N‐Heterocyclic‐Carbene‐Catalyzed Asymmetric Oxidative Hetero‐Diels–Alder Reactions with Simple Aliphatic Aldehydes

N-heterocyclic carbene (NHC) catalysis has emerged as a powerful tool for synthesis.[1] Among its involvement in several cycloaddition-type reactions for the construction of lactams and lactones, abundant in biologically active molecules[2] and broadly used as synthons for complex molecules,[3] NHC catalysis via formal [3+3] or [4+2] strategies is noteworthy.[4–10] In particular, [4+2] cycloadditions have received more attention than others. In the literature, most NHC-catalyzed [4+2] hetero-Diels-Alder reactions involve an enolate intermediate.[5–10] To date, NHC-catalyzed enolate formation is achieved from functionalized aldehydes, ketenes or esters (Scheme 1, A1–5). Treatment of these precursors with dienes presents certain drawbacks. Prime among them is that all precursors are prefunctionalized, limiting substrate scope. Thus, a stable, readily available, general enolate precursor is desirable for this kind of [4+2] cycloaddition. Herein, we report that simple aliphatic aldehydes serve as enolate precursors for highly enantioselective synthesis of lactones and lactams under oxidative conditions via NHC catalysis. Scheme 1 Known enolate precursors. Aliphatic aldehydes are bench-stable when properly stored and readily available. Although they provide great advantages compared to known enolate precursors, to the best of our knowledge no approach has been documented using them as enolate precursors without prefunctionalization.[11] We envisioned that aliphatic aldehydes could serve as enolate precursors with an NHC catalyst and proposed that they could react with dienes to form sixmembered products as shown in Scheme 2. Interception of the aliphatic aldehyde by an NHC would give the Breslow intermediate. Consequent oxidation[12] and deprotonation of the intermediate would yield an enolate.[13] Ultimately, [4+2] cycloaddition would provide a six-membered product. In the proposed process, judicious choice of oxidant and base would be the key to the successful transformation. Scheme 2 Proposed Diels-Alder reactions through oxidative enolate formation. We first treated distilled butyraldehyde (1a) with tosyl-protected α,β-unsaturated ketimine 2a in the presence of 20 mol% mesityl triazolium salt C1 as the catalyst, DBU as the base, and one equivalent phenazine ([O]A) as the oxidant.[14] The reaction provides trans-lactam 3a[15] in trace amount (Table 1, entry 1). To shed light on the issue, NMR experiments were performed using 2a, the catalyst C1 and DBU, which revealed an interaction between carbene and 2a causing catalyst inactivation. Table 1 Reaction optimization.[a] According to our previous finding that acid plays an important role in carbene catalysis,[16] we added 10 mol% acetic acid to the reaction. Gratifyingly, the conversion increased to >99% to give trans-lactam in >99% ee and 8:1 dr (Table 1, entry 2). An increase of acid loading decreases diastereoselectivity (entry 3). Diisopropyl ethyl amine as the base is not efficient (entry 4) and K2CO3 delivers lower dr in THF presumably due to poor solubility (entry 5). The oxidant [O]B, popularized by Studer for use in NHC catalysis,[17] is not effective for this transformation (entry 6). Use of [O]A as the oxidant makes purification difficult as its polarity is similar to that of the desired product. We investigated a more polar oxidant [O]C. Lower diastereoselectivity was observed when using DBU or K2CO3 as the base in THF (entries 7–8). To increase the solubility of base in the solvent, a mixed solvent system (THF/CH3CN, 1:10, v/v) proved beneficial generating trans-product in 88% isolated yield, 99% ee and 9:1 dr (entry 9).[18] Interestingly, when 0.2 eq oxidant is used, the desired product is formed in good yield, 99% ee and 17:1 dr (entry 10), which suggests that the use of catalytic oxidant is possible to give product in high conversion.[19] With optimized conditions in hand, the substrate scope of ketimines was evaluated. A variety of six-membered lactams could be obtained in good yields and excellent enantioselectivities (Table 2). Smaller propionaldehyde and larger pentanal deliver the corresponding lactams 3b and 3c in 97% ee and 20:1 dr, respectively. When sterically more hindered isovaleraldehyde is utilized, the desired product is generated in trace amount. In contrast, 3-cyclohexylpropanal is an effective substrate for this annulation to give product 3d in good yield, excellent enantioselectivity and high dr. With electron-withdrawing or electron-donating groups on the aromatic ring at either side of ketimine, the reactions work quite well to give products 3e–h in good to excellent yields (74–98%) and excellent ee's (>99% for all). Table 2 Lactam synthesis from α,β-unsaturated ketimines.[a] When similar conditions are applied to the cycloaddition with chalcones, lactones are generated but with a cis relationship between stereocenters (Table 3). A variety of aliphatic aldehydes give lactones 5a–d in good yields, excellent ee's and high dr. When an electron-withdrawing group, i.e., 4-Cl- or 4'-Cl- group, is on the aromatic ring of chalcones, the reactions proceed to give the products 5e and 5f in the same efficiency. However, the reactions become slower when an electron-donating group 4-MeO- or thiophene is incorporated onto the chalcone, but still give the desired products in excellent ee's (99%) and dr (5g and 5h). Beyond chalcones as substrates, the desired product 5i can be generated smoothly when a keto ester is employed as the starting material using the oxidant [O]C instead of [O]A in the mixed solvent THF/CH3CN. Although lactones such as 5i have been generated using Bode's system,[6a] the somewhat less reactive chalcones have not been incorporated into cycloadditions by previously developed methods using NHC catalysis,[6,20] or by cinchonidine catalysis or enamine catalysis/oxidation approaches.[21] Table 3 Lactone sythesis from α,β-unsaturated ketones.[a] The proposed mechanism for trans-lactam formation is shown in Scheme 3. Base deprotonates triazolium salt to generate free carbene. Free carbene may react with α,β-unsaturated ketimine to form an adduct by 1,2- or 1,4-addition. In the presence of acid, the adduct releases the carbene. Reaction with aliphatic aldehyde gives Breslow intermediate A followed by oxidation to generate acyl azolium B. Its deprotonation at the α-position gives enolate C. [4+2] Cycloaddition of C with α,β-unsaturated ketimine gives zwitterion D. The carbene is released from D, and the desired lactam is formed. Scheme 3 Proposed pathway for trans-Lactam formation. The mechanism for lactone formation is slightly different from the above pathway. After carbene generation, addition of the carbene to chalcone does not form stable adducts, suggesting that free carbene is present in the reaction. Therefore, addition of acid is not necessary for lactone synthesis. Interestingly, cis-lactone is formed in the reaction, the reasons for which are unclear at this time. The possible intervention of both the enolate (C) and enol (C') intermediates in the two cycloaddition protocols cannot be discounted. In conclusion, we have developed an NHC-catalyzed[22] approach to efficiently synthesize trans-lactams and cis-lactones in high yields, high enantioselectivities and good to excellent dr with simple aliphatic aldehydes. The method involves a new way to generate enolate intermediates via oxidation and deprotonation, and has obvious advantages compared to known enolate precursors. It is quite interesting that trans-lactams and cis-lactones are formed under similar conditions.[23] A study aimed at elucidating the factors responsible for the different stereochemistry between trans-lactams and cis-lactones is in progress.