A new synthesis of 2-aminothiazoles and 5H-thiazolo[3,2-a]pyrimidin-5-ones was developed as a domino alkylation-cyclization reaction of propargyl bromides with thioureas and thio¬pyrimidinones, respectively. Domino reactions were performed under microwave irradiation leading to desired compounds in a few minutes and high yield

Bernardini, Martina

Botta, Maurizio

Castagnolo, Daniele

Pagano, Mafalda

English

A new synthesis of 2-aminothiazoles and 5H-thiazolo[3,2-a]pyrimidin-5-ones was developed as a domino alkylation-cyclization of propargyl bromides with thioureas and thiopyrimidinones, resp.  Domino reactions were performed under microwave irradn. leading to the desired compds. in a few minutes and high yields

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Domino alkylation-cyclization reaction of propargyl bromides with thioureas/thiopyrimidinones: a new facile synthesis of 2-aminothiazoles and 5H-thiazolo[3,2-a]pyrimidin-5-ones

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Citation:  Botta,  Maurizio,  Castagnolo,  Daniele,  Pagano,  Mafalda and Bernardini,  Martina (2009)  Domino  alkylation-cyclization  reaction  of  propargyl  bromides  with thioureas/thiopyrimidinones: A new facile synthesis of 2-aminothiazoles and 5H-thiazolo[3,2-a]pyrimidin-5-ones. Synlett, 2009 (13). pp. 2093-2096. ISSN 0936-5214 Published by: Georg Thieme VerlagURL: http://dx.doi.org/10.1055/s-0029-1217700 <http://dx.doi.org/10.1055/s-0029-1217700>This  version  was  downloaded  from  Northumbria  Research  Link: http://nrl.northumbria.ac.uk/10985/Northumbria University has developed Northumbria Research Link (NRL) to enable users to access the University’s research output. Copyright © and moral rights for items on NRL are retained by the individual author(s) and/or other copyright owners.  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To read and/or cite from the published version of the research, please visit the publisher’s website (a subscription may be required.)Domino alkylation-cyclization reaction of propargyl bromides and thioureas: a new facile synthesis of 2-aminothiazoles and 5H-thiazolo[3,2-a]pyrimidin-5ones.  Daniele Castagnolo,a Mafalda Pagano,a Martina Bernardinia and Maurizio Bottaa,b,*  a) Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena, via A. de Gasperi 2, 53100 Siena, Italy. b) Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, BioLife Science Bldg., Suite 333, 1900 N 12th Street, Philadelphia, PA 19122, USA.  The 2-aminothiazole ring system is an useful structural element in medicinal as well as agricultural chemistry and has found a broad application in drug development for the treatment of allergies, hypertension, inflammation, schizophrenia, and bacterial and HIV infections.1 A few methods for the synthesis of 2-aminothiazoles have been reported so far.2-3 Among them the Hantzsch synthesis2 which consists in the condensation of -haloketones or haloacetaldehydes with monosubstituted thioureas still remains the widely used method for the preparation of 2-aminothiazoles. However, the difficulties that can be found in the preparation and isolation of not always commercially available -haloketones together with their well known lacrimatory properties might represent a serious limitation to the Hantzsch approach. As a consequence, it seems reasonable that the development of a new, easy and fast procedure for the synthesis of 2-aminothiazole ring system is higly desiderable. Herein, the synthesis of 2-aminothiazoles with general structure A (Figure 1) through a domino alkylation-cyclization reaction between propargylbromides and thioureas was reported. This synthetic route was particularly attractive in light of the large availability of alkynes and constitutes a valid alternative to the classical use of -haloketones in Hantzsch synthesis. In addition, the synthesis of 5H-thiazolo[3,2-a]pyrimidin-5ones with general structure B (Figure 1)  was also reported. These latter compounds could be considered as the bicyclic analogues of 2-aminothiazoles and represent attractive scaffolds in medicinal chemistry endowed with interesting antiulcer and anti-inflammatory activity after oral admistartion.4 Moreover, due to our synthetic and biological experience in the field of antiviral agents such as the highly active S-DABO compounds,5 we reasoned that the new methodology could be applied for the synthesis of 5H-thiazolo[3,2-a]pyrimidin-5ones C (Figure 1). These latter compounds could be considered as the bicyclic analogues of S-DABOs and, as a consequence, could be evaluated for their anti-HIV activity.  SNNHR1NNSOR2R3A BRRHNNSOMeO F FS-DABO compound  EC50 = 0.0002 M  against HIV-1 wild typeNNOF FSMeO       S-DABO bicyclic                analogues with potential anti-HIV activityC Figure 1.   A series of propargyl bromides precursors was first synthesised. Alkyne 1 was reacted with benzoyl chloride through Sonogashira coupling affording compound 2’ which was directly converted into the deprotected propargyl alcohol 2 after chromatographic purification on silica gel. Alcohol 2 was then converted into bromide 3 derivative through a two step one pot mesylation-bromination procedure.6 Sonogashira coupling of alkyne 4 with the appropriate iodide (phenyliodide and iodoanisole) led to alcohols 5a-b which were in turn converted into bromide 6a-b using the mesylation-bromination protocol described above. (Scheme 1).  ArBrOHArOHOTMSOHOBrO1 2 34 5a-bi. iii.iv. v.6a  Ar = Ph 6b  Ar = 4-MeO-PhOTMSO2'ii. Scheme 1. Reagents and conditions: i. PhCOCl, Et3N, CuI, PdCl2(PPh3)2, DMF. ii. Silica gel chromotography. iii. a) MsCl, Et3N, DCM, then b) LiBr, THF. iv. ArI, Et3N, CuI, PdCl2(PPh3)2, DMF. v. a) MsCl, Et3N, DCM, then b) LiBr, THF.   The commercially available propargyl bromide 7 and the bromides 3 and 6a-b were then used as substrates for the domino alkylation-cyclization synthesis of 2-aminothiazoles 9. Alkynes 3, 6a-b, 7 were reacted with thioureas 8a-c at 130 °C in the presence of stechiometric amount of K2CO3 and under microwave irradiation (Scheme 2) leading in only 10 minutes (2 runs, 5 minutes each) to 2-aminothiazoles 9a-i (Entries 1-9).7 Yields are reported in Table 1.   SNNHR'R9a-iBrR3, 6a-b, 7H2N NHR'S+i.8a-c  Scheme 2. Reagents and conditions: i. K2CO3, DMF, W, 2 x 5min., 130 °C.   The reaction of propargyl bromide 7 with thiopyrimidinones was then investigated. Propargylbromide 7 was first reacted with thiouracyl 10 leading to derivative 11 as the only product and in high yield (Entry 10). The reaction of propargyl bromide 7 with the S-DABO compound 125 led to a mixture of two isomers 13a-b which were isolated in a 2:1 ratio (Entry 11). On the contrary reaction of alkyne 6b with S-DABO 12 led to the formation of compound 14a together with traces of its isomers 14b (Entry 12). The observed regioselectivity might be due to the steric hyndrance of p-MeO-Ph moiety on the alkyne 6b which could reduce the rate of formation of 14b over 14a during the thiazole cyclization step. Structures of compounds 11, 13 and 14 were confirmed by 2D-NOESY experiments and are in agreement with spectroscopic data reported in the literature for similar compounds.4b-8 Reaction yields are summarized in Table 1.  RBrHNNHOSHNNHOSF FNNOSF FNNOSNNOF FS+RRR6b, 7101211 R = H13a R = H14a   R = 4-MeO-Ph13b R = H14b   R = 4-MeO-Phi. Scheme 3. Reagents and conditions: i. K2CO3, DMF, W, 2 x 5min., 130 °C. Table 1. SNNHR'R9a-iNNOS11NNOS13a-14aRRF FNNO13b-14bSRFFBrR3, 6a-b, 7 Entry Propargyl bromide R Product R1 Yield (%)a 1 3 Bz 9a H 61 2 3 Bz 9b Me 65 3 6a Ph 9c H 70 4 6a Ph 9d Me 73 5 6b 4-MeO-Ph 9e H 78 6 6b 4-MeO-Ph 9f Me 75 7 7 H 9g H 90 8 7 H 9h Me 83 9 7 H 9i Allyl 87 10 7 H 11  62 11 7 H 13a/13b  56 : 32  12 6b 4-MeO-Ph 14a/14b  77 : traces a) Isolated yields were reported.  The proposed mechanism for the domino alkylation-cyclization reaction of propargyl bromides and thioureas is described in Scheme 4. The first alkylation step is supposed to be the alkylation of thiourea resulting in the formation of the intermediate I. Two possible pathways could then explain the cyclization step: (i) the nucleophilic imino group undergoes a 5-exo-dig cyclization directly on the triple bond leading to intermediate IV which isomerizes into the final product V (path a). (ii) The alkaline enviroment promotes the isomerization of the triple bond into allene III. Then the imino group attacks on the central carbon of III leading to IV which isomerizes into final aminothiazole V (path b). We hypothesised that the reaction proceeds following the pathway a. In fact, the isomerization of  the triple bond into allene is generally promoted by strong bases such as tBuOK or EtONa. It seems reasonable to think that K2CO3 is a too weak base to favour the formation of allene intermediate III and it is higly probable that carbonate is consumed in the alkylation step  by the quenching of the formed HBr.  RBrS NHR'NH2+S NHR'NHRS NHR'NR+H+-HBrS NHR'NRAlkylation   stepCyclization   stepHHS NHR'NHRS NHR'NHRPath  aPath  bIIIIIIIVV Scheme 4. Proposed mechanism for the tandem alkylation-cyclization reaction of propargyl bromides with thioureas.   In conclusion, a new approach for the synthesis of 2-aminothiazoles 9a-i and 5H-thiazolo[3,2-a]pyrimidin-5ones 11, 13 and 14 starting from different substituted propargylbromides and thioureas/thiopyrimidinones was developed.9-11 All the compounds were obtained in good-high yields in a few minutes, through a domino alkylation-cyclization reaction under microwave irradiation. The new methodology represents an effective and versatile method for the synthesis of 2-aminothiazoles in addition to Hantzsch synthesis. Finally the synthesis of bicyclic S-DABOs analogues 13-14 was reported. Biological evaluation of 13-14 as HIV inhibitors is currently in progress.    References  1. (a) Hargrave, K. D.; Hess, F. K.; Oliver, J. T. J. Med. Chem. 1983, 26, 1158-1163. (b) Patt, W. C.; Hamilton, H. W.; Taylor, M. D.; Ryan, M. D.; .Ryan, M. J.; Taylor, D. J. J.; Connoly, C. J. C.; Doherty, A. M.; Klutchko, S. R.; Sircar, I.; Steinbaugh, B. A.; Batly, B. L.; Painchaud, C. A.; Rapundalo, S. T.; Michniewicz, B. M.; Olson, S. C. J. J. Med. Chem. 1992, 35, 2562-2672. (c) Haviv, F.,; Ratajczyk, J. D.; DeNet, R. W.; Kedesky, F. A.; Walters, R. L.; Schmidt, S. P.; Holms, J. H.; Young, P. R.; Carter, G. W. J. Med. Chem. 1988, 31, 1719-1728; (d) Bell, F. W.; Cantrell, A. S.; Hoberg, M.; Jaskunas, S. R.; Johansson, N. G.; Jodon, C. L.; Kinnik, M. D.; Lind, P.; Morin, J. M.; Zhang, H.; Zhou, X.-X. J. Med. Chem. 1995, 38, 4929-4936. 2. Hantzsch, A. R.; Weber, J. H. Ber. 1887, 20, 3118. 3. (a) Zav’yalov, S. I.; Dorofeeva, O. V.; Rumyantseva, E. E.; Kulikova, L. B.; Ezhova, G. I.; Kravchenko, N. E.; Zavozin, A. G. Pharm. Chem. J. 2001, 35, 96-98. (b) Aoyama, T.; Murata, S.; Arai, I.; Araki, N.; Takido, T.; Suzuki, Y.; Kodomari, M. Tetrahedron 2006, 62, 3201-3213. (c) Kodomari, M., Aoyama, T.; Suzuki, Y. Tetrahedron Lett. 2002, 43, 1717-1720. (d) Astle, M. J.; Pierce, J. B. J. Org. Chem. 1955, 20, 178-181. (e) Wipf, P.; Venkatraman, S. J. Org. Chem. 1996, 61, 8004. (f) Miyamoto, K.; Nishi, Y.; Ochiai, M. Angew. Chem. Int. Ed. 2005, 44, 6896-6899 4. (a) Doria, G.; Passarotti, C.; Sala, R.; Magrini, R.; Sberze, P.; Tibolla, M.; Cesarini, R.; Castello, R.; Toti, D. Farmaco 1985, 40, 885. (b) Bonacorso, H, G.; Lourega, R. V.; Wastowski, A. D.; Flores, A. F. C.; Zanatta, N.; Martins, M. A. P. Tetrahedron Lett. 2002, 43, 9315-9318. 5. (a) Manetti, F.; Esté, J. A.; Clotet-Codina, I.; Armand-Ugón, M.; Maga, G.; Crespan, E.; Cancio, R.; Mugnaini, C.; Bernardini, C.; Togninelli, A.; Carmi, C.; Alongi, M.; Petricci, E.; Massa, S.; Corelli, F.; Botta, M. J. Med. Chem. 2005, 48, 8000–8008. (b) Mugnaini, C.; Alongi, M.; Togninelli, A.; Gevariya, H.; Brizzi, A.; Manetti, F.; Bernardini, C.; Angeli, L.; Tafi, A.; Bellucci, L.; Corelli, F.; Massa, S.; Maga, G.; Samuele, A.; Facchini, M.; Clotet-Codina, I.; Armand-Ugón, M.; Esté J. A.; Botta, M. J. Med. Chem. 2007, 50, 6580–6595. 6. Dai, W.; Petersen, J. L.; Wang, K. K. Org.Lett., 2006, 8, 4665-4667. 7. Reaction of alkyne 7 with thiourea 8a was also carried out under the same reaction condition but in the absence of K2CO3. No traces of aminothiazole 9g were detected in this case and only side products, whose characterization resulted to be difficoult, were isolated. 8. Danel, K.; Pedersen, E. B.; Nielsen, C. J. Med. Chem. 1998, 41, 191-198. 9. Synthesis of 2-aminothiazoles 9a-i. General procedure. Alkyne 3-6-7 (1.0 mmol) and the appropriate thiourea 8a-c (1.0 mmol) were suspended in anhydrous DMF (1.0 mL) in a 10 mL glass vial equipped with a small magnetic stirring bar. K2CO3 (1.0 mmol) was then added to this solution and the mixture was irradiated under microwaves for 2 x 5 minutes at 130 °C, using an irradiation power of 300 W. Microwave irradiations were conducted using a CEM Discover Synthesis Unit (CEM Corp., Matthews, NC). The mixture was then poured into water (10 mL) and then extracted with AcOEt (2 x 10 mL). The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude products were purified by flash column chromatography (SiO2) using 1:1 AcOEt/hexanes as the eluent, to yield the 2-aminothiazoles 9a-i as tan oils.   10. Characterization of 13a: 1H NMR (CDCl3): δ 7.54 (s, 1H, SCHCHCH3) 7.08-7.06 (m, 1H, Ph), 6.75-6.71 (m, 2H, Ph), 4.56-4.54 (m, 1H, CH3CHPh), 2.34 (s, 3H, NCCH3), 1.94 (s, 3H, CH3), 1.58 (d, 3H, CHCH3) ppm. 13C-NMR (CDCl3): δ 162.61, 160.13, 159.36, 128.10, 124.85,119.38, 117.84, 111.64, 111.39, 34.27, 17.88, 13.47, 10.35 ppm. MS (ESI) m/z 321 [M+H]+, 343 [M+Na]+. Characterization of 13b: 1H NMR (CDCl3): δ 7.08-7.04 (m, 1H, Ph), 6.76-6.72 (m, 2H, Ph), 6.27 (s, 1H, SCHCHCH3), 4.54-4.49 (m, 1H, CH3CHPh), 2.70 (s, 3H, NCCH3), 1.89 (s, 3H, CH3), 1.58 (d, 3H, CHCH3) ppm. 13C-NMR (CDCl3): δ 162.63, 162.24, 160.14, 135.98, 128.09, 119.37, 112.86, 111.38, 105.68, 34.07, 18.56, 17.77, 10.23 ppm. MS (ESI) m/z 321 [M+H]+, 343 [M+Na]+. 11. Characterization of 14: 1H NMR (CDCl3): δ 7.11-7.04 (m, 3H, Ph), 6.81-6.72 (m, 4H, Ph), 5.97 (s, 1H, SCH), 4.54-4.49 (m, 1H, CH3CHPh), 3.71 (s, 3H, OCH3), 1.91 (s, 3H, CH3), 1.59 (d, 3H, CHCH3) ppm. 13C-NMR (CDCl3): δ 162.60, 161.85, 158.61, 140.31, 130.62, 129.99, 114.38, 113.84, 111.77, 111.30, 107.22, 106.19, 55.40, 37.06, 33.96, 17.80, 10.77 ppm. MS (ESI) m/z 427 [M+H]+, 449 [M+Na]+.                           Graphical Abstract SNNHR'RBrRH2N NHR'SHNNHOSNNOSRR''R''   Keywords: Domino reaction, 2-aminothiazole, thiazolopyrimidinone, microwave synthesis, antiviral agents.   Abstract A new synthesis of 2-aminothiazoles and 5H-thiazolo[3,2-a]pyrimidin-5ones was developed by a domino alkylation-cyclization reaction of propargylbromides and thioureas/thiopyrimidinones. Domino reactions were performed under microwave irradiation leading to desired compounds in a few minutes and high yields.  

Domino alkylation-cyclization reaction of propargyl bromides with thioureas/thiopyrimidinones: A new facile synthesis of 2-aminothiazoles and 5H-thiazolo[3,2-a]pyrimidin-5-ones

Daniele Castagnolo

Mafalda Pagano

Martina Bernardini

Maurizio Botta

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Domino Alkylation-Cyclization Reaction of Propargyl Bromides with Thioureas/Thiopyrimidinones: A New Facile Synthesis of 2-Aminothiazoles and 5H-Thiazolo[3,2-a]pyrimidin-5-ones

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Domino alkylation-cyclization reaction of propargyl bromides with thioureas/thiopyrimidinones: A new facile synthesis of 2-aminothiazoles and 5H-thiazolo[3,2-a]pyrimidin-5-ones

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