Selective Access to 4-Substituted 2-Aminothiazoles and 4-Substituted 5-Thiocyano-2-aminothiazoles from Vinyl Azides and Potassium Thiocyanate Switched by Palladium and Iron Catalysts

Article abstract of DOI:10.1021/acs.orglett.5b02152

A highly selective construction of 4-substituted 2-aminothiazoles and 4-substituted 5-thiocyano-2-aminothiazoles, respectively, catalyzed by palladium(II) acetate and promoted by iron(III) bromide from vinyl azides and potassium thiocyanate has been developed. Use of readily available starting materials, high selectivity, as well as mild reaction conditions make this practical method particularly attractive.

Full text of DOI:10.1021/acs.orglett.5b02152

Letter
pubs.acs.org/OrgLett
Selective Access to 4‑Substituted 2‑Aminothiazoles and
4‑Substituted 5-Thiocyano-2-aminothiazoles from Vinyl Azides and
Potassium Thiocyanate Switched by Palladium and Iron Catalysts
Binhui Chen, Shanshan Guo, Xiao Guo, Guolin Zhang,* and Yongping Yu*
Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou
310058, P. R. China
S
* Supporting Information
ABSTRACT: A highly selective construction of 4-substituted 2-
aminothiazoles and 4-substituted 5-thiocyano-2-aminothiazoles,
respectively, catalyzed by palladium(II) acetate and promoted
by iron(III) bromide from vinyl azides and potassium
thiocyanate has been developed. Use of readily available starting
materials, high selectivity, as well as mild reaction conditions
make this practical method particularly attractive.
2-Aminothiazoles and their derivatives are one of the most
important aza-heterocycles widely found in natural products
and pharmaceutical compounds. The broad spectrum biological
activities exhibited by this structure include anticancer,1
antiviral,2 antimicrobial,3 antiprion,4 anti-inflammatory,5 and
psychotropic activities.6
we found that the reaction of α-azidostyrene and potassium
thiocyanate with Pd(OAc)2 in n-propanol gave 4-phenyl-2-
aminothiazole 3a in 90% yield. The most favorable reaction
conditions for the formation of 3a were established by further
investigation of a number of experimental variables such as
catalysts, reaction temperature, solvents, equivalents of
catalysts, and potassium thiocyanate (Table S1, Supporting
Information). The reaction proceeded smoothly to give the
corresponding product 3a in 90% yield by the catalytic use
(0.05 equiv) of Pd(OAc)2 under mild reaction conditions
without any other additives (entry 10, Table S1).
Surprisingly, we obtained the unexpected 4-phenyl-5-
thiocyanato-2-aminothiazole 4a accompanied by a trace
amount of 3a when FeSO4·7H2O was used as the catalyst
(entry 1, Table S2, Supporting Information). No corresponding
product was observed in the absence of transition-metal salts. A
range of other metal catalysts were screened (entries 2−6,
Table S2), and application of FeBr3 behaved the best in the
conversion (entry 6, Table S2). In order to investigate the
effects of solvents on this reaction, various solvents (entries 6−
10, Table S2) were tested. The conversion was achieved in 92%
yield without the detection of 3a by using CH3CN as the
solvent instead of n-propanol (entry 9, Table S2). In addition,
the conversion was maintained when a smaller amount of FeBr3
was applied (entry 11, Table S2). The reaction was also
assessed under different reaction temperatures and with
different equivalents of potassium thiocyanate, but there was
no improvement in the conversion (entries 14−18, Table S2).
With the optimized reaction conditions in hand, the scope of
the reaction was studied using a set of vinyl azides. For the
Pd(OAc)2-catalyzed reaction, various substituted vinyl azides
bearing several functional groups worked well with potassium
thiocyanate to provide the desired 4-substituted 2-amino-
The most widely used synthetic method to access 2-
aminothiazoles is the Hantzsch cyclocondensation of α-
halocarbonyl compounds with thiourea.7 Many other strategies
to synthesize 2-aminothiazoles have also been developed.8
However, traditional methods to synthesize 2-aminothiazoles
often suffer from low yields, harsh reaction conditions, and less
environmentally friendly reagents. In particular, there are no
prior examples covering the direct synthesis of 4-substituted 5-
thiocyano-2-aminothiazoles, although organic thiocyanates not
only exhibit insecticidal and other biological activities9 but also
can easily be transformed to sulfur-containing compounds such
as thiols,10 sulfides,11 and sulfur heterocycles.12 The only
reported method for the synthesis of 5-thiocyano-2-amino-
thiazoles is a stepwise synthesis starting from bromination of 2-
aminothiazoles followed by thiocyanation of 5-bromo-2-amino-
thiazoles by inorganic thiocyanates.13 Thus, the discovery of
new, direct, and general synthetic routes to such heterocycles
remains a formidable challenge.
Vinyl azides have been widely used as versatile synthons for
the synthesis of aza-heterocycles.14 Vinyl azides can react
smoothly with incipient anions with the elimination of
molecular nitrogen.15 They can also produce iminyl radicals
when radicals attack vinyl azides.16 It is known that the
thiocyanate anion can be easily oxidized by hypervalent iodine
reagents, CAN, or other oxidants to afford the thiocyanate
radical.17 We envisioned that 2-aminothiazoles could be
achieved by the reaction of vinyl azides and potassium
thiocyanate with transition metals serving as the oxidants.
During the course of our study on the reactions of vinyl
azides and potassium thiocyanate with various transition metals,
Received: July 26, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02152
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Letter
a,b
thiazoles in relatively high yields without the detection of 4-
substituted 5-thiocyano-2-aminothiazoles (Scheme 1). The
Scheme 2. Scope of the FeBr3-Promoted Reaction
a,b
Scheme 1. Scope of the Pd(OAc)2-Catalyzed Reaction
a
a
Reactions were carried out in CH3CN (2.0 mL) with 1 (1 mmol, 1.0
equiv), 2 (3 mmol, 3.0 equiv), and FeBr3 (0.5 mmol, 0.5 equiv), 80 °C,
Reactions were carried out in n-propanol (2.0 mL) with 1 (1 mmol,
1.0 equiv), 2a (3 mmol, 3.0 equiv), and Pd(OAc)2 (0.05 mmol, 0.05
b
c
b
12 h. Isolated yield. Refluxed under 100 °C for 24 h.
equiv), 80 °C, 12 h. Isolated yield.
To gain insight into the possible mechanism of the selective
access to 4-substituted 2-aminothiazoles and 4-substituted 5-
thiocyano-2-aminothiazoles, a series of experiments were
conducted. Since a mixture of 4-substituted 2-aminothiazoles
and 4-substituted 5-thiocyano-2-aminothiazoles was detected at
the very beginning of the FeBr3-promoted reaction, we
envisioned that 4-substituted 2-aminothiazoles might be the
key intermediate of the FeBr3-promoted reaction. When 3a was
subjected to the standard conditions of the FeBr3-promoted
reaction, we obtained 4a as the sole product in 98% yield (eq 1,
Scheme 3), which further confirmed that the key intermediate
reaction efficiencies were not significantly affected by the
substituted groups at different positions of the phenyl ring of
vinyl azides (3b compared to 3c,d, Scheme 1). Generally,
substrates with electron-withdrawing groups on the phenyl ring
performed a little worse (3g,h compared to 3a, Scheme 1).
When electron-withdrawing groups, such as the ester group and
benzoyl group, were directly linked to the α-position of vinyl
azides, there was totally no reaction (3j,k, Scheme 1). In
addition, other aromatic motifs such as 1-naphthyl (3i, Scheme
1) and alkyl substitution (3l,m, Scheme 1) at the α-position of
vinyl azides were also successfully incorporated. Notably,
substrates bearing the carbon−carbon double bond were also
compatible with the reaction (3m, Scheme 1), which can hardly
be synthesized by the traditional Hantzsch-type condensation
of α-halocarbonyl compounds with thiourea because applica-
tion of the halogen reagents in preparing α-halocarbonyl
compounds is destructive to unsaturated carbon−carbon
bonds.
Scheme 3. Investigation of the Reaction Mechanism
Then the scope of the FeBr3-promoted reaction was
examined (Scheme 2). Vinyl azides with various substituted
phenyl groups (4a−i, Scheme 2) or other aromatic motifs (4j,
Scheme 2) were well tolerated without the detection of 4-
substituted 2-aminothiazoles. However, substrates with elec-
tron-withdrawing groups (4k, Scheme 2) and alkyl groups (4l,
4m, Scheme 2) at the α-position of vinyl azides were not
compatible with the reaction, probably due to their low
activities. N-(2-Azidoallyl)aniline readily reacted with potas-
sium thiocyanate under the standard conditions of the
Pd(OAc)2-catalyzed reaction (3l, Scheme 1) but performed
poorly under the standard conditions of the FeBr3-promoted
reaction (4l, Scheme 2). The problem was considered to be the
free-radical thiocyanation on the phenyl ring of N-(2-
azidoallyl)aniline,17e decomposition of N-(2-azidoallyl)aniline,
and other resulting side reactions in the FeBr3-promoted
reaction.
B
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4-substituted 2-aminothiazoles were generated in the FeBr3-
promoted reaction. Then, 2,2,6,6-tetramethyl-1-piperidinyloxy
(TEMPO) was added as a radical scavenger to demonstrate the
difference between these two catalytic systems. Neither 3a nor
4a was detected when TEMPO was added to the reaction of α-
azidostyrene under the standard conditions of the FeBr3-
promoted reaction (eq 2, Scheme 3), which indicated that the
pathway of α-azidostyrene to the intermediate 3a of the FeBr3-
promoted reaction probably proceeded via a free-radical mode.
Furthermore, when TEMPO was added to the reactions of 3a
under the standard conditions of the FeBr3-promoted reaction,
the reaction was also totally suppressed (eq 3, Scheme 3),
which indicated that the conversion of the intermediate 3a to
4a was also through a free-radical path. In addition, the low
yield obtained in the control reaction under the nitrogen
atmosphere indicated that oxygen was critical to the turnover of
the catalytic cycle of the FeBr3-promoted reaction (eq 4,
Scheme 3). However, when TEMPO was added to the
reactions of α-azidostyrene under the standard conditions of
the Pd(OAc)2-catalyzed reaction (eq 5, Scheme 3) the yield
was not significantly influenced, which suggested that the
Pd(OAc)2-catalyzed reaction was not through a radical pathway
but probably in an ionic manner.
The structures of the 4-substituted 2-aminothiazoles and 4-
substituted 5-thiocyano-2-aminothiazoles were characterized by
1H NMR, 13C NMR, and HRMS. On the basis of the above
experimental results and previous related reports, plausible
mechanisms for the highly selective transformations of these
two catalytic systems were proposed. For the Pd(OAc)2-
catalyzed reaction (path a, Scheme 4), initial coordination of
palladium(II) to the azide group provides palladium(II)−azide
complex I, increasing the electrophilicity of the pendant
olefin.18 The nucleophilic attack of potassium thiocyanate
expels N2 to produce the intermediate II, and its intramolecular
nucleophilic attack to the cyano group gives cyclized
intermediate III. Protonation of intermediate III, followed by
aromatization, would generate 4-substituted 2-aminothiazoles.
The FeBr3-promoted reaction (path b, Scheme 4) was
thought to be initiated by one-electron oxidation of thiocyanate
anion by iron(III) bromide, giving thiocyanate radical with the
release of reduced iron(II) species. Vinyl azide 1 was reduced
by iron(II) species to afford iminyl iron(III) radical A with the
elimination of molecular nitrogen.19 Thiocyanate radicals add
readily to radical A to produce alkylideneaminoiron(III) B,
which undergoes an intramolecular nucleophilic attack to afford
cyclized intermediate C. Then 1,5-H migration of intermediate
C generates 2-aminothiazole intermediate D, which can be
easily converted to 4-substituted 2-aminothiazoles by proto-
nation. Thiocyanate radicals attack the electron-rich site of the
2-aminothiazole intermediate D to yield radical E, which was
further oxidized by the iron(III) species to form cation F with
oxygen serving as a co-oxidant.20 Deprotonation of cation F,
followed by protonation, yields the target 4-substituted 5-
thiocyano-2-aminothiazoles with the regeneration of iron(III)
species.
In conclusion, we have demonstrated a novel and efficient
protocol to access 4-substituted-2-aminothiazoles and 4-
substituted-5-thiocyano-2-aminothiazoles switched by palladi-
um and iron catalysts from vinyl azides and potassium
thiocyanate. Further investigation of the reaction mechanism
showed that this reaction probably proceeded through an ionic
pathway and a radical pathway, respectively, to afford different
products in the presence of palladium(II) acetate and iron(III)
bromide. The use of readily available starting materials, high
selectivity, and mild reaction conditions make this method
quite attractive. Further studies on the scope, mechanism, and
synthetic applications of this reaction are in progress.
ASSOCIATED CONTENT
■
Scheme 4. Proposed Reaction Pathway
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b02152.
Experimental procedures, optimization of the reaction
conditions, characterization, and spectra data of the final
products (PDF)
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: guolinzhang@zju.edu.cn.
*E-mail: yyu@zju.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This project was supported from the National Natural Science
Foundation of China (81273356 and 81473074), the National
Science & Technology Major Projects for “Major New Drugs
Innovation and Development” of China (2014ZX09304002-
007), the Program for Zhejiang Leading Team of S&T
Innovation Team (2011R50014), and Arthritis & Chronic
Pain Research Institute, USA, to Y.Y.
C
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Letter
(15) (a) Chen, W.; Hu, M.; Wu, J.; Zou, H.; Yu, Y. Org. Lett. 2010,
12, 3863. (b) Hu, B.; DiMagno, S. G. Org. Biomol. Chem. 2015, 13,
3844.
(16) (a) Bamford, A. F.; Cook, M. D.; Roberts, B. P. Tetrahedron Lett.
1983, 24, 3779. (b) Montevecchi, P. C.; Navacchia, M. L.; Spagnolo,
P. J. Org. Chem. 1997, 62, 5846.
REFERENCES
■
(1) Smith, B.; Chang, H.-H.; Medda, F.; Gokhale, V.; Dietrich, J.;
Davis, A.; Meuillet, E.; Hulme, C. Bioorg. Med. Chem. Lett. 2012, 22,
3567.
(2) Liu, R.; Huang, Z.; Murray, M. G.; Guo, X.; Liu, G. J. Med. Chem.
2011, 54, 5747.
(17) (a) De Mico, A.; Margarita, R.; Mariani, A.; Piancatelli, G.
Tetrahedron Lett. 1996, 37, 1889. (b) Nair, V.; Nair, L. G. Tetrahedron
Lett. 1998, 39, 4585. (c) Nair, V.; George, T. G.; Nair, L. G.; Panicker,
S. B. Tetrahedron Lett. 1999, 40, 1195. (d) Wu, G.; Liu, Q.; Shen, Y.;
Wu, W.; Wu, L. Tetrahedron Lett. 2005, 46, 5831. (e) Pan, X. Q.; Lei,
M. Y.; Zou, J. P.; Zhang, W. Tetrahedron Lett. 2009, 50, 347. (f) Fan,
W.; Yang, Q.; Xu, F.; Li, P. J. Org. Chem. 2014, 79, 10588.
(18) For prior studies on the coordination of the internal nitrogen of
an organic azide with metal complexes, see: (a) Chiba, S.; Wang, Y. F.;
Lapointe, G.; Narasaka, K. Org. Lett. 2008, 10, 313. (b) Dong, H.;
Shen, M.; Redford, J. E.; Stokes, B. J.; Pumphrey, A. L.; Driver, T. G.
Org. Lett. 2007, 9, 5191. (c) Stokes, B. J.; Dong, H.; Leslie, B. E.;
Pumphrey, A. L.; Driver, T. G. J. Am. Chem. Soc. 2007, 129, 7500.
(19) Wang, Y. F.; Toh, K. K.; Lee, J.-Y.; Chiba, S. Angew. Chem., Int.
Ed. 2011, 50, 5927.
(3) Annadurai, S.; Martinez, R.; Canney, D. J.; Eidem, T.; Dunman,
P. M.; Abou-Gharbia, M. Bioorg. Med. Chem. Lett. 2012, 22, 7719.
(4) Ghaemmaghami, S.; May, B. C. H.; Renslo, A. R.; Prusiner, S. B.
J. Virol. 2010, 84, 3408.
(5) (a) Franklin, P. X.; Pillai, A. D.; Rathod, P. D.; Yerande, S. G.;
Nivsarkar, M.; Padh, H.; Sudarsanam, V.; Vasu, K. K. Eur. J. Med.
Chem. 2008, 43, 129. (b) Inamdar, G. S.; Pandya, A. N.; Thakar, H.
M.; Sudarsanam, V.; Kachler, S.; Sabbadin, D.; Moro, S.; Klotz, K.-N.;
Vasu, K. K. Eur. J. Med. Chem. 2013, 63, 924.
(6) Zablotskaya, A.; Segal, I.; Germane, S.; Shestakova, I.;
Domracheva, I.; Nesterova, A.; Geronikaki, A.; Lukevies, E. Chem.
Heterocycl. Compd. 2002, 38, 859.
(7) (a) Hantzsch, A. R.; Weber, J. H. Ber. Dtsch. Chem. Ges. 1887, 20,
3118. (b) Arutyunyan, S.; Nefzi, A. J. Comb. Chem. 2010, 12, 315.
(c) Kumar, D.; Kumar, N. M.; Patel, G.; Gupta, S.; Varma, R. S.
Tetrahedron Lett. 2011, 52, 1983.
(8) (a) Bailey, N.; Dean, A. W.; Judd, D. B.; Middlemiss, D.; Storer,
R.; Watson, S. P. Bioorg. Med. Chem. Lett. 1996, 6, 1409. (b) Aoyama,
T.; Murata, S.; Arai, I.; Araki, N.; Takido, T.; Suzuki, Y.; Kodomari, M.
Tetrahedron 2006, 62, 3201. (c) Dahiya, R.; Pujari, H. K. Indian J.
Chem. 1986, 25B, 966. (d) Wang, Y.; Zhao, F.; Chi, Y.; Zhang, W. X.;
Xi, Z. F. J. Org. Chem. 2014, 79, 11146. (e) Potewar, T. M.; Ingale, S.
A.; Srinivasan, K. V. Tetrahedron 2008, 64, 5019. (f) Baer, R.;
Masquelin, T. J. Comb. Chem. 2001, 3, 16. (g) Wipf, P.; Venkatraman,
S. J. Org. Chem. 1996, 61, 8004.
(20) (a) Yang, H.; Duan, X. H.; Zhao, J. F.; Guo, L. N. Org. Lett.
2015, 17, 1998. (b) Pan, X. Q.; Lei, M. Y.; Zou, J. P.; Zhang, W.
Tetrahedron Lett. 2009, 50, 347.
(9) (a) Buchel, K. H. Chemie der Pflanzen Schutz-Und Schadlingsbe
Kampfungsmittle; Springer: Berlin, 1970. (b) Dutta, S.; Abe, H.;
Aoyagi, S.; Kibayashi, C.; Gates, K. S. J. Am. Chem. Soc. 2005, 127,
15004. (c) Yasman, Y.; Edrada, R. A.; Wray, V.; Proksch, P. J. Nat.
Prod. 2003, 66, 1512.
(10) (a) Houk, J.; Whitesides, G. M. J. Am. Chem. Soc. 1987, 109,
6825. (b) Linderoth, L.; Fristrup, P.; Hansen, M.; Melander, F.;
Madsen, R.; Andresen, T. L.; Peters, G. H. J. Am. Chem. Soc. 2009,
131, 12193.
(11) Billard, T.; Langlois, B. R.; Medebielle, M. Tetrahedron Lett.
2001, 42, 3463.
(12) (a) Kelly, T. R.; Kim, M. H.; Curtis, A. D. M. J. Org. Chem.
1993, 58, 5855. (b) Li, L.; Ganesh, M.; Seidel, D. J. Am. Chem. Soc.
2009, 131, 11648. (c) Falck, J. R.; Gao, S.; Prasad, R. N.; Reddy, K. S.
Bioorg. Med. Chem. Lett. 2008, 18, 1768.
(13) (a) Misra, R. N.; Xiao, H. Y.; Kim, K. S.; Lu, S. F.; Han, W. C.;
Barbosa, S. A.; Hunt, J. T.; Rawlins, D. B.; Shan, W. F.; Ahmed, S. Z.;
Qian, L. G.; Chen, B. C.; Zhao, R. L.; Bednarz, M. S.; Kellar, K. A.;
Mulheron, J. G.; Batorsky, R.; Roongta, U.; Kamath, A.; Marathe, P.;
Ranadive, S. A.; Sack, J. S.; Tokarski, J. S.; Pavletich, N. P.; Lee, F. Y.
F.; Webster, K. R.; Kimball, S. D. J. Med. Chem. 2004, 47, 1719.
(b) Blank, B.; DiTullio, N. W.; Owings, F. F.; Deviney, L.; Miao, C. K.;
Saunders, H. L. J. Med. Chem. 1977, 20, 572. (c) Lin, T. A.; McIntyre,
K. W.; Das, J.; Liu, C. J.; O’Day, K. D.; Penhallow, B.; Hung, C. Y.;
Whitney, G. S.; Shuster, D. J.; Yang, X. X.; Townsend, R.; Postelnek, J.;
Spergel, S. H.; Lin, J.; Moquin, R. V.; Furch, J. A.; Kamath, A. V.;
Zhang, H. J.; Marathe, P. H.; Perez-Villar, J. J.; Doweyko, A.; Killar, L.;
Dodd, J. H.; Barrish, J. C.; Wityak, J.; Kanner, S. B. Biochemistry 2004,
43, 11056.
(14) (a) Wang, Y. F.; Lonca, G. H.; Chiba, S. Angew. Chem., Int. Ed.
2014, 53, 1067. (b) Zhang, G.; Ni, H.; Chen, W.; Shao, J.; Liu, H.; Yu,
Y. Org. Lett. 2013, 15, 5967. (c) Liu, S.; Chen, W.; Luo, J.; Yu, Y.
Chem. Commun. 2014, 50, 8539. (d) Jung, N.; Brase, S. Angew. Chem.,
Int. Ed. 2012, 51, 12169. (e) Wang, Y.; Toh, K. K.; Ng, E. P. J.; Chiba,
S. J. Am. Chem. Soc. 2011, 133, 6411. (f) Hu, B.; Wang, Z.; Ai, N.;
Zheng, J.; Liu, X.; Shan, S.; Wang, Z. Org. Lett. 2011, 13, 6362.
D
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