Frustrated Lewis Pair (FLP)-Catalyzed Hydrogenation of Aza-Morita-Baylis-Hillman Adducts and Sequential Organo-FLP Catalysis. ACS Catalysis (11),

: Herein we report the metal-free diastereoselective frustrated Lewis pair (FLP)-catalyzed hydrogenation of aza-Morita − Baylis − Hillman (aza-MBH) adducts, accessing a diverse range of stereode ﬁ ned β -amino acid derivatives in excellent isolated yields (28 examples, 89% average yield, up to 90:10 d.r.). Furthermore, sequential organo-FLP catalysis has been developed. An initial organocatalyzed aza-MBH reaction followed by in situ FLP formation and hydrogenation of the electron-de ﬁ cient α , β -unsaturated carbonyl compounds can be performed in one-pot, using DABCO as the Lewis base in both catalytic steps.

S ince the pioneering reports of Stephan 1 and Erker, 2 there has been an explosion of research into frustrated Lewis pair (FLP) chemistry. 3 Of particular interest is the ability of FLPs to activate hydrogen for various metal-free catalytic reduction processes, presenting an attractive alternative to more traditional precious metal-catalyzed hydrogenation that has found ubiquitous application in industrial processes. 4 FLP-catalyzed hydrogenation of various substrates including imines, silyl enol ethers, N-heterocycles, aldehydes, and ketones is now wellestablished, with B(C 6 F 5 ) 3 being the most commonly employed Lewis acid. 5 In comparison, FLP-catalyzed hydrogenation of α,β-unsaturated carbonyl compounds has received considerably less attention. 6 This can partly be attributed to the requirement for more specialized Lewis acids that are designed according to one or both of the following strategies: (1) increased steric shielding (size exclusion principle), e.g. B(C 6 F 5 ) 2 (Mes); 7 (2) attenuated Lewis acidity by replacing one or more of the C 6 F 5 groups within B(C 6 F 5 ) 3 . 8 Such boranes exhibit increased functional group tolerance and can be used in combination with unhindered, highly nucleophilic Lewis bases, 9 such as 1,4diazabicyclo[2.2.2]octane (DABCO), forming FLPs that, in the presence of hydrogen, catalytically reduce various α,βunsaturated carbonyl compounds including acrylates, malonates, enones, and ynones (Scheme 1, eqs 1 and 2). 7,8 Inspired by these reports, and cognizant that DABCO can serve as the Lewis base component of an FLP, we envisaged a new catalytic platform, namely sequential organo-FLP catalysis. In such processes, the same Lewis base would serve as both the organocatalyst (step 1) and the Lewis base component of the FLP (step 2) in sequential catalytic transformations in one-pot. 10 This approach would expand the reactivity profile of FLP-catalyzed hydrogenation to include more complex and challenging substrates while demonstrating the wider applications of FLPs in organic synthesis and catalysis. Herein, we report the successful implementation of this strategy and describe: (1) the first metal-free diastereoselective hydrogenation of aza-Morita−Baylis−Hillman (MBH) adducts; 11 and (2) the sequential organocatalytic formation and in situ FLP-catalyzed hydrogenation of aza-MBH adducts, 12 accessing a range of bespoke β-amino acid derivatives in one-pot (Scheme 1, eq 3).
For the purposes of assessing the scope of this protocol, the standard reaction conditions ( Table 1, entry 1) were used to ensure full conversion across a range of substrates (Table 2).
Having successfully developed the diastereoselective metalfree hydrogenation of aza-MBH adducts, we switched focus toward exploring sequential organo-FLP catalysis (Table 3). We envisaged an initial DABCO-catalyzed aza-MBH reaction, generating adducts that could be used directly without isolation in the previously optimized FLP-catalyzed hydrogenation, simply via addition of the borane Lewis acid (FLP formation) and placing the reaction mixture under a H 2 atmosphere. The catalyst loading was increased to 15 mol % in order to achieve acceptable conversion within 24 h to the aza-MBH adduct during the organocatalytic step. 24 To our delight, under these reaction conditions, a selection of β-amino esters can be accessed in synthetically useful yields directly from the corresponding acrylates and N-sulfonyl aldimines in one-pot Table 2. Scope of FLP-Catalyzed Hydrogenation of aza-MBH Adducts a a Reactions performed using 0.5 mmol of (±)-aza-MBH adduct. All yields are isolated yields after chromatographic purification as a mixture of diastereoisomers unless stated otherwise in brackets. Diastereomeric ratio (d.r.) as determined by 1 H NMR analysis of the crude reaction mixture. b B(2,4,6-F 3 C 6 H 2 ) 3 (2.5 mol %), DABCO (2.5 mol %). c 48 h reaction time. Table 3. Sequential Organo-FLP-Catalysis a a Reactions performed using 0.5 mmol of both aldimine and acrylate starting materials. All yields are isolated yields after chromatographic purification as a mixture of diastereoisomers unless stated otherwise in brackets. Diastereomeric ratio (d.r.) as determined by 1 H NMR analysis of the crude reaction mixture.
In conclusion, we have developed the first metal-free diastereoselective hydrogenation of aza-MBH adducts using FLP catalysis, accessing a diverse array of stereodefined βamino acid derivatives in excellent isolated yields. Furthermore, this protocol was used to introduce a new catalytic platform, sequential organo-FLP catalysis, where DABCO is used as both organocatalyst and the Lewis base component of the FLP in sequential catalytic steps. Ongoing studies are focused on further applications of FLPs in catalysis, and these results will be reported in due course.

* S Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acscatal.7b03077.
Optimization data, experimental procedures, characterization of new compounds, and spectral data (PDF)