Electrochemical C-H phosphorylation of arenes in continuous flow suitable for late-stage functionalization

Aryl phosphorus compounds are valuable in medicinal chemistry, materials science, and catalysis. Traditional C–P bond formation via the Hirao reaction requires aryl halide prefunctionalization and metal catalysis. Direct C–H phosphorylation is attractive but existing approaches often depend on directing groups, transition-metal catalysis, or photochemical oxidation, and typically work best for electron-rich arenes or azoles. The need to oxidize arenes to radical cations and the moderate reactivity of neutral phosphorus radicals limit scope, and excess arene is often required. Prior electrochemical methods addressed subsets of substrates (electron-rich heteroarenes or directed systems), while electron-deficient arenes required metal catalysts and divided cell setups. Motivated by the higher reactivity observed upon protonation of aminyl radicals (forming aminium radical cations), the authors hypothesized that P-radical cations could enable non-directed C–H phosphorylation across broader arene electronics. They recognized challenges including the unknown reactivity of P-radical cations toward electron-deficient arenes and potential dimerization of phosphite radical cations. They proposed using continuous-flow electrochemistry to enhance generation and rapid trapping of P-radical cations via high surface-area-to-volume ratios and efficient mass transfer.

The work situates itself against: (1) metal-catalyzed, directing-group-assisted arene C–H phosphorylation (e.g., Pd-, Rh-catalyzed), which limit scope due to directing group requirements; (2) non-directed radical C–H phosphorylation via photoredox or transition-metal catalysis that typically favors electron-rich arenes/azoles due to arene radical cation formation and limited neutral P-radical reactivity; (3) electrochemical C–H phosphorylation of electron-rich substrates or directed systems; reactions of electron-deficient arenes previously required metal catalysis and divided cells. The authors cite extensive advances in organic electrochemistry and continuous-flow electrosynthesis as enabling technologies that improve sustainability, scalability, and selectivity. They also reference foundational studies on radical cations of phosphites and their dimerization, as well as the enhanced reactivity of protonated N-centered radicals, providing conceptual precedent for employing P-radical cations. This context underscores the need for a catalyst- and oxidant-free, broadly applicable, scalable C–H phosphorylation method.

Reactions were performed in an undivided continuous-flow electrochemical cell equipped with a graphite anode and a platinum cathode, with a fluorinated ethylene propylene (FEP) spacer defining a 0.25 mm interelectrode gap and 10 cm² electrode surface area. Standard conditions for the model system (benzoate 1 with triethyl phosphite P(OEt)3) employed MeCN as solvent with arene (0.05 M; 1 equiv), P(OEt)3 (5 equiv), HBF4·Et2O (2 equiv), and H2O (2 equiv). The solution was pumped at 0.2 mL min−1 at room temperature under constant current (45–55 mA; typical charge 3.4 F mol−1), giving a calculated residence time tR ≈ 75 s. Effluent (4 mL) was collected after stabilization, quenched with saturated NaHCO3, extracted with EtOAc, concentrated, and purified by silica gel chromatography. Optimization showed HBF4 and H2O were essential; alternative acids (TFA, AcOH, TfOH) or Lewis acid Sc(OTf)3 were ineffective or gave low yields. P(OEt)3 loading was critical (5 equiv optimal); 7 equiv reduced yield (likely due to self-trapping of the P-radical cation), 3 equiv was ineffective; replacing P(OEt)3 with HPO(OEt)2 gave no product. Batch electrolysis under analogous charge conditions gave substantially lower yield. Scope studies used the standard flow conditions across a range of arenes (electron-rich to electron-deficient), heteroarenes (thiophenes), trialkyl phosphites (varying alkyl chains), and complex molecules for late-stage functionalization. Scale-up/continuous production was demonstrated using two parallel flow cells, in-line mixing of mesitylene/P(OEt)3 stream with HBF4/H2O stream in MeCN, operating continuously for 231 h. Product derivatizations included hydrolysis of phosphonate to phosphonic acid (TMSBr), conversion to phosphonochloridate (SOCl2/DMF, reflux), and subsequent substitutions (PhMgBr; amines/diols) to access phosphinates, phosphonamidates, mixed phosphonates, triarylphosphine oxide, and P-heterocycles. Mechanistic probes included cyclic voltammetry (vs SCE), 31P NMR analyses under varying water/HPO(OEt)2 conditions, crossover with HPO(OnBu)2, 18O-labeling with H2 18O, and a KIE competition (benzene vs benzene-d6).

- Developed a catalyst- and external oxidant-free electrochemical C–H phosphorylation of arenes using trialkyl phosphites in continuous flow, proceeding via anodically generated P-radical cations. - Optimization (flow cell, MeCN, rt, 45–55 mA, 0.2 mL min−1, 3.4 F mol−1): model benzoate 1 + P(OEt)3 (5 equiv) + HBF4 (2 equiv) + H2O (2 equiv) afforded phosphonate 2 in up to 78% 1H NMR yield (70% isolated). Key control data (Table 1): • No HBF4: 0% product (85% 1 recovered). • No H2O: 0% product (72% 1 recovered). • 7 equiv P(OEt)3: 18% (70% 1 recovered). • 3 equiv P(OEt)3: 0% (83% 1 recovered). • HPO(OEt)2 instead of P(OEt)3: 0% (90% 1 recovered). • TFA or AcOH instead of HBF4: 0% (90% 1 recovered each). • TfOH: 30% (50% 1 recovered). • Sc(OTf)3: 0% (80% 1 recovered). • Batch electrolysis: 36% (52% 1 recovered). - Scope: Broad across arenes of diverse electronic properties, including electron-deficient substrates (e.g., dimethyl terephthalate 4, 26%; dimethyl phthalate 5, 42% with C1:C2 = 1:1). Highest yields up to 94% (20). Regioselectivity analogous to Friedel–Crafts (ortho/para to electron-donating groups unless hindered). 2-Substituted thiophenes functionalized at the 4-position (29, 62%; 30, 70%). Trialkyl phosphites with varied primary alkyl chains gave 31–36 in 45–77% yields. - Late-stage functionalization: Diverse complex molecules (natural products and drugs) delivered phosphonates in 37–90% yields with defined regioisomer ratios (e.g., 42 from ibuprofen, 90%, C1:C2 = 2.4:1; 44 from epiandrosterone, 83%, C1:C2 = 3.4:1; 46 from celecoxib, 67%, C1:C2 = 1.7:1). X-ray structure of major isomer of 44 (CCDC 2079646). - Continuous production: Two parallel flow cells operated 231 h with in-line mixing furnished 55.0 g (214 mmol) mesitylphosphonate 27 in 83% isolated yield, exceeding small-scale yield (70%), indicating stable reactor performance without passivation/blockage. Improved yield attributed to in situ mixing minimizing acid-promoted decomposition of P(OEt)3. - Product transformations: 27 hydrolyzed to phosphonic acid 47 (79%); conversion to phosphonochloridate enabled synthesis of phosphinate 48 (72%), phosphonamidate 49 (63%), mixed phosphonate 50 (82%), triarylphosphine oxide 51 (80%), and P-heterocycles 52–54 (67–78%). - Mechanistic insights: CV shows P(OEt)3 is easiest to oxidize (Ep/2 = 1.50 V vs SCE). 31P NMR indicates P(OEt)3 decomposes without H2O; with water or catalytic HPO(OEt)2, cleaner spectra with 2, HPO(OEt)2, and OP(OEt)3 observed; adding 0.2 equiv HPO(OEt)2 restored high yield (79%). Crossover with HPO(OnBu)2 gave 2 (51%) with only trace of mixed product 55, and no 18O incorporation from H2 18O into 2, indicating PO(OR)2 originates from P(OR)3. KIE = 1.0 (benzene vs benzene-d6) suggests C–H cleavage is not rate-limiting. Proposed mechanism: anodic oxidation of P(OR)3 to P-radical cation, addition to arene, further oxidation and deprotonation to phosphonium, then alkyl loss to nucleophiles; H2 evolution at Pt cathode; HBF4 serves as acid/supporting electrolyte and suppresses undesired cathodic reductions; HPO(OR)2 likely forms a reversible adduct with the radical cation, stabilizing it against decomposition.

The study demonstrates that anodically generated P-radical cations can be harnessed for non-directed arene C–H phosphorylation across a wide electronic spectrum, addressing the longstanding limitation of radical-based methods that favor only electron-rich substrates. The continuous-flow setup enhances radical cation generation and immediate trapping due to efficient mass transfer and short residence time, overcoming issues like dimerization/decomposition. The essential roles of HBF4 and H2O are multifold: promoting controlled hydrolysis to HPO(OR)2, providing conductivity and a proton source for selective H2 evolution at the cathode, and avoiding reduction of reactive intermediates. Mechanistic experiments support oxidation of P(OEt)3 as the initiating step, exclusion of product oxygen incorporation from water, and a non-rate-limiting C–H cleavage. Collectively, the findings validate the hypothesis that P-radical cations are sufficiently reactive to engage even electron-deficient arenes under mild, catalyst-free electrochemical conditions, enabling late-stage functionalization and scalable production.

A catalyst- and external oxidant-free continuous-flow electrochemical method achieves direct C–H phosphorylation of arenes using trialkyl phosphites. The approach exhibits broad substrate scope, good functional group tolerance, regioselectivity consistent with electrophilic aromatic substitution patterns, and compatibility with complex molecules for late-stage diversification. Continuous operation furnished 55.0 g of a phosphonate product with sustained performance, highlighting practical scalability. Mechanistic studies support a pathway via anodic generation of P-radical cations, arene addition, and subsequent oxidation/deprotonation to phosphonium species. Future research could explore expanding nucleophile types derived from phosphites, asymmetric variants, integration with other flow-unit operations, alternative electrolytes/acids to further tune selectivity, and extension to heteroarenes and polyfunctional pharmaceuticals with precise site selectivity.

- The method requires acidic conditions (HBF4) and added water; alternative acids were ineffective or low-yielding, indicating limited flexibility in acid choice. - Excess phosphite (typically 5 equiv) is needed; lower or higher loadings reduce efficiency (self-trapping or insufficient radical cation concentration). - Batch conditions deliver substantially lower yields than flow, implying dependence on flow hardware for optimal outcomes. - Some electron-deficient substrates give modest yields and/or mixtures of regioisomers, necessitating chromatographic separation in certain cases. - The scope is demonstrated primarily with trialkyl phosphites; H-phosphonates do not substitute directly under standard conditions. - Regioselectivity follows electronic control but can be tempered by sterics; multiple isomers are sometimes formed.