Metal free oxidation of vinamidine derivatives: a simple synthesis of α-keto-β-diimine ligands

Abstract

Oxidation of vinamidinium salts with meta-chloroperbenzoic acid is the key synthetic step towards new persistent 1,3-di(amino)oxyallyl radical cations. When applied to parent vinamidines, this protocol allows for a simple straightforward synthesis of α-keto-β-diimine ligands, for which no convenient synthesis was previously available.

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β-Diketiminates, so-called NacNac ligands (Scheme 1), have been a focus in coordination chemistry for decades.¹ Structural modifications include a large variety of N-substituents, as well as bulky,² electron-withdrawing,³ or electron donating⁴ R groups. Substitution at the central carbon atom (R′ ≠ H) has also been explored as a strategy to tame this reactive position and enhance the chemical stability of the complex.⁵ The α-keto-β-diimines are among rare representatives with a more significant modification at the central carbon. These electron-deficient ligands have found applications in the design of highly active nickel(II) initiators for the synthesis of high molecular weight polyethylenes and poly-α-olefins.⁶ Interestingly, low-disperse semi-crystalline polymers could be obtained under living conditions and remarkable enantiomorphic site control could be achieved.⁷

Scheme 1 Previously reported synthesis of α-keto-β-diimines and synthesis of air-persistent radical 4˙⁺ from vinamidinium 3.

The low availability of α-keto-β-diimines has clearly hampered further development. Their metal complexes have been known for long, but only as occasional by-products from the air-decomposition of unprotected NacNac complexes (R′ = H).⁸ To date only a rare selective oxygen-degradation of copper(II) complexes allows for the synthesis of a handful of 2,4-di(arylimino)pentan-3-ones 2 from the corresponding vinamidines 1.^6a,d,9 The procedure requires (i) the synthesis of the NacNac–Cu(II) complex, (ii) oxidation at the ligand with dioxygen in a methanol/dichloromethane mixture, (iii) the decomplexation and hydrolysis of the resulting hemiacetal ligand (Scheme 1). In turn, we had to synthesize 2,4-bis((2,6-diisopropylphenyl)imino)pentan-3-one 2a and experienced firsthand the length and limitations of this methodology. Among the three steps, the oxidation of the NacNac–copper complex is especially inconvenient and wasteful, as it consists of a continuous bubbling of pure dioxygen in a warm solution for two days.^6a Recently, we released a parented, though in principle far simpler, oxidation of tetrakis(dimethylamino) vinamidinium 3 into di(amidinium)ketone 4²⁺ with meta-chloroperbenzoic acid (m-CPBA) as oxidant. Our initial focus was on the corresponding radical 4˙⁺, which was found remarkably air-persistent, despite minimal steric hindrance.¹⁰ Herein we report how further assessment of such 1,3-(diamino)oxyallyl radical cations ultimately led to a straightforward protocole for the synthesis of α-keto-β-diimines from NacNac precursors.

Prior to 4˙⁺, only two oxyallyl radical cations had been synthesized from the reaction of rare stable electrophilic carbenes with carbon monoxide.^11–13 In principle, the oxidation of vinamidinium salts should provide for a more simple and general route, with no need of sophisticated N-substituents. To probe this assumption, we first considered the oxidative functionalization of the chloride salt of vinamidinium 5⁺, which was synthesized from N,N-dimethyl-benzamide and 1-dimethylamino-1-phenylethene.¹⁴ Addition of m-CPBA at room temperature yielded 2-chlorovinamidium 6 in 71% yield (Scheme 2). This result indicated the competitive formation of meta-chlorobenzoyl hypochlorite Cl(C₆H₄)CO₂Cl, from the reaction of chloride anions with m-CPBA.¹⁵ Therefore we proceeded to an anion metathesis. The resulting tetrafluoroborate salt reacted with m-CPBA, but this time to afford 7·H⁺, which was fully characterized and isolated in 74% yield. Of note, the NMR spectra of vinamidiniums 6 and 7·H⁺ mostly differ in the ¹³C chemical shift of their central carbon: 94 and 127 ppm, respectively. They were unambiguously characterized by mass spectrometry analyses and X-ray diffraction studies (Fig. 1).

Scheme 2 Redox transformations of di(imidazole)methane and 1,3-di(phenyl) vinamidinium derivatives.

Fig. 1 X-ray structures of 6, 7·H⁺ and 2c,d with thermal ellipsoids drawn at 50% probability level. Most hydrogen atoms, solvent molecules and counter-anions were omitted for clarity.

Solutions of 7·H⁺ featured an EPR signal upon exposure to air. This slow reaction could be brought to fast completion in presence of potassium hydrogenocarbonate. The remarkable persistency under aerobic conditions of the resulting radical (in aerated solutions for several hours) was reminiscent of our previously reported stable oxyallyl radicals, some being similarly synthesized by auto-oxidation of parented enol-cations.^11a Therefore, we hypothesized the formation of radical 7˙⁺. Although the radical ultimately decayed and couldn't be isolated, the excellent fit between the experimental EPR hyperfine coupling constants¹⁶ and the calculated values¹⁷ for 7˙⁺ strongly supported this reasonable assumption (Fig. 2a). The reaction of 7·H⁺ with excess meta-chloroperbenzoic acid or stronger oxidants, such dibromine or potassium ferricyanate, led to over oxidation and directly afforded EPR-silent mixtures of trione 8 and the corresponding hydrated gem-diol 8·H₂O,¹⁸ likely through the formation and subsequent hydrolysis of electron-poor di(iminium)ketone 7²⁺.

Fig. 2 Experimental isotropic X-band EPR spectra in dichloromethane at room temperature (plain black line) of 7˙⁺ (a), 10˙⁺ (b) and a crude reaction mixture of m-CPBA and 1a (c). Simulated spectra (dashed blue line) were obtained with (a) a Lorentzian line-broadening parameter of 0.22 and the following set of hyperfine constants: a(¹⁴N) = 8.6 MHz (2 nuclei) and a(¹H) = 12.0 MHz (12 nuclei); (b) with a Lorentzian line-broadening parameter of 0.013 and the following set of hyperfine constants: a(¹⁴N) = 3.1 MHz (4 nuclei), a(¹H) = 6.5 MHz (12 nuclei) and a(¹H) = 0.86 MHz (4 nuclei); (c) with a Lorentzian line-broadening parameter of 0.37 and the following set of hyperfine constants: a(¹⁴N) = 7.8 MHz (2 nuclei), a(¹H) = 16.5 MHz (1 nucleus) and a(¹H) = 15.6 MHz (6 nuclei).

We turned to mono(methine)cyanine 9 featuring electron-richer benzimidazole patterns.¹⁹ However, the reaction of 9 with m-CPBA afforded known²⁰ 1,3-dimethyl- benzimidazolium 10, and not the expected di(benzimidazolium)ketone 13²⁺ (Scheme 2). Note that uncompleted, but clean, formation of 10 was still observed when adding sub-stoichiometric (one equivalent) m-CPBA over one hour at −78 °C. Importantly, dication 13²⁺ could be finally synthesized by the oxidation of di(imine)methane 11¹⁹ by m-CPBA, followed by di(alkylation) of the resulting di(imine)ketone 12. Given that 13²⁺ was found almost unreactive towards water, the formation of 10 from 9 results from further oxidative cleavages of 13²⁺, and not its hydrolysis.²¹ According to cyclic voltammetry experiments, 13²⁺ undergoes successive reductions at E_1/2 = −0.12 V vs. Fc/Fc⁺ (reversible) and E_pc = −0.9 V (with further chemical evolution), which we attributed to the formation of radical cation 13˙⁺ and zwitterionic oxyallyl 13, respectively (see ESI†). We performed the electrochemical reduction of a solution of 13²⁺ in acetonitrile at E = −0.5 V. The stoichiometry (one coulomb per mole of substrate), the observation of a strong EPR signal, as well as an excellent fit between experimental and theoretical hyperfine coupling constants, confirmed the formation of persistent 13˙⁺ (Fig. 2b), which ultimately decayed at room temperature after several hours.

The formation of di(imine)ketone 12 from 11 was so clean that it prompted us to explore further the direct oxidation of NacNac precursors. To our delight, treatment of 1a²² afforded 2a in 98% yield. In contrast with the former long and tedious syntheses from literature, the one-step reaction was completed after one hour at room temperature on multigram scales. EPR monitoring of the reaction showed the formation of a paramagnetic intermediate. Simulation of the hyperfine structure of the spectra required significant coupling with a single proton, in addition to two equivalent nitrogen atoms and six protons (Fig. 2c). This suggested the transient formation of N-protonated radical 1a·H˙⁺, parented to 4˙⁺, 7˙⁺ and 13˙⁺, thus implying closely related pathways for the m-CPBA oxidation of vinamidiniums and vinamidine 1a.

The only few reported β-di(imine)ketones were derivatives of acetylacetone and ortho-substituted anilines. Apart from 1a, which can be stored for several days, they were described as unstable ligands, to be used as soon as synthesized.^6d We applied our protocole to vinamidine 1b²¹ with 2,4,6-trimethylaryl N-substituents and, indeed, the resulting ketone 2b decayed into a complex mixture within hours. Fast work-up allowed for its isolation in 75% yield (Scheme 3). However, even freshly crystalized 2b contained an impurity with similar NMR chemical shifts, except for a ¹³C NMR signal (quarternary carbon) at 94 ppm in place of the CO band of 2b at 194 ppm. Although the instability of 2b limited further investigations, drying crystals in vacuo in presence of P₂O₅ decreased the amount of impurity, allowing us to assign this latter to the corresponding hydrated gem-diol 2b·H₂0.^23,24

Scheme 3 One-step synthesis of α-keto-β-diimines 2a–d from vinamidines 1a–d.

Finally, we considered vinamidines 1c²⁵ and 1d,^4b,d with phenyl and di(methyl)amino R groups, respectively. The corresponding di(imine)ketones 2c,d, which are out of reach of previous methods, were isolated in 86–87% yield. They features similar key structural data (IR_ATR: ν = 1700 cm⁻¹; ¹³C NMR δ_CO = 194–191 ppm). Their structures were asserted by a structural X-ray diffraction study (Fig. 1). Importantly, in ketones 2c,d were found remarkably bench stable and have been stored for month with no noticeable degradation.

In conclusion, the synthesis and characterization of radicals 7˙⁺ and 13˙⁺ are further evidences that introducing 1,3-di(amino)oxyallyl patterns is a robust principle for the design of persistent radical cations. However, the outcome of the reaction of vinamidiniums with m-CPBA is too dependent of the substitution pattern to constitute a general route and over-oxidation is only manageable with extra electron-donating amino groups. In contrast, when applied to vinamidines, this protocol allows for a straightforward synthesis of α-keto-β-diimines. In addition to its simplicity, stable derivatives were isolated, with unprecedented bulky or electron-donating R groups. We are now evaluating these new ligands for nickel-initiated polymerization of ethylene.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This work was supported by the French National Agency for Research (ANR-14-CE06-0013-01 and ANR-17-ERC2-0015). University of Grenoble-Alpes contributed through ICMG Chemistry Nanobio Platform, the LabEx ARCANE (ANR-11-LABX-0003-01), the “Centre de Calcul Intensif en Chimie de Grenoble” and AGIR-POLE (grant for MT).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: ¹H and ¹³C spectra of all new compounds, computational and crystallographic (CCDC 1866491–1866494) details. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c8ra08220k

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