Bifunctional Iminophosphorane-Catalyzed Enantioselective Sulfa-Michael Addition to Unactivated α,β-Unsaturated Amides.

The first metal-free catalytic intermolecular enantioselective Michael addition to unactivated α,β-unsaturated amides is described. Consistently high enantiomeric excesses and yields were obtained over a wide range of alkyl thiol pronucleophiles and electrophiles under mild reaction conditions, enabled by a novel squaramide-based bifunctional iminophosphorane catalyst. Low catalyst loadings (2.0 mol %) were achieved on a decagram scale, demonstrating the scalability of the reaction. Computational analysis revealed the origin of the high enantiofacial selectivity via analysis of relevant transition structures and provided substantial support for specific noncovalent activation of the carbonyl group of the α,β-unsaturated amide by the catalyst.

Introduction

Conjugate additions are among the most prevalent transformations in organic chemistry due to their ability to quickly generate complexity from simple starting materials with perfect atom economy.[1] Despite the maturity of the field, examples of enantioselective conjugate additions to α,β-unsaturated amides remain scarce. Contrary to other carboxylic acid derivatives, the electron-withdrawing property of the carboxamide functionality is greatly diminished.[2−5] Over the past two decades, multiple strategies relying on structural modification of α,β-unsaturated amides have been disclosed, enabling enantioselective conjugate additions. These, however, are reliant on tailored activating groups, such as imides, N-acyl pyrroles, and thioamides among others, curtailing the synthetic efficiency of these procedures.[6] To date, only a handful of catalytic enantioselective methods have been described featuring 1,4-additions to nonactivated α,β-unsaturated amides. Pioneering studies by Kobayashi employed chiral crown ethers in the presence of KHMDS to gain reactivity and enantiofacial control in the conjugate addition between α,β-unsaturated amides and carbon centered pronucleophiles,[7] while Harutyunyan,[8] employed chiral bisphosphine ligated copper(I) catalysis for the conjugate addition of alkyl Grignard reagents to α,β-unsaturated amides. Most recently the enantioselective copper(I)-catalyzed hydrophosphination and rhodium(I)-catalyzed hydroboration of α,β-unsaturated amides in the presence of chiral bisphosphine ligands were reported by Yin and Li, respectively.[9] While elegant, these methods required the use of bespoke and sensitive ligated metal systems sometimes combined with super stoichiometric activators. However, the enantioselective addition of (pro)nucleophiles to unactivated α,β-unsaturated amides under metal-free catalysis remains an unsolved problem. In 2013, our group disclosed a new class of superbasic catalysts, the bifunctional iminophosphorane (BIMP), which has proven to be exceptionally active in catalyzing challenging enantioselective conjugate additions.[10−14] Recognizing the limitations in enantioselective conjugate additions to α,β-unsaturated amides and seeking the opportunity to test the capabilities of new BIMP catalyst systems on conjugate acceptors at the bottom end of Mayr’s electrophilicity scale (Figure ),[5c] we sought to realize the first nonmetal-catalyzed enantioselective conjugate addition reaction to α,β-unsaturated amides. We chose to exemplify this with the sulfa-Michael addition (SMA). Enantioselective carbon–sulfur bond-forming reactions are prevalent transformations in organic chemistry due to the abundance of sulfur atoms in biomolecules and pharmaceutical compounds.[15a] Recently developed β-thioamide Tyclopyrazflor, for example, is a powerful pesticide.[15b−15f] If successful, our new methodology could be applied to the rapid assembly of libraries of novel, otherwise difficult-to-obtain enantiomerically enriched β-thioamides. Our hope was to identify a suitable BIMP superbase catalyst capable of significant activation of the α,β-unsaturated amide electrophile and simultaneous deprotonation of high pKa alkyl thiol pronucleophile, and here we wish to report our findings.

Figure 1

Mayr’s electrophilicity scale (bottom). Previous BIMP catalysts for SMAs to unsaturated carboxylic acid derivatives and this work (top).

Results and Discussion

Readily available (E)-N,N-dibenzyl crotonamide 1a, being sterically and electronically unbiased, was selected as the model substrate for the enantioselective SMA.[5e] A preliminary performance investigation of catalysts (at 10 mol %) was carried out in THF at room temperature in the presence of 3.0 equiv of 1-propanethiol 2a (Table ). Initial experiments revealed that cinchona-derived catalyst C was essentially inactive in the transformation, resulting in <3% product 3a formation after more than 1 week reaction time (entry 1). First-generation thiourea and amide-containing BIMP catalysts B1 and B2 bearing a single stereocenter provided 3a in high yield, albeit with 37% and 55% ee, respectively (entries 2 and 3). Diastereomeric second-generation catalysts B3 and B4 bearing an additional stereocenter flanking the hydrogen-bond-donor group efficiently furnished product 3a in 25% and 51% ee, respectively (entries 4 and 5), demonstrating enantiocontrol was arising from both stereogenic centers. Further architectural fine-tuning of catalyst B4 did not allow for significantly higher enantiocontrol, thus we turned our attention to the nature of the hydrogen-bond-donor moiety of the catalyst. Due to the inherently high Lewis basicity of carboxamides, we speculated that a hydrogen-bond donor with an increased Brønsted acidity could offer enhanced binding and thus better stabilization of the transition structure (TS). Based on this reasoning, and inspired by the pioneering work of Rawal and Jacobsen, a squaramide-containing catalyst appeared to be a rational choice, due to its enhanced hydrogen-bonding properties.[16,17] To our delight, switching to squaramide-based catalyst B5 and the solvent to toluene afforded 3a in 90% yield and 66% ee (entry 6). In a bid to boost enantiocontrol, we introduced an additional stereocenter on the distal side of the squaramide motif to give third-generation BIMP catalyst, B6. We were pleased to find this structural modification provided 70% ee and 82% yield (entry 7). Changing the catalyst to one bearing two anti-configured tert-butyl groups, and switching the solvent to EtOAc, boosted the ee to 85% (entry 8). The convenient late-stage formation of the iminophosphorane moiety then allowed for facile tuning of the BIMP catalyst by simply varying the phosphine component of the Staudinger reaction. This systematic structural variation revealed the importance of peripheral, bulky, and electron-donating groups, leading to catalyst B8, which provided 3a in 95% ee and 88% isolated yield (entry 9).[18] Additionally, the inclusion of air in the reaction vessel did not change the outcome of the transformation, and with the optimized conditions in hand, the scope of the protocol was then explored (Scheme ). Initially the effects of substituents on the amide nitrogen were evaluated (3a–3s). Pleasingly, switching one benzyl group on 1a to a methyl group was well tolerated, and corresponding product 3b was formed with 83% yield and 92% ee. Dimethylamine derivative 1c afforded product 3c in 87% ee, and no major change in reactivity was observed. Dibutylamine derivative product 3d was obtained in 84% yield and 94% ee. Product 3e and unprotected indole derivative 3f were formed smoothly under the optimized conditions in 94% ee and 95% ee, respectively. Substrates bearing cyclic N-substituents afforded products 3g–3i with excellent enantioselectivities and moderate to high yields. Amides 1j and 1k proved to be exceptionally reactive, and consequently cooling to −20 °C was exploited to enhance enantioselectivity and control, and products 3j and 3k were yielded with 83% ee and 74% ee, respectively. Pharmaceutically relevant[19] isoquinoline derivative 3l and thienopyridine derivative 3m were both compatible with our method providing nearly quantitative yield and high ee. Even N-methylaniline-derived substrate 1n was well tolerated, furnishing 3n with 88% yield and 81% ee. Encouraged by the high degree of tolerance of heterocyclic moieties, we explored the enantioselective SMA to α,β-unsaturated amide 1o. The reaction proceeded smoothly under the optimized conditions, furnishing 3o, an analogue of Tyclopyrazoflor[15b−15e] with 90% ee and 90% isolated yield. Secondary amide 1p was also a competent substrate in this reaction, albeit a solvent switch to toluene was required to better solubilize the starting material. When six- and seven-membered α,β-unsaturated lactams 1q and 1r were used as substrates, products 3q and 3r were obtained in 93% yield and 87% ee and 40% yield and 76% ee, respectively. Product 3s, bearing an α-stereogenic center, could also be obtained (via enantioselective reprotonation) employing the same catalyst in 35% yield and 80% ee. We then turned our attention to the β-substituents on the enoyl backbone. Particularly unreactive[5c] cinnamide derivative 3t was obtained with excellent enantioselectivity (95% ee) but moderate yield. Product 3u, on the contrary, was easily obtained, likely due to the phenyl groups present on the amide moiety, twisting the N atom out of conjugation.[5e] Product 3v was obtained with moderate yield and ee and was used to determine absolute stereochemical configuration.[18] Cinnamides 1w and 1x bearing electron-withdrawing groups were smoothly converted to the corresponding thioethers with high levels of selectivity and reactivity. Pyridine-containing derivative 1y was well tolerated, furnishing 3w in near quantitative yield and 85% ee. The introduction of a longer alkyl chain in substrate 1z was well tolerated, albeit with a slight decrease in reactivity. Substrate 1aa bearing an additional methyl group compared to 1z exhibited decreased reactivity (most probably due to additional steric encumbrance), and therefore more forcing conditions had to be applied to afford product 3aa in 58% yield and 74% ee. Finally, a thorough assessment of the nucleophile scope was performed using primary, secondary alkyl, and benzyl-substituted thiols. Primary alkyl thiols were broadly tolerated, affording the corresponding thioethers with high enantioselectivity and reactivity (3ab–3af). Notably, a thiol bearing an ester functionality afforded product 3af in 66% yield and 90% ee. A decrease in ee was observed in the case of 3ag which contained a proximal CF3 group. Secondary alkyl thiols provided products with high enantioselectivities albeit with slightly diminished reactivity (3ah–3ai), while benzylic thiols underwent the transformation with high levels of reactivity at a modest expense of ee (3aj–3am).[20]

Table 1

Selected Reaction Optimization (0.1 mmol Scale)

Isolated yield.

NMR yield after 7 days. Ee determined by HPLC on a chiral stationary phase. PMP: p-methoxyphenyl.

Scheme 1

Reaction Scope for the BIMP B8-Catalyzed Enantioselective SMA to α,β-Unsaturated Amides (0.1 mmol Scale)

Reactions were conducted under air. Reaction carried out using: a10.0 equiv, b4.0 equiv, c3.0 equiv thiol. Reaction carried out at: d–20 °C and e40 °C. fReaction carried out in toluene. g0.5 M concentration. *Absolute stereochemical configuration of product 3v was determined by chemical correlation.[18]

After establishing the scope and limitations of this new methodology, we wanted to demonstrate its scalability using model substrate 1a and 1-propanethiol 2a. Doubling the reaction concentration and reducing catalyst loading to 2.0 mol % allowed a 400-fold (40.0 mmol) scale-up of the model reaction, and product 3aS was obtained in 96% isolated yield (13.2 g) and 93% ee (Scheme ). Next, a series of transformations were performed using 3aS to showcase the synthetic utility of this product. When treated with lithium aluminum hydride, aminosulfide 4a was obtained in 79% isolated yield and was subsequently debenzylated in the presence of CbzCl in PhMe at 60 °C to afford protected secondary amine 4b in 50% yield and 92% ee. A cyclopropane motif could be installed via the Kulinkovich–de Meijere reaction[21] using ethylmagnesium bromide and titanium(IV) isopropoxide. Aminocyclopropane 4c was obtained in 43% yield and 92% ee. Oxidation in the presence of oxone provided sulfone 4d in 87% yield with no loss of optical purity. Oxidation with mCPBA furnished sulfoxides 4e and 4e′ in 91% yield but low diastereoselectivity; however, the two diastereoisomers could be separated, providing single diastereoisomers with practically no erosion in ee.

Scheme 2

Decagram-Scale Enantioselective SMA

(I) Azide A8 on the left, phosphine P19 on the right; (II) crude catalyst B8 after removal of THF; (III) substrate 1a; (IV) product 3aS (left) and product derivatization (right).

Unintentionally, substrate binding/activation of the new catalyst system was effectively revealed using N,N-dibenzyl 4-nitrocinnamide 1x and thiol 2a. Substrate 1x can undergo nucleophilic addition reactions to the conjugated alkene at either the α or β position with respect to the amide functionality, and thus regioselectivity of the addition to this dual-mode Michael acceptor can be used to probe catalyst function (Table ). Performing the reaction under the optimized conditions using an achiral organic superbase bearing no hydrogen-bond donor (BEMP) revealed that the inherent reactivity of 1v is governed by the 4-nitrostyrene moiety, providing a 1:10 mixture of 3x:3x′, implying that this functionality is indeed more electron withdrawing than the amide moiety (entry 1). However, running the reaction using catalyst B8 under the same conditions reversed the regioselectivity, furnishing products 3x and 3x′ in a 4:1 ratio, thus providing convincing evidence for the activation of the amide moiety by the BIMP catalyst (entry 2). Subjecting the 1:1 mixture of B8 catalyst’s azide precursor A8 and BEMP to the optimal reaction conditions afforded a 1.0:1.6 ratio of 3x:3x′ and a significantly lower ee of 3x compared to B8-catalyzed reaction, accentuating the importance of the chiral tether between the iminophosphorane superbase and hydrogen-bond donor in B8 (entry 3).

Table 2

Mechanistic Investigation Employing a Dual-mode Michael Acceptor#

Yields were determined by quantitative 1H NMR (0.1 mmol scale).

Computational Study

A DFT study using the ADF program[22] was performed to elucidate the origins of stereocontrol in the BIMP-catalyzed SMA to α,β-unsaturated amides (Figure ).[23] The reaction proceeds via the sequential complexation between the catalyst and substrates, leading to a TS, a subsequent conjugate addition, and finally an irreversible protonation of the enolate. In this study, we have focused on the stereoselectivity-determining conjugate addition step, as no kinetic isotope effect (KIE = 1.0) or a change in ee was observed when performing the reaction with propanethiol-d1, suggesting that the protonation step is neither rate- nor enantio-determining.[18] Initially, the iminophosphorane moiety of the BIMP catalyst deprotonates the thiol and forms zwitterionic intermediate RC1, stabilized by the two hydrogen-bond donors of the squaramide, and the protonated iminophosphorane. Prior to the conjugate addition step, the amide electrophile coordinates to RC1 and generates intermediate RC2. Due to the conformational freedom and the existence of two potential activation modes of the BIMP catalyst, we computed and compared all the possible TSs during the enantio-determining conjugate addition step, involving amide 1c and methyl thiol as the model nucleophile (Figure S9).[11k,12c,14f,14h] Both side chains of the BIMP squaramide catalyst can freely rotate and the two most stable conformations for its “left arm” (LA) and “right arm” (RA) were explored.[18] As originally hypothesized by Pápai, there are two modes (mode A and B) in which the catalyst may bind to the substrate in the TSs.[18,24] In the case of mode A, the electrophile is activated by the hydrogen-bond-donor moiety, while the nucleophile is bound to the protonated iminophosphorane. In the case of mode B, the nucleophile is coordinated to the hydrogen-bond donor and the electrophile is activated by the protonated iminophosphorane. Our computational analysis utilizes the terminology discussed above (Figure ).[18]

Figure 2

Possible binding modes and terminology used for computational studies.

All 16 possible TSs for the stereoselectivity-determining conjugate addition step were located (Figure S9). The lowest-energy conjugate addition TS was TS1 that forms the (S)-product, which is in agreement with the experimentally confirmed absolute stereochemical outcome of the reaction (Figure ). The relatively low-energy barrier of 20.5 kcal mol–1 is furthermore consistent with the mild reaction conditions required to perform the transformation. The lowest-energy TS, responsible for the formation of the minor (R)-product, is TS1′, which proceeds through a higher energy barrier than TS1 (ΔΔG⧧ = 4.1 kcal mol–1). The stereoselectivity for this transformation originates from the TS geometry that benefits from multiple inter- and intramolecular stabilizing interactions, including hydrogen bonding, CH−π, and π–π interactions. These stabilizing features are enhanced in TS1 compared to TS1′. The intramolecular hydrogen bonding between the O(squaramide)–H(amide) fixes the conformational freedom of the “LA” of the BIMP catalyst, creating a three-dimensionally defined pocket within which the α,β-unsaturated amide can fit without considerable steric repulsion during the C–S bond forming event. Furthermore, the thiolate anion interacts with the aromatic ring of the iminophosphorane moiety for additional satbilization. Analysis of noncovalent interaction (NCI) plots allows one to qualitatively visualize these weak interactions between the catalyst and substrates (Figure S12).[25] The observed NCIs were then quantified using energy decomposition analysis (EDA) for the comparison of the stabilization effects between TS1 and TS1′ (Figures S13 and S14).[18,26] In addition, to understand why both the reactivity and enantioselectivity were improved by the exchange of a thiourea with a squaramide in the catalyst structure, a computational comparison between these motifs was performed. Our findings indicate that the squaramide BIMP catalyst can facilitate a faster conguate addition (lower ΔG⧧) with a greater degree of enantioselectivity (larger ΔΔG⧧ relative to the next most favorable TS) compared to the thiourea BIMP catalyst. These findings were supported by experimental studies comparing analogous squaramide and thiourea-based BIMPs (Figure S11).[18] Overall, our state-of-the-art computations have enabled us to understand the origin of the enantioselectivity for this transformation and open up new avenues toward the rational design of novel catalysts.

Figure 3

Computed potential energy surface (ΔG [kcal mol–1]) of the BIMP squaramide-catalyzed sulfa-Michael addition computed at COSMO(EtOAc)-ZORA-M06-2X/TZ2P//COSMO(EtOAc)-ZORA-BLYP-D3(BJ)/DZP. Energies (kcal mol–1) and forming bond lengths (Å) of the TS geometries are provided in the inset.

Conclusion

Exemplified by the alkyl thiol SMA, the first metal-free catalytic enantioselective intermolecular conjugate addition to unactivated α,β-unsaturated amides has been developed. A thorough investigation of substrate types revealed a general methodology that furnishes a wide range of SMA products, including heterocyclic derivatives, in high yields and ee. Computational and mechanistic studies revealed the origins of selectivity and the important substrate/catalyst binding modes. Efforts continue in our laboratories to uncover new BIMP designs and to expand the range of BIMP-enabled transformations.