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DOI: 10.1055/s-0035-1561985
Microwave-Assisted Domino Reactions of Propargylamines with Isothiocyanates: Selective Synthesis of 2-Aminothiazoles and 2-Amino-4-methylenethiazolines
Publication History
Received: 08 February 2016
Accepted after revision: 15 March 2016
Publication Date:
07 April 2016 (online)
Abstract
A simple and versatile microwave-assisted protocol for the synthesis of 2-aminothiazoles has been developed. The domino reaction of propargylamines and isothiocyanates in the presence of catalytic PTSA leads to the selective synthesis of 2-aminothiazoles at temperatures above 130 °C and in a few minutes. The same reaction carried out at lower temperatures leads to the formation of the tautomeric 2-amino-4-methylenethiazolines.
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Key words
2-aminothiazole - thiazoline - propargylamine - isothiocyanate - microwave chemistry - imidazol-thioneThe 2-aminothiazole ring is an important heterocyclic nucleus that has found broad application in organic and medicinal chemistry. Thiazole and aminothiazole scaffolds have been recognised as privileged structural motifs in medicinal chemistry. Several drug candidates endowed with potent biological activity against hypertension, allergies, inflammation, schizophrenia, cancer, bacterial, and viral infections contain a 2-aminothiazole moiety.[2] As a consequence, a number of methodologies for the synthesis of 2-aminothiazole derivatives has been developed,[3] including the Hantzsch[4] and the Cook–Heilborn syntheses.[5] The Hantzsch synthesis still represents the most widely used method for preparing aminothiazoles, despite the limitations arising from the low availability of hazards associated with the lachrymatory α-haloketone starting materials. Improvements of the Hantzsch synthesis have been recently reported and are based on the in situ generation of the α-halo carbonyl reagents from ketones.[6] Other protocols for the synthesis of aminothiazole derivatives include the use of catalysts such as iodine,[7] silica chloride,[8] 1,3-di-n-butylimidazolium tetrafluoroborate,[9] and cyclodextrins.[10] [11] Recently, a microwave domino alkylation–cyclization reaction of propargyl bromides with thioureas leading to a variety of 2-aminothiazoles substituted at the C4 position was described by our group[12] (Scheme [1]).
In continuation of our work on the development of novel, atom economical methods for the synthesis of heterocyclic compounds, and due to our experience in propargylamine chemistry and microwave synthesis,[12] [13] we became interested in studying the reaction of propargylamines A with isothiocyanates B with the aim to develop a one-pot approach to substituted 2-aminothiazoles D (Scheme [1]).
Dillard and coworkers in 1964, and later Eloy and Deryckere,[14] first reported that the reaction of propargylamines and isothiocyanates led to 2-amino-4-methylenethiazolines C under mild temperature conditions in basic medium after extended reaction times (Scheme [1]). More recently, this approach has been adopted by Clausen and coworkers as an efficient conjugation method in aqueous medium.[15] In all cases, the thiazoline C was obtained as the only reaction product, whilst no traces of the corresponding thiazole D were detected. We reasoned that, under microwave irradiation and using an appropriate catalyst, the thiazoline C could tautomerise leading to the formation of the corresponding thiazole D in a one-pot process. Herein, a novel microwave domino amine nucleophilic addition–cyclization approach to 2-aminothiazole from propargylamines is described (Scheme [1]).
a Calculated by 1H NMR integration.
b Isolated yields are reported.
The reaction of propargylamine 1a with allylisothiocyanate 2a under microwave irradiation at different temperatures and in the presence of different catalysts was first investigated (Table [1]). According to our previous method,[12] 1a and 2a were reacted at 130 °C in DMF and in the presence of a stoichiometric amount of K2CO3. The reaction was carried out under microwave irradiation for 2 × 5 min, leading to the formation of the thiourea 3 as the only product (Table [1], entry 1). The same product was isolated when the reaction was carried out at lower temperature and in a different solvent (Table [1], entry 2). Heating the mixture at 160 °C in DMF led to the cyclization of the thiourea 3 and to the formation of two products in 1:1 ratio (Table [1], entry 3). 1H NMR analysis of the reaction mixture revealed the formation of the desired 2-aminothiazole 4a, showing the characteristic NH broad peak at δ = 5.79 ppm, together with the imidazole derivative 6, showing the SH broad singlet at δ = 11.44 ppm. The structures of 4a and 6 were determined by 1H NMR, 13C NMR, and MS analyses. When DIPEA was used as a base under the same reaction conditions, a mixture of isomers 4a and 6 was also obtained in a 2:1 ratio. Interestingly, the replacement of K2CO3 with a stoichiometric amount of p-toluenesulfonic acid (PTSA) led to 4a as the major isomer (Table [1], entry 5). Only a small amount of 6 was detected by 1H NMR analysis. In the presence of the Lewis acid ZnCl2 (1 equiv) the desired thiazole 4a was obtained, again as the major reaction product (Table [1], entry 6), whilst a 4:1 and a 3:1 mixture of 4a/6 was obtained when 1a and 2a were reacted in the presence of CuI and FeCl3, respectively (Table [1], entries 7 and 8). The use of a catalytic instead of stoichiometric amount of PTSA did not affect the outcome of the reaction, leading to 4a/6 in 9:1 ratio (Table [1], entries 9 and 10). In a further attempt to reduce the amount of the imidazole 6, the compounds 1a and 2a were reacted at lower temperature. When the reaction was carried out in the presence of catalytic PTSA at 130 °C in DCE (Table [1], entry 11), the thiazole 4a was obtained as the only product. On the other hand when the temperature was lowered to 100 °C, using both DCE or MECN as solvent, no traces of 4a were detected whilst the 2-allylamino-4-methylenethiazoline 5a was isolated as single product (Table [1], entries 12 and 13).
The proposed mechanism for the formation of the three isomers 4a, 5a, and 6 is outlined in Scheme [2]. The propargylamine 1a reacts almost instantaneously with the isocyanate 2a leading to the formation of the thiourea intermediate 3. The latter can then undergo a 5-exo-dig cyclization through two different pathways.[14a] In basic medium and at high temperatures, the thiourea N1 nitrogen preferably acts as the nucleophile, attacking the alkyne and leading to the imidazole 6 (Scheme [2], path b). On the other hand, in acidic medium, the N1 nitrogen of the thiourea intermediate is likely to be protonated leaving the sulfur to act as the nucleophile and leading at 100 °C to the formation of 5a. Upon heating at 130 °C, 5a can tautomerise, leading to thiazole 4a (Scheme [2], path a). When the reaction is carried out in the presence of base at high temperatures (Table [1], entry 3), it is likely that both pathways occur due to a combination of catalytic and heating effects, thus leading to a mixture of 4a and 6.
On the basis of these results, the reaction of propargylamine 1a–e [16] [13a] with different isothiocyanates 2a–c was further investigated. The results are reported in Table [2].
a Calculated by 1H NMR integration.
b Isolated yields are reported.
c The reaction was carried out in an oil bath and refluxing MeCN for 12 h and in the presence of 1 equiv of K2CO3.
d Unreacted starting material (45–50% yield) 1e was recovered from the reaction mixture.
When propargylamine 1a was reacted with phenylisothiocyanate 2b and benzylisothiocyanate 2c at 130 °C in DCE and in the presence of catalytic PTSA, the thiazoles 4b and 4c were isolated as the only products in high yields (Table [2], entries 1 and 3). On the other hand, when the same reaction was carried out in MeCN at 100 °C, the thiazolines 5b and 5c were obtained as major products in good yields together with a lesser amount of the corresponding thiazoles 4 (Table [2], entries 2 and 4).
The introduction of a phenyl ring onto the propargylamine backbone proved to affect the selectivity of the reaction. In fact, when 1-phenylpropargylamine 1b and the allyl isothiocyanate 2a were reacted in DCE at 130 °C a mixture of 4d and 5d in a 1:2 ratio was unexpectedly obtained (Table [2], entry 5). However, heating the mixture to 160 °C in DMF led to 4d [17] as a single product (Table [2], entry 6). No traces of 5d or the corresponding imidazole derivative were observed. Similarly, compound 4e [18] was obtained as a single product when 1b and 2c were reacted in DMF at high temperatures (Table [2], entry 7). A similar trend was observed when 1c was reacted with 2a leading to a mixture of thiazole/thiazoline 4f/5f at 130 °C; whilst 4f was selectively obtained at higher temperatures (Table [2], entries 8 and 9). When 1-(2,4-dichloropheny)propargylamine (1d) was used as substrate and reacted with 2a, the thiazoline 5g was formed as the sole product at 130 °C (Table [2], entry 10); whilst at 160 °C only 4g was isolated (Table [2], entry 11). Thiazole 4h was also obtained as a single isomer when the reaction was carried out at 160 °C in DMF (Table [2], entry 12). It is clear that the aryl substituent on the propargylamine affects the outcome of the reaction, probably due to a combination of steric and electronic effects. In general, higher temperatures favour the tautomerisation of 5 into 4. Intrigued by the effect of the aromatic ring on the outcome of the reaction, we then focused on the reaction of the 3-phenylpropargylamine 1e with different isothiocyanates. When 1e was reacted with 2a–c at 130 °C, the imidazolethione derivatives 7i–k were obtained as the only reaction products.[19] No traces of the thiazole/thiazoline 4 and 5 were detected (Table [2], entries 13–16). At higher temperature the imidiazolethiones 7i–k were also recovered as the only products (Table [2], entries 17–19). A substantial amount of starting material 1e was also recovered from all the reaction mixtures. Finally, amine 1e was reacted with 2a under standard heating conditions (reflux in oil bath) at 130 °C in the presence of one equivalent of K2CO3 and, in this case, the imidazoline 7i was also recovered as the sole product together with starting material 1e.
Interestingly, Dethe and coworkers recently described the formation of imidazolethiones from propargylamines under basic conditions at room temperature.[19] However, at high temperature we observed the cyclization of 1e and formation of imidazolethiones 7 both in acidic and basic medium. The proposed mechanism for the formation of 7 is outlined in Scheme [3]. The reaction of 1e with isothiocyanates leads to the thiourea intermediate 8. The presence of a phenyl ring on the alkyne moiety seems to favour the attack of the nitrogen leading to the tautomeric imidazoline intermediates 9 and 10 that upon reaction with an additional isothiocyanate equivalent, lead to the final product 7.
In conclusion, an efficient and versatile microwave method for the synthesis of 2-aminothiazole and 2-aminothiazolines from propargylamines has been developed.[20] [21] [22] A set of compounds 4 and 5 has been synthesised in short reaction times and high yields. The formation of thiazoline derivatives 5 occurs when propargylamines and isothiocyanates are reacted in the temperature range 100–130 °C, depending on the substrate. At higher temperatures the selective formation of the 2-aminothiazoles 4 is favoured. The effect of aromatic substituents on the propargylamine substrate has been also investigated, showing that the presence of a phenyl ring on the propargylamine backbone affects the selectivity of the reaction.
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Acknowledgment
DC thanks the Royal Society of Chemistry for financial support (Research Fund 2015). CP is grateful to the European Union (Erasmus Placement Program, Università degli Studi di Parma −Italy) for the mobility grant.
Supporting Information
- Supporting information for this article is available online at http://dx.doi.org.accesdistant.sorbonne-universite.fr/10.1055/s-0035-1561985.
- Supporting Information
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References and Notes
- 1 Most of this work has been carried out at Northumbria University Newcastle (UK), Department of Applied Sciences, before DC relocated to King’s College London (UK), Institute of Pharmaceutical Science, 150 Stamford Street, SE1 9NH, London, UK.
- 2a Hargrave KD, Hess FK, Oliver JT. J. Med. Chem. 1983; 26: 1158
- 2b Patt WC, Hamilton HW, Taylor MD, Ryan MJ, Taylor DJ. J, Connoly CJ. C, Doherty AM, Klutchko SR, Sircar I, Steinbaugh BA, Batly BL, Painchaud CA, Rapundalo ST, Michniewicz BM, Olson SC. J. J. Med. Chem. 1992; 35: 2562
- 2c Haviv F, Ratajczyk JD, De Net RW, Kedesky FA, Walters RL, Schmidt SP, Holms JH, Young PR, Carter GW. J. Med. Chem. 1988; 31: 1719
- 2d Bell FW, Cantrell AS, Hoberg M, Jaskunas SR, Johansson NG, Jodon CL, Kinnik MD, Lind P, Morin JM, Zhang H, Zhou XX. J. Med. Chem. 1995; 38: 4929
- 3a Zav’yalov SI, Dorofeeva OV, Rumyantseva EE, Kulikova LB, Ezhova GI, Kravchenko NE, Zavozin AG. Pharm. Chem. J. 2001; 35: 105
- 3b Singh MS, Nandi GC, Chanda T. RSC Adv. 2013; 3: 14183
- 4 Hantzsch A, Weber JH. Ber. Dtsch. Chem. Ges. 1887; 20: 3118
- 5 Cook AH, Heilbron I, MacDonald SF, Mahadevan AP. J. Chem. Soc. 1949; 1064
- 6a Zhu YP, Yuan JJ, Zhao Q, Lian M, Gao QH, Liu MC, Yang Y, Wu AX. Tetrahedron 2012; 68: 173
- 6b Xue WJ, Zheng KL, Li HZ, Geo FF, Wu AX. Tetrahedron Lett. 2014; 55: 4212
- 6c Zhao R, Gove S, Sundeen JE, Chen B.-C. Tetrahedron Lett. 2001; 42: 210
- 7 Siddiqui HL, Iqbal A, Ahmed S, Weaver G. Molecules 2006; 11: 206
- 8 Karade H, Sathe M, Kaushik MP. Catal. Commun. 2007; 8: 741
- 9 Potewar TP, Ingale SA, Srinivasan KV. Tetrahedron 2007; 63: 11066
- 10 Das B, Reddy SV, Ramu R. J. Mol. Catal. A: Chem. 2006; 252: 235
- 11 Narender M, Somi Reddy M, Sridhar R, Nageswar K, Nageswar K, Rama Rao K. Tetrahedron Lett. 2005; 46: 7779
- 12 Castagnolo D, Pagano M, Bernardini M, Botta M. Synlett 2009; 2093
- 13a Chachignon H, Scalacci N, Petricci E, Castagnolo D. J. Org. Chem. 2015; 80: 5287
- 13b Castagnolo D, Dessì F, Radi M, Botta M. Tetrahedron: Asymmetry 2007; 11: 1345
- 13c Castagnolo D, Giorgi G, Spinosa R, Corelli F, Botta M. Eur. J. Org. Chem. 2007; 22: 3676
- 14a Easton NR, Cassady DR, Dillard RD. J. Org. Chem. 1964; 29: 1851
- 14b Eloy F, Deryckere A. Chim. Ther. 1973; 4: 437
- 15 Viart HM.-F, Larsen TS, Tassone C, Andresen TL, Clausen MH. Chem. Commun. 2014; 50: 7800
- 16 1-Arylpropargylamines were prepared according to previous work: Castagnolo D, Armaroli S, Corelli F, Botta M. Tetrahedron: Asymmetry 2004; 15: 941
- 17 Thompson CM, Poole JL, Cross JL, Akritopoulou-Zanze I, Djuric SW. Molecules 2011; 16: 9161
- 18 Aoyama T, Murata S, Arai I, Araki N, Takido T, Suzuki Y, Kodomari M. Tetrahedron 2006; 62: 3201
- 19 Ranjan A, Yerande R, Wakchaure PB, Yerande SG, Dethe DH. Org. Lett. 2014; 16: 5788
- 20 General Procedure for the Synthesis of 2-Aminothiazoles 4 and 2-Amino-4-methylenethiazolines 5 Propargylamine 1a–e (1.0 mmol) and the appropriate isothiocyanate 2a–c (1.0 mmol) were suspended in an appropriate solvent (DCE, MeCN, DMF, 1.0 mL) in a 10 mL glass vial equipped with a small magnetic stirring bar. PTSA (0.5 mmol) was then added to this solution, and the mixture was irradiated under microwave conditions at the appropriate temperature (see Tables 1 and 2) for 2 × 5 min, using an irradiation power of 300 W. The mixture was then poured into NaHCO3 solution (10 mL) and then extracted with EtOAc (2 × 10 mL). The combined organic phases were washed with brine, dried over Mg2SO4, filtered, and concentrated under reduced pressure. The crude products were purified by flash column chromatography (SiO2; hexanes–EtOAc, 4:1), to yield the desired products as tan-coloured oils.
- 21 2-Aminothiazole 4a 1H NMR (400 MHz, CDCl3): δ = 6.67 (s, 1 H), 5.95–5.85 (m, 1 H), 5.79 (br s, 1 H), 5.30–5.25 (d, 1 H, J = 20 MHz), 5.17–5.14 (d, 1 H, J = 12 MHz), 3.82 (d, 2 H, J = 4 MHz), 2.25 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 169.0, 135.5, 134.1, 121.1, 116.8, 48.2, 12.0 ppm. ESI-MS: m/z = 155 [M + H]+, 177 [M + Na]+.
- 22 2-Amino-4-methylenethiazoline 5a 1H NMR (400 MHz, CDCl3): δ = 5.92–5.83 (m, 1 H), 5.24–5.19 (d, 1 H, J = 20 MHz), 5.14–5.08 (m, 3 H), 4.68 (m, 2 H), 3.89–3.88 (d, 2 H, J = 4 MHz) ppm. 13C NMR (100 MHz, CDCl3): δ = 158.3, 148.8, 134.3, 116.5, 102.5, 67.0, 46.6 ppm. ESI-MS: m/z = 155 [M + H]+, 177 [M + Na]+.
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References and Notes
- 1 Most of this work has been carried out at Northumbria University Newcastle (UK), Department of Applied Sciences, before DC relocated to King’s College London (UK), Institute of Pharmaceutical Science, 150 Stamford Street, SE1 9NH, London, UK.
- 2a Hargrave KD, Hess FK, Oliver JT. J. Med. Chem. 1983; 26: 1158
- 2b Patt WC, Hamilton HW, Taylor MD, Ryan MJ, Taylor DJ. J, Connoly CJ. C, Doherty AM, Klutchko SR, Sircar I, Steinbaugh BA, Batly BL, Painchaud CA, Rapundalo ST, Michniewicz BM, Olson SC. J. J. Med. Chem. 1992; 35: 2562
- 2c Haviv F, Ratajczyk JD, De Net RW, Kedesky FA, Walters RL, Schmidt SP, Holms JH, Young PR, Carter GW. J. Med. Chem. 1988; 31: 1719
- 2d Bell FW, Cantrell AS, Hoberg M, Jaskunas SR, Johansson NG, Jodon CL, Kinnik MD, Lind P, Morin JM, Zhang H, Zhou XX. J. Med. Chem. 1995; 38: 4929
- 3a Zav’yalov SI, Dorofeeva OV, Rumyantseva EE, Kulikova LB, Ezhova GI, Kravchenko NE, Zavozin AG. Pharm. Chem. J. 2001; 35: 105
- 3b Singh MS, Nandi GC, Chanda T. RSC Adv. 2013; 3: 14183
- 4 Hantzsch A, Weber JH. Ber. Dtsch. Chem. Ges. 1887; 20: 3118
- 5 Cook AH, Heilbron I, MacDonald SF, Mahadevan AP. J. Chem. Soc. 1949; 1064
- 6a Zhu YP, Yuan JJ, Zhao Q, Lian M, Gao QH, Liu MC, Yang Y, Wu AX. Tetrahedron 2012; 68: 173
- 6b Xue WJ, Zheng KL, Li HZ, Geo FF, Wu AX. Tetrahedron Lett. 2014; 55: 4212
- 6c Zhao R, Gove S, Sundeen JE, Chen B.-C. Tetrahedron Lett. 2001; 42: 210
- 7 Siddiqui HL, Iqbal A, Ahmed S, Weaver G. Molecules 2006; 11: 206
- 8 Karade H, Sathe M, Kaushik MP. Catal. Commun. 2007; 8: 741
- 9 Potewar TP, Ingale SA, Srinivasan KV. Tetrahedron 2007; 63: 11066
- 10 Das B, Reddy SV, Ramu R. J. Mol. Catal. A: Chem. 2006; 252: 235
- 11 Narender M, Somi Reddy M, Sridhar R, Nageswar K, Nageswar K, Rama Rao K. Tetrahedron Lett. 2005; 46: 7779
- 12 Castagnolo D, Pagano M, Bernardini M, Botta M. Synlett 2009; 2093
- 13a Chachignon H, Scalacci N, Petricci E, Castagnolo D. J. Org. Chem. 2015; 80: 5287
- 13b Castagnolo D, Dessì F, Radi M, Botta M. Tetrahedron: Asymmetry 2007; 11: 1345
- 13c Castagnolo D, Giorgi G, Spinosa R, Corelli F, Botta M. Eur. J. Org. Chem. 2007; 22: 3676
- 14a Easton NR, Cassady DR, Dillard RD. J. Org. Chem. 1964; 29: 1851
- 14b Eloy F, Deryckere A. Chim. Ther. 1973; 4: 437
- 15 Viart HM.-F, Larsen TS, Tassone C, Andresen TL, Clausen MH. Chem. Commun. 2014; 50: 7800
- 16 1-Arylpropargylamines were prepared according to previous work: Castagnolo D, Armaroli S, Corelli F, Botta M. Tetrahedron: Asymmetry 2004; 15: 941
- 17 Thompson CM, Poole JL, Cross JL, Akritopoulou-Zanze I, Djuric SW. Molecules 2011; 16: 9161
- 18 Aoyama T, Murata S, Arai I, Araki N, Takido T, Suzuki Y, Kodomari M. Tetrahedron 2006; 62: 3201
- 19 Ranjan A, Yerande R, Wakchaure PB, Yerande SG, Dethe DH. Org. Lett. 2014; 16: 5788
- 20 General Procedure for the Synthesis of 2-Aminothiazoles 4 and 2-Amino-4-methylenethiazolines 5 Propargylamine 1a–e (1.0 mmol) and the appropriate isothiocyanate 2a–c (1.0 mmol) were suspended in an appropriate solvent (DCE, MeCN, DMF, 1.0 mL) in a 10 mL glass vial equipped with a small magnetic stirring bar. PTSA (0.5 mmol) was then added to this solution, and the mixture was irradiated under microwave conditions at the appropriate temperature (see Tables 1 and 2) for 2 × 5 min, using an irradiation power of 300 W. The mixture was then poured into NaHCO3 solution (10 mL) and then extracted with EtOAc (2 × 10 mL). The combined organic phases were washed with brine, dried over Mg2SO4, filtered, and concentrated under reduced pressure. The crude products were purified by flash column chromatography (SiO2; hexanes–EtOAc, 4:1), to yield the desired products as tan-coloured oils.
- 21 2-Aminothiazole 4a 1H NMR (400 MHz, CDCl3): δ = 6.67 (s, 1 H), 5.95–5.85 (m, 1 H), 5.79 (br s, 1 H), 5.30–5.25 (d, 1 H, J = 20 MHz), 5.17–5.14 (d, 1 H, J = 12 MHz), 3.82 (d, 2 H, J = 4 MHz), 2.25 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 169.0, 135.5, 134.1, 121.1, 116.8, 48.2, 12.0 ppm. ESI-MS: m/z = 155 [M + H]+, 177 [M + Na]+.
- 22 2-Amino-4-methylenethiazoline 5a 1H NMR (400 MHz, CDCl3): δ = 5.92–5.83 (m, 1 H), 5.24–5.19 (d, 1 H, J = 20 MHz), 5.14–5.08 (m, 3 H), 4.68 (m, 2 H), 3.89–3.88 (d, 2 H, J = 4 MHz) ppm. 13C NMR (100 MHz, CDCl3): δ = 158.3, 148.8, 134.3, 116.5, 102.5, 67.0, 46.6 ppm. ESI-MS: m/z = 155 [M + H]+, 177 [M + Na]+.
