Mechanism and Selectivity of N-Triflylphosphoramide Catalyzed (3⁺ + 2) Cycloaddition between Hydrazones and Alkenes

Abstract

Brønsted acid catalyzed (3(+) + 2) cycloadditions between hydrazones and alkenes provide a general approach to pyrazolidines. The acidity of the Brønsted acid is crucial for the catalytic efficiency: the less acidic phosphoric acids are ineffective, while highly acidic chiral N-triflylphosphoramides are very efficient and can promote highly enantioselective cycloadditions. The mechanism and origins of catalytic efficiencies and selectivities of these reactions have been explored with density functional theory (M06-2X) calculations. Protonation of hydrazones by N-triflylphosphoramide produces hydrazonium-phosphoramide anion complexes. These ion-pair complexes are very reactive in (3(+) + 2) cycloadditions with alkenes, producing pyrazolidine products. Alternative 1,3-dipolar (3 + 2) cycloadditions with the analogous azomethine imines are much less favorable due to the endergonic isomerization of hydrazone to azomethine imine. With N-triflylphosphoramide catalyst, only a small distortion of the ion-pair complex is required to achieve its geometry in the (3(+) + 2) cycloaddition transition state. In contrast, the weak phosphoric acid does not protonate the hydrazone, and only a hydrogen-bonded complex is formed. Larger distortion energy is required for the hydrogen-bonded complex to achieve the "ion-pair" geometry in the cycloaddition transition state, and a significant barrier is found. On the basis of this mechanism, we have explained the origins of enantioselectivities when a chiral N-triflylphosphoramide catalyst is employed. We also report the experimental studies that extend the substrate scope of alkenes to ethyl vinyl ethers and thioethers.

Brønsted Acid Catalyzed Asymmetric Hydroamination of Alkenes: Synthesis of Pyrrolidines Bearing a Tetrasubstituted Carbon Stereocenter

“…[4j, 13,14] Thea bsolute configuration of 2q was determined to be S by X-ray crystallographic analysis ( Figure S1), [15] which is in accordance with the configuration predicted based on Simon and Goodmans model. [14] Furthermore, the lack of reactivity observed with methyl-protected thiourea derivative 1x,b enzoyl amide 1y,a nd tosyl amide 1z (Scheme 2a nd Scheme S2) clearly indicates that the thiourea plays ac rucial role in determining the asymmetric induction:B oth acidic NÀHb onds are thus involved in cooperative hydrogen bonding interactions with the catalyst and the double bond.…”

“…To improve the reactivity and stereoselectivity,weturned our attention to the more acidic N-triflyl phosphoramides B1 and B2 (entries 2and 3), which were first reported by Yamamoto and Nakashima. [12] As expected, in the presence of either of these catalysts,t he reaction was remarkably accelerated to provide 2a in nearly quantitative yield with up to 87 % ee.W e next resorted to Brønsted acids A2-A4,w hich feature as pirocyclicb ackbone [13] (entries 4-6). Among the catalysts screened, (R)-SPINOL-derived A2 gave both agood yield of 95 %and an excellent enantioselectivity of 94 % ee (entry 4).…”

1,3-Dipolar cycloadditions of azomethine imines

“…The corresponding cis-pyrazolidines 24 (XR 2 = OEt) were obtained in good yields and enantioselectivities (Scheme 14). 31 However, for the cycloaddition with ethyl vinyl thioether 23 (XR 2 = SEt) the Spinol-derived N-triflylphosphoramide 35 was the best organocatalyst affording pyrazolidines 24 (XR 2 = SEt) in good yields, diastereo-and enantioselectivities. The mechanism of N-triflylphosphoramide-catalyzed asymmetric [3+2] cycloadditions was explored with DFT (MO6-2X) calculations.…”

“…The mechanism of N-triflylphosphoramide-catalyzed asymmetric [3+2] cycloadditions was explored with DFT (MO6-2X) calculations. 31 Protonation of hydrazones 20 by these Brønsted acids produces ion-pair complexes, which are more reactive than those formed from azomethine imines by 1,2-prototropy of the hydrazone through the transition state I (Scheme 15). These ionpairs hydrazonium-phosphoramide anions are reactive in [3 + +2] cycloadditions and only small distortion 32 of them are required in the transition state II giving in this case the cis-pyrazolidines 24.…”

Chiral Brønsted Acid‐Catalyzed Asymmetric Synthesis of N‐Aryl‐cis‐aziridine Carboxylate Esters

“…described a mechanism and origins of catalysis DFT and experimental study in which a similarly N ‐protonated, to 60 , reactive hydrazonium‐phosphoramide18 anion (not shown) was formed from a BINOL N ‐triflylphosphoramide and a hydrazone. Activation of 31 is crucial; the widely accepted aza‐Darzens mechanism19 invokes attack of a diazo nucleophile (i.e.…”