Amino Acid-Based Dithiocarbamates as Efficient Intermediates for Diversity-Oriented Synthesis of Thiazoles

Article abstract of DOI:10.1002/ejoc.202001050

Amino acid-based dithiocarbamates were introduced as efficient intermediates for the synthesis of a diverse library of novel di- and tri-substituted thiazoles via condensation with various reagents such as anhydrides, acyl halides, benzene sulfonyl chloride, trifluoromethanesulfonic anhydride, chloroethyl formate, and diethyl chlorophosphate. The utilities of adducts in further organic synthesis were confirmed by Sonogashira and oxidation reactions. In addition, reaction of aspartic acid-based dithiocarbamates with anhydrides affords the corresponding fused 6,6a-dihydrofuro[3,2-d]thiazol-5(3aH)-ones diastereoselectively in excellent yields.

Full text of DOI:10.1002/ejoc.202001050

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Amino Acid-Based Dithiocarbamates as Efficient Intermediates
for Diversity-Oriented Synthesis of Thiazoles
Authors: Azim Ziyaei Halimehjani, Maryam Khalesi, and Bernhard Breit
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1/2020

European Journal of Organic Chemistry
10.1002/ejoc.202001050
COMMUNICATION
Amino Acid-Based Dithiocarbamates as Efficient Intermediates
for Diversity-Oriented Synthesis of Thiazoles
Azim Ziyaei Halimehjani,*[a,b] Maryam Khalesi, and Bernhard Breit*
[a]
[b]
[
a]
Prof. Dr. A. Ziyaei Halimehjani, M. Khalesi
Faculty of Chemistry, Kharazmi University,
P. O. Box 15719-14911, 49 Mofateh Street, Tehran, Iran.
E-mail: ziyaei@khu.ac.ir
https://chem.khu.ac.ir/cv/140/Azim-ziyaei-Halimehjani
Prof. Dr. Bernhard Breit
[
b]
DepartmentInstitut für Organische Chemie, Albert-Ludwigs-Universität Freiburg,
Albert strasse 21, 79104 Freiburg im Breisgau, Germany.
E-mail: bernhard.breit@chemie.uni-freiburg.de
https://www.breit-group.uni-freiburg.de/Prof_Breit
Supporting information for this article is given via a link at the end of the document.((Please delete this text if not appropriate))
Abstract: Amino acid-based dithiocarbamates were introduced as
efficient intermediates for the synthesis of a diverse library of novel di-
and tri-substituted thiazoles via condensation with various reagents
such as anhydrides, acyl halides, benzene sulfonyl chloride,
trifluoromethanesulfonic anhydride, chloroethyl formate and diethyl
chlorophosphate. The utilities of adducts in further organic synthesis
were confirmed by Sonogashira and oxidation reactions. In addition,
reaction of aspartic acid-based dithiocarbamates with anhydrides
affords the corresponding fused 6,6a-dihydrofuro[3,2-d]thiazol-
5(3aH)-ones diastereoselectively in excellent yields.
The 1,3-thiazole heterocyclic core is the most important among
various N,S-heterocyclic frameworks as it is a key structural
element of many pharmacologically active substances and
natural products (vitamin B1- thiamine).[1] Compounds containing
thiazoles have shown bioactivities as anti-inflammatory,[
antitumor,[ antiviral,[4] antifungal,[5] antipiron, herbicidal,[7] and
antimicrobial[8] agents and the representative examples such as
febuxostat, dasatinib, nizatidine, fentiazac, abafungin, niridazole,
ritonavir, and sulfathiazole are available in market. In addition, the
methylsulfanyl analogue of epothilone B (ABJ879) and SNS-032
are under clinical trials (Figure 1).[9] Beside bioactivities, thiazoles
have found wide applications in industrial dyes,[10] functional
materials,[11] ligand chemistry,[12] and as intermediates[13] in
organic synthesis.
Figure 1. Representative examples of biologically active thiazoles
2]
Due to the widespread applications of thiazole derivatives, easy
access to thiazoles with various substituent patterns will be
beneficial for different branches of chemistry, especially for the
development of novel drugs. While numerous synthetic strategies
have been developed for the synthesis of di- and tri-substituted
thiazoles,[14] fewer methods are available for the preparation of 2-
3]
[6]
(
alkylsulfanyl)thiazoles. General methods for the synthesis of
these compounds include (a) the Asinger reaction of β-keto thiols
with alkyl thiocyanates[15] (b) the reaction of thiazole-2(3H)-
thiones with alkylating agents,[16] and (c) the condensation of
propargyl amines with carbon disulfide and alkyl halides (Scheme
1 [
). Recently, we have developed two methods for the synthesis
17]
of 2-(alkylsulfanyl)thiazoles via the Hantzsch condensation of
ammonia-based
dithiocarbamates
with
α-halocarbonyl
compounds[ (scheme 1d) and nitroepoxides (scheme 1e).
However, these methods are limited to the availability of the
starting materials, toxicity, harsh reaction conditions, and limited
access to thiazoles of high diversity. Therefore, finding more
efficient and general strategies for the preparation of thiazoles
with high flexibility of the substituent patterns is highly desirable.
Herein we report a simple and highly efficient method for the
18]
[19]
1
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European Journal of Organic Chemistry
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COMMUNICATION
synthesis of unknown 2-(alkylsulfanyl)-5-(oxysubstituted)
thiazoles using amino acid-based dithiocarbamates.
excellent yields were obtained (Scheme 2). In addition, excellent
yields were obtained by varying the alkyl group (butyl, hexyl, allyl,
and benzyl) in dithiocarbamates. Furthermore, other anhydrides
such as propionic anhydride and pivalic anhydride (Scheme 2, 3g)
were applied successfully in this protocol. In the case of tyrosine
dithiocarbamate, the corresponding thiazole 3v was obtained in
95% yield along with acylation of the hydroxyl group on the phenyl
ring.
Scheme 1. Published and proposed methods for the synthesis of functionalized
2-(alkylsulfanyl)-thiazoles
Dithiocarbamates are efficient intermediates in synthetic
organic chemistry. They have been extensively applied for the
synthesis of thioureas,[20] isothiocyanates,
[21]
2-imino-1,3-
dithiolanes,[22] cyanamides,
[23]
the protection of aldehydes,
protection of amino groups in peptide
synthesis and in the synthesis of various N,S-heterocyles.[18-19,
[24]
[
25]
amide bond formation,
[
26]
2
7]
First, amino acid-based dithiocarbamates were prepared via a
one-pot three-component reaction of commercially available
natural and unnatural amino acids, CS
and alkyl halides.[25] Then,
2
reaction of the prepared amino acid-based dithiocarbamates 1
with anhydrides 2 was investigated for the synthesis of unknown
2-(alkylsulfanyl)-5-acyloxy-1,3-thiazoles 3 (Scheme 2). Reaction
of benzyl glycine dithiocarbamate with acetic anhydride was
selected as a model reaction for optimization of the reaction
conditions. We found that the best yield (95%) was obtained when
one equivalent of dithiocarbamate 1 reacted with 3 equivalents of
acetic anhydride in the presence of sodium acetate (60 mol%, 0.6
equivalent) under solvent-free conditions at 50-60 °C for 1 h.
Under optimized reaction conditions, the generality of this
protocol was investigated using various dithiocarbamates 1
prepared from natural and unnatural aminoacids including glycine,
alanine, phenylalanine, tryptophane, aspartic acid amide,
glutamic acid, valine and phenylglycine and in all the cases,
a
Reaction conditions: amino acid-dithiocarbamate (1 mmol), anhydride (3 mmol) and
ᵒ
NaOAc (0.6 mmol, 60 mol%), 50-60 C, 1 h. b Yield for 5g scale synthesis.
Scheme 2. Diversity in the synthesis of di- and tri-substituted thiazoles a,b
When the reactions of aspartic acid-dithiocarbamate 4 with
acetic anhydride and propionic anhydride were investigated under
optimized reaction conditions described in Scheme 2, the
corresponding
2-(benzylthio)-3a-alkyl-6,6a-dihydrofuro[3,2-
d]thiazol-5(3aH)-ones 5 were obtained diastereoselectively with
2
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European Journal of Organic Chemistry
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COMMUNICATION
excellent yields (Scheme 3). The relative configuration of 5a and
Table 1. Reaction of glycine-based dithiocarbamate with various electrophiles
5b was confirmed through NOE, to have cis ring junction.
However, by using enantiomerically pure starting material 4,
compounds 5a and 5b were also obtained as racemates. This
suggests that the reaction proceeds via a Dakin-West mechanism
to form intermediate IV, followed by intramolecular cyclization
(
Intermediate V) and lactonization (Scheme 4).
Entry
R´X
R
method
Product (yield %)a
3a (93)
1
2
3
4
5
6
7
8
a
MeCOCl
EtCOCl
PhCOCl
PhCOCl
EtOCOCl
H
A
A
A
A
A
A
B
B
H
3b (88)
H
6a (91)
CH
H
2
OH
6b (88)
6c (95)
(EtO)
2
POCl
H
6d (65)
Scheme 3. Reaction of aspartic acid-dithiocarbamate with anhydrides
TsCl
H
6e (66)
6f(56, 54b)
2
Tf O
H
Isolated yields. b Yield for 5 gram scale synthesis.
The presence of triflate and alkylsulfanyl groups on the
prepared thiazoles provides a straightforward approach towards
a wide range of thiazole derivatives via subsequent cross coupling
reactions and oxidation reaction. To confirm this potential, the
Sonogashira coupling reaction of 6f with 4-ethynylanisole was
2 3
carried out using Pd(OAc) /PPh as a catalyst to afford the
corresponding product in 49% yield (Scheme 5). In addition,
selective oxidation of alkylsulfanyl group in 3a and 6f to
alkylsulfonyl and alkylsulfoxide functional groups was performed
using mCPBA as oxidant with excellent yields (Scheme 5).
Attempts to perform Suzuki and Stille coupling reactions under
standard conditions were not successful.
Scheme 4. Proposed reaction pathways for the formation of 5a-b
In continue, we explored the generality and scope of this
reaction to other cyclizing agents. We found that using acyl
halides instead of anhydrides under optimized reaction conditions
described in Scheme 2 afforded low yields of the thiazoles. It may
be due to the release of hydrogen chloride as byproduct during
the reaction. To overcome this problem, we had to switch the
reaction conditions to the use of THF as solvent and excess
3
amount of Et N (3 equivalents) as a base at room temperature for
overnight (Procedure A in Table 1). Under these conditions,
excellent yields of products 3a-b and 6a were obtained (Table 1,
entries 1-4). Reaction of serine-dithiocarbamate with benzoyl
chloride afforded the corresponding thiazole 6b along with
benzoylation of the hydroxyl group on the side chain (Table 1,
entry 5). In addition, under similar conditions to acyl halides
(
Procedure A in Table 1), we were able to introduce the carbonate
and phosphate group on the thiazole ring by using ethyl
chloroformate and diethyl chlorophosphate to provide the
corresponding thiazolyl carbonate 6c and phosphate 6d in high to
excellent yields (Table 1, entries 6-7). Furthermore, we tried to
extend this strategy to introduce the tosylate and triflate groups
on the position 5 of the thiazole rings using benzenesulfonyl
chloride and trifuoromethanesulfonic anhydride. By varying the
reaction conditions (Procedure B in Table 1), we could prepare
Scheme 5. Cross coupling and oxidation reactions of the selected products
In conclusion, an efficient and general method for the synthesis
of a novel class of di- and tri-substituted thiazoles was developed
via the condensation of amino acid-based dithiocarbamates with
various coupling reagents including anhydrides, acyl halides,
benzene sulfonyl chloride, trifluoromethanesulfonic anhydride,
ethyl chloroformate and
diethyl chlorophosphate. The
the corresponding thiazolyl tosylate 6e and triflate 6f in high yields, alkylsulfanyl group on the position 2 of the products can be simply
even in gram scale (two gram scale, 54% yield) (Table 1, entries
converted to the corresponding sulfoxides and sulfones via
7-8).
selective oxidation with mCPBA. In addition, the triflate group in
3
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European Journal of Organic Chemistry
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position 5 of thiazole can be substituted with alkynes using the
Sonogashira cross coupling. This new strategy allows the
introduction of various sensitive functional groups at positions 2
and 5 of the thiazole ring, broadening the arsenal of synthetic
Org. Biomol. Chem. 2005, 3, 3184–3187; e) J. F. Sanz-Cervera, R.
Blasco, J. Piera, M. Cynamon, I. Ibꢁꢂez, M. Murguía, S. Fustero, J. Org.
Chem. 2009, 74, 8988–8996; f) T. R. Swaroop, H. Ila, K. S. Rangappa,
Tetrahedron Lett. 2013, 54, 5288–5292; g) G. S. Lingaraju, T. R.
Swaroop, A. C. Vinayaka, K. S. S. Kumar, M. P. Sadashiva, K. S.
Rangappa, Synthesis 2012, 44, 1373–1379; h) T. Miura, Y. Funakoshi,
Y. Fujimoto, J. Nakahashi, M. Murakami, Org. Lett. 2015, 17, 2454–2457;
i) D. Castagnolo, M. Pagano, M. Bernardini, M. Botta, Synlett 2009,
2093–2096; j) Y. Ishiwata, H. Togo, Synlett 2008, 2008, 2637–2641; k)
U. Kazmaier, A. Persch, Org. Biomol. Chem. 2010, 8, 5442–5447; l) A.
Srivastava, G. Shukla, D. Yadav, M. S. Singh, J. Org. Chem. 2017, 82,
methods to obtain such scaffolds. Furthermore,
diastereoselective access to 6,6a-dihydrofuro[3,2-d]thiazol-
(3aH)-ones was found through the reaction of aspartic acid-
a
5
based dithiocarbamates with anhydrides in excellent yields.
1
0846−10854; m) B. Shi, A. J. Blake, W. Lewis, I. B. Campbell, B. D.
Acknowledgements
Judkins, C. J. Moody, J. Org. Chem. 2010, 75, 152–161; n) X. Huang, H.
Chen, Z. Huang, Y. Xu, F. Li, X. Ma, Y. Chen, J. Org. Chem. 2019, 84,
15283-15293; o) K. Shibasaki, H. Togo, Eur. J. Org. Chem. 2019, 2520-
2527; p) M. A. Ali, C. Okolo, Z. A. Alsharif, J. Whitt, S. A. Chambers, R.
S. Varma, M. A. Alam, Org. Lett. 2018, 20, 5927-5932; q) Y. Wang, X.
Liu, B. Zhu, P. Guo, Y. Pei, Q. He, H. Cao, J. Org. Chem. 2020, DOI:
Azim Ziyaei Halimehjani thanks to Alexander von Humboldt
foundation for supporting his research in Freiburg University. In
addition, we are thankful to the research council of Kharazmi
University for supporting this work.
1
0.1021/acs.joc.0c01381.
15] F. Asinger, K. Fabian, H. Vossen, K. Hentschel, Liebigs Ann. Chem.
975, 410–414.
16] a) G. Vernin, C. Siv, J. Metzger, J. Heterocycl. Chem. 1978, 15, 1361–
366; b) C. Gibson, K. Schnatbaum, J. R. Pfeifer, E. Locardi, M. Paschke,
[
[
1
1
Keywords: Thiazoles• Dithiocarbamates • Aminoacids •
Coupling agents • Dakin-West
U. Reimer, U. Richter, D. Scharn, A. Faussner, T. Tradler, J. Med. Chem.
2009, 52, 4370–4379.
[
[
17] T. S. A. Heugebaert, L. P. D. Vervaecke, C. V. Stevens, Org. Biomol.
Chem., 2011, 9, 4791–4794; b) D. Kikelj, U. Urleb, Science of Synthesis
[
1]
a) J. V. Metzger, J. V. In Comprehensive Heterocyclic Chemistry;
Katritzky, A. R., Rees, C. W., Eds.; Pergamon Press: New York, 1984;
Vol. 6, p 235 and references cited therein; b) J. Zhong, Nat. Prod. Rep.
2002, 11, 627–628.
18] a) A. Ziyaei Halimehjani, L. Hasani, M. A. Alaei, M. R. Saidi, M. R.
Tetrahedron Lett. 2016, 57, 883–886.
2016, 33, 1268–1317; c) T. S. Jagodzinski, Chem. Rev. 2003, 103, 197–
[
[
[
[
19] A. Ziyaei Halimehjani, Y. Lotfi Nosood, Org. Lett. 2017, 19, 6748–6751.
20] H. Sugimoto, I. Makino, K. Hirai, J. Org. Chem. 1988, 53, 2263–2267.
21] R. Wong, S. J. Dolman, J. Org. Chem. 2007, 72, 3969–3971.
22] A. Ziyaei-Halimehjani, H. Maleki, M. R. Saidi, Tetrahedron Lett. 2009, 50,
2
28; d) A. Ayati, S. Emami, A. Asadipour, A. Shaiee, A. Foroumadi, Eur.
J. Med. Chem. 2015, 97, 699–718; e) A. Rouf, C. Tanyeli, Eur. J. Med.
Chem. 2015, 97, 911–927.
[
[
[
[
2]
3]
4]
5]
R. G. Kalkhambkar, G. M. Kulkarni, H. Shivkumar, R. N. Rao, Eur. J. Med.
Chem. 2007, 42, 1272–1276.
2
747–2749.
23] L. Jamir, U. B. Sinha, J. Nath, B. K. Patel, Synth. Commun. 2012, 42,
51–958.
[
[
[
[
[
T. I. de Santana, M. O. Barbosa, P. A. T. M. Gomes, A. C. N. da Cruz, T.
G. da Silva, A. C. L. Leite, Eur. J. Med. Chem. 2018, 144, 874–886.
K. M. Dawood, T. M. Eldebss, H. S. El-Zahabi, M. H. Yousef, Eur. J. Med.
Chem., 2015, 102, 266–276.
9
24] A. Ziyaei Halimehjani, M. Hajiloo Shayegan, M. M. Hashemi, B. Notash,
Org. Lett. 2012, 14, 3838–3841.
25] A. Ziyaei Halimehjani, M. A. Ranjbari, H. Pasha Zanussi, RSC Adv. 2013,
C. I. Lino, I. G. de Souza, B. M. Borelli, T. T. S. Matos, I. N. S. Teixeira,
J. P. Ramos, E. M. de Souza Fagundes, P. O. Fernandes, V. G.
Maltarollo, S. Johann, R. B. de Oliveira, Eur. J. Med. Chem., 2018, 151,
3
, 22904–22908.
26] T. W. Greene, P. G. M. Wuts, Protecting Groups in Organic Synthesis
3rd ed.), Wiley Interscience, New York (1999).
27] A. Ziyaei Halimehjani, K. Marjani, A. Ashouri, Tetrahedron Lett. 2012, 53,
490–3492; b) A. Ziyaei Halimehjani, A. Ashouri, K. Marjani, J.
(
248–260.
[
[
[
6]
7]
8]
A. Gallardo-Godoy, J. Gever, K. L. Fife, B. M. Silber, S. B. Prusiner, A.
R. Renslo, J. Med. Chem. 2011, 54, 1010–1021.
3
Heterocycl. Chem. 2012, 49, 939–942; c) F. Aryanasab, A. Ziyaei
Halimehjani, M. R. Saidi, Tetrahedron Lett. 2010, 51, 790–792; d) A.
Ziyaei Halimehjani, Y. Lotfi Nosood, S. Didaran, F. Aryanasab, SynOpen
A. Andreani, M. Rambaldi, A. Leoni, A. Locatelli, F. Andreani, J. C.
Gehret, Pharm. Acta Helv. 1996, 71, 247–252.
S. Cascioferro, B. Parrino, D. Carbone, D. Schillaci, E. Giovannetti, G.
2017, 1, 138–142.
Cirrincione,
P.
Diana,
J.
Med.
Chem.
2020,
https://doi.org/10.1021/acs.jmedchem.9b01245 and references cited
therein.
[
9]
a) R. Chen, W. G. Wierda, S. Chubb, R. E: Hawtin, J. A. Fox, M. J.
Keating, V. Gandhi, W. Plunkett, Blood 2009, 113, 4637–4645; b) K. H.
Altmann, B. Pfeiffer, S. Arseniyadis, B. A. Pratt, K. C. Nicolaou, Chem.
Med. Chem. 2007, 2, 396–423.
[
[
10] Y. Kutsunugi, C. Coudret, J. C. Micheau, T. Kawai, Dyes Pigm. 2012, 92,
38–846.
8
11] a) T. Murai, F. Hori, T. Maruyama, Org. Lett. 2011, 13, 1718–1721; b) S.
Ando, R. Murakami, J. Nishida, H. Tada, Y. Inoue, S. Tokito, Y.
Yamashita, J. Am. Chem. Soc. 2005, 127, 14996–14997.
[
[
12] Y. Cubota, S. Tanaka, K. Funabiki, M. Matsui, Org. Lett. 2012, 14, 4682–
4685.
13] a) N. F. Langille, L. A. Dakin, J. S. Panek, Org. Lett. 2002, 4, 2485–2488;
b) X. W. Liu, J. L. Shi, J. X. Yan, J. B. Wei, K. Peng, L. Dai, C. G. Li, B.
Q. Wang, Z. J. Shi, Org. Lett., 2013, 15, 5774–5777.
[
14] a) P. W. Sheldrake, M. Matteucci, E. McDonald, Synlett 2006, 2006,
4
60–462; b) J. Roger, F. Pogan, H. Doucet, J. Org. Chem. 2009, 74,
179–1186; c) B. Liꢀgault, D. Lapointe, L. Caron, A. Vlassova, K. Fagnou,
1
J. Org. Chem. 2009, 74, 1826–1836; d) S. Ackermann, U. A. Kazmaier,
4
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Entry for the Table of Contents
Heterocycles, thiazoles
A novel category of di- and tri-substituted thiazoles were synthesized via the condensation of aminoacid-based dithiocarbamates with
various reagents such as anhydrides, acyl halides, benzene sulfonyl chloride, trifluoromethanesulfonic anhydride, chloroethyl formate
and diethyl chlorophosphate.
5
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