Palladium‐catalyzed Asymmetric 1,4‐Addition of Diarylphosphines to α,β‐Unsaturated Carboxylic Esters

Abstract

Chiral phosphorus compounds have widespread utility not only as coordinating ligands for transition metals, but also as organocatalysts in asymmetric reactions. [1] Conventionally, the synthesis of phosphorus compounds starts from enantiopure materials or entails the optical resolution of racemates with chiral reagents. Recently, methods that involve asymmetric catalysis have appeared and are efficient for synthesizing chiral phosphorus compounds. [2,3] Among such methods, the asymmetric phosphorus-Michael addition to electron-deficient alkenes is a direct route to furnish chiral phosphorus molecules. [4] Successful examples with a,b-unsaturated carbonyl compounds, including enones, enals, nitro alkenes, and N-acylpyrroles, with secondary phosphines, phosphine oxides, and phosphinates as nucleophiles have been reported. [5][6][7][8] However, the readily available substrates a,b-unsaturated carboxylic esters have not yet been used as electrophilic components. [9] Herein, we describe an asymmetric Michael addition of diarylphosphines to a,b-unsaturated carboxylic esters catalyzed by a bis(phosphine) (PCP) pincer-Pd complex to afford chiral phosphine derivatives with good yields and excellent enantioselectivity.We began with the addition reaction of diphenylphosphine to 4-chloro-trans-cinnamic acid methyl ester (1 a, Table 1) in the presence of chiral PCP-PdOAc ((S,S)-4) [5a, 10, 11] as the catalyst. To facilitate purification, H 2 O 2 was added as the oxidant and the product was isolated as the phosphine oxide because the trivalent phosphine atom is oxygen sensitive. However, 1 a did not react (Table 1, entry 1), which may be a result of its inherent low electrophilicity compared with similar enone substrates. We assumed that changing the methyl group of the ester to a stronger electron-withdrawing group may increase its reactivity toward the phosphorus-addition reaction. Thus, trans-cinnamic acid trifluoroethyl ester (1 b) was prepared and tested under the same conditions. The reaction proceeded with 52 % yield and 96 % ee (Table 1, entry 2). The use of t-amyl alcohol as the solvent increased the substrate conversion and an 88 % yield of the adduct was isolated with 91 % ee (Table 1, entry 3). The more electrophilic 6fluoro-isopropyl ester of cinnamic acid was examined and the reaction gave the product with full conversion and 95 % ee (Table 1, entry 4). [12] Changing the solvent to toluene and lowering the temperature to À70 8C finally increased the ee value of the product to 98 % (Table 1, entry 7). Alternatively, the phenyl ester of cinnamic acid was also a suitable substrate for this reaction; the 1,4adduct was isolated with 99 % ee at room temperature (Table 1, entry 8).With the optimum conditions in hand, different substrates were examined and the results are shown in Table 2. Various electron-rich and electron-deficient substituted cinnamic acid aryl esters were treated with diphenylphosphine to provide the corresponding phosphination products in 92-99 % yield and 97-99 % ee (Table 2, entries 1-6). Substr...

Pd‐Catalyzed Enantiodivergent and Regiospecific phospha‐Michael Addition of Diphenylphosphine to 4‐oxo‐Enamides: Efficient Access to Chiral Phosphinocarboxamides and Their Analogues

“…We began our studies with the catalytic AHP of 1 a , as well as its corresponding carboxylic acid 2 and ester 3 counterparts, in the presence of a palladacycle catalyst ( R )‐ 4 ; the organometallic compound 4 and its amino analogue 5 have proven to be versatile and efficient promoters/catalysts in an assortment of reactions 14. 15, 16b, 18, 20 It was disappointing to find that substrate 2 was inert to nucleophilic attack, and although the reaction of compound 3 was regiospecific, it gave racemic adducts even when the reaction was conducted at reduced temperatures. Considering that the electronic properties of compound 1 are substantially different from derivatives 2 and 3 , we proceeded with the screening of 1 in the hope of achieving our desired objectives.…”

“…Catalytic AHP methodologies are superior as they epitomize fundamental principles of green chemistry, especially regarding atom economy and derivative reduction 12. Accordingly, in recent years, momentum has been gained in uncovering the classes of substrates that are suitable for AHP reactions, which include unsaturated aldehydes,13 ketones,14 imines,15 esters,16 nitroalkenes17, and vinyl heterocycles18 as favorable acceptors.…”

Recent Progress in Palladium-Catalyzed Asymmetric Hydrophos­phination

“…29 The PCP pincer system of Duan and co-workers proved its efficacy for the hydrophosphination of α,β-unsaturated carboxylic esters. 36 During initial attempts with methyl trans-4-chlorocinnamate, no reaction was obtained due to the low electrophilicity of the substrate. However, changing the methyl group of the ester to a more electron-withdrawing trifluoroethyl moiety rectified the problem.…”

An Approach to the Efficient Syntheses of Chiral Phosphino‐ Carboxylic Acid Esters

“…However, reports on the direct catalytic asymmetric hydrophosphination of α,β‐unsaturated mono esters and amides are scarce, notably due to poor activation at the electrophilic site 7. To the best of our knowledge, only 2 known reports have been published in recent years on their preparation,9b,14 with substituents bound to both O and N atoms being predominantly electron‐withdrawing moieties. To overcome this severe limitation, we envisioned developing a substrate bearing a sufficiently activating analogue bound to the enoyl moiety, while concurrently functioning as an efficient leaving group to be displaced by strong nucleophiles after the hydrophosphination reaction (Scheme ).…”