, as shown in Table
2.12 We subjected various N-protected α-amino acid methyl ester
and TBDMS-protected methyl-L-lactate substrates to this reaction
protocol and all of them were successfully converted to the
corresponding products in good yields. We were particularly
delighted to find that there was no sign of racemization in
forming 3b even though enantiomerically-rich phenylglycines are
often highly prone to racemization during their peptide bond
formations.11 The 1h-m substrates (entry 8 to 13) did not require
an additional stoichiometry and yielded the corresponding
thiazolyl carboxamides by using 1.0 equiv of 2-aminothiazole
and 1.0 equiv of t-BuMgCl. No variation in reaction conditions
was necessary for handling the aryl ester substrates like 1h-j.
11b
12b
13b
83.2
87.4
77.6
a Unless otherwise stated, all the reaction were conducted in 2.0
equiv of 2-aminothiazole, 1.0 equiv of ester, 2.0 equiv of, t-
butylmagnesiumchloride stirred at 0 ºC for 2 h. b 1.0 equiv of 2-
aminothiazole, 1.0 equiv of ester, 1.0 equiv of t-
butylmagnesiumchloride stirred at 0 ºC to rt for 2 h. c isolated yields

3
Wiȩlaw, K.; Korchowiec, B.; Corvis, Y.; Korchowiec, J.;
Guermouche, H.; Rogalska, E. Langmuir 2009, 25, 1417; (d)
Mezei, T.; Mesterházy, N.; Bakó, T.; Porcs-Makkay, M.; Simig,
G.; Volk, B. Org. Process Res. Dev. 2009, 13, 567.
The lactones and lactam 1k-m were also well tolerated in this
reaction conditions and the ring opening proceeded smoothly in
all cases furnishing functionalized thiazolylcarboxamides in good
to excellent yields.
6.
(a) Hampshire, A. J.; Khairallah, H.; Khalaf, A. I.; Ebrahimabadi,
A. H.; Waigh, R. D.; Suckling, C. J.; Brown, T.; Fox, K. R.
Bioorg. Med. Chem. Lett. 2006, 16, 3469; (b) Alniss, H. Y.;
Salvia, M. V.; Sadikov, M.; Golovchenko, I.; Anthony, N. G.;
Khalaf, A. I.; Mackay, S. P.; Suckling, C. J.; Parkinson, J. A.
ChemBioChem 2014, doi: 10.1002/cbic.201402202; (c)Alniss, H.
Y.; Anthony, N. G.; Khalaf, A. I.; MacKay, S. P.; Suckling, C. J.;
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711.
In summary, we have developed a novel and direct formation
of thiazolyl carboxamides via utilizing the magnesium amidate of
2-aminothiazole. We hope this method would become a very
useful tool for synthetic or medicinal chemists performing
amidation reactions. We believe the presented new methodology
offers distinguished advantages over the conventional methods
especially for sterically or electronically challenged peptide bond
formations.
7. Joshua, R.; Dunetz.; Xiang, Y.; Aaron, B.; Justin, R. Org. Lett.
2011, 13, 5048-5051; (b) Sarah, E. E.; David, A. S.; Samuel. H.
G.; Shannon. S. S. J. Am. Chem. Soc. 2003, 125, 3422-3423.
8.
Williams, J. M.; Jobson, R. B.; Yasuda, N.; Marchesini, G.;Dolling,
Ulf-H.; Grabowski, J. J. Tetrahedron Lett. 1995, 36, 5461
9. The reason why the use of i-PrMgCl afforded 3a in relatively low
yield is unclear at the present time.
10. When the conventional carbodiimides-based amidation protocols
were used, the oxazolone was obtained as a major byproduct. For
an example of the amide coupling between the carboxylic acid and
the substituted 2-aminothiazole, see: Forster, C. J.; Kwak, Y.-S.;
Nakajima, K; Wang, B. PCT Int. Appl. 2010007046
11. See the supporting information for the general procedure and
spectral data.
Acknowledgments
This research was supported by Medical Research Center
Program (2008-0062275), KRIBB Research Initiative Program,
the Ministry of Land, Transport and Maritime Affairs, Korea and
the research grant of Chungbuk National University in 2011.
12. No racemization occurred. (2% <)
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