4-Chloro-6-ethoxy-2-( methylthio ) pyrimidine

4,6-Dichloro-2-(methylthio)pyrimidine (3) reacts with EtONa in EtOH, at ca. 20 ◦C, for 2 h, to give exclusively 4-chloro-6-ethoxy-2-(methylthio)pyrimidine (5) in 89% yield. The latter is presented as a useful multifunctionalised pyrimidine scaffold.


Introduction
Pyrimidines are well known owing to their presence in biological systems as components of the nucleic acid bases cytosine, thymine, and uracil, as well as the vitamin thiamine, which illustrates their importance.The presence of pyrimidines has been reported for over a century and their chemistry has been reviewed [1].Pyrimidines also find a plethora of uses as pharmaceuticals, as anti-inflammatory [2], anti-microbial [3], anti-HIV [4], anti-malarial [5] and anti-tumour [6] agents.

Introduction
Pyrimidines are well known owing to their presence in biological systems as components of the nucleic acid bases cytosine, thymine, and uracil, as well as the vitamin thiamine, which illustrates their importance.The presence of pyrimidines has been reported for over a century and their chemistry has been reviewed [1].Pyrimidines also find a plethora of uses as pharmaceuticals, as antiinflammatory [2], anti-microbial [3], anti-HIV [4], anti-malarial [5] and anti-tumour [6] agents.
Polyhalogenated pyrimidines are useful scaffolds as they can be modified either by nucleophilic aromatic substitution or by palladium coupling reactions.However, these reactions often suffer from regioselectivity issues.For example, the Suzuki-Miyaura coupling of 2,3,4,5-tetrachloropyrimidine with arylboronic acids gives either the 2- [12] or the 4-arylpyrimidine [13].Moreover, on the same scaffold, while nucleophilic substitution by alkoxide occurs at C2 [14], hydroxide attacks the C4 position [15].On the other hand, nucleophilic substitution by amine nucleophiles often gives mixtures of products [16,17].The complexity of the chemistry of pyrimidines means that it is often difficult to access specific pyrimidine targets from a simple and symmetrical pyrimidine scaffold, indicating the necessity for asymmetrical and sometimes multi-functionalized scaffolds.
Polyhalogenated pyrimidines are useful scaffolds as they can be modified either by nucleophilic aromatic substitution or by palladium coupling reactions.However, these reactions often suffer from regioselectivity issues.For example, the Suzuki-Miyaura coupling of 2,3,4,5-tetrachloropyrimidine with arylboronic acids gives either the 2- [12] or the 4-arylpyrimidine [13].Moreover, on the same scaffold, while nucleophilic substitution by alkoxide occurs at C2 [14], hydroxide attacks the C4 position [15].On the other hand, nucleophilic substitution by amine nucleophiles often gives mixtures of products [16,17].The complexity of the chemistry of pyrimidines means that it is often difficult to access specific pyrimidine targets from a simple and symmetrical pyrimidine scaffold, indicating the necessity for asymmetrical and sometimes multi-functionalized scaffolds.

Materials and Methods
The reaction mixture was monitored by chromatography (TLC) using commercial glass backed TLC plates (Merck Kieselgel 60 F254, Darmstadt, Germany).The plates were observed under UV light at 254 and 365 nm.The melting point was determined using a PolyTherm-A, Wagner and Munz, Kofler hot-stage microscope apparatus (Wagner and Munz, Munich, Germany).The solvent used for recrystallization is indicated after the melting point.The UV-VIS spectrum was obtained using a Perkin-Elmer Lambda-25 UV-VIS spectrophotometer (Perkin-Elmer, Waltham, MA, USA) and inflections are identified by the abbreviation "inf".The IR spectrum was recorded on a Shimadzu FTIR-NIR Prestige-21 spectrometer (Shimadzu, Kyoto, Japan) with Pike Miracle Ge ATR accessory (Pike Miracle, Madison, WI, USA) and strong, medium, and weak peaks are represented by s, m, and w, respectively. 1H and 13 C-NMR spectra were recorded on a Bruker Avance 500 machine (at 500 and 125 MHz, respectively (Bruker, Billerica, MA, USA)).Deuterated solvents were used for homonuclear Scheme 2. Synthesis of 4-chloro-6-ethoxy-2-(methylthio)pyrimidine ( 5) and attempted synthesis of 5-chlorinated pyrimidines 4 and 6.

Materials and Methods
The reaction mixture was monitored by chromatography (TLC) using commercial glass backed TLC plates (Merck Kieselgel 60 F 254 , Darmstadt, Germany).The plates were observed under UV light at 254 and 365 nm.The melting point was determined using a PolyTherm-A, Wagner and Munz, Kofler hot-stage microscope apparatus (Wagner and Munz, Munich, Germany).The solvent used for recrystallization is indicated after the melting point.The UV-VIS spectrum was obtained using a Perkin-Elmer Lambda-25 UV-VIS spectrophotometer (Perkin-Elmer, Waltham, MA, USA) and inflections are identified by the abbreviation "inf".The IR spectrum was recorded on a Shimadzu FTIR-NIR Prestige-21 spectrometer (Shimadzu, Kyoto, Japan) with Pike Miracle Ge ATR accessory (Pike Miracle, Madison, WI, USA) and strong, medium, and weak peaks are represented by s, m, and w, respectively. 1H-and 13 C-NMR spectra were recorded on a Bruker Avance 500 machine (at 500 and 125 MHz, respectively (Bruker, Billerica, MA, USA)).Deuterated solvents were used for homonuclear lock and the signals are referenced to the deuterated solvent peaks.APT (Advance Proton Test) NMR studies identified carbon multiplicities, which are indicated by (s), (d), (t) and (q) notations.The MALDI-TOF (Matrix Assisted Laser Desorption/Ionization-Time of Flight) mass spectrum (+ve mode) was recorded on a Bruker Autoflex III Smartbeam instrument (Bruker).The elemental analysis was run by the London Metropolitan University Elemental Analysis Service.4,6-Dichloro-2-(methylthio)pyrimidine (3) was prepared according to the literature procedure [18].