2-Diphenylphosphinomethyl-3-methylpyrazine

: The lateral metalation-electrophilic trapping reaction of alkyl-substituted pyrazines has always been challenging and poorly regioselective, with the corresponding derivatives often being isolated in moderate yield. In this contribution, we ﬁrst report on the preparation of an unsymmetrically-substituted pyrazine, that is 2-diphenylphosphinomethyl-3-methylpyrazine, by subjecting to metalation with n -BuLi the commercially available 2,3-dimethylpyrazine, followed by interception of the putative lithiated benzyl-type intermediate with Ph 2 PCl. Such a functionalization has been successfully carried out in the absence of additional ligands, working either in THF at − 78 ◦ C or in a more environmentally friendly solvent like cyclopentyl methyl ether at 0 ◦ C, with the desired phosphine derivative being isolated in 70–85% yield. The newly synthesized adduct has been fully characterized by means of multinuclear magnetic resonance spectroscopic techniques, and also by preparing a selenium derivative, which furnished single crystals that were suitable for X-ray analysis.

Heteroatom-promoted lateral lithiation of benzylic alkyl groups closest to the heteroatom, followed by trapping reaction with electrophiles, represents a valuable tool to elaborate (hetero)aromatic systems by providing either a chain extension at the benzylic position or the synthesis of fused carbo-and heterocyclic systems via the annulation of chain-extended adducts [13][14][15][16].
In this Short Note, we report on the synthesis and the structural characterization of a novel, unsymmetrical diphenylphosphinomethyl pyrazine (2), by selectively deprotonating one of the methyl group of 2,3-dimethylpyrazine (1) with an organolithium compound, followed by trapping of the resulting putative lithium intermediate 1-Li with diphenylchlorophosphine (Ph 2 PCl) (Scheme 1). A comparison has been made on the effectiveness of using more eco-friendly solvents in place of traditional volatile organic compounds (VOCs). To date, only symmetrical pyrazine-based aryl-or alkyldiphosphines have been made accessible when using in the deprotonation reaction of the corresponding precursors a mixture of n-BuLi and tetramethylethylenediamine (TMEDA) as a privileged ligand, and working in ethereal solutions of VOCs at −78 • C [42].

Results and Discussions
Treatment of a solution of 1 in THF with n-BuLi (1 equiv) (1.4 M solution in cyclohexane), under Ar at room temperature (RT), followed by dropwise quenching with Ph 2 PCl (1 equiv) in THF after 45 min, gave no reaction. Lowering the temperature to −78 • C was found to be similarly ineffective. Pleasingly, upon first stirring a THF solution of 1 with n-BuLi for 45 min at RT under Ar, and then adding dropwise the resulting mixture to a pre-cooled (−78 • C) THF solution of Ph 2 PCl, adduct 2 could now be isolated in 85% yield (Scheme 2a). The latter was fully characterized by multinuclear ( 1 H, 13 C and 31 P) magnetic resonance spectroscopy (Supplementary Materials).
Further characterization of 2 came by allowing it to react at RT with chalcogens like selenium (2 equiv) directly in an NMR tube, and subsequently monitoring the appearance of phosphine selenide 3, which formed with >98% conversion within a few minutes (Scheme 2c). The structure and the connectivity of 3 were unambiguously assigned by means of mono-( 1 H, 13 C, 31 P and 77 Se) and two-dimensional (( 1 H-1 H)-COSY, ( 1 H-13 C)-HMBC and HMQC)) NMR techniques (Supplementary Materials), and by X-ray analysis ( Figure 1 and Supplementary Materials). The major resonance displayed in the 31 P NMR spectrum at δ 32.4 (C 6 D 6 ) is that typical of phosphine selenides [43]. 31 P-77 Se NMR coupling could be seen either in 31 P NMR spectrum as satellites ( 1 J P-Se = 756.3 Hz) or directly in the 77 Se NMR spectrum (Supplementary Materials).
Upon switching THF for an environmentally friendly solvent such as cyclopentyl methyl ether (CPME) (relatively high boiling point, non-inflammability, low toxicity and low peroxide formation rate, and stability under acidic and basic conditions) [44], compound 2 could be isolated in 70% yield when a CPME solution of 1-Li (prepared by reacting 1 with n-BuLi (1.4 M in cyclohexane, 1 equiv) and aging the resulting solution at 0 • C for 45 min) was cannulated into a solution of Ph 2 PCl (1 equiv) in CPME, which was kept at 0 • C (Scheme 2b).

Materials and Methods
Tetrahydrofuran (THF) and cyclopentyl methyl ether (CPME) were dried over sodium/ benzophenone ketyl under argon, and distilled prior to use. All reactions involving airsensitive reagents were performed under argon in oven-dried glassware using syringeseptum cap technique.
GC-MS analyses were performed on a HP 5995C model. High-resolution mass spectrometry (HRMS) analyses were performed using a Bruker microTOF QII mass spectrometer equipped with an electrospray ion source (ESI). Reagents and solvents, unless otherwise specified, were purchased from Sigma-Aldrich (Sigma-Aldrich, St. Louis, MO, USA) and used without any further purification. Ethyl acetate was used as the solvent in the work-up procedures. n-BuLi (1.4 M in cyclohexane) was used as the lithiating agent.

X-ray Diffraction Studies on Compound 3 · C 6 D 6
A suitable crystal of 3 immersed in perfluorinated oil was mounted and measured by means of an Oxford Diffraction Excalibur diffractometer equipped with a Spellman generator (50 kV, 40 mA) and a Kappa CCD detector, using MoKα radiation (λ = 0.71073 Å). Data collection was performed with the program CrysAlis CCD. Data reduction was carried out with the program CrysAlis RED (CrysAlis RED, 2006) [46]. The intensities were corrected for Lorentz and polarization effects, and an absorption correction based on the multi-scan method using SCALE3 ABSPACK [47] in CrysAlisPro was applied. The structure was solved by direct methods using the program SIR97 [48], refined by means of full matrix least-squares based on F2 using the program SHELXL-97 [49], and checked with PLATON [50]. Non-hydrogen atoms were refined anisotropically. Hydrogen atoms involved in hydrogen bonds were located in the Fourier difference map. Data collection and refinement parameters are given in Tables S1-S4 (Supplementary Material). Interactions between selenium and the neighbouring protons are shown in Figure S13 (Supplementary Informations). Illustrations of the molecular structure were drawn with DIAMOND [45]. CCDC-2092648 contains supplementary crystallographic data for this compound. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif [51].

Synthetic Procedure for the Synthesis of 2 in THF
To a solution of 1 (18.55 mmol) in 30 mL of dry THF, n-BuLi (1 equiv) (13.25 mL of a solution 1.4 M in cyclohexane) was rapidly added under Ar at RT. The resulting dark red mixture was vigorously stirred for 45 min. This solution was then cannulated into a pre-cooled (−78 • C) THF solution of Ph 2 PCl (1 equiv) (18.55 mmol in 20 mL of dry THF) under Ar. The mixture was allowed to warm to RT. After 4 h, the organic layer was filtered through a silica pad under Ar, using ethyl acetate as the eluent. The solvent was removed under reduced pressure to provide the desired product 2 in 85% yield.

Synthetic Procedure for the Synthesis of 2 in CPME
To a solution of 1 (1 mmol) in 1 mL of dry CPME, n-BuLi (1 equiv) (0.7 mL of a solution 1.4 M in cyclohexane) was rapidly added under Ar at 0 • C. The resulting dark red mixture was vigorously stirred for 45 min. This solution was then cannulated into a pre-cooled (0 • C) CPME solution of Ph 2 PCl (1 equiv) (1 mmol in 1 mL of dry CPME) under Ar. The mixture was allowed to warm to RT. After 4 h, the organic layer was filtered through a silica pad under Ar, using ethyl acetate as the eluent. The solvent was removed under reduced pressure to provide the desired product 2 in 70% yield.

Synthetic Procedure for the Synthesis of 3
In an NMR tube containing a solution of 2 in C 6 D 6 , 2 equiv. of selenium were added at RT. The reaction was monitored by NMR. After a few minutes, phosphine selenide 3 was obtained with 98% conversion. Single crystals were obtained directly from the NMR tube by slow evaporation of the solvent, and were subjected to X-ray diffraction studies.

Conclusions
The preparation of an unsymmetrically substituted pyrazine, 2-diphenylphosphinomethyl-3-methylpyrazine, was presented, by subjecting to lithiation the commercially available 2,3-dimethyl pyrazine followed by an electrophilic interception of the putative benzyltype intermediate with Ph 2 PCl. The chemical structure of the synthesized adduct was unambiguously secured by using NMR and mass techniques, and by preparing a selenium derivative, which furnished single crystals that were suitable for X-ray analysis. The described lateral lithiation/functionalization was proven to be regioselective in the absence of additional ligands, and was successfully achieved either working in a VOC such as THF at −78 • C (85% yield) or in an environmentally friendly solvent like CPME at 0 • C (70% yield). Further investigation is in progress to prepare transition-metal complexes of such a P,N-heterocyclic phosphine motif to investigate their biological properties and their applications as auxiliary ligands in organometallic catalysis.
Supplementary Materials: The following are available online at: copies of 1 H-, 13 C-and 31 P-NMR spectra of compound 2; copies of 1 H-, 13 C-, 31 P-and 77 Se-NMR spectra of compound 3; copies of 2D 1 H-1 H-COSY, 2D 1 H-13 C HMQC, 2D 1 H-13 C HMBC spectra of compound 3; crystallographic data, geometric parameters and bond angles for compound 3 · C 6 D 6 ; X-ray ellipsoid plot of compound 3 · C 6 D 6 showing interactions between selenium and the neighbouring protons.
Funding: This work was carried out under the framework of the National PRIN project "Unlocking Sustainable Technologies Through Nature-Inspired Solvents" (Code: 2017A5HXFC_002) and financially supported by the University of Bari.

Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.

Data Availability Statement:
The data presented in this study are available in this article and in its Supplementary Materials. The X-ray data are deposited at CCDC as stated above.