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Short Note

2-Diphenylphosphinomethyl-3-methylpyrazine

1
Dipartimento di Farmacia-Scienze del Farmaco, Università di Bari “Aldo Moro”, Consorzio C.I.N.M.P.I.S., Via E. Orabona 4, 70125 Bari, Italy
2
Department Chemie, Ludwig-Maximilians-Universität München, Butenandstrasse S-13, Haus D, 81377 München, Germany
*
Authors to whom correspondence should be addressed.
Equally contributing authors.
Academic Editor: Nicholas E. Leadbeater
Molbank 2021, 2021(3), M1267; https://doi.org/10.3390/M1267
Received: 28 June 2021 / Revised: 12 July 2021 / Accepted: 2 August 2021 / Published: 5 August 2021

Abstract

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 Ph2PCl. 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.
Keywords: pyrazines; lithiation; organophosphorus compounds; heterocycles; X-ray diffraction studies; NMR studies pyrazines; lithiation; organophosphorus compounds; heterocycles; X-ray diffraction studies; NMR studies

1. Introduction

Pyrazine-based skeletons are present in many natural bioactive products and have been extensively incorporated in clinically used drugs and molecules exhibiting noteworthy antibiotic, antifungal, antitubercular, antidepressant, antineoplastic, diuretic, antiulcerogenic, and anti-infective effects [1,2,3,4,5,6]. Moreover, they can also serve as important building blocks for the preparation of dyes and electroluminescent materials, and were found to act as suitable ligands in coordination chemistry [7,8,9,10,11,12].
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].
Among nitrogen-containing heterocyclic systems, lateral metalation of pyrazines-bearing Me groups has largely remained unexplored [17,18,19,20,21]. Kamal and Levine pioneered the use of sodium amide in liquid ammonia to promote acylation, alkylation and hydroxyalkylation reactions of dimethylpyrazines [22,23]. Later on, Houminer et al. prepared 2-(2-hydroxy-2-arylethyl)pyrazines by benzylic lithiation of alkylpyrazines with lithium diisopropylamide (LDA) in ether or diglyme, followed by electrophilic interception of the corresponding anions with aromatic aldehydes, with the desired adducts, however, being isolated in poor-to-moderate yields (25–60%) [24,25].
Based on our long lasting interest in the functionalization of heterocycles by direct [26,27,28,29,30,31,32,33], ortho- [34,35], and lateral [36,37] lithiation reactions, we became interested in synthesizing a pyrazine derivative incorporating a phosphine unit into its scaffold as transition metal-phosphine complexes are known to be powerful catalytic tools for numerous C–C bond-forming reactions in modern organic synthesis [38,39,40,41].
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 (Ph2PCl) (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].

2. 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 Ph2PCl (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 Ph2PCl, adduct 2 could now be isolated in 85% yield (Scheme 2a). The latter was fully characterized by multinuclear (1H, 13C and 31P) 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- (1H, 13C, 31P and 77Se) and two-dimensional ((1H-1H)-COSY, (1H-13C)-HMBC and HMQC)) NMR techniques (Supplementary Materials), and by X-ray analysis (Figure 1 and Supplementary Materials). The major resonance displayed in the 31P NMR spectrum at δ 32.4 (C6D6) is that typical of phosphine selenides [43]. 31P-77Se NMR coupling could be seen either in 31P NMR spectrum as satellites (1JP-Se = 756.3 Hz) or directly in the 77Se 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 Ph2PCl (1 equiv) in CPME, which was kept at 0 °C (Scheme 2b).

3. 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 air-sensitive reagents were performed under argon in oven-dried glassware using syringe-septum 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.
NMR spectra were recorded on a Jeol EX 400 Eclipse spectrometer operating at 400.182 MHz (1H), 100.626 MHz (13C), 161.997 MHz (31P) and 76.321 MHz (77Se). Chemical shifts are reported in parts per million (δ) using the following standards Me4Si (1H, 13C), 85% H3PO4 (31P), Me2Se (77Se). Coupling constants are expressed in Hz using C6D6 as the solvent. The following abbreviations have been used to explain the multiplicities: s = singlet, d = doublet, dd = double of doublets, quin = quintuplet, m = multiplet.

3.1. X-ray Diffraction Studies on Compound 3 · C6D6

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].

3.2. 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 Ph2PCl (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.

3.3. 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 Ph2PCl (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.
2-Diphenylphosphinomethyl-3-methylpyrazine (2). 1H NMR (400.182, C6D6): δ 2.35 (s, 3 H, CH3), 3.48 (s, 2 H, CH2), 7.04–7.11 (m, 6 H, arom-H), 7.42–7.49 (m, 4 H, arom-H), 7.88–7.91 (m, 2 H, arom-H); 13C NMR (100.626 MHz, C6D6): δ 21.9 (d, 4JC-P = 4.9 Hz, CH3), 36.0 (d, 1JC-P = 18.1 Hz, CH2), 128.4 (d, 3JC-P = 6.4 Hz, CH), 128.8 (s, CH), 133.1 (d, 2JC-P = 19.4 Hz, CH), 134.4 (d, 1JC-P = 12.7 Hz, C), 138.7 (d, 2JC-P = 15.6 Hz, C), 141.3 (d, 3JC-P = 7.6 Hz, C), 152.6 (d, J = 0.8 Hz, CH), 152.7 (s, CH); 31P NMR (161.997 MHz, C6D6) δ = −14.8 (quin, 3JPH = 5.9 Hz); GC-MS (70 ev) m/z (%): 292 (36), 277 (1), 215 (3), 183 (100), 152 (8), 133 (3), 107 (13), 91 (1), 77 (4); HR-MS (ESI), (M.W.:292): m/z [M + H+] calculated for C18H18N2P: 293.1114, found: 293. 1171.

3.4. Synthetic Procedure for the Synthesis of 3

In an NMR tube containing a solution of 2 in C6D6, 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.
[(3-Methylpyrazin-2-yl)methyl]diphenylphosphine selenide (3). 1H NMR (400.182 MHz, C6D6): δ 2.46 (s, 3 H, CH3), 3.98 (d, 2JPH = 12.0 Hz, 2 H, CH2), 6.95–6.98 (m, 6 H, m-H, p-H), 7.67 (d, 3JHH = 4.0 Hz, 1 H, pyrazine-H), 7.80 (dd, 3JHH = 4.0 Hz, 5JPH = 4.0 Hz, 1 H, pyrazine-H), 7.85–7.91 (m, 4 H o-H); 13C NMR (100.626 MHz, C6D6): δ 23.0 (d, 4JPC = 4.0 Hz, CH3), 39.7 (d, 1JPC = 43.2 Hz, CH2), 128.2 (d, 3JPC = 12.1 Hz, CH-m), 131.2 (d, 4JPC = 3.0 Hz, CH-p), 132.2 (d, 2JPC = 13.1 Hz, CH-o), 132.9 (d, 1JPC = 19.1 Hz, C-i), 140.9 (d, 5JPC = 3.0 Hz, CH-3), 142.1 (d, 4JPC = 4.0 Hz, CH-4), 148.6 (d, 3JPC = 8.0 Hz, C-2), 154.9 (d, 2JPC = 5.0 Hz, C-1); 31P NMR (161.997 MHz, C6D6): δ 32.35 (s, 1JPSe = 755.9 Hz);77Se NMR (76.321 MHz, C6D6): δ-316.45 (d, 1JPSe = 756 Hz).

4. 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 benzyl-type intermediate with Ph2PCl. 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 1H-, 13C- and 31P-NMR spectra of compound 2; copies of 1H-, 13C-, 31P- and 77Se-NMR spectra of compound 3; copies of 2D 1H-1H-COSY, 2D 1H-13C HMQC, 2D 1H-13C HMBC spectra of compound 3; crystallographic data, geometric parameters and bond angles for compound 3 · C6D6; X-ray ellipsoid plot of compound 3 · C6D6 showing interactions between selenium and the neighbouring protons.

Author Contributions

Conceptualization, K.K. and V.C.; methodology, all authors; validation, T.B., L.C. and A.F.Q.; formal analysis, T.B., L.C., A.F.Q., F.M.P. and P.V.; investigation, K.K., F.M.P. and P.V.; resources, K.K. and V.C.; data curation, F.M.P. and P.V.; writing—original draft preparation, V.C.; writing—review and editing, all authors; supervision, K.K. and V.C.; funding acquisition, V.C. and K.K. All authors have read and agreed to the published version of the manuscript.

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.

Acknowledgments

University of Bari and Ludwig-Maximilians-Universität München are gratefully acknowledged for participating in an Erasmus scholarship programme.

Conflicts of Interest

The authors declare no conflict of interest.

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Scheme 1. Synthesis of phosphine 2 by deprotonating 2,3-dimethylpyrazine 1 with an organolithium, followed by a trapping reaction of the intermediate 1-Li with Ph2PCl.
Scheme 1. Synthesis of phosphine 2 by deprotonating 2,3-dimethylpyrazine 1 with an organolithium, followed by a trapping reaction of the intermediate 1-Li with Ph2PCl.
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Scheme 2. (a) Synthesis of phosphine 2 by deprotonation of 1 and reaction of 1-Li with Ph2PCl in THF; (b) synthesis of phosphine 2 by deprotonation of 1 and reaction of 1-Li with Ph2PCl in CPME; (c) synthesis of phosphine selenide 3 by reacting 2 with Se.
Scheme 2. (a) Synthesis of phosphine 2 by deprotonation of 1 and reaction of 1-Li with Ph2PCl in THF; (b) synthesis of phosphine 2 by deprotonation of 1 and reaction of 1-Li with Ph2PCl in CPME; (c) synthesis of phosphine selenide 3 by reacting 2 with Se.
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Figure 1. Molecular structure of compound 3 ∙ C6H6 in the crystal, DIAMOND [45] representation, thermal ellipsoids are drawn at 50% probability level.
Figure 1. Molecular structure of compound 3 ∙ C6H6 in the crystal, DIAMOND [45] representation, thermal ellipsoids are drawn at 50% probability level.
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