Straightforward Approach Toward Dihydrothiazoles via Intramolecular Bromocyclization

Abstract An intramolecular bromonium ion–assisted cyclization with sulfur as an internal nucleophile is described. Starting from benzoyl chlorides, this method provides an easy procedure for the synthesis of dihydrothiazole derivatives in moderate to good yields. GRAPHICAL ABSTRACT


INTRODUCTION
The electrophilic addition of halogens to alkenes has been utilized by chemists since 1851. [1] The resulting intermediate exhibited considerable synthetic applications to access further functionality or complexity. [2] In particular, the nucleophilic attack to this reactive intermediate, the halonium electrophile, in an intra-or intermolecular fashion afforded an array of useful products. Halocyclization is a well-known intramolecular attack to halogen-activated double bonds for the construction of heterocyclic compounds [3] even with asymmetric induction. [4] In this protocol, different nucleophiles such as carbon, nitrogen, and oxygen are applicable and make this method more attractive for the construction of halogenated natural products. [5] 2-Aminothiazolines have been regarded as privileged scaffolds possessing a wide range of biological activities, including neuronal acetylcholine receptor modulators, [6] antimicotic agents, [7] antimicrobial agents, [8] and nitric oxide synthase inhibitors. [9] Thiazolines were also investigated as an alternative substituent to find new riluzol-like drugs. Riluzol is known as the only drug for the suppression of amyotrophic lateral sclerosis (ALS) progress. [10] Among the molecular recognition processes based on the photophysical behaviors, [11] thiazoline-metal-based receptors have found an important place as fluorescent probe for specific anion species in biomedical studies. [12] The predominant strategy toward the thiazoline core involves dehydrative cyclization of hydroxyethyl-thioureas using HCl [13] and carbonyl-and thiocarbonyldiimidazoles. [14] The Mitsunobu reaction is also considered as an alternative method but tends to produce mixtures of N and S cyclization products. [15] With these results in hand, finding new approaches to this valuable core seems inevitable. Accordingly, we tried to investigate the intramolecular addition of sulfur to the activated double bond to synthesize 2-aminothiazoline derivatives containing possible handles for further derivatization.

RESULTS AND DISCUSSION
In continuation of our previous efforts to report versatile methodologies for the synthesis of heterocycles, [16] herein we report a straightforward approach for the synthesis of N-(5-(bromomethyl)-4,5-dihydrothiazol-2-yl)benzamide derivatives 4a-g.
Based on the application of N,N-disubstituted thiourea derivatives, [17] which were identified as potentially useful substrates in the synthesis of thiazoles, [18] we tried to generate a molecule containing thiourea and a double bond at the same time. Focusing on this strategy, the reaction of benzoyl isothiocyanate derivatives, prepared in situ by the reaction of benzoyl chlorides and ammonium thiocyanate, with allyl amine in a one-pot manner was chosen. [19] Then, adducts 3a-g were separated and subjected without further purification to 1 equiv. of N-bromosuccinimide (NBS) in refluxing acetone to afford 4a-g in 50-77% yields (Scheme 1). Among different double-bond activators, we have chosen NBS as an inexpensive, commercially available, and effective cyclization reagent. [20] Scheme 1. Synthesis of N-(5-(bromomethyl)-4,5-dihydrothiazol-2-yl)benzamides 4a-g.

STRAIGHTFORWARD ROUTE TOWARD DIHYDROTHIAZOLES
A survey on the solvent and temperature in the cyclization step revealed that acetone at room temperature is the best solvent among tetrahydrofuran (THF), dimethylformamide (DMF), dimethylsulfoxide (DMSO), dioxane, dichloromethane, and acetonitrile after 12 h (Table 1, entries 1-7). It is noteworthy that increasing the temperature led to the reaction completion within 1.5 h and afforded the desired product in improved yields ( Table 1, entry 8).
After optimization, we turned our attention to evaluate the generality of this reaction. A series of benzoyl chlorides were investigated for the synthesis of substituted thiazolines. It was found that the introduction of different electronwithdrawing groups in either the ortho, meta, or para positions did not affect the isolated yield and the reaction time, just in the case of fluorine as substituent a significant drop in yield was observed ( Table 2).
The structures of compounds 4a-g were determined from their infrared (IR), mass spectroscopic (MS), and 1 H and 13 C NMR spectral data. The molecular ion peak at m=z 331, 11 distinct signals in 13 C NMR spectrum, and the broad peak at 8.73 ppm in 1 H NMR confirmed the proposed structure of 4c. The absorption bonds at 3307, 1703 cm À1 related to secondary amide proton and C=O are also in agreement with the desired product.

CONCLUSION
In conclusion, we have reported the NBS-driven intramolecular 5-exo attack heterocyclization of N-(allylcarbamothioyl)benzamides. The presence of halogens on the phenyl ring and in the side chain made this product amenable for further functionalizations, considering the fact that the thiazoline core along with other heterocyclic units would be useful for biological responses or lowering toxicity. Further applications of this scaffold in medicinal chemistry are in progress in our laboratory.

EXPERIMENTAL
Melting points were taken on a Kofler hot-stage apparatus and are uncorrected. 1 H and 13 C NMR spectra were recorded on Bruker FT-400 and 500 instruments, using tetramethylsilane (TMS) as an internal standard. The infrared (IR) spectra were obtained on a Nicolet Magna FTIR 550 spectrophotometer (KBr disks). Mass spectra were recorded on an Agilent Technology (HP) mass spectrometer operating at an ionization potential of 70 eV. Elemental analyses were carried out with a Perkin-Elmer model 240-C apparatus.

SUPPLEMENTAL MATERIAL
Full experimental details and 1 H and 13 C NMR spectra for this article can be accessed on the publisher's website.