Strategic Utilization of Multifunctional Carbene for Direct Synthesis of Carboxylic–Phosphinic Mixed Anhydride from CO₂

Mixed anhydrides comprising carboxylic and phosphinic acids are frequently employed for the preparation of carbonyl compounds such as carbamates and peptides.¹ In particular, mixed anhydrides could be of great utility in organic synthesis when three conditions exist: when the compounds are stable towards thermal disproportionation, when they can be reacted with external nucleophiles specifically at the carbon center of the carbonyl moiety, and when they are isolable as shelf-stable solids.^1d These anhydrides are prepared in the presence of a suitable base by either the reaction of a carboxylic acid with a phosphinic chloride or the reaction of an activated carboxylic acid derivative with a phosphinic acid; however, the concomitant production of a significant amount of salt is inevitable. Furthermore, carboxylic acid derivatives can be prepared from carbon dioxide.² Thus, the direct synthesis of carboxylic–phosphinic mixed anhydrides from carbon dioxide is attractive from the aspects of step- and atom-economy.³

Recently, we reported the synthesis of N-phosphine oxide-substituted imidazolylidenes (PoxIms) as a novel class of isolable N-heterocyclic carbenes (NHCs) (Scheme 1).^{4, 5} PoxIms are equipped with two distinct Lewis bases, phosphine oxide and carbene, that led to the formation of either classical phosphine oxide–borane at −90 °C or carbene–borane adducts at room temperature (Scheme 1 a). The later adduct was used as a precursor for frustrated Lewis pairs⁶ comprising carbene and borane.⁴ On the other hand, the phosphine oxide moiety can also function as an electrophile (Scheme 1 b). Given this intriguing multifunctionality, we envisioned that the reaction of PoxIms with carbon dioxide could give an imidazolium-2-carboxylate followed by the nucleophilic addition of the carboxylate to the phosphine oxide to directly yield a novel type of carboxylic–phosphinic mixed anhydride. The formation of imidazolium-2-carboxylates by the reaction of NHCs and carbon dioxide was studied extensively.⁷ Furthermore, the imidazole moiety in the expected mixed anhydride can be easily transformed into an imidazolium moiety, which can be applied to the preparation of a variety of carbonyl compounds via dual substitution processes. Herein, we describe the use of strategically designed multifunctional carbenes as powerful tools for carbon dioxide transformation.

Treatment of PoxIm 1 a with carbon dioxide (5 atm) in toluene resulted in the formation of mixed anhydride 2 a, which was isolated in >99 % yield (Scheme 2). This reaction also proceeded quantitatively under 1 atm of carbon dioxide. The molecular structure of 2 a was identified by NMR spectroscopy and X-ray crystallography (Figure S6 in the Supporting Information), clearly showing the fixation of carbon dioxide and a migration of the phosphine oxide moiety to the carboxylic portion.⁸ In the ¹³C NMR spectrum, the resonances of C1 and C2 are observed at δ_C 137.8 (²J_C,P=4.0 Hz) and 153.0 ppm (³J_C,P=10.0 Hz), respectively, both of which appeared with the simultaneous disappearance of the resonance of the carbene carbon (δ_C 221.6 ppm, ²J_C,P=26.0 Hz). In the ³¹P NMR spectrum, the resonance of the phosphinate moiety is observed at δ_P 69.2 ppm, following a downfield shift via the migration of the phosphorus center (1 a: δ_P 61.4 ppm). PoxIms 1 b–e also reacted with carbon dioxide to give the corresponding mixed anhydride 2 b–e, all of which were isolated as solids in excellent yields. The isolated solids of 2 b–e can be stored in the presence of air and moisture (20–30 °C, 30–50 % humidity) for at least 2 days without significant decomposition. Furthermore, no disproportionation was observed under ambient conditions in C₆D₆ for at least 21 days, which was confirmed using 2 b. Thus, these mixed anhydrides are ideal reagents for transfer of the carbonyl group. In fact, 2 b was converted into N-isopropyl imidazole derivatives efficiently (see the Supporting Information for details). N-Phosphine oxide-substituted imidazolinylidene (SPoxIm) 1 f gradually reacted with carbon dioxide at room temperature to afford 2 f in 76 % yield after 11 h. Heating promoted the reaction, and afforded 2 f in >99 % yield after 1 h at 80 °C.

PoxIm 1 g containing bis-N-phosphine oxide groups did not react with carbon dioxide under the ambient conditions, although 1 g was totally consumed in toluene at 80 °C after 1 h (Scheme 3). The quantitative formation of 2 g was confirmed when the product was dissolved in CD₃CN at 22 °C; however, a mixture of 2 g and 2 g′ was given in yields of 58 and 42 %, respectively, after changing the solvent from CD₃CN to C₆D₆ (Figure S8–S10). The formation of 2 g′, which was generated via the intermolecular addition of imidazole nitrogen to N-phosphine oxide in another 2 g, was expected according to NMR analyses in C₆D₆ (showing the resonances attributed to the imidazolium moiety) as well as to ESI-MS analysis (2 g′ of n=2 was detected).⁸ Replacement of the solvent from C₆D₆ to CD₃CN again afforded 2 g as the sole product in >99 yield, which indicates that the intermolecular addition giving 2 g′ is reversible. Treatment of a mixture of 2 g and 2 g′ in C₆D₆ with B(C₆F₅)₃ (1.0 equiv) resulted in the quantitative formation of 2 g⋅B(C₆F₅)₃ as a sole product (Scheme 3), which also shows that the imidazole nitrogen in 2 g would be key for the generation of 2 g′.

The formation of an imidazolium-2-carboxylate intermediate (A) was confirmed in CD₂Cl₂ at −90 °C when the reaction of 1 b with carbon dioxide (1 atm) was monitored by NMR spectroscopy (Scheme 4). A 16 % yield of 2 b was also detected when the reaction mixture was cooled to −90 °C in the NMR apparatus. An anti-orientation is proposed for the phosphine oxide moiety against the C1−C2 bond based on the results of theoretical studies (see below). The conversion of A into 2 b was observed even at 0 °C, and the quantitative formation of 2 b was confirmed when the reaction mixture was allowed to warm to room temperature, suggesting the rate-limiting step includes an irreversible transformation from A to 2 b.

Plausible reaction mechanisms are further evaluated by DFT calculation at the B3LYP/6-31G+(d) level of theory (in toluene, at 25 °C, Figure 1 a), and 2 c was employed as a model substrate.⁸ Two conformers, aPxm and sPxm, are found depending on the orientation of the phosphine oxide moiety with respect to the lone pair of the carbene. The relative energy of sPxm is higher than that of aPxm by +5.5 kcal mol⁻¹. The theoretical activation energy of the rotation of the phosphine oxide is +12.5 kcal mol⁻¹, indicating its facile occurrence at 25 °C.⁴ While it was difficult to form the classical carbene–borane adduct using B(C₆F₅)₃ and the anti-conformer PoxIm with N-aryl groups due to the steric repulsion between them, the formation of aPxm-CO₂ (+5.2 kcal mol⁻¹) by the reaction of aPxm with CO₂ is expected to proceed more easily than the formation of sPxm-CO₂ (+10.8 kcal mol⁻¹). The latter takes place via the transformation of aPxm to sPxm followed by the reaction with CO₂. TS_2b (+15.7 kcal mol⁻¹) is a more stable activation complex than TS_2a (+19.8 kcal mol⁻¹). The optimized structure of TS_2b is given in Figure 1 b, where the carbene is approaching CO₂ (C1⋅⋅⋅C2=2.210 Å) and the angle between the planes of the imidazolylidene ring and CO₂ is out of perpendicular (67.5°). A similar plane angle of 71.4° is observed in the optimized structure of aPxm-CO₂ (Figure 1 c), which is significantly smaller than the corresponding plane angle of 89.0° found in the IPr–CO₂ adduct,^7c but larger than the angles in the imidazolium-2-carboxylate with bis-N-methyl groups (29.1°).^7b The bond length of C1−C2 in aPxm-CO₂ is 1.550 Å, which is comparable with those found in other reported NHC–CO₂ adducts showing experimental results of 1.52–1.54 Å.⁷ A slight elongation of the C1−C2 bond and an increment of the plane angle are found in sPxm-CO₂ (1.557 Å and 86.6°, Figure 1 e) compared with those in aPxm-CO₂. Although the formation of sPxm-CO₂ might also be possible under the reaction conditions, sPxm-CO₂ is expected to undergo rapid decarboxylation and eventually give aPxm-CO₂. A direct transformation of aPxm-CO₂ to sPxm-CO₂ via TS₃ (+25.2 kcal mol⁻¹) would hardly occur since the theoretical activation barrier for this step is much larger than that for the migration of the phosphine oxide to give mxd ahd via TS_4b (+21.0 kcal mol⁻¹). Theoretical prediction for the formation of TS_4b suggests that cleavage of the imidazolium–phosphine oxide bond (N2−P) and formation of the carboxylate–phosphine oxide bond (O2−P) occur in a concerted manner.⁹ The plane angle between the imidazolium and the carboxylate moieties in TS_4b becomes 5.0° with interatomic distances of N2⋅⋅⋅P and P⋅⋅⋅O2 of 2.144 and 2.045 Å, respectively (Figure 1 d). The P atom adopts a distorted trigonal bipyramidal geometry with O2 and O3 atoms at the axial position. These calculation results are consistent with experimental observation, which means that the pathways affording mxd ahd via TS_4b, in which overall activation energy is +21.0 kcal mol⁻¹, are thus likely.

Treatment of 2 b (3.40 g, 10.82 mmol) with an equimolar amount of MeOTf in CH₂Cl₂ (5 mL) gave imidazolium salt 3 b (5.17 g, 10.81 mmol), which was isolated in 99 % yield as a shelf-stable solid under a dried nitrogen atmosphere (Scheme 5 a). The two potential leaving groups in 3 b are the imidazolium and the phosphinate moieties, which makes it a useful synthetic precursor for a variety of carbonyl compounds. In fact, dual substitution reactions of 3 b with two different nucleophiles in a one-pot manner gave ester 5 (1^st; ZnAr₂: 2^nd; MeOH) and amide 6 (1^st; ZnAr₂: 2^nd; CyNH₂) in excellent yields, where Ar is p-OMeC₆H₄ (Scheme 5 b). In situ formation of 4 b and the zinc phosphinate salt by the reaction of 3 b and ZnAr₂ (1.0 equiv) was directly observed by NMR analyses (Figures S17, S18). Furthermore, 3 b was utilized as a novel precursor for the preparation of unsymmetrical ketones (Scheme 5 c). Efficient synthetic method for unsymmetrical ketones is particularly of high utility when it can be carried out in a one-pot and straightforward manner.¹⁰ The reaction of 4 b generated in situ with NaCH₂NO₂ and NaCH(CO₂Et)₂ in DMF afforded unsymmetrical ketones 7 and 8 in 90 and 93 % isolated yield, respectively.¹¹ Synthesis of unsymmetrical diaryl ketone was also examined to give 9 in 36 % isolated yield by utilizing two equivalents of ZnAr₂ at the second substitution step. It should be noted that the present synthetic method for unsymmetrical ketones was conducted at mild temperature without tedious experimental procedures such as strict regulation of the reaction temperature and the concentration of nucleophiles. Thus, preliminary results shown herein ensure the promising reactivity of 3 b as a precursor for unsymmetrical ketones. The key for these dual substitution is utilizing arylzinc nucleophiles in the first substitution step in order to avoid an overreaction yielding a ketone and/or a tertiary alcohol given by aryl lithium and magnesium reagents.⁸

A one-pot transformation of CO₂ proceeding via key intermediate 3 b was conducted to afford 8 in 75 % isolated yield (Scheme 6), which also manifests this straightforward transformation processes of carbon dioxide toward unsymmetrical ketones.

In summary, a synthetic route affording a novel carboxylic–phosphinic mixed anhydride directly from carbon dioxide has been achieved by using N-phosphine oxide substituted imidazolylidenes (PoxIms). The obtained carboxylic–phosphinic mixed anhydrides were utilized in the preparation of a variety of carbonyl compounds. A thorough one-pot transformation of CO₂ into an unsymmetrical ketone is also demonstrated. Remarkably, PoxIm played dual key roles. It was nucleophile in the activation of carbon dioxide, and it also acted as an electrophile to transfer the phosphine oxide moiety to the carboxylic portion. The present work shows that strategically designed multifunctional carbene reagents offer a novel utility for carbon dioxide in organic synthesis.