Aryloxide‐Facilitated Catalyst Turnover in Enantioselective α,β‐Unsaturated Acyl Ammonium Catalysis

Abstract A new general concept for α,β‐unsaturated acyl ammonium catalysis is reported that uses p‐nitrophenoxide release from an α,β‐unsaturated p‐nitrophenyl ester substrate to facilitate catalyst turnover. This method was used for the enantioselective isothiourea‐catalyzed Michael addition of nitroalkanes to α,β‐unsaturated p‐nitrophenyl esters in generally good yield and with excellent enantioselectivity (27 examples, up to 79 % yield, 99:1 er). Mechanistic studies identified rapid and reversible catalyst acylation by the α,β‐unsaturated p‐nitrophenyl ester, and a recently reported variable‐time normalization kinetic analysis method was used to delineate the complex reaction kinetics.

Abstract: An ew general concept for a,b-unsaturated acyl ammonium catalysis is reported that uses p-nitrophenoxide release from an a,b-unsaturated p-nitrophenyl ester substrate to facilitate catalyst turnover.T his method was used for the enantioselective isothiourea-catalyzed Michael addition of nitroalkanes to a,b-unsaturated p-nitrophenyl esters in generally good yield and with excellent enantioselectivity (27 examples,u pt o7 9% yield, 99:1 er). Mechanistic studies identified rapid and reversible catalyst acylation by the a,bunsaturated p-nitrophenyl ester,a nd ar ecently reported variable-time normalization kinetic analysis method was used to delineate the complex reaction kinetics.
Lewis base organocatalysis is aw idely studied field due to the diverse range of molecular frameworks that can be produced with high levels of regio-, chemo-and stereocontrol. [1] At the carboxylic acid oxidation level av ariety of ammonium intermediates with differing reactivity can be accessed from readily available substrates using tertiary amine Lewis bases (Scheme 1a). Acyl ammonium and ammonium enolate intermediates have been extensively studied and applied in enantioselective acyl transfer processes and formal cycloadditions,respectively. [2,3] Aless studied but equally powerful reactivity mode is that of a,b-unsaturated acyl ammonium intermediates. [4] These species contain electrophilic centres at the C1 and C3 positions,a nd al atent nucleophilic centre at C2, providing new opportunities for reaction design to target previously inaccessible product architectures. [5] Seminal work by Fu first demonstrated the feasibility of this concept in af ormal [3+ +2] cycloaddition using a,bunsaturated acyl fluorides as the a,b-unsaturated acyl ammonium precursor (Scheme 1b). [6] Recent studies from ourselves,R omo,a nd Matsubara, has built on this precedent to achieve highly enantioselective Michael addition-annulation, formal cycloaddition and complex cascade methodologies. [7] These examples used a,b-unsaturated acid anhydrides or halides as the a,b-unsaturated acyl ammonium precursors.In addition, these methodologies require the reactive partner to contain two distinct nucleophilic functionalities to 1) undergo conjugate addition to the a,b-unsaturated acyl ammonium intermediate,a nd 2) enable turnover of the Lewis base catalyst (Scheme 1b). This requirement inherently limits a,b-unsaturated acyl ammonium catalysis and must be overcome to allow more diverse processes.I na ddition only preliminary experimental mechanistic work has been undertaken, with no kinetic analysis reported to date. [8] Here we report the development of anew general concept for a,b-unsaturated acyl ammonium catalysis.C atalyst turnover is not facilitated by the nucleophilic reaction partner,but by an aryloxide counterion released in situ during the reaction by using an a,b-unsaturated aryl ester as the a,b-unsaturated acyl ammonium precursor (Scheme 1c). [9][10][11] This allows the use of simple nucleophiles as reaction partners,p roviding enhanced potential for further advancement of the field. Mechanistic work including kinetic analysis,catalyst labeling and crossover studies are also reported to deliver af undamental understanding of this process. Scheme 1. Nomenclature, reactivity and applicationsofammonium intermediates in catalysis.
As initial proof of concept, the Michael addition of nitroalkanes to a,b-unsaturated aryl esters using aLewis basic isothiourea catalyst was investigated. [12] Although the organocatalytic enantioselective Michael addition of nitroalkanes to enones or enals is well precedented, [13] Lewis base catalysis of this process has not been demonstrated at the carboxylic acid oxidation level.
Initial investigations focused on the reaction of arange of a,b-unsaturated aryl esters 1-4,bearing different aryl groups, with excess nitromethane using HyperBTM 5 as catalyst ( Table 1, entries 1-4). TheM ichael addition products 6-9 were formed in each case in moderate to excellent yield (48-81 %) but with uniformly high enantioselectivity (up to 96:4 er) and with complete regioselectivity. [14] Theh ighest yields were obtained using p-nitrophenyl (PNP) and 3,5bis(trifluoromethyl)phenyl esters 1 and 4,w ith PNP ester 1 chosen for further studies due to the higher enantioselectivity obtained. Mixed solvent systems proved ineffective, with lower yields obtained in the presence of both THF and MeCN (entries 5and 6). Theaddition of abase (2,6-lutidine) did not prove beneficial (entry 7), [15] whilst heating the reaction at 70 8 8Cr esulted in complete decomposition (entry 8). Alternative isothiourea catalysts did not provide improved results,a nd lower catalyst loadings resulted in incomplete conversion, which complicated product isolation. [16] Thes cope and limitations of the method was then investigated. Given the moderate isolated yields of PNP ester products,t he addition of as uitable nucleophile at the end of the reaction was used to give arange of readily isolable functionalized products (Table 2). Theu se of primary and secondary amines gave secondary and tertiary amides 10-14 in good yield, whilst addition of methanol gave methyl ester 15.A ll amide and ester products were obtained with high enantioselectivity indicating no significant loss in enantiopurity during the derivatization process.T he scope of bsubstituted a,b-unsaturated aryl esters amenable to the process was then investigated. Methyl-, isopropyl-and benzyl esters gave the addition products 16-18 in good yield and with excellent enantioselectivity.T he incorporation of amides at the b-position was also well tolerated, giving unsymmetrical succinamide derivatives 19 and 20 in equally high yield and levels of enantiocontrol. Thea bsolute configuration of 19 was confirmed by single crystal X-ray analysis, with all other examples assigned by analogy. [17] Limitations of this methodology include incompatibility of substrates such as g-keto ester derivative 22,w hich gave ac omplex mixture of products,a nd cinnamic acid derivative 23,w hich was completely unreactive.Aderivative bearing b-alkyl substitution however gave product 21 with excellent enantiocontrol, albeit in low yield. Thesynthesis of aquaternary stereogenic carbon centre was also attempted, however application of b,bdisubstituted derivative 24 failed to give the desired Michael addition product.
Thee ffect of olefin configuration was investigated using maleate PNP ester derivative 25 (Scheme 2). Interestingly,  [a] Isolated yields given;e rdetermined by chiral HPLC analysis.
the Michael addition product 12 was obtained in the same enantiomeric form (93:7 er) as when using the isomeric fumarate PNP ester 1 (95:5 er). Monitoring reaction progress by 1 HNMR spectroscopy revealed rapid isomerization of maleate 25 to fumarate PNP ester 1 on afaster timescale than formation of product, with control reactions in [D 6 ]DMSO indicating reversible aryloxide conjugate addition as ap ossible mechanism for this isomerization process. [16,18] Attention was next turned to the use of alternative nitroalkanes and subsequent derivatization of the products. Nitroethane and nitropropane were suitable nucleophiles giving addition products 26 and 27 in good yield. Although only minimal diastereocontrol was observed, both diastereoisomers were obtained with excellent enantioselectivity (99:1 er, Table 3). Pleasingly,t he use of 2-nitropropane and nitrocyclopentane was also successful, giving amide and ester products 28-31 in moderate yield but with excellent enantiocontrol.
Reduction of g-nitro methyl esters 15, 29 and 31 and subsequent cyclization was achieved with no loss in enantiopurity to give pyrrolidinone derivatives 32-34 in excellent yield and highly enantioenriched form (Table 4). [19] The biological importance of pyrrolidinones,and g-aminobutryric acid (GABA) derivatives in general, is well precedented. [20] To provide greater insight into this methodology,t he reaction mechanism and kinetics were investigated to identify reaction intermediates and determine the reaction order with respect to each component. Quantitative reaction monitoring was achieved by in situ 19 F{ 1 H} NMR spectroscopy using 19 Flabeled PNP ester 35 and (2R,3S)-8F-HyperBTM 36 in MeNO 2 using PhF as internal standard and aC 6 D 6 -filled capillary reference (Figure 1a,b). Attempts to interrogate the kinetic data revealed as ubstantial reduction in reaction rate over the course of the reaction, suggesting deactivation of the catalyst. During the reaction, the 19     Using an independently synthesized sample of 36·HCl as ar eference (d F = À116.72 ppm), the proportion of freebase isothiourea 36 in the reaction was calculated as afunction of its chemical shift (Figure 1b, ). [16,21] Low concentrations ( 0.4 mm)o fp roposed acyl isothiouronium species 38 (*)a nd 39 (~)were also identified by the downfield chemical shift of the isothiouronium fluorine label (d F = À111.79 and À111.97 ppm) (Figure 1a and b, inset). [10d] Addition of an isolated a,b-unsaturated acyl isothiouronium 38 (where X = Cl, d F = À111.81 ppm) [22] to areaction in progress resulted in significant enhancement of both signals,providing support for this assignment. In addition, mixing (2R,3S)-8F-HyperBTM 36 and Michael addition product 37 gave aminor species with d F = À111.97 ppm, consistent with nucleophilic addition of 36 to 37 to give the post-Michael addition acyl isothiouronium 39. [16] These studies are consistent with speciation of the isothiourea catalyst between at least four forms,w ith the dominant, resting state,the freebase isothiourea 36.
Having established amethod for quantifying the temporal concentration of reaction components,d etermination of the reaction order with respect to each component was sought.
Thec omplex catalyst speciation, in addition to slow hydrolysis of starting material over the reaction course,i ndicated that kinetic analysis may be challenging.H owever,a st he temporal concentrations of each component were easily measured, the innovative variable time normalization graphical analysis method reported recently by BurØsw as applied. [23] Kinetic analysis was performed for three reactions with different starting concentrations of a,b-unsaturated ester 35 and (2R,3S)-8F-HyperBTM 36 (Figure 1a), with the concentration of MeNO 2 assumed to remain constant (pseudo-zero order in MeNO 2 ). Ap lot of concentration of product 37 against an ormalized time axis of S[35] a [36] b Dt (where a and b represent the respective reaction orders of each component) allowed graphical interrogation of the kinetic profiles.S ystematically varying a and b provided optimal overlay for a = 1.0 and b = 1.0, indicating the reaction is first order in both ester substrate and catalyst. [16] Despite good overlay,t he curvature of the plot suggested an additional reaction variable had been omitted from the analysis. Further studies showed that addition of product 37 (10 mm)at the start of the reaction resulted in rate retardation, consistent with product inhibition. [16] Incorporation of [37] g into the normalized time axis (S[35] a [36] b [37] g Dt)r esulted in good overlay and linearity at an arbitrary value of g = À0.5 (Figure 1c).
Aseries of crossover reactions was used to investigate the reversibility of the primary catalytic steps (Scheme 3). Treatment of a,b-unsaturated esters 40 and 41 bearing two distinct PNP ester groups (2-fluoro and 3-fluoro) and two distinct bsubstituents (amide and ester) under catalytic conditions was monitored by in situ 19 F{ 1 H} NMR spectroscopy (Scheme 3a). Rapid equilibration gave am ixture of all four possible a,bunsaturated esters 40-43 within 5m inutes,w ith subsequent formation of the four corresponding Michael addition products 44-47. [24] As econd crossover experiment between two Michael addition products, 44 and 45,b earing distinct PNP ester groups and b-substituents,a lso resulted in rapid exchange (Scheme 3b). These experiments show that the isothiourea undergoes rapid and reversible acylationbyboth the a,b-unsaturated PNP ester and the reaction product. Competitive acylationo ft he catalyst 5 by the product and starting material is consistent with the observed product inhibition and partial negative order in product.
Based on these studies the following catalytic cycle is proposed (Scheme 4). Thep rocess begins with rapid and reversible catalyst acylation by the a,b-unsaturated PNP ester 48 to give a,b-unsaturated acyl isothiouronium 49,w ith the position of equilibrium favoring the free catalyst 5 and a,bunsaturated PNP ester 48.M ichael addition of nitronate to a,b-unsaturated acyl isothiouronium 49,f ollowed by protonation, gives acyl isothiouronium 51. [25] It is conceivable that the p-nitrophenoxide counterion released upon acylation may facilitate deprotonation of nitromethane, [26] with subsquent protonation of the isothiouronium enolate 50 facilitated by either nitromethane or p-nitrophenol. Finally,c atalyst turnover by p-nitrophenoxide gives the Michael addition product 52 and regenerates isothiourea 5.Based on kinetic studies and the rapid crossover between 19 F-labeled a,b-unsaturated PNP esters 40 and 41 relative to the overall rate of reaction, it is likely that Michael addition of nitronate to a,b-unsaturated acyl isothiouronium 49 is the turnover rate-limiting step. Based on previous experimental and computational studies it is believed the a,b-unsaturated acyl isothiouronium 49 adopts an s-cis conformation, with a syn-coplanar non-covalent 1,5-S···O interaction between the acyl Oand catalyst Sproviding aconformational lock. [7b,d,8,10d, 27] Thestereochemical outcome of the process can therefore be rationalized by Michael addition of nitronate to the a,b-unsaturated acyl isothiouronium 49 anti-tothe stereodirecting phenyl substituent of the isothiourea catalyst.
In conclusion, anew general concept for a,b-unsaturated acyl ammonium catalysis has been developed which exploits p-nitrophenoxide release from an a,b-unsaturated p-nitrophenyl ester substrate to facilitate catalyst turnover.T his method allows the use of simple nucleophilic reaction partners for the first time.T he concept was demonstrated in an enantioselective Michael addition of nitroalkanes to a,bunsaturated p-nitrophenyl esters in generally good yield and with excellent enantioselectivity (27 examples,u pt o7 9% yield, 99:1 er). Mechanistic studies identified rapid and reversible catalyst acylationb yt he a,b-unsaturated p-nitrophenyl ester to give ak ey a,b-unsaturated acyl isothiouronium intermediate.P roduct inhibition and catalyst deactivation by protonation were identified under the reaction conditions,a nd application of ar ecently-reported variable time normalization graphical analysis method was required to allow the complex reaction kinetics to be probed. It is hoped that the report of this new reaction paradigm in a,bunsaturated acyl ammonium catalysis will enable and encourage further advancement of this burgeoning field. [28]