Dialkoxyphosphinyl-Substituted Enols of Carboxamides

Reactions of isocyanates XNCO (e.g., X = p-An, Ph, i-Pr) with (MeO)2P(O)CH2CO2R [R = Me, CF3CH2, (CF3)2CH] gave 15 formal “amides” (MeO)2P(O)CH(CO2R)CONHX (6/7), and with (CF3CH2O)2P(O)CH2CO2R [R = Me, CF3CH2] they gave eight analogous amide/enols 17/18. X-ray crystallography of two 6/7, R = (CF3)2CH systems revealed Z-enols of amides structures (MeO)2P(O)C(CO2CH(CF3)2)C(OH)NHX 7 where the OH is cis and hydrogen bonded to the OP(OMe)2 group. The solid phosphonates with R = Me, CF3CH2 have the amide 6 structure. The structures in solution were investigated by 1H, 13C, 19F, and 31P NMR spectra. They depend strongly on the substituent R and the solvent and slightly on the N-substituent X. All systems displayed signals for the amide and the E- and Z-isomers. The low-field two δ(OH) and two δ(NH) values served as a probe for the stereochemistry of the enols. The lower field δ(OH) is not always that for the more abundant enol. The % enol, presented as Kenol, was determined by 1H, 19F, and 31P NMR spectra, increases according to the order for R, Me < CF3CH2 < (CF3)2CH, and decreases according to the order of solvents, CCl4 > CDCl3 ∼ THF-d8 > CD3CN >DMSO-d6. In DMSO-d6, the product is mostly only the amide, but a few enols with fluorinated ester groups were observed. The Z-isomers are more stable for all the enols 7 with E/Z ratios of 0.31−0.75, 0.15−0.33, and 0.047−0.16 when R = Me, CF3CH2, and (CF3)2CH, respectively, and for compounds 18, R = Me, whereas the E-isomers are more stable than the Z-isomers. Comparison with systems where the OP(OMe)2 is replaced by a CO2R shows mostly higher Kenol values for the OP(OMe)2-substituted systems. A linear correlation exists between δ(OH)[Z-enols] activated by two ester groups and δ(OH)[E-enols] activated by phosphonate and ester groups. Compounds (MeO)2P(O)CH(CN)CONHX show ≤7.3% enol in CDCl3 solution. For [(MeO)2P(O)]2CHCONHX, activated by two OP(OMe)2 groups, only the amides were observed in solution and in the solid. DFT calculations reproduce the general effect of R on Kenol, but the correlation between observed and calculated Kenol values is not linear. The roles of electron withdrawal by the activating phosphonate and ester groups, and the importance of N−H and O−H hydrogen bonding to them in stabilizing the enols are discussed.异氰酸酯XNCO（例如X为对甲氧基苯基（p-An）、苯基（Ph）、异丙基（i-Pr)）与(MeO)₂P(=O)CH₂CO₂R[R为甲基（Me）、三氟乙基（CF₃CH₂）、1,1,1,3,3,3-六氟异丙基（(CF₃)₂CH）]反应，得到15种形式上为"酰胺"的化合物(MeO)₂P(=O)CH(CO₂R)CONHX（6/7）；而与(CF₃CH₂O)₂P(=O)CH₂CO₂R[R为Me、CF₃CH₂]反应则生成8种类似的酰胺/烯醇异构体17/18。对两种R=(CF₃)₂CH的6/7类化合物进行X射线晶体学（X-ray crystallography）分析，结果显示其结构为酰胺的Z型烯醇(MeO)₂P(=O)C(CO₂CH(CF₃)₂)=C(OH)NHX（7），其中羟基（OH）处于顺式构型，并与O=P(OMe)₂基团形成氢键。固态下，R为Me、CF₃CH₂的膦酸酯类化合物以酰胺6的结构存在。通过¹H、¹³C、¹⁹F和³¹P核磁共振光谱（NMR）对溶液中的化合物结构进行了研究，其结构强烈依赖于取代基R与溶剂，仅轻微受N取代基X的影响。所有体系均出现了酰胺以及E型和Z型异构体的信号。低场区域的两个δ(OH)与两个δ(NH)化学位移可作为烯醇立体化学的探针。场强更低的δ(OH)并不总是对应含量更高的烯醇。以Kenol表示的烯醇百分含量通过¹H、¹⁹F和³¹P NMR光谱测定，其随R的变化顺序为Me < CF₃CH₂ < (CF₃)₂CH（含量依次升高），随溶剂的变化顺序为CCl₄ > CDCl₃ ≈ THF-d₈ > CD₃CN > DMSO-d₆（含量依次降低）。在DMSO-d₆中，产物几乎仅以酰胺形式存在，仅观察到少量带有氟化酯基的烯醇。对于所有7类烯醇，Z型异构体更稳定：当R分别为Me、CF₃CH₂、(CF₃)₂CH时，其E/Z比值依次为0.31~0.75、0.15~0.33和0.047~0.16；对于R=Me的18类化合物，同样Z型异构体更稳定，而其余体系则E型异构体稳定性优于Z型。将O=P(OMe)₂基团替换为CO₂R的体系进行对比，结果显示O=P(OMe)₂取代的体系的Kenol值普遍更高。在由两个酯基活化的Z型烯醇的δ(OH)与由膦酸酯和酯基共同活化的E型烯醇的δ(OH)之间存在线性相关性。化合物(MeO)₂P(=O)CH(CN)CONHX在CDCl₃溶液中的烯醇含量≤7.3%。对于[(MeO)₂P(=O)]₂CHCONHX，其由两个O=P(OMe)₂基团活化，在溶液和固态中均仅观察到酰胺结构。密度泛函理论（Density Functional Theory, DFT）计算重现了R对Kenol值的整体影响趋势，但实测与计算得到的Kenol值之间并不存在线性相关性。本文讨论了活化基团膦酸酯与酯基的吸电子作用，以及N-H和O-H氢键与这些基团的相互作用在稳定烯醇结构中的重要性。