Axially Chiral N-Oxide Catalysts for the Allylation and Crotylation of Aromatic Aldehydes: Exploiting Nonlinear Effects

Axially Chiral N-Oxide Catalysts for the Allylation and Crotylation of Aromatic Aldehydes: Exploiting Nonlinear Effects Antonio Romero-Arenas,[a] Pedro Ramírez-López,[c] Javier Iglesias-Sigüenza,[b] Rosario Fernández,[b] Abel Ros,*[a, b] and José M. Lassaletta*[a] A new family of IAN-type amine N-oxides is presented as catalysts for the allylation and crotylation of aromatic aldehydes with allyltrichlorosilanes. These reaction exhibit a remarkably positive nonlinear effect which enables utilization of the catalysts in subenantiopure form. As enantiopure catalysts are not required under this regime, the synthesis of these N-oxides is straightforward through catalytic asymmetric synthesis, avoiding lenghty synthesis from the chiral pool or resolution of diastereoisomers. Studies of the corresponding crotylation with Zand E-crotylsilanes suggest that the reaction proceeds through a chair-like transition state. Introduction The asymmetric allylation of carbonyl compounds to afford enantioenriched homoallylic alcohols is an essential tool in Organic Chemistry, as these products are crucial building blocks for the synthesis of natural products and biologically active compounds,[1] owing to the orthogonal reactivity of their functional groups and their chiral nature. As such, developing new affordable catalysts that enable precise control of enantioand diastereoselectivity is essential to obtain these synthetically relevant compounds. Different methods have been developed based on the type of allylating agents and catalysts.[2] In particular, the addition of allylsilanes to carbonyls can be catalyzed by Lewis acids and bases. However, Lewis base catalysts present a significant advantage in terms of diastereoselectivity. While acid catalysis only promotes syn addition, reactions catalyzed by Lewis bases exhibit syn or anti addition, depending on the geometry of the substituted allylsilane. The catalytic effect of organic Lewis bases was initially reported in 1993 by Kobayashi and Nishio,[3] who demonstrated that the basic properties of DMF played a crucial role in catalyzing the reaction, as their basic properties enhanced the nucleophile properties of the silane while preserving its Lewis acid character to coordinate the aldehyde and form a closed cyclic transition state. Soon afterward, Denmark and co-workers introduced the first enantioselective version of the reaction using a chiral phosphoramide as a promoter,[4a] but the method was limited by the lack of turnover and low enantioselectivities. Since then, other families of Lewis base organocatalysts have been developed, including chiral formamides reported by Iseki[5] pyridine-based N-oxides I–Vreported by Nakajima,[6] Hayashi[7] and Malkov,[8] and Zhu,[9] among others[10] (Figure 1). While these catalysts are highly effective in the allylation and crotylation of aldehydes, they are limited by their lengthy and complex synthesis, which often involves stoichiometric metalmediated coupling reactions,[8,9,11] chiral auxiliaries,[7,12] or the resolution of racemates,[8c–d,10b,13] adding additional steps to obtain the final enantiopure catalyst. In sharp contrast to this approach, in which the enantiopurity of the catalyst is key to ensuring high stereoselectivities, the catalytic synthesis of ligands often leads to the generation of sub-enantiopure catalysts. In principle, these ligands are expected to induce a lower level of enantioselectivity, limited by the maximum enantiopurity of the catalyst, but offer a much more straightforward synthesis using catalytic methods. However, deviations from linearity in the enantioselectivity of reactions are observed in some cases. When this deviation is positive, an amplification of the enantiomeric excess can be obtained with catalysts with lower enantiopurity.[14] Only two examples of nonlinear effects have been reported for the addition of allyl trichlorosilanes to aldehydes when using organic promoters. In fact, Denmark observed a positive linear effect when using phosphoramide VI in his seminal work[4] and [a] A. Romero-Arenas, A. Ros, J. M. Lassaletta Instituto Investigaciones Químicas (CSIC-US) and Centro de Innovación en Química Avanzada (ORFEO-CINQA), C/ Américo Vespucio 49, 41092 Sevilla, Spain E-mail: [email protected] [email protected] [b] J. Iglesias-Sigüenza, R. Fernández, A. Ros Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla and Centro de Innovación en Química Avanzada (ORFEO-CINQA), C/ Prof. García González, 1, 41012 Sevilla, Spain [c] P. Ramírez-López Departamento de Química en Ciencias Farmacéuticas, Facultad de Farmacia, Universidad Complutense de Madrid, Plz. Ramón y Cajal S/N, 28040 Madrid, Spain Supporting information for this article is available on the WWW under https://doi.org/10.1002/cctc.202400806 © 2024 The Author(s). ChemCatChem published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. Wiley VCH Donnerstag, 07.11.2024 2421 / 366646 [S. 488/493] 1 ChemCatChem 2024,16, e202400806 (1 of 6) © 2024 The Author(s). ChemCatChem published by Wiley-VCH GmbH ChemCatChem www.chemcatchem.org Research Article doi.org/10.1002/cctc.202400806 De Sio, Massa and Scettri[15] found a similar behavior with a chiral sulfoxide VII (Figure 2). Still, both were used in stoichiometric amounts and only ~60% ee was obtained for the allylation of benzaldehyde. Thus, the effective application of nonlinear effects in the organocatalyzed allylation of aldehydes remains elusive. In the allylation of aldehydes, the nonlinear effect is attributed to one of the reaction pathways in which silicon is activated by two molecules of the Lewis base catalyst.[4b,15] We speculated that the incorporation of an additional acidic site could promote the formation of inactivated racemic dimers through acid-base interactions. On this basis, we considered axially chiral IAN-type N-oxides (IAN =Isoquinoline-Amino Naphthalene) as appealing nonracemic catalyst candidates for the allylation and crotylation of aldehydes for the following reasons: 1) Axially chiral N-oxides can be directly related to QUINOX, which is a powerful catalyst in this reaction.[8c,d] 2) The amine group functions as a hydrogen bond donor, facilitating the formation of heterodimers. 3) There is a facile catalytic synthesis for these compounds based on a dynamic kinetic asymmetric Buchwald-Hartwig amination of readily available heterobiaryl electrophiles,[16] avoiding resolution of racemates or long and tedious derivatization sequences from the chiral pool. On the basis of these assumptions, we report herein on the implementation of IAN-derived N-oxides as convenient organocatalysts for the asymmetric allylation and crotylation of aldehydes. Results and Discussion Based on this hypothesis, a family of IAN N-oxides C1–C4 was prepared in two steps. First, the corresponding IAN-type amines 2a–dwere synthesized from readily available heterobiaryls 1a– dusing our previously reported Buchwald-Hartwig amination.[16] The direct oxidation of the isoquinoline moiety with metachloroperbenzoic acid (mCPBA) afforded the corresponding Noxides C1–C4 in moderate to good yields (Scheme 1). Next, we tested the catalytic activity of these axially chiral N-oxides in the model reaction of benzaldehyde 3A (0.20 mmol) with allyltrichlorosilane 4a (0.24 mmol) at 40°C in CH2Cl2using N,N-diisopropylethylamine (DIPEA) as an additive[6] and 5 mol% catalyst loading of C1 as the catalyst. The desired product 5Aa was obtained in 71% yield and 89% ee (Table 1, entry 1), confirming the catalytic activity and a promising enantioselectivity. Dissapointlying, though, we did not observe any chiral amplification. However, since our design is based on the formation of racemic dimers through hydrogen bond interactions, we thought that this would be highly dependent on factors such as concentration, temperature, and solvent, prompting us to pursue further optimization (Table 1). Figure 1. Enantioselective allylation of aromatic aldehydes. Representative Noxide catalysts. Figure 2. Nonlinear effects in the base-catalyzed allylation of aromatic aldehydes. Scheme 1. Synthesis of catalysts C1–C4. [a] Amine 2d was prepared using (R)-QUINAP. Wiley VCH Donnerstag, 07.11.2024 2421 / 366646 [S. 489/493] 1 ChemCatChem 2024,16, e202400806 (2 of 6) © 2024 The Author(s). ChemCatChem published by Wiley-VCH GmbH ChemCatChem Research Article doi.org/10.1002/cctc.202400806 18673899, 2024, 21, Downloaded from https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/cctc.202400806 by Readcube (Labtiva Inc.), Wiley Online Library on [22/04/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Surprisingly, changing the temperature from 40°C to 0°C (Table 1, entries 1 and 2) resulted in the formation of the homoallylic alcohol 5Aa in a lower yield. Similarly, we observed lower enantiomeric excesses when the reagent concentration was increased two-fold (Table 1, entries 1 and 3). We also tested other N-oxide catalysts available from in group under the initial conditions. These catalysts, which had the same naphthyl-isoquinoline skeleton, such as naphthol C5[17] and alkyne N-oxide C6[18] (entries 4 and 5), showed no improvement in either conversion or selectivity. From the results obtained with catalyst C6, we can conclude that the naphthyl-isoquinoline N-oxide moiety can catalyze the reaction and induce enantioselectivity to some extent. Naphthol C5 was expected to have a performance similar to that of C1 because it also contains a hydrogen donor group; however, only traces of the product were found. Hence, it was clear that these catalysts were not suitable for this transformation, suggesting the intervention of beneficial noncovalent substrate-catalyst interactions involving the NHAr moiety in C1–C4. Returning to the model catalyst, C1, a solvent screening was conducted using acetonitrile (ACN), tetrahydrofuran (THF), toluene, and chloroform. For the polar solvents, the selectivities were maintained, but the reactions afforded lower yields (Table 1, entries 10 and 11). In contrast, nonpolar solvents such as toluene and chloroform showed better conversion and enantioselectivity (Table 1, entries 6 and 12). Moreover, a strong positive nonlinear effect was observed when these solvents were used. Since the stereocontrol was slightly higher when using toluene, we used this solvent to perform the rest of the reactions. The other IAN-type N-oxides were tested for the allylation of benzaldehyde. Every catalyst showed a very good yield for the reaction (�95%), except for C3, which gave a moderate yield (73%). Additionally, the enantioselectivities were excellent (>94% ee in all cases; Table 1), suggesting that the nonlinear effect is general for this family of catalysts. The nonlinear effect was particularly remarkable in the case of C4, as alcohol 5Aa was obtained with 96% ee when the enantiopurity of the catalyst was only 84%. To further study the nonlinear effect of this family of catalysts and determine the minimum enantiopurity required to obtain over 90% ee of the alcohol, we conducted a series of experiments utilizing C1 with different enantiopurities. The results of these experiments showed a remarkable positive nonlinear effect, with a selectivity of 95% ee when the optical purity of catalyst C1 was approximately 75% ee (Figure 3). Although we did not analyze the nonlinear effect of the other ligands of the set, we assume that their behavior is similar due to chemical analogy. In addition, the enantioselectivities obtained with these catalysts C2–C4 match those obtained with C1. Because the deviation of the linearity is positive, the minor Table 1. Optimization of the reaction conditions. Entry[a] Cat. Solvent T (°C) Yield (%)[b] ee (%)[c] 1C1 CH2Cl240 71 89 2C1 CH2Cl20 50 85 3[d] C1 CH2Cl240 71 70 4C5 CH2Cl240 <10[e] nd 5C6 CH2Cl240 63[e] 57 6C1 Toluene 40 >95[e] (88)[b] 97 7C2 Toluene 40 >95 98 8C3 Toluene 40 73 96 9C4 Toluene 40 95 94 10 C1 ACN 40 58 88 11 C1 THF 40 ~20[e] 90 12 C1 CHCl340 >95[e] 96 [a] Reactions were performed at 40°C on a 0.20 mmol scale using anhydrous solvent (1 mL) and DIPEA (0.26 mmol). [b] Isolated yield. [c] Determined by HPLC analysis. [d] 0.5 mL of DCM was used. [e] Estimated yield by 1H NMR. Figure 3. Nonlinear effect of allylation with catalysts C1–C4. Reactions were performed at 40°C on a 0.2 mmol scale (3A) using anhydrous toluene (1 mL), 1.2 equiv. of 4 a and 1.3 equiv. of DIPEA. Enantiomeric excesses were analyzed by HPLC. Wiley VCH Donnerstag, 07.11.2024 2421 / 366646 [S. 490/493] 1 ChemCatChem 2024,16, e202400806 (3 of 6) © 2024 The Author(s). ChemCatChem published by Wiley-VCH GmbH ChemCatChem Research Article doi.org/10.1002/cctc.202400806 18673899, 2024, 21, Downloaded from https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/cctc.202400806 by Readcube (Labtiva Inc.), Wiley Online Library on [22/04/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License enantiomer of the catalyst must be removed or inactivated during the reaction; otherwise, the maximum enantiomeric excess would be limited to that of the catalyst. IAN-type N-oxides are designed to maximize intermolecular interactions to favor dimerization. In this regard, these catalysts contain both donor and acceptor hydrogen-bonding groups, that is, NH and NO. To shed light on the origin of this deviation, we attempted to crystallize the catalyst in its enantiopure and in racemic forms, expecting the latter to be more crystalline. Unfortunately, neither of the crystallizations occurred. Thus, we decided to conduct an alternative experiment, in which we recrystallized a non-racemic mixture (72% ee) of catalyst C1, affording X-ray quality crystals to our delight. Subsequent SCXRD analysis revealed that the crystals were composed of racemic heterodimers. HPLC analysis of the mother liquor also revealed an increase in the enantiopurity of the catalyst from 72% to 98% ee. Notably, recrystallization was achieved by mimicking the reaction conditions, that is, using the same solvent, toluene, at low temperatures. X-ray diffraction analysis of the heterodimer revealed the nature of the interaction between the two enantiomers. Based on our hypothesis, we expected an intermolecular hydrogen bond between NH and NO. However, this interaction occurred in an intramolecular manner (Figure 4). Surprisingly, the dimer was held together via hydrogen bonding between the relatively acidic aromatic CH at the C3 position of the isoquinoline ring and the NO. On the basis of this data and the similarity of C1 with QUINOX (which showed first-order kinetics[8d]) we initially ascribed the observed NLE to the formation of insoluble heterodimers.[19] However, Denmark and co-workers observed higher-order kinetics in the reaction catalyzed by chiral phosphoramides, thereby supporting that the observed NLE arises from a mechanism involving two molecules of the catalyst bound to the chlorosilane.[4b] Therefore, we decided to perform kinetic experiments to assess this possibility. To evaluate the order of the reaction in the catalyst, we used the Burés method[20] conducting reactions at 2.5 mol%, 5 mol% and 10 mol% of catalyst (see SI for details). Unexpectedly, the kinetic data ruled out first-order kinetics in C1, suggesting that the nonlinear effect (NLE) could be attributed to a mechanism involving second-order kinetics in the catalyst. However, the possibility of inactive heterodimer formation contributing to the effect cannot be disregarded. Because C1 was obtained in better yields than the other catalysts, and catalyzed the model reaction with the higher enantioselectivity within the series, it was selected as the optimal catalyst to further explore the scope of the reaction. We performed the allylation reaction using different aromatic aldehydes 3 A–Nwith diverse electronic properties and substitution patterns (Scheme 2). In general, the reaction proceeded with excellent enantioselectivity (>90% ee in most cases and up to 99% ee). Comparing the optical purity of the psubstituted series A–E, it is worth noting that this method is highly tolerant to the electronic properties of the substrate. In fact, the enantioselectivity difference between the products of p-nitrobenzaldehyde, 5Ba, and p-anisaldehyde, 5Ea, was only 4%, albeit the latter was obtained in lower yield.[20] This represents a significant improvement over the most competitive analog, QUINOX, which fails to achieve high levels of enantioselectivity in reactions with electron-rich aldehydes.[8c,d] Additionally, this small range of enantiomeric excess might indicate that there must be an efficient, unique and common transition state for the stereodetermining step, irrespective of the electronic properties of the substrate. Regarding the reaction yields, aldehydes with electron-withdrawing groups behaved better than those with electron-donating groups, regardless of the substitution pattern. As previously mentioned, extreme cases were represented by the products obtained from p-nitrobenzaldehyde (5Ba,>99%) and p-anisaldehyde (5Ea, 37%). It should be noted that, in the former case, chloroform was used as the solvent because the aldehyde was poorly soluble in toluene. At any rate, the p-substituted series 3A–Eis the most reactive as a whole, while the o-substituted series 3J– Mis the least reactive one, presumably due to the steric hindrance they cause next to the electrophilic center. In addition, catalyst C1 has a better performance with electronwithdrawing aldehydes; just opposite to most N-oxide catalysts and in line with QUINOX.[8c,d] In addition, the allylation of heterocyclic derivatives such as thiophene and pyridine aldehydes 3N and 3O were also explored with divergent results. While the pyridine product 5Oa was isolated in poor yield and in racemic form, the thiophene derivative 5Na was obtained with an excellent 98% ee, albeit in moderate yield. We also attempted the allylation of more challenging substrates such as cinnamaldehyde or dihydrocinnamaldehyde. Unfortunately, the corresponding homoallylic alcohol was obtained in low yield and selectivity in the former case, while no reaction takes place in the latter.[20] To extend the scope and shed light on the reaction mechanism, we performed the reaction with the corresponding Figure 4. X-Ray structure of C1 heterochiral dimer. Wiley VCH Donnerstag, 07.11.2024 2421 / 366646 [S. 491/493] 1 ChemCatChem 2024,16, e202400806 (4 of 6) © 2024 The Author(s). ChemCatChem published by Wiley-VCH GmbH ChemCatChem Research Article doi.org/10.1002/cctc.202400806 18673899, 2024, 21, Downloaded from https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/cctc.202400806 by Readcube (Labtiva Inc.), Wiley Online Library on [22/04/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License (E)4b and (Z)4c crotyltrichlorosilanes. In these cases, we found that the reaction was slower, requiring 48 h and 72 h for (E)4b and (Z)4 c silanes, respectively. Interestingly, contrary to the reaction catalyzed by QUINOX, (E)-crotylsilane reacted faster than the (Z)-isomer when C1 was used.[8d] After performing the reaction with several aldehydes 3, diastereoselectivities were as high as expected for Lewis base-catalyzed crotylations, being higher for the (Z)-isomer, even though the reaction was slower. In any case, the observed diastereoselectivity is in agreement with a chair-like transition state[3,8c,d,21] because it explains the synor antiaddition depending on the stereoisomerism of the crotylsilane (Scheme 2). Interestingly, the strong positive nonlinear effect was observed not only for the allylation reactions but also for the (E)- and (Z)-crotylations. Conclusions In conclusion, axially chiral IAN-type N-oxides have been shown to be excellent catalysts for the enantioselective allylation and crotylation of aromatic aldehydes with a remarkable positive nonlinear effect, unprecedented in this type of reaction. In contrast to other chiral N-oxide derivatives, these catalysts were prepared in a straightforward manner, avoiding lengthy synthetic routes from the chiral pool or resolution of diastereomers, which are common procedures for this type of catalysts. The origin of this nonlinear effect can be explained by the observed second-order kinetics in the catalyst, although the formation of off-cycle heterodimers stabilized by intermolecular hydrogen bond interactions cannot be disregarded as a contributing factor. X-Ray diffraction analysis revealed that, contrary to our expectations, the heterodimer was stabilized through hydrogen bonding between the NO and the acidic C(3)H of the isoquinoline ring, instead of the NH. Owing to this nonlinear effect, homoallylic alcohols were obtained in moderate to high yields and enantioselectivities of up to 99% ee with a non-racemic catalyst with 90% enantiopurity. This method was also extended to the crotylation of aromatic aldehydes, where a similar nonlinear effect was observed, affording the corresponding alcohols in high yields and diastereoand enantiopurities. Supporting Information Summary Crystallographic data, spectroscopic data and experimental details are provided in the Supporting Information. Deposition Number 2351851 (for rac-C1), contains the supplementarycrystallographic data for this paper. These data are provided free of charge by the joint Cambridge Crystallographic Data Centre and Fachinformationszentrum Karlsruhe Access Structures service. The authors have cited additional references within the Supporting Information (Ref. [24–31]). Acknowledgements We thank the Spanish MICINN (grants PID2019–106358GBC21, PID2019–106358GB-C22, PID2022–137888NB-I00, PID2022– Scheme 2. Allylation and crotylation of aldehydes catalyzed by C1: Scope.[a] Wiley VCH Donnerstag, 07.11.2024 2421 / 366646 [S. 492/493] 1 ChemCatChem 2024,16, e202400806 (5 of 6) © 2024 The Author(s). ChemCatChem published by Wiley-VCH GmbH ChemCatChem Research Article doi.org/10.1002/cctc.202400806 18673899, 2024, 21, Downloaded from https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/cctc.202400806 by Readcube (Labtiva Inc.), Wiley Online Library on [22/04/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 143230NB-I00; European FEDER funds and the Junta de Andaluciá (Grants P18-FR-3531, P18-FR-644, US-1262867) for financial support. Conflict of Interests The authors declare no conflict of interest. Data Availability Statement The data that support the findings of this study are available in the supplementary material of this article. Keywords: Organocatalysis ·Nonlinear effects ·N-oxides · Allylation ·Trichlorosilanes [1] a) E. M. Carreira, L. Kvaerno, Classics in Stereoselective Synthesis, WileyVCH, Weinheim, 2009, 153–185; b) M. Yus, J. C. González-Gómez, F. Foubelo, Chem. Rev. 2013,113, 5595–5698; c) T. A. Fattah, A. Saeed, New J. Chem. 2017,41, 14804–14821; d) Z. Boiarska, T. Braga, A. Silvani, D. Passarella, Eur. J. Org. Chem. 2021,2021, 3214–3222; e) S. E. Denmark, J. Fu, Org. 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