Facile synthesis of novel functionalized 1,3-selenazoles

The reaction of selenourea with diethyl 2,4-dibromo-3-oxoglutarate afforded ethyl 2-(2-amino-5-ethoxycarbonyl-1,3-selenazol-4-yl)-2-bromoethanoate. Treatment of the latter with acylating agents and various nucleophiles gave a series of new 4,5-disubstituted 2-amino-1,3-selenazoles. All compounds were characterized spectroscopically. The crystal structure determination of ethyl 2-(2-amino-5-ethoxycarbonyl-1,3-selenazol-4-yl)-2-bromoethanoate is reported.


Results and Discussion
Dibromination of diethyl 3-oxoglutarate 1 with NBS in carbon tetrachloride produced diethyl 2,4dibromo-3-oxoglutarate 12 2 as a mixture of diastereomers, which was directly used in the next reaction step.The reaction of dibrominated carbonyl compound 2 with selenourea was carried out under argon in ethanol at room temperature for 48 h.Then the reaction mixture was treated with a base and the separated material was extracted with an organic solvent.The purification of the crude product by flash chromatography gave ethyl 2-(2-amino-5-ethoxycarbonyl-1,3-selenazol-4-yl)-2bromoethanoate (3) in 61% yield (Scheme 1).

Scheme 1
The structure assignment of 3 was based on spectral data.The IR spectrum shows a broad band at 3151 cm -1 for NH 2 and sharp bands at 1737 and 1718 cm -1 , which are due to diester C=O groups.The 1 H NMR spectrum contains the characteristic methine proton (CHBr) signal at 6.52 ppm.The C NMR spectrum of 3 shows the characteristic signals of the 1,3-selenazole ring skeleton carbons at 113.2, 155.3 and 162.7 ppm, while a signal of the methine carbon (CHBr) is situated at 42.2 ppm.
The single crystal X-ray structure (Figure 2) 13 shows that the skeleton of the asymmetric unit contains five-membered 1,3-selenazole ring, with bromo(ethoxycarbonyl)methyl group attached to the atom C(4) and ethoxycarbonyl group attached to the atom C(5).The C(2)-Se and C(5)-Se bond lengths in the molecule 3 are 1.898(4) and 1.881(15) Å, respectively, and they are similar to that found in related structures. 6,14 he bond angle C(2) _ Se _ C(5) is 84.3(6)°.In order to evaluate the synthetic utility of 2-amino-1,3-selenazole 3 acylation reactions of the amino group have been investigated.2-Amino-1,3-selenazole 3 was subjected to acetylation with acetic anhydride in the presence of DMAP to give the amide 4a.The IR spectrum of 4a contains the primary amide bands at ν N-H = 3159 and ν C=O = 1659 cm -1 , while the 1 H NMR spectrum shows a singlet of the acetyl group protons at 2.20 ppm.Treatment of the amine 3 with Boc 2 O in the presence of DMAP gave the N-Boc protected product 4b.The 1 H NMR spectrum of 4b contains a singlet of the tert-butoxy group at 1.48 ppm.Next, we investigated representative nucleophilic substitution reactions of compound 3 with KSCN, NaN 3 , amines and thiols.The nucleophilic displacement of a bromide at the saturated carbon with the thiocyanate group gave a substituted product 5.The IR spectrum of 5 showed a sharp band at 2158 cm -1 assigned to the thiocyanate group. 15In its 13 C NMR spectrum, the characteristic resonance signal of the thiocyanate carbon appeared at 103.6 ppm.
Treatment of 3 with sodium azide in DMSO at 60 °C for 6 h, followed by work-up consisting of dilution with dichloromethane, washing the organic layer with water and concentration under reduced pressure, gave the azido derivative 6.The absorption band at 2122 cm -1 , which is due to the azido group, 15 is observed in the IR spectrum of 6.
Then we turned our attention to study the possibility of substitution of a bromide by an amino group.The reaction of the bromide 3 with methyl amine hydrochloride in ethanol in the presence of bases, led to the formation of the secondary amine 7a.The IR spectra of 7a showed broad bands in the area 3324 -3180 cm -1 for the NH 2 and NH groups and the intense bands at 1738 and 1696 cm -1 assigned to the carbonyl groups of the diester.When compound 3 was reacted with benzylamine, the secondary amine 7b was obtained in 62% yield.To assess further its reactivity, compound 3 was treated with thiols.However, the reaction of the bromide 3 with ethanethiol in the presence of TEA did not give the desired sulfide, instead debrominated compound 8 was obtained.The reaction with methyl thioglycolate in similar conditions afforded the same product 8.The 1 H NMR spectrum of 8 revealed a singlet at 3.85 ppm for methylene protons (CH 2 CO). 13 C NMR spectrum showed the presence of three methylene carbons at 36.6 (CH 2 CO), 60.0 (OCH 2 ), 60.1 (OCH 2 ), respectively.Similarly, treatment of 2acetylamino-1,3-selenazole 4a with ethanethiol afforded the corresponding debrominated compound 9.The latter compound was also obtained by reaction of 8 with acetic anhydride in the presence of DMAP.
The use of thiols as catalysts and hydrogen donors for radical chain reduction of organic halides is well documented in the literature. 16For example, 1,2,2,6,6-pentamethylpiperidine/ mercaptoethanol system was shown to be an effective reducing agent for the radical chain reduction of bromoesters.16c Therefore, it can be assumed, that ethanethiol/TEA or methyl thioglycolate/TEA systems possess similar reductive properties and accomplish dehalogenation of bromoesters 3 and 4a by a radical-chain mechanism.

Conclusions
In summary, an efficient route for the preparation of a wide variety of highly functionalized 1,3selenazoles has been developed.This method allows functionalized 1,3-selenazoles to be easily available for further investigations into their chemical and biological properties.

Experimental Section
General.Melting points were determined in open capillary tubes with a Büchi B-540 melting point apparatus and are uncorrected.Infrared spectra were recorded on a Perkin Elmer Spectrum One spectrometer using potassium bromide pellets. 1 H NMR spectra were recorded at 300 MHz on a Varian Unity Inova spectrometer. 13C NMR spectra were registered at 75 MHz using the instrument mentioned above.Chemical shifts, expressed in ppm, were relative to tetramethylsilane (TMS).Mass spectra were measured using Waters ZQ 2000 instrument (ion spray).Diffraction data were collected on Bruker-Nonius KappaCCD diffractometer at room temperature and also at -100 °C.The crystal structures were solved using known programs. 17Elemental analyses were performed by the Microanalytical Laboratory, Department of Organic Chemistry, Kaunas University of Technology, Lithuania.For thin layer chromatographic (TLC) analyses, Merck precoated TLC plates (silica gel 60 F254) were used.