N-Propargylamines: versatile building blocks in the construction of thiazole cores

Thiazoles and their hydrogenated analogues are not only key structural units in a wide variety of natural products but they also constitute important building blocks in medicinal chemistry. Therefore, the synthesis of these compounds using new protocols is always interesting. It is well known that N-propargylamines can undergo a number of cyclization reactions to produce various nitrogen-containing heterocycles. In this review, we highlight the most important developments on the synthesis of thiazole and its derivatives starting from N-propargylamines. This review will be helpful in the development of improved methods for the synthesis of natural and biologically important compounds.

N-Propargylamines are one of the most specific class of alkynes having diverse reaction patterns. It is well known that they can undergo a number of cyclization reactions to produce various N-heterocycles and complex natural products. In this context we recently reviewed their role in the syntheses of pyrrole [65], pyridine [66], quinoline [67], pyrazine [68], 1,4-oxazepane, and 1,4-diazepane [69] derivatives. The synthesis of thiazoles and their hydrogenated analogues from N-propargylamines offers several advantages, such as high functional group tolerance and high atom and step economy. In continuation of our works [69][70][71][72][73][74], in this review, we will highlight the most important developments on the synthesis of thiazole and its derivatives from N-propargylamines ( Figure 3) which will be helpful in the de-

Scheme 1:
The synthesis of thiazole-2-thiones 3 through the thermal cyclocondensation of N-propargylamines 1 with carbon disulfide as developed by Batty and Weedon [75]. velopment of improved methods for the synthesis of natural and biologically important compounds. The review is organized by the type of starting materials.

Review 1 From N-propargylamines and carbon disulfide
The first example of a cyclization of N-propargylamines 1 with carbon disulfide to lead to 5-methylenethiazolidine-2-thiones 2 was reported in 1949 by Batty and Weedon. The reaction took place in refluxing ethanol and generally afforded the corresponding products in good yields. It was also observed that products 2 rapidly formed by reaction of 1 with carbon disulfide in the presence of sodium hydroxide as the base in water at 20 °C. Further, the authors showed that treatment of methylene compound 2 with cold concentrated sulfuric acid gave the corresponding isomeric thiazole-2-thiones 3 in high yields (Scheme 1) [75]. Thirty-six years later, Hanefeld and Bercin synthesized a series of 2-(alkylthio)thiazoles by employing the aforementioned method as the key step [76]. In 2001, Shi and Shen found that using a Pd(PPh 3 ) 4 /toluene system clearly accelerated this cyclocondensation and the desired products were ob-tained in excellent yields [77]. Other systems such as Pd(OAc) 2 / THF [78], D301R (a tertiary amine-functionalized ion-exchange resin)/biphenyl [79], and diethylamine/NaOH/H 2 O [80] were also successfully employed in this transformation. Despite all these successes, the number of reported examples in this interesting field is limited. There is still further need to study the scope and limitations of this approach for the preparation of thiazolidine-2-thione derivatives.

From N-propargylamines and isothiocyanates
The first example of a synthesis of thiazole derivatives from N-propargylamines and isothiocyanates was reported in 1964 by Easton et al. The authors obtained 2-iminothiazolidines 11 in good yields by the treatment of secondary α,α-disubstituted N-propargylamines 9 with isothiocyanates 10 through a catalyst-free thiourea formation/intramolecular thia-Michael cyclization in ether (Scheme 3a). They also showed that the treatment of primary α,α-disubstituted N-propargylamines with isothiocyanates led to the corresponding N-propargylthioureas that converted to the cyclic forms upon standing for several days at room temperature [83]. Thirteen years later, Arya and co-workers applied this method for the synthesis of 3-thia-1azaspiro [4,5]decane ring systems [84]. In 1993, U. Urleb extended the scope of the reaction from isothiocyanates to heterocyclic isothiocyanates and some reported examples are shown in Scheme 3b [85].
This strategy was elegantly used by Sasmal and co-workers in the preparation of 2-aminothiazoles 17 from ethyl 4-aminobut-2-ynoate salts 15 and isothiocyanates 16. Several bases and solvents were screened and the combination of Et 3 N and THF at room temperature was found to be superior. Under the optimized conditions, the reaction tolerates both aryl and alkyl isothiocyanates 16 and gave the corresponding 2-aminothiazoles 17 in good to high yields (Scheme 4a). The authors further expanded the scope of N-propargylamines to diethyl 3-aminoprop-1-ynylphosphonate salts 18 leading to 5-diethyl methylphosphonate-substituted 2-aminothiazoles 19 in good yields (Scheme 4b) [86].
An interesting approach towards the synthesis of 2-aminothiazole derivatives by treatment of N-propargylamines with isothiocyanates in the presence of p-toluenesulfonic acid (PTSA) as catalyst under microwave irradiation was developed by Castagnolo et al. Following this route, several 4-substituted 5-methylthiazol-2-amines 22 were synthesized from terminal N-propargylamines 20 and isothiocyanates 21 in DMF at 160 °C. Interestingly, when internal N-propargylamines were treated with 21, exclusively imidazolthiones 24 in yields ranging from 15 to 33% instead of the expected 2-aminothiazoles were obtained. The authors also found that with decreasing reaction temperature the yield of 22 decreased in favor of the thiazolines 23. Some reported examples are collected in Table 1 [87].
Recently, to develop an efficient protocol for the synthesis of 5-(iodomethylene)-3-methylthiazolidines 27 from N-propargylamines, X. Zhou and co-workers have investigated the threecomponent halocyclization of N-propargylamines 25, aryl isothiocyanates 26, and iodine in ethyl acetate. Excellent yields of desired products were observed (Scheme 5). The mechanism shown in Scheme 6 was proposed for this transformation and comprises the following key steps: (i) the reaction of N-propargylamine 25 and isothiocyanate 26 forms the thiourea   [88].
Seeking for a greener approach towards thiazolidines of type 30, the group of Clausen has proposed a base-catalyzed protocol using t-BuOH in water at 20 °C for a quite efficient cyclization between secondary N-propargylamines 28 and fluorescein isothiocyanate 29 (Scheme 7) [89].
More recently, Beauchemin and co-workers reported the syntheses of a series of multiply substituted thiazolidines 33 via the cyclization reaction of secondary N-propargylamines 32 with blocked N-isothiocyanate precursors 31. The desired

From N-propargyl thioamides
The first example of a thiazole synthesis from N-propargyl thioamides has been reported by Short and Ziegler in 1993. N-Propargyl thiocarbamate 34 cyclized to disubstituted thiazole 35 through an addition-cycloelimination strategy by the treatment with sodium benzenesulfinate and I 2 in ethyl acetate and water at 80 °C (Scheme 9a) [91]. Later, the P. Wipf research team found that N-propargylamines 36 were converted to the corresponding vinylthiazolines 38 through the treatment with dithioic acids 37 in the presence of EDCI in dichloromethane. This transformation is believed to occur through a tandem coupling-cyclization reaction. The authors showed that the treatment of 38 with DBU at 0 °C provided thiazoles 39 in good yields (Scheme 9b) [92].
Along this line, Junjappa and co-workers reported an efficient route for the synthesis of 2-substituted 5-methylenethiazolidines 42 through the reaction of β-oxodithioesters 40 with N-propargylamine (41). The mechanism proposed by the authors to explain this reaction is based on the formation of β-oxo-N-propargyl thioamides A as intermediates, followed by their spontaneous ring closure. This reaction was run in refluxing ethanol and provided in all cases the desired thiazolidines 42 in high to excellent yields (Scheme 10) [93]. along with the product originating from a 6-endo-dig cyclization [97].
Recently, Foroumadi and co-workers studied the possibility of synthesizing thiazole derivatives from N-propargylthioureas through a regioselective 5-exo-dig cyclization-proton transfer-isomerization sequential process. They found that the easily available N-(propargylcarbamothioyl)amides 53 in the presence of 1,4-diazabicyclo[2.2.2]octane (DABCO) as the base in refluxing ethanol, rapidly cyclized and produced the corresponding dihydrothiazol-2-ylamides 54 in good yields (Scheme 16a). The mechanism for this cyclization as proposed by the authors is depicted in Scheme 16b [98].
Following this work, the Čikotienė group studied the metal-free halogen, chalcogen, or oxocarbenium ion-mediated cyclization of a series of N-propargylthioureas 55 ( Table 2) [99].

Miscellaneous
Recently, Stevens and co-workers reported a robust protocol towards dihydrothiazoles through an Au(III)-catalyzed intramolecular cyclization of the corresponding dithiocarboimidates. Thus, the corresponding 5-alkylidene-dihydrothiazoles 58 were synthesized in good to excellent yields from N-(propargyldithiocarbo)imidates 57 through a 5-exo-dig cyclization followed by a thio-Claisen-type rearrangement with AuCl 3 as the catalyst in dichloromethane (Scheme 18). It is worth mentioning that the required N-(propargyldithiocarbo)imidates were easily prepared in high yields through a condensation of commercially available and cheap N-propargylamine, allyl bromide, and carbon disulfide [100].

Conclusion
Much work has been carried out during the past decade and has demonstrated that N-propargylamines are one of the most useful and versatile precursors in the synthesis of various nitrogen heterocycles and complex natural products. In this regard, recently an impressive increase in the number of publications on the preparation of thiazoles and their hydrogenated analogues through inter-and intramolecular cyclization of N-propargylamine derivatives appeared in the literature. In this review we discussed the most representative and interesting reports on this emerging field. As illustrated, the processes provided the title compounds in good yields with fewer steps and higher atom economy than previously reported examples. We hope that this review will encourage synthetic organic chemists to employ these valuable methodologies to the synthesis of important new thiazole derivatives.