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Review

Organocatalysis: A Tool of Choice for the Enantioselective Nucleophilic Dearomatization of Electron-Deficient Six-Membered Ring Azaarenium Salts

Normandie University, UNIROUEN, INSA Rouen, CNRS, COBRA, 76000 Rouen, France
*
Author to whom correspondence should be addressed.
Submission received: 28 September 2021 / Revised: 15 October 2021 / Accepted: 16 October 2021 / Published: 18 October 2021

Abstract

:
Nucleophilic dearomatization of azaarenium salts is a powerful strategy to access 3D scaffolds of interest from easily accessible planar aromatic azaarene compounds. Moreover, this approach yields complex dihydroazaarenes by allowing the functionalization of the scaffold simultaneously to the dearomatization step. On the other side, organocatalysis is nowadays recognized as one of the pillars of the asymmetric catalysis field of research and is well-known to afford a high level of enantioselectivity for a myriad of transformations thanks to well-organized transition states resulting from low-energy interactions (electrostatic and/or H-bonding interactions…). Consequently, in the last fifteen years, organocatalysis has met great success in nucleophilic dearomatization of azaarenium salts. This review summarizes the work achieved up to date in the field of organocatalyzed nucleophilic dearomatization of azaarenium salts (mainly pyridinium, quinolinium, quinolinium and acridinium salts). A classification by organocatalytic mode of activation will be disclosed by shedding light on their related advantages and drawbacks. The versatility of the dearomatization approach will also be demonstrated by discussing several chemical transformations of the resulting dihydroazaarenes towards the synthesis of structurally complex compounds.

Graphical Abstract

1. Introduction

Dihydropyridines and their azaarene counterparts like dihydroisoquinolines, dihydroquinolines and dihydroacridines are widespread backbones in naturally occurring products or drugs and are interesting building blocks for the construction of complex architectures (Figure 1a) [1]. For example, 1,4-dihydropyridines are present in the well-known NAD (nicotinamide adenine dinucleotide), a co-enzyme found in living cells which exists under two red-ox forms (NAD+/NADH), in the so-called Hantzsch ester, a useful hydride transfer reagent in organic synthesis, or in Nifedipine, a drug used for the treatment of hypertension. Although less stable, 1,2-dihydropyridines were reported as useful reactive building blocks, for example in the synthesis of (−)-Oseltamivir (Tamiflu®), a drug used in the treatment of influenza [2]. Therefore, several strategies were developed for the enantioselective synthesis of these scaffolds based upon two major approaches (Figure 1b). The first one involving the construction of the dihydroazaarenes, a strategy that will not be covered in this review [3,4,5,6]. The second one involves the dearomatization of azaarenes by nucleophilic addition or reduction (addition of hydride) to the corresponding azaarenium salt. Dearomatization is very appealing since it produces 3D scaffolds from readily available aromatic precursors. Whereas enantioselective hydride addition requires the use of pre-functionalized azaarenes (introduction of Nu prior to the addition of the hydride) and leads to tetrahydro products (and therefore will not be discussed herein) [7,8,9], nucleophilic dearomatization (Nu ≠ H) offers the advantage of introducing chemical diversity simultaneously to the dearomatization step. Nevertheless, the azaarenes suffer from poor electrophilicity and thus generally require an activation step to undergo a nucleophilic addition (Figure 1c). The activation step can occur by introducing a carbamate on the nitrogen of the azaarene to afford the corresponding azaarenium as more electrophilic species. As far as N-alkyl azaareniums are concerned, the introduction of an extra electron-withdrawing group at the C3 position is generally mandatory to ensure good reactivity towards a wide array of nucleophiles. Moreover, azaarenium salts exhibit two different electron-deficient sites at positions C2 (mainly for pyridinium, isoquinolinium and quinolinium salts) and C4 (mainly for pyridinium, quinolinium or acridinium salts). The regioselectivity of the addition is related to the HSAB theory, hard nucleophiles generally add at the C2 position whereas soft nucleophiles add to the C4 position [10], albeit the catalyst might also influence this issue.
Taking into account the above-mentioned challenges, enantioselective nucleophilic dearomatization of azaarenium salts has attracted a great deal of attention mostly by using metal catalysts with chiral ligands [11,12,13,14,15,16,17,18,19,20]. Nevertheless, in the last fifteen years and due to the advent of organocatalysis [21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36], which was recently highlighted through the Nobel Prize of Prof. B. List and Prof. D. MacMillan, several enantioselective organocatalytic dearomatization reactions of azaarenium salts have been reported [11,13,14,15,16,18,19,37,38]. Organocatalysts can be classified following the mode of activation of either the electrophilic and/or nucleophilic partners involved in a given reaction [24,25]. Activation can be performed through covalent and/or noncovalent interactions with the substrates (Figure 1d). As far as non-covalent interactions are concerned, anion binding or H-bonding interactions can be achieved thanks to chiral (thio)urea or oligotriazole catalysts for instance. Covalent catalysis generally involves chiral primary or secondary amines (also known as aminocatalysis) or N-heterocyclic carbenes (NHC) catalysts. Whatever the type of catalysts, well-organized transition states are favored by low energy interactions (coulombic or H-bonding interactions) and eventually enhanced by at least two modes of activation occurring simultaneously thanks to the so-called bifunctional organocatalysis results in a high level of enantioselectivity [39]. These unique features of organocatalysis are of particular interest in order to better control the regioselectivity of the enantioselective nucleophilic addition to azaarenium salts along with affording a high level of enantioselectivity.
With all these prerequisites in mind, this review intends to summarize the work reported so far (September 2021) in the field of organocatalyzed nucleophilic dearomatization reactions of azaarenium salts (i.e., isoquinolinium, quinolinium, pyridinium and acridinium salts) giving access to corresponding enantioenriched dihydroazaarenes. Publications will be classified according to the organocatalytic mode of activation employed for the dearomatization reaction. Moreover, special attention will be paid to the specific advantages and drawbacks of the modes of activation with respect to specific substrates. Further transformations of dihydroazaarenes allowing the introduction of chemical diversity will also be underlined.

2. Anion-Binding Catalysis

2.1. Activation Mode of Azaarenium Salts in Anion-Binding Catalysis

In organocatalysis, H-bonding donor catalysts (thioureas, squaramides…) are better known for their ability to activate neutral electrophiles (Figure 2a) [33,40]. As mentioned earlier, the dearomatization reaction of azaarenes generally requires an activation step namely the formation of an azaarenium flanked by an anion (chloride or bromide in most of the cases) resulting from the reaction of azaarenes with acyl halide derivatives (in situ protocols) or with alkyl halides (preformed ion pair). The ion pair thus formed, allows H-bonding donor catalysts to complex the anion of the substrate thereby forming a well-organized supramolecular chiral entity responsible for the high level of enantioselectivity generally observed through the so-called “anion binding” strategy (Figure 2b). Moreover, even if simple H-bonding donor catalysts provided a high level of enantioselectivity, bifunctional organocatalysts were developed in order to tackle the regioselectivity issue associated with the nucleophilic dearomatization of azaareniums salts. Thus, in addition, to bind the counter ion of the azaarenium salts, these bifunctional catalysts can either (1) guide the nucleophilic partner to a specific electrophilic center of the azaarenium salt thanks to extra H-bonding interactions (Figure 2c) or (2) block one of the electrophilic positions of the azaarenium salts through a first addition thus allowing the second addition of the nucleophile in a highly regioselective fashion (Figure 2d).

2.2. Isoquinolinium Salts

Pioneering work in anion-binding catalysis applied to the nucleophilic dearomatization of azaarenes was published by Jacobsen et al. concerning a Reissert-type addition of silyl ketene acetal 2a on isoquinolinium salts formed in situ by reaction between isoquinoline 1 and acyl or carboxyalkyl chloride (Scheme 1) [41]. The optimization of the reaction conditions showed that the Troc moiety on the isoquinolinium salt as well as thiourea catalyst C1 were necessary to achieve high level of enantioselectivity. With these conditions, a small array of dihydroisoquinolines 3 (8 examples) were then synthesized in acceptable to very good yields (67–86%) and up to 92% ee (60–92% ee) (Scheme 1a). The synthetic utility of enantioenriched dihydroisoquinoline 3a was demonstrated by accessing unprotected tetrahydroisoquinoline 4a via the reduction of the enamide followed by cleavage of the Troc moiety without any racemization. The absolute configuration was assigned by comparing the optical rotation of transesterification product (R)-4b with literature data (Scheme 1b).
Following this achievement, Mattson et al. developed, in 2013, a similar Reissert-type addition catalyzed with chiral silanediol C2 (Scheme 2) [42]. Although silanediols have been used as H-bonding donor catalysts in the past [43], this was the first report of silanediols as anion binding catalysts as well as the first synthesis of enantiopure silanediol C2 with axial chirality. This catalyst proved to be able to promote the enantioselective addition of silyl ketene acetals 2 to isoquinolinium salts, leading to the corresponding dihydroisoquinolines 3 in acceptable to very good yields (55–80%) and low to moderate ees (8–50%); bigger silyl groups SiR3 leading to higher ees (TMS: 8% ee; TBS: 18% ee; TIPS: 28% ee) (Scheme 2a). As far as the mechanism of the reaction is concerned, an NMR study demonstrated that silanediols were able to efficiently bind chloride ions (Scheme 2b), which was further evidenced by crystallization of an ion pair between hydrochloride isoquinolinium salt and achiral silanediol (Scheme 2c).
Thereafter, in 2016, García Mancheño et al. reported on the dearomatization of isoquinolines during the addition of silyl ketene acetals 2 by means of an original oligotriazole with helicoidal chirality as catalyst (Scheme 3) [44]. An extensive screening showed that an oligotriazole composed of four triazole moieties gave the best results. Among all the tetratriazoles tested, C3 yielded the best enantioselectivity, leading to dihydroisoquinoline 3a in 84% yield and an encouraging 38% ee despite a strong background reaction (44% yield without catalyst). After further optimization, a range of dihydroisoquinolines 3 were obtained in moderate to excellent yields (44–92%) and ees up to 72% (Scheme 3a). It is worth noting that the use of TrocBr instead of TrocCl did not affect the yield of the reaction (Br: 82% yield vs. Cl: 79% yield) although a significant loss of ee was observed (Br: 32% ee vs Cl: 56% ee), suggesting that bromide also binds to C3 but it does so with a lower efficiency than chloride (Scheme 3b). Finally, kinetic studies evidenced a surprisingly retarded reaction during the first 3 h followed by a marked acceleration of the process. This “delay” was ascribed to the period required for oligotriazole C3a to efficiently bind the chloride anion of the isoquinolinium salt (Scheme 3c).
In 2016, Mukherjee et al. expanded the range of possible nucleophiles by reporting the addition of silyl dialkyl phosphites 5 on isoquinolinium salts leading to α-aminophosphoranes (Scheme 4) [45]. Catalyst C4 gave the best results at −80 °C, leading to a wide array of dihydroisoquinolines 6 in acceptable to excellent yields and ees generally above 80%, although in some cases a longer reaction time or higher temperature was required to bring the reaction to completion (Scheme 4a). Additionally, this reaction was applicable to dihydroisoquinolines and quinoline, leading respectively to tetrahydroisoquinolines 7 in 77 to 96% isolated yield and up to 90% ee and dihydroquinoline 8a in 70% yield and 62% ee (Scheme 4b). The removal of the activating Troc group proved to be challenging. However, Mukherjee’s team successfully applied this transformation to N-Fmoc-activated quinolinium salt leading to the corresponding N-Fmoc-dihydroisoquinoline 7a (73%, 75% ee). Treatment of 7a by piperidine led to N-H tetrahydroisoquinoline 9a in 91% yield and 62% ee (Scheme 4c).
More recently, Lassaletta’s team tackled the addition of N-tert-butyl hydrazones 10 in the dearomatization of isoquinolines 1 (Scheme 5) [46]. It was envisioned that both the catalyst C5 and the hydrazone would be able to bind the chloride anion of the in situ-formed isoquinolinium salt, therefore rigidifying the transition state and leading to high levels of enantioselectivity. This working hypothesis was supported by computational studies of non-covalent interactions and eventually allowed to determine the lowest-energy transition structure leading to the major enantiomer. The optimized conditions yielded the corresponding dihydroisoquinolines 11 in acceptable to good yields, complete diastereoselectivity towards the anti-product and excellent ees (generally above 90%) (Scheme 5a). However, this reaction was limited to dihydroisoquinolines, as no reaction was observed with pyridines. Moreover, only chloroformates were tolerated as activating groups, since no other activating group (Cbz, Alloc, Ac, Bn) triggered the reaction. The authors performed various synthetic transformations among which the oxidation of the hydrazone moiety in dihydrophenanthridine 12a (84% yield, >98:2 dr, 94% ee) (Scheme 5b). It was also evidenced that the hydrazone could be transformed to the corresponding ketone 13a without any racemization via oxidation of the intermediate imine (70% yield, 94% ee).
As part of an effort to develop new dual-catalysis approaches in organocatalysis, Seidel’s group reported on the enantioselective addition of azlactones 14 to isoquinolines 1 (Scheme 6) [47]. Unlike previous reactions in this chapter, there was no need for an external activating group such as TrocCl since the carboxyalkyl moiety of the azlactone was able to interact with isoquinoline 1 to form the corresponding isoquinolinium salt in situ. The enantioselective addition of the enolate (complexed by catalyst C4) to the isoquinolinium salt at the C1 position led to the corresponding dihydroisoquinolines 15. During the optimization, it was found that the strong background reaction (95% yield at −10 °C for 3 h in mesitylene) could be avoided both by lowering the temperature and using more apolar solvents. These optimized conditions were then applied to a variety of isoquinolines 1 and azlactones 14, yielding differently substituted dihydroisoquinolines 15 in excellent yields (81–95%), diastereoselectivities (87:13 to 96:4 dr) and high enantioselectivities (88–93% ee).

2.3. Quinolinium Salts

In 2014, García Mancheño et al. reported on the dearomatization of quinolines 16 via Reissert-type addition of silyl ketene acetals 2 catalyzed by a chiral oligotriazole C6 (Scheme 7) [48]. The reaction occurred in a one-pot sequence involving (1) the activation of the quinoline into a quinolinium salt and (2) addition of the silyl ketene acetals 2 onto the quinolinium salt. During the optimization of the reaction conditions, bistriazole C6 (Scheme 7c) was tested but provided very low selectivity (91%; 18% ee), therefore underlining the need for helicoidal chirality to ensure an efficient chirality transfer. Tetratriazole C6 was therefore chosen as the best catalyst, and an array of dihydroquinolines 17 (15 examples) were synthesized on average to excellent yields (67–86%) and up to 92% ee (60–92% ee) (Scheme 7a). In order to demonstrate the synthetic utility of the so-obtained enantioenriched dihydroquinolines 17, substrate 17a was reduced into the corresponding tetrahydroisoquinoline 18a without any racemization (Scheme 7b). Absolute configuration was assigned by comparison of the optical rotation with literature data of the unprotected product 18a. Finally, NMR and circular dichroism studies provided mechanistic insight by highlighting the accommodation of the chloride anion inside the chiral cavity of catalyst C6 through H-bonding interactions.
In 2017, García Mancheño et al. extended this methodology to the addition of silyl dialkyl phosphites 5 on quinolines 16 catalyzed by chiral oligotriazole C6 (Scheme 8) [49]. The desired dihydroquinolines 8 were obtained in average to good yields (59–95%) and generally very good ees (up to 94% ee) (Scheme 8a). If the 1,2-dihydroquinolines remained the major regioisomer in all cases (vs 1,4-dihydroquinolines), the authors observed that the presence of residual moisture decreases both yield and regioselectivity. The authors showed that aminophosphorane 8b (84% ee) could undergo further transformations such as the reduction of the dihydroquinoline core to tetrahydroquinoline 19a (99%, 84% ee) or the transesterification of the phosphite (8a, 71% over three steps, 84% ee) without any observable racemization (Scheme 8b).
In order to further expand the scope of this organocatalytic dearomatization of quinolines 16, García Mancheño et al. tested the conditions they had previously developed on other nucleophiles (Scheme 9) [50]. Among them, electron-rich heterocycles 20 and metal allyl reagents 21 led to the corresponding 1,2-dihydroquinolines 23 as the major product with almost no enantioselectivity by using C6 as organocatalyst. On the other hand, encouraging results were obtained with silyl enol derivatives, and especially with silyl ketene thioacetal 22 (R2 = St-Bu, 50% yield, 70% C-2/C-4, 44% ee), which was therefore subjected to further optimization.
The optimization of the reaction with silyl ketene thioacetal 22 provided a range of 1,2-dihydroquinolines 23 with 39 to 62% yield, good to complete regioselectivity and ees up to 84% (Scheme 10a). Other silyl-based nucleophiles were then tested under these conditions to provide the corresponding 1,2-dihydroquinolines 24–26 (Scheme 10b). The best ee was obtained with Danishefsky’s diene, yielding 1,2-dihydroquinoline 24a with 64% yield and 72% ee. The synthetic utility of the thioesters 23a was shown through a four-step synthesis furnishing the corresponding N-tosyl tetrahydroquinoline 27a without any racemization (Scheme 10c).
More recently, García Mancheño et al. reported on the addition of formaldehyde-derived hydrazones 27 to quinolines 16 catalyzed by chiral oligotriazole C8 (Scheme 11) [51]. During the optimization, catalyst C8 proved to be superior to tetratriazole C6 and it was hypothesized that the anion-binding affinity could be enhanced through H-bonding between the CF3 group of C8 and carbonyl hydrogen of the hydrazone. A large range of dihydroquinolines 28 (39 examples) were obtained in low to excellent yields (11–97%) and generally very good ees (up to 90% ee) (Scheme 11a). It is worthy of note that the reaction was also applied to a couple of pyridine derivatives (18–30%, 70–80% ee), albeit less efficiently. Dihydroquinoline 28a could be transformed either to the corresponding aldehyde 29 or carbonitrile derivatives 30, which could, in turn, be subjected to further modifications to afford compounds 31–35 without any racemization (Scheme 11b). Finally, DFT calculations allowed the authors to propose a lowest-energy transition state that thanks to the H-bonding network and preorientation of the nucleophile provides the desired products with (S)-absolute configuration.
Takemoto et al. described a Petasis-type addition of vinyl boronic acids 36 to quinolines 16 using a dual-catalysis approach but making use of a different type of anion-binding activation strategy (Scheme 12) [52]. During the optimization, the addition of H2O and NaHCO3 in the reaction was beneficial to the reaction. Water seemingly enhanced the enantioselectivity by assisting the regeneration of the catalyst, while with NaHCO3, an increase of the yield was observed, which was attributed to the trapping of the boronic acid formed during the reaction. With the optimized conditions in hand, an array of 1,2-dihydroquinolines 37 were synthesized with complete regioselectivity, and yields ranging from 28 to 78% as well as very good to excellent ees (82–97% ee) (Scheme 12a). In this reaction, bifunctional catalyst C9 is composed of a thiourea moiety that binds the intermediate N-acyl quinolinium while the 1,2-aminoalcohol part complexes the boronic acid, bringing the substrates in close proximity to obtain 1,2-dihydroquinoline 37 (Scheme 12b). In order to showcase the use of these substrates, (+)-Galipinine 38a was synthesized from dihydroquinoline 37a, which also enabled the authors to determine the absolute configuration of the obtained products by comparison to the literature (Scheme 12c).

2.4. Pyridinium Salts

As previously seen, the dearomatization of azaarenium salts gave rise to highly functionalized N-heterocycles but, dearomatization of pyridines poses additional challenges. Firstly, the complete loss of aromaticity during the reaction (unlike quinolines and isoquinolines) heightens the energetic cost of the reaction, rendering pyridines less reactive than their N-heteroarenes counterparts. Moreover, the three electrophilic positions on the pyridinium nucleus (C2, C4 et C6) make the control of the regioselectivity very challenging.
In 2015, García Mancheño’s team was the first to report the enantioselective organocatalytic dearomatization of pyridinium salts using oligotriazole catalyst C6 (Scheme 13) [53]. The authors successfully transposed their previous work describing the “anion-binding” catalysis-mediated addition of silyl ketene acetals 2 on the in situ-formed quinolinium to pyridininium counterparts. After careful optimization, the scope of the reaction was studied on a variety of pyridines 39, leading to the corresponding dihydropyridines 40-41 in 50 to 87% yield and up to 98% ee (Scheme 13a). However, in this reaction, regioselectivity was highly dependent upon the substitution of the pyridine on positions C2, C3 and/or C4. As a general trend, substitution of the pyridine on position C2 or C4 led to the corresponding 1,6-dihydropyridines 40 (94:6 to 100:0 C6/C4) whereas substitution on position C-3 yields 1,4-dihydropyridines 41 as the major product (95:5 to 0:100 C6/C4 except for R = 3-CN, 61:39 C6/C4), as it is also the case with the unsubstituted pyridine (35:65 C6/C4). The authors further modified dihydropyridines 40a and 41a by reduction to the corresponding tetrahydropyridines 43a and 42a respectively and removing the Troc activating group without observing any racemization (Scheme 13b).
The conditions, previously reported by the same group for the addition of dialkyl phosphites 5 to quinolinium salts (see Scheme 8), were also extended to pyridinium salts (Scheme 14) [49]. The desired dihydropyridines 44 were generally obtained in lower ees (52–78% ee) (Scheme 14a). Complete control of the regioselectivity could be achieved in most cases, but low noticeable amounts of 1,4-dihydropyridines were observed with 3-picoline and pyridine (C6/C4: 93:7 and 92:8 respectively). The dearomatization was also performed with CbzCl as an activating agent albeit less successfully (44a, 79% yield, 30% ee), followed by reduction and Cbz-removal of the intermediate dihydropyridine 44a, thus yielding pipecolic phosphonic acid 45 in 50% over 2 steps, whose absolute configuration has been assigned based on the literature data (Scheme 14b).
After García Mancheño’s pioneering work on the organocatalytic dearomatization of pyridinium salts, Bernardi et al. described the regio- and enantioselective addition of indoles 46 to N-alkyl pyridinium salts 47 (substituted by an electron withdrawing group on C3 position) catalyzed by chiral thiourea C10 (Scheme 15) [54]. It is worthy to note that this is the only reaction to date that involves both anion-binding catalysis and N-alkyl azaarenium salts, affording highly regioselective addition at the C4 position. However, the optimization proved to be tricky: a base had to be added to neutralize the HBr formed in the reaction, but consequently, an undesired racemic product from the base-promoted N-addition of the indole 46 was observed (71:29 C/N ratio) (Scheme 15b). This problem was overcome by adding the base with a syringe pump over 10 h (75:25 to >95:5 C/N ratio). Moreover, a sterically hindered benzyl group was necessary to reach good levels of enantioselection. Under these optimized conditions, 1,4-dihydropyridines 48 were obtained with complete regioselectivity in moderate to very good yields (45–80%) and ees up to 91% (Scheme 15a). Interestingly, 3-nitropyridinium salts 47 (EWG = NO2) led to better results (70–80%, 90–91% ee for the corresponding product 48) compared to 3-cyanopyridinium salts 47 (EWG = CN) (45–55% and 80–89% ee with 15 mol% C10 at room temperature for the corresponding product 48). The authors showed the synthetic potential of the resulting 1,4-dihydropyridine 48a by performing (1) an iodoetherification to provide 50a (72%, >95:5 dr, 87% ee) and (2) a reduction furnishing the tetrahydropyrdine 51a (>90%, >95:5 dr, 90% ee) (Scheme 15d). An NMR study led to a proposal for the transition state where the quinuclidine moiety of thiourea C10 adds to the C6 position of the pyridinium salt to form an aminal thus avoiding the addition of the nucleophile at this position. Accordingly, the indole addition occurs regioselectively at the C4 position through an SN2′ type-mechanism (Scheme 15c).

2.5. Others

Up to date, the topic of diazaarene dearomatization has remained elusive in the literature and only one paper comes from García Mancheño’s team who reported the addition silyl ketene acetal 2a on a range of diazaarenes catalyzed by chiral triazole C6 (Scheme 16) [55]. Optimization of the reaction for quinazoline 52 led to the corresponding product with an excellent 92% ee (Scheme 16a). However, attempts to transpose the reaction to other azaarenes (naphhyridine, phthalazine, pyridazine, naphthyridine…) resulted in a steep loss of enantioselectivity at best and, at worst, complete decomposition of the product (pyrazole, quinoxaline). The authors successfully performed further synthetic transformations from quinazoline adduct 53a, such as sodium borohydride-mediated reduction of the pyrimidine cycle (54a, 64%, 88% ee) or transesterification of the Troc moiety to a methylcarbonate (55a, 84%, 94% ee); both reactions were conducted without erosion of the enantioselectivity (Scheme 16b).
Very recently, the group of García-Mancheño extended the dearomatization of quinazoline derivatives 52 by implementing a vinylogous-Mukaiyama type addition of silyl dienol ethers 56 (Scheme 17) [56]. In the presence of only 3 mol% of catalyst C6, a highly regioselective C4-addition (>25:1) occurred providing several dearomatized adducts 57 in modest to high isolated yields (39–99%) and fair to excellent level of enantioselectivity (54–95% ee) (Scheme 17a). The aromatic ring of the quinazoline can be substituted by a wide array of substituents (F, NO2, Br, Me, Bpin…) at the 5-, 6- or 7-position. It is worthy of note that the absolute configuration was assigned thanks to X-ray crystallographic analysis. Regarding the substitution of the silyl dienol ethers 56, several R2 groups were evaluated (OMe, Ot-Bu, OPh, SMe) showing that except for the SMe substituent, excellent levels of enantioselectivity were obtained (R1 = H, 92% ee vs 64% ee respectively). Interestingly, catalyst C6 can be recovered from the reaction mixture in 90% yield and re-used without any loss in both yield and ee (Scheme 17b). This strategy has also been successfully applied to quinoline and pyridine derivatives provided that the conditions were slightly modified (10 mol% of C8 in Et2O:C6F6 (3:1) at −30 °C or in C6F6 at 6 °C respectively) (Scheme 17c). Whereas quinoline derivatives afforded the corresponding dihydroazaarenes 58 in high yields and enantiomeric excesses (57–81%, 64–82% ee), the only example reported in the pyridine series yielded lower yield and ee (59a, 46%, 40% ee). Finally, dihydroquinazoline 57a has been derivatized into chiral lactam 61 by N-deprotection of the Troc group followed by selective hydrogenation of the double bond of 60a in a modest 47% yield over two steps but without any racemization (Scheme 17d).

3. Aminocatalysis

3.1. Activation Mode of Azaarenium Salts in Aminocatalysis

Since the advent of organocatalysis in the early 2000s, aminocatalysis (or catalysis by primary or secondary amines) has been defined as the method of choice for the activation at the α-CH or β-CH position of carbonyl compounds by the formation of an iminium or an enamine species respectively [57]. In the next paragraphs, we will focus on the nucleophilic addition of carbonyl compounds mostly aldehydes to azaarenium salts catalyzed by chiral primary or secondary amines derived from proline or Cinchona alkaloids through the formation of iminium/enamine intermediates (Figure 3). Generally speaking, this mode of activation provides excellent regioselectivity for the addition (1,4- vs. 1,2-addition) depending on the azaarenium salt involved, and modest to high diastereoselectivity and excellent enantioselectivity. Nevertheless, despite these promising features, several drawbacks remain to be addressed. The first one deals with the low electrophilicity of the azaarenium salt especially for N-alkyl pyridinium salts thus requiring the introduction of an electron-withdrawing substituent generally at the C3 position of the ring. Moreover, addition products are sometimes difficult to purify due to their poor stability thus, requiring an additional chemical transformation prior to the isolation of the product. The most widespread one is the carbonyl reduction into the corresponding alcohol but the Wittig reaction was also reported to be efficient. Finally, the last step of the catalytic cycle, namely the hydrolysis of the iminium intermediate to afford the desired product along with the regeneration of the chiral catalyst, results in the formation of a stoichiometric amount of HX that could be detrimental for the next catalytic cycles. In order to prevent any problems, the addition of an extra achiral Brønsted base, at least, in a stoichiometric amount is mandatory. Considering the aforementioned points, the set-up of optimized conditions for the aldehyde addition to azaarenium under aminocatalytic conditions proves to be challenging as shown below.

3.2. Isoquinolinium Salts

The first report using aminocatalysis for the dearomatization of isoquinolinium salts 62 was published by the group of Jørgensen in 2005 by making use of (2S,5S)-2,5-dibenzylpyrolidine C11 as a catalyst (Scheme 18) [58]. By taking advantage of the presence of an aldehyde on the 2-(5-oxopentyl)isoquinolinium derivative 62, an enamine intermediate was formed in the presence of the chiral catalyst C11 and added to the electrophilic carbon of the isoquinolinium moiety. Then, after the ring closure, hydrolysis of the transient iminium ion provided the 1,2-dihydroquinoline derivatives 63. The generated HX was trapped by external base Et3N, to allow the catalyst regeneration. 1,2-dihydroquinoline derivatives 63 were obtained in high conversions but revealed to be unstable and, thus, first required the in situ protection of the enamine by a trifluorocetylation reaction catalyzed by DMAP (for compound without substituent at C-4 position) to afford 64 which could be isolated. Finally, the reduction of the aldehyde function of 64 to the corresponding alcohol gave a fully analyzable product 65 (Scheme 18b). Generally speaking, moderate isolated yields (over three steps) below 73% were obtained. Nevertheless, high diastereomeric ratios (15:1 to >98:2) and an excellent level of enantioselectivity (85–96% ee) were observed for products 65. Even phtalazine skeleton (Y = N) was well-tolerated providing dihydrophtalazines 65 with interesting yield, dr and ee (59%, >98:2, 93% respectively) (Scheme 18a). It is worthy of note that the presence of electron-donating groups on the aromatic part of the isoquinoline ring (R1 = 5,7-(OMe)2) was the main limitation resulting in a drastic drop of the conversion (50%), diastereomeric ratio (10:1) and enantioselectivity (49% ee).
Several years later, Cozzi et al. reported on an intermolecular addition of aldehydes 66 to in situ-generated isoquinolinium salts in the presence of Hayashi–Jørgensen catalyst C12 (Scheme 19) [59]. Indeed, the quinolinium salt was generated upon slow addition of CbzCl via a syringe pump to the reaction mixture composed of the isoquinoline 1, the catalyst C12 (20 mol%), NaHCO3 (3 equiv) in TBE/DCM (8/2) (Scheme 19a). It should be noted that MacMillan catalyst C13 (see Scheme 22 for the structure) failed to promote the reaction due to a lower rate of production of the enamine intermediates compared to Hayashi–Jørgensen catalyst C12. Thus, by reacting several aliphatic aldehydes 66 with C3, C4, C5, C6 or C7-substituted isoquinoline derivatives 1, dihydroisoquinolines 67 were isolated, provided that the aldehyde intermediate was reduced into the corresponding alcohol (NaBH4, MeOH), as a mixture of syn/anti diastereomers (19:81 to 87:13; in most cases the diastereomers were inseparable) in low to moderate yields (9–75%) but with a high level of enantioselectivity for both syn and anti-isomers (eesyn 54–99% and eetrans 7–98%). Interestingly, a reverse anti-selectivity was observed in some cases (for example for R1 = Ph and R2 = R3 = R4 = R5 = R6 = H or for R1 = Me, R2 = R3 = R4 = H, R5 = R6 = OMe). Generally speaking, a wide array of substituents was well-tolerated, except for 5-(N)-pyrrolidnyl substituent (no reaction), substitution of position C6 (drop of both dr and ee) and 3-methyl (low yield and ee but high dr). Then, several conditions for the reductive removal of the protecting groups from 67a were set up to afford the corresponding tetrahydroisoquinoline 68a or the quinoline 1a without racemization (Scheme 19b). Finally, this dearomatization reaction was used as a key step in the multi-step synthesis of the enantioenriched 13-methyl tetrahydroprotoberberine 69a (95% ee) in 18% overall yield over 8 steps from dihydroquinoline 67b (Scheme 19c). The reaction conditions were slightly modified (100 mol% C12, DCM, 0 °C) to yield the corresponding dihydroisoquinoline 67c in excellent yield (92%), high diastereoselectivity in favor of the anti-isomer (anti/syn 78:22) and excellent enantiomeric excesses for both diastereoisomers (eeanti 95% and eesyn 85%). Further transformations led to the enantioselective synthesis of tetrahydroprotoberberine alkaloid 69.

3.3. Quinolinium Salts

In 2015, the group of Pineschi tackled the enantioselective dearomatization of the quinolinium salt 72 formed in situ from N-carbamate-2-ethoxy-1,2-dihydroquinolines 70, by nucleophilic addition of aldehydes 66 under synergistic catalytic conditions consisting of a Hayashi–Jørgensen catalyst ent-C12 and TsOH used as a Brønsted acid (BA) (Scheme 20) [60]. By using 20 mol% of both ent-C12 and TsOH in toluene at 0 °C followed by reduction of the carbonyl group to the corresponding alcohol, several enantioenriched dihydroquinolines 71 were obtained in moderate to high isolated yields as a mixture of syn/anti diastereomers which are, in general, inseparable (Scheme 20a). The reaction proved to be syn-selective with a moderate level of diastereoselectivity (63:37 to 83:17). Nevertheless, excellent levels of enantioselectivity (>90% ee in most cases) were observed for the syn diastereomer except when acetaldehyde (R1 = H) was used (PG = CO2Me or Cbz, R2 = H: 11 and 25% ee respectively). Regarding the mechanism, this reaction is based upon the synergistic role of two catalysts namely (1) an aminocatalyst (ent-C12) able to catalytically generate a chiral enamine 73 from the corresponding aldehydes 66 and (2) a Brønsted acid (TsOH) which provides the quinolinium intermediate 72 (Scheme 20b).
The same year and following the same synergistic strategy but in presence of a metal Lewis acid instead of a Brønsted acid, Liu et al. reported on the enantioselective dearomatization of the quinolinium salt formed in situ from N-carbamate-2-ethoxy-1,2-dihydroquinolines 70 by nucleophilic addition of aldehydes 66 (Scheme 21) [61]. Among all the Lewis acid/aminocatalyst couples tested, the best results were obtained by making use of Cu(OTf)2 (10 mol%) and imidazolidinone C14 (20 mol%). Thus, by applying optimal conditions (1 equiv of EtOH in Et2O at rt), several dihydroquinoline derivatives 71 were obtained after reduction of the aldehyde moiety into the corresponding alcohol (Scheme 21a). Generally speaking, high isolated yields (72–91%), modest to high drs in favor of the syn-diastereomer (52:48 to 82:18) and excellent levels of enantioselectivity (eesyn 75–99%; eeanti 64–99%) were obtained for a wide array of substituents on both aldehyde and quinoline partners. It is worthy of note that a one-pot protocol was set up for the synthesis of dihydroquinoline 71a (R1 = n-Pr, R2 = H) from quinoline 16a allowing the in situ generation of the dihydroquinoline 70a which was then subjected to alkylation reaction under standard conditions developed above (Scheme 21b). Nevertheless, this one-pot protocol gave lower diastereo- and enantioselectivity than the classical protocol with pentanal 66b (syn/anti 63:37, eesyn 90%, eeanti 66% vs syn/anti 74:26, eesyn 99%, eeanti 99% respectively). The absolute and relative configurations of compounds 71 were determined by X-ray single crystal analysis after esterification of the alcohol. Finally, the optimized conditions proved to be very specific to quinoline derivatives as an attempt to extend the protocol to dihydroisoquinoline 74a failed (only traces of the desired product were observed) (Scheme 21c).
Almost simultaneously, Rueping et al. reported a rather similar approach as above by using a slightly different synergistic Lewis acid/aminocatalyst catalytic system (Scheme 22) [62]. Thus, in the presence of chiral imidazolidinone C13 (20 mol%) and In(OTf)3 (10 mol%), aldehydes 66 reacted smoothly with N-carbamate-2-ethoxy-1,2-dihydroquinolines 70 providing 1,2-dihydroquinolines 71 after reduction of the aldehyde group to the corresponding alcohol with sodium borohydride. High isolated yields (63–85%) and a modest level of diatereoselectivity ((R,R)/(R,S): 1.5:1 to 4:1) were obtained along with high to excellent enantioselectivity for the major (R,R)-diastereomer (71–97% ee) (Scheme 22a). The absolute configuration of 1,2-dihydroquinolines 71 was ascertained by X-ray single crystal analysis. Then, further derivatizations of product 71b (R1 = Me, R2 = H) were addressed (Scheme 22b). Under hydrogenation conditions (Conditions A), tetrahydroquinoline 75a was obtained in 94% isolated yield without racemization (93% ee). Under basic treatment (conditions B), a deprotection of the carbamate and a re-aromatization occurred to provide the enantioenriched quinoline 16b in 89% isolated yield and almost no racemization (92% ee). Finally, under hydroetherification conditions (Conditions C), bridged quinoline 76a was obtained in good yield and enantioselectivity (86%, 93% ee).
In 2016, the group of Cozzi and Gualandi reported on an organocatalytic stereoselective addition of aldehydes 66 to acylquinolinium ions catalyzed by the Hayashi–Jørgensen catalyst C12 (Scheme 6) [63]. The one-pot sequence is divided in three steps (1) the in situ generation of the quinolinium salt by reaction between quinolines 16 and CbzCl (TrocCl failed to promote the reaction), (2) enantioselective nucleophilic addition of aldehydes 66 catalyzed by Hayashi–Jørgensen catalyst C12, and (3) the reduction of the aldehyde by NaBH4. This simple procedure was then applied to several quinolines 16 and aldehydes 66 providing the corresponding 1,2-dihydroquinoline derivatives as a syn/anti mixture of separable diastereomers along with a small amount of the 1,4-dihydroquinolines derivatives 77 (syn-71/anti-71/77 ratio: 46:39:15 to 74:15:11) (Scheme 23a). Generally speaking, low to moderate yields for the syn-adduct syn-71 (but in agreement with the diastereoselectivity) were obtained (28–58%). Regarding the enantioselectivity, enantiomeric excesses for the syn and anti-diastereomers were excellent in all cases (77–99% ee, except for R1 = Ph, eetrans 34%). In order to demonstrate the usefulness of the 1,2-dihydroquinolines 71, the authors have studied different derivatization conditions (Scheme 23b). Indeed, when syn-71c (R1 = Me, R2 =H) was submitted to hydrogenation conditions (conditions A: H2, Pd/C), N–H tertahydroquinoline 78a was observed in good isolated yield (79%) but as a mixture of anti/syn isomers resulting from a partial epimerization occurring during the Cbz cleavage. Others hydrogenation conditions (Conditions B: 1) Et3SiH, Pd/C, 2) H2, DCM) gave a 1.5:1 mixture of re-aromatized quinoline ent-16b and desired deprotected product 78a (syn/anti 1.7:1). Finally, treatment of syn-71c (eesyn 94%) by aqueous KOH in EtOH (conditions C) afforded the re-aromatized quinoline ent-16b in good yield and enantioselectivity (83%, 88% ee).
Recently, Chen and Du published the synthesis of polycyclic compounds 81 through a cascade reaction involving N-benzyl quinolinium salts 79 bearing an electron-withdrawing group and o-hydroxyenone derivatives 80 catalyzed by chiral primary amine organocatalyst derived for Cinchona alkaloids C15 (Scheme 24) [64]. The reaction in the presence of 20 mol% of C15 and 20 mol% of racemic mandelic acid co-catalyst afforded the enantioenriched polycyclic product 81 as a single diastereoisomer in modest to high isolated yields (44–85%) and high level of enantiocontrol (61–89% ee). Moving from an o-hydroxyenone derivatives 80 (X = OH) to an o-aminoenone derivatives 80 (X = N-Ph) was possible but at the expense of both isolated yield and ee (63%, 61% ee vs 70%, 89% ee respectively). Interestingly, the presence of an electron-withdrawing group (NO2 or CN) at position 6 or 7 was crucial from the reactivity point of view.

3.4. Pyridinium Salts

The approach reported by Chen and Du (see Scheme 24) proved to be quite general as pyridinium salts 47 were also tolerated after a slight modification of the reaction conditions (C16 (20 mol%), salicylic acid (20 mol%), potassium salicylate (1.1 equiv), DCM) (Scheme 25) [64]. Polycyclic compounds 82 were thus obtained in low to high yields (23–89%) and excellent enantiomeric excesses (61–98% ee) (Scheme 25a). It has to be noted that for R2 ≠ H, no or modest diastereoselectivity was observed (R1 = H, R2 = OAc, 3.6:1; R1 = H, R2 = OAc, 1:1). Finally, a chemical transformation of compound 82a (R1 = R2 = H, R3 = Bn, 98% ee) to the more complex structure 83a through a Friedlander reaction was performed in high isolated yield and without racemization (83%, 99% ee) (Scheme 25b).
In 2017, Bernardi and Fochi have achieved nucleophilic dearomatization of pyridinium salts 47 under enamine catalysis using Jørgensen catalyst C17 (10 mol%) and phenyl acetic acid (10 mol%) as co-catalyst (Scheme 26) [65]. This acid co-catalyst was proposed to buffer the unreacted amount of Et3N at the end of the reaction thus slowing post-addition epimerization. In the presence of Et3N (1 equiv, in order to trap HBr formed during the reaction) in toluene at −30 °C, regioselective addition at C4 position occurred to afford the enantioenriched 1,4-dihydropyridines 84 providing that the aldehyde group was transformed into α,β-unsaturated ester by Wittig reaction to solve stability issues. Thus, 1,4-dihydropyridines 84 were isolated in low to high yields (35–89%), high drs (71:29–95:5) and excellent levels of enantioselectivity (90–99% ee) (Scheme 26a). In most cases, the diastereomeric purity could be improved to >95:5 after purification. The relative and absolute configurations were determined by NMR and ECD spectroscopy and confirmed by X-ray diffraction analysis. In order to demonstrate the potency of their approach, the authors have tackled the synthesis of compound 85a possessing a pyrrolo[2,3-c]pyridine core which is encountered in anticancer peptidomimetics (Scheme 26b). Compound 85a was thus obtained in 30% overall yield over four steps in 95% ee from 1,4-dihydropyridine 84a (75%, >95:5 dr, 95% ee) which was synthesized under standard conditions and transformed into the corresponding acetal in 75% yield.
In 2018, Chen and Liang have published an asymmetric dearomative formal [4 + 2] cycloaddition of enones 80 and dialkyl pyridinium salts 47 providing azaspiro[5.5]undecane scaffolds 86 thanks to an iminium ion/enamine activation sequence (Scheme 27) [66]. Thus, in the presence of chiral primary amine catalyst C18 (10 mol%), chiral carboxylic acid 87 (40 mol%) and AcONa (1.2 equiv) in CHCl3 at 5 °C, cycloadducts 86 were obtained in moderate to excellent yields (52–95%), diastereoselectivity (4:1->19:1) and enantioselectivity (72–95% ee) (Scheme 27a). Interestingly, one example in quinolinium series was reported although the yield, dr and enantiomeric excess (67%, 3:1 dr, 58% ee) of product 88a were lower than those obtained in the pyridinium series (Scheme 27b). Finally, synthetic transformations were reported starting from compound 86a (R1 = Ph, R2 = R4 = H, R3 = Bn) (Scheme 27c). Under hydrogenation conditions (H2 (2 MPa), Pd/C) in the presence of Boc2O, reduction of the nitro group occurred concomitantly with N-debenzylation to furnish N,N’-Bis(Boc)-protected product 89a in 80% isolated yield but with fair diastereoselectivity (2:1 dr) and almost no modification of the ee (92% ee and 91% ee respectively for the two diastereomers). Interestingly, treatment of 86a with BF3·Et2O yielded the 4-methylene 1,4-dihydropyridine derivative 90a in excellent yield and enantiomeric excess (93%, 92% ee).

3.5. Acridinium Salts

Intermolecular 1,4-addition of aldehydes 66 to N-Methyl acridinium salt 91a is seldom reported in the literature. The first example was illustrated by Cozzi et al. in 2010. Using 20 mol% of MacMillan catalyst ent-C14·CF3CO2H, the authors were able to add a few aldehydes 66 to acridinium 91 providing 1,4-dihydroacridine 92 in fair isolated yields (51–66%) and low to modest enantiomeric excesses (7–64% ee) (Scheme 28) [67]. The reaction conditions were found to be sensitive in terms of solvent and counter-ion as only DMF and iodide respectively allowed the reaction to occur. It is worth mentioning that reaction with hydrocinnamaldehyde (R1 = Bn) led to a poor ee of 7%, much lower compared to octanal (64% ee). In order to explain this difference of behavior, the authors proposed that this gap in ee was due to detrimental π interactions between the aldehyde 66 and the acridinium salt 91.
The group of Xiao and Li improved Cozzi’s results by moving to the Jørgensen-Hayashi catalyst ent-C12 (Scheme 29) [68]. Thus, in the presence of 10 mol% of ent-C12 and 1 equiv of DMAP, 1,4-dihydroacridines 93 were obtained from acridinium salts 91 and aldehydes 66 in high yields (82–96%) and excellent levels of enantioselectivity (86–99% ee) after reduction of the aldehyde to the corresponding alcohol (NaBH4, EtOH). It is worthy of note that N-methyl phenanthridinium iodide 94a failed to provide the addition product.
Instead of starting directly from acridinium salt 91a, Zhang et al. generated the acridinium in situ by oxidation of 1,4-dihydroacridine 95a under O2 atmosphere [69]. In this case, using 20 mol% of MacMillan’s catalyst C13·CF3CO2H, a moderate isolated yield (52%) and enantiomeric excess (45% ee) could be obtained for the substituted 1,4-dihydroacridine 96a despite good results were achieved with xanthene (O instead of N-Me) (Scheme 30).

4. Nucleophilic Catalysis

The asymmetric dearomatization process based on nucleophilic catalysis has met important developments while addressing major selectivity issues. First of all, these organocatalytic strategies led to the dearomatization of two kinds of heterocyclic architectures such as N-iminoazolium ylide derivatives (Figure 4, case A) and pyridinium salt derivatives (Figure 4, case B) which underwent either C2 or C4-addition reaction as formal electrophilic species. Most of the work has been achieved by means of NHC catalysis which highlighted enolate or homoenolate type of chemistry of Breslow intermediates (Figure 4, cases C and D) together with acylation reactions (Figure 4, case E). On the other hand, the phosphine-based catalysis, encompassing the addition to allenes in order to generate phosphonium zwitterionic species, has met fewer but important achievements for the dearomatization of N-iminoazolium ylide compounds (Figure 4, case F). Finally, isothiourea catalysis allows the nucleophilic addition of C(1)-ammonium enolate intermediates generated by the addition of the catalyst to substituted phenyl acetate derivatives (Figure 4, case G).

4.1. Isoquinolinium Salts

The group of Glorius tackled the dearomatization sequence of N-iminoisoquinolinium ylides 97 by means of unsaturated aldehydes 98 and the triazolinium salt C19 as a N-heterocyclic carbene (NHC) precursor (Scheme 31) [70]. In the presence of K2CO3 as a base, the NHC catalyst was generated to form the transient homoenolate species 4 upon the addition sequence onto aldehydes 98, leading subsequently to a (3 + 3) cycloaddition with azomethine imines 97 allowing the formation of lactams 99 with high ees and good diastereoselectivies (Scheme 31a). The authors showed that lactam 99a underwent a facile reductive-ring opening sequence to give the corresponding ester 101a (Scheme 31b). Under reductive conditions (H2, Raney Ni), allowing the nitrogen-nitrogen bond cleavage, the pyrrolidinone derivative 102a was eventually synthesized, without loss of ee, and displays the polycyclic structure of indolizidine alkaloids proving thereby the utility of these compounds. Worthy of note, this enantioselective process was also demonstrated during the dearomatization of N-iminopyridinium yield which complements the developments described below in Section 4.2.
The authors investigated in detail the reaction conditions highlighting that the basicity of the base in a given solvent markedly influences the reaction pathway [70]. Indeed, moving from THF to toluene and in the presence of the pre-catalyst C20, it was observed that the homoenolate intermediate 100 was in equilibrium with the enolate 104 (Scheme 32), the latter leading to a (3 + 2) cycloaddition onto the N-iminoisoquinolinium 97. Thus, the pyrrolidinones 103 were obtained in excellent ees and dr in a diversity-oriented synthesis fashion from the same precursors 97 and 98 (Scheme 32 vs. Scheme 31). Wang, Wei et al. performed DFT calculations on these novel sequences and proved that K2CO3 was a suited base to secure the equilibrium between homoenolate-enol species (100 vs. 104) while the stereoselectivity issues would stem from π–π and hydrogen bonding interactions with NHC intermediates [71].
In 2018, Liu and Xu reported on a (3 + 2) dearomatizing annulation of N-iminoisoquinolinium ylides 97 by saturated carboxylic esters 105 in the presence of the triazolinium salt C21 as a N-heterocyclic carbene (NHC) precursor following a similar approach as reported by Glorius (Scheme 33) [72]. The pyrrolidinones 103 were thus obtained in good isolated yield and dr (60–80%, 6:1–20:1) and excellent levels of enantioselectivity (92–99% ee) for a wide array of substituents on both ester and N-iminoisoquinolinium ylide partners (Scheme 33a). Indeed, in this case, the enolate intermediate 107 was generated after the addition of the NHC catalyst to the phenolic ester 105 followed by a deprotonation with Cs2CO3. The reactive enolate led to nucleophilic addition to the electrophilic carbon of the N-iminoisoquinolinium ylide 97 (Scheme 33b). Synthesis of indolizidine derivatives 108, important structural motifs in natural alkaloids, was then tackled by implementing a simple reduction of the double bound of 103 in moderate isolated yields (60 and 62%), high dr (10:1 and 8:1) and with almost no racemization (95% and 97% ee from 99% and 96% ee respectively) (Scheme 33c).
Tan et al. envisaged an alternative dearomatization sequence making use of the two electrophilic sites at C1 and C2 of isoquinolinium salts 109 (Scheme 34) [73]. Then, upon NHC catalysis, from the triazolium precursor C22 and unsaturated aldehydes 98, the formal reactive species 111 was formed and able to trigger a double Mannich-type reaction to isoquinolinium salt 109. Thus, the tropane derivatives 110, displaying a known bridge-skeleton of naturally occurring and bioactive compounds, were obtained in a complete diastereoselectivity and excellent ees. Although a large array of compounds was constructed, this reaction proceeded essentially from α,β-unsaturated aldehydes 98 flanked by an aromatic moiety. The one-pot, albeit stepwise four components sequence, was also successfully developed by the in-situ formed isoquinolinium precursor 109 followed by the addition of the other components. Based on the recent DFT computational investigations by Qu, Wei and colleagues, this domino reaction is believed to proceed through a stepwise fashion starting with the regio- and enantioselective Mannich reaction at C1, followed by the diastereoselective cyclization [74]. Importantly, the use of ethanol as an additive was crucial to secure the ethanolysis event of the acyltriazolium intermediate C22 in order to regenerate the NHC catalyst.

4.2. Pyridinium Salts

The dearomatization of pyridinium salts allows a versatile entry to biologically relevant dihydropyridines, while having to overcome regioselective issues in connection to the differentiation of the C2 and C4 electrophilic positions. The group of Rovis tackled the C4-selective addition reaction of Breslow intermediates, such as homoenolates 100 (see Scheme 31), generated from unsaturated aldehydes 98 upon the catalytic reaction of triazolium C23 as an NHC precursor (Scheme 35) [75]. Several key parameters were adjusted to succeed in this process such as (1) the exploitation of activated pyridinium salt 47 having a cyano group at C3 (an acetyl led to lower selectivities), (2) the strict exclusion of oxygen and the use of acetic acid additive (vide infra). Then, the major 1,4-dihydropyridine products 112 were obtained in moderate to good yields (31–71%) and good ees (up to 91%), in parallel to the minor regioisomer 113(Scheme 35a). The best results were observed with non-hindered aldehydes 98, whereas counterparts 98 with R2 = i-Pr and Ar led to decreased selectivities. A mechanistic insight, thanks to labeling experiments, led the authors to propose a competitive addition of the transient carbene (formed from C23) to the pyridinium salt, giving aza-Breslow intermediates which could equilibrate back to starting material thanks to the use of acetic acid. Subsequently, DFT computation allowed to address the selectivity issues by showing that the largest electrophilic value was found at the C4-position of the pyridinium salt 47a (R = Ph), while the enantioselective addition was controlled by hydrogen bonding like C–H---F and O–H---N [76]. In order to showcase the obtained dihydropyridines such as 112a, the authors demonstrated the possibility to reduce selectively either partially (with Pd(OH)2, H2 giving 114a) or completely (Et3SiH, TFA giving 115a) one or the two C–C double bonds to provide tetrahydropyridine 114a or piperidine 115a respectively without altering the enantiomeric excess of the starting material 112a (Scheme 35b).
In the same vein, the group of Mazzanti has reported on an efficient dearomatization sequence of N-benzyl pyridinium 47 upon the formal addition reaction of aldehydes 105, provided that a cyano functional group was present at the C3 position; other EWG did not afford any reaction (Scheme 36) [77]. A screening of various pre-NHC catalysts revealed that triazolium C24 was competent to generate the so-called Breslow intermediate 117 in the presence of Na2CO3 as a base leading, eventually, to 1,4-dihydropyridines 116 with a complete regioselectivity and ees up to 78% (Scheme 36a). The best selectivities (>70% ee) were obtained with aliphatic aldehydes bulkier than R2 = Et (60% ee for R1 = Ph) but the ees dropped with α-branched aldehydes as testified with cyclopropyl derivatives giving 52% ee (R1 = Ph, R2 = CyPr) while the one with R2 = i-Pr did not allow any conversion. Contrariwise to the aforementioned Rovis achievement [45], the authors demonstrated that their conditions did not furnish any addition reaction of cinnamaldehyde and the competitive addition of the transient carbene was ruled out. In order to showcase the use of these substrates, selective reduction of the ketone moiety with NaBH4 (118a, 87% yield) was carried out while the hydrogenation of the C–C double bond occurred in the presence of Pearlman palladium-based catalyst giving rise to the tetrahydropyridine 119a in 95% and 70% ee (Scheme 36b).
Very recently, the group of Smith has studied the synthesis of 1,4-dihydropyridines 120 by addition of aryl ester 105 to N-alkyl pyridinium salts 47 bearing an electron-withdrawing group at the 3-position catalyzed by (R)-BTM isothiourea chiral catalyst C25 (Scheme 37) [78]. In the presence of 20 mol% of C25, 1.5 equivalent of DABCO in toluene at 0 °C, the reaction proceeded smoothly to provide several 1,4-addition products in low to moderate isolated yields (29–70%), good diastereoselectivities (80:20 to 95:5 dr) and variable level of enantioselectivity (0–96% ee) (Scheme 37a). For stability purposes, the 1,4-addition product 120 bearing a phenolic moiety must be transformed into the corresponding amide prior to purification by treatment of the crude mixture with amine nucleophile (benzyl amine, piperidine, morpholine or N-Boc piperazine) (Scheme 37b). In addition, some interesting features were noticed by the authors: 1) contrarywise to most others reported approaches which have been shown to be sensitive to variation of the EWG group of the pyridinium salt, CN, PhSO2 and CO2Et-substituted pyridinium salts were efficient in terms of reactivity and selectivity (except for CO2Et which result in the production of a racemate); (2) the R1 group must be a benzyl (pyridinium salt with Me substituent being unreactive) presumably to provide stabilization of the transition state thanks to π–π or π–cation interactions; (3) the nature of the counter-cation of the pyridinium salt is crucial for the reaction to occur. Non-coordinating anions (BF4 or PF6) were less efficient both in terms of enantioselectivity and reactivity than halide ones (Cl or Br). This phenomenon was tentatively attributed to the capability of the alkyl ammonium salts to act as H-bonding donors that bind to the halides ions hanks to +NC–H···X interactions. From a mechanistic point of view, the reaction proceeds through the formation of a C(1)-ammonium enolate intermediate resulting from the nucleophilic addition of the catalyst C25 to the aryl ester 105 followed by deprotonation by the DABCO used as a Brønsted base (Scheme 37c).

4.3. Others

Quinazoline derivatives are useful building blocks in synthesis while the core structure is found in numerous bioactive compounds. In this context, Guo et al. designed an original [4+3] annulation to quinazoline derived cyclic azomethine imines 121 in order to build the corresponding seven-membered ring heterocyclic products 123 (Scheme 38) [79]. It was found that commercially available Kwon’s phosphine C26 catalyzed efficiently the addition reaction of allenoates 122 to dipole 121 in a regioselective fashion, through the likely catalytic formation of phosphonium enolate zwitterion species 124 involving complex prototropic events. Then, a large range of tricyclic products 123 were obtained in excellent yields and ees up to 96% (Scheme 38a). The authors performed various synthetic transformations among which the oxidative cleavage of the imine motif of 123a upon the influence of meta-chloroperbenzoic acid as oxidant, to give the nitro-aldehyde product 125a for instance (Scheme 38b). Next, it was demonstrated that the reduction of the acrylate moiety of 123a could occur in the presence of lithium aluminum hydride reagent to yield 126a (72%, 93% ee). During all these transformations, the ees and dr were preserved.

5. Miscellaneous

In 2017, an asymmetric reductive coupling of isoquinolines 1 promoted by a chiral diboron compound C27 was reported by Tang et al., providing expeditious access to a large variety of substituted bisisoquinoline 127 (20 examples) in moderate to good yields (27–94%) with complete diastereoselectivity and excellent level of enantioselectivity (71–99% ee) (Scheme 39a) [80]. The best results were obtained using the chiral diboron reagent C27 derived from (1S,2S)-1,2-diphenylethane-1,2-diol. The labile coupling product intermediate 127 was stabilized by adding AcCl at the end of the reaction to afford the corresponding more stable bisisoquinoline diacetamide 128. A mechanistic investigation led the authors to rule out a radical mechanism and to suggest a (3,3)-sigmatropic rearrangement via a 6-membered chair-form transition state involving two isoquinolines 1 and a single diboron C27 as the template. From bisisoquinoline 128a (R = H), further useful synthetic transformations could be conducted such as hydrogenation affording the cyclic diamine 129a (78%) or the ozonolysis providing acyclic diamine 130a (93%), as well as bromination (131a: 96%) and borylation (132a: 49%) at 4,4′- and 3,3′-position respectively (Scheme 39b).

6. Conclusions

Despite the long-standing interest towards the dihydroazaarenes (pyridine, (iso)quinoline and acridine principally) which are interesting scaffolds encountered in several naturally occurring compounds, the stereoselective access to such architectures is still a challenging goal. In that context, nucleophilic dearomatization of azaarenium salts has emerged as a versatile choice. Nevertheless, several problems remain to be addressed such as (1) the regioselectivity of the addition of the nucleophilic species, (2) the lack of electrophilicity of the azaarenium salts thus requiring an extra-activation and (3) of course the control of the stereoselective outcome of the dearomatization event. To address these current limitations, organocatalytic processes were successfully designed by capitalizing on the full range of activation modes reported in the literature, including ion-binding catalysis, aminocatalysis and nucleophilic catalysis. Indeed, thanks to covalent and/or non-covalent interactions between the catalyst and the substrates, transition states with a high degree of organization allow excellent control of both regio- and stereoselectivities. It is worthy of note that the panel of nucleophiles eligible to the organocatalyzed nucleophilic dearomatization still remains limited. Thus, there is still a need for the development of enantioselective catalytic approaches. One can imagine that in the near future, new synthetic methodology merging organocatalysis and different modes of activation such as photocatalysis or organic electrosynthesis will emerge thus allowing to pave the way to a larger array of suited nucleophiles.

Author Contributions

Conceptualization, C.S. and S.O.; writing—original draft preparation, writing—review and editing, C.S., P.-A.N., J.-F.B., V.L. and S.O.; supervision, J.-F.B., V.L. and S.O.; funding acquisition, S.O. All authors have read and agreed to the published version of the manuscript.

Funding

P.-A.N. thanks the Labex SynOrg for a grant. C.S. thanks the MNERT for a grant. This work has been partially supported by the University of Rouen Normandy, INSA Rouen Normandy, the Centre National de la Recherche Scientifique (CNRS), European Regional Development Fund (ERDF), Labex SynOrg (ANR-11-LABX-0029), the graduate school for research XL-Chem (ANR-18-EURE-0020 XL CHEM), and by Region Normandie.

Conflicts of Interest

The authors declare no conflict of interest.

Abbreviations and Symbols

Cbzbenzyloxycarbonyl
CSAcamphorsulfonic acid
Boctert-butyloxycarbonyl
DCMdichloromethane
DMAP4-dimethylaminopyridine
MMPPmagnesium monoperoxyphtalate hexahydrate
MTBEmethyl tert-butyl ether
NHCN-heterocyclic carbene
PIFA[bis(trifluoroacetoxy)-iodo]benzene
TBStert-butyl(dimethyl)silyl
TFAtriluoroacetic acid
Troc2,2,2-trichloroethoxycarbony
Tstosyl

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Figure 1. Dearomatization of azaarene: general considerations. * was used to indicate that catalysts are chiral.
Figure 1. Dearomatization of azaarene: general considerations. * was used to indicate that catalysts are chiral.
Catalysts 11 01249 g001
Figure 2. H-bonding catalysis in action.
Figure 2. H-bonding catalysis in action.
Catalysts 11 01249 g002
Scheme 1. Reissert-type addition of silyl ketene acetal 2a catalyzed by chiral thiourea C1.
Scheme 1. Reissert-type addition of silyl ketene acetal 2a catalyzed by chiral thiourea C1.
Catalysts 11 01249 sch001
Scheme 2. Reissert-type addition of silyl ketene acetals catalyzed by chiral silanediol C2.
Scheme 2. Reissert-type addition of silyl ketene acetals catalyzed by chiral silanediol C2.
Catalysts 11 01249 sch002
Scheme 3. Reissert-type addition of silyl ketene acetals catalyzed by chiral oligotriazole C3.
Scheme 3. Reissert-type addition of silyl ketene acetals catalyzed by chiral oligotriazole C3.
Catalysts 11 01249 sch003
Scheme 4. Addition of silyl phosphites 6 to isoquinolininium salts catalyzed by chiral thiourea C4.
Scheme 4. Addition of silyl phosphites 6 to isoquinolininium salts catalyzed by chiral thiourea C4.
Catalysts 11 01249 sch004
Scheme 5. Addition of hydrazones to isoquinolininium salts catalyzed by chiral thiourea C5.
Scheme 5. Addition of hydrazones to isoquinolininium salts catalyzed by chiral thiourea C5.
Catalysts 11 01249 sch005
Scheme 6. Addition of azlactones to isoquinolininium salts catalyzed by chiral thiourea C4.
Scheme 6. Addition of azlactones to isoquinolininium salts catalyzed by chiral thiourea C4.
Catalysts 11 01249 sch006
Scheme 7. Addition of ketene silyl acetals 2 to quinolinium salts catalyzed by chiral oligotriazole C6.
Scheme 7. Addition of ketene silyl acetals 2 to quinolinium salts catalyzed by chiral oligotriazole C6.
Catalysts 11 01249 sch007
Scheme 8. Addition of silyl phosphites 5 to quinolinium salts catalyzed by chiral oligotriazole C6.
Scheme 8. Addition of silyl phosphites 5 to quinolinium salts catalyzed by chiral oligotriazole C6.
Catalysts 11 01249 sch008
Scheme 9. Nucleophiles screening in the dearomatization of quinolinium salts catalyzed by chiral oligotriazole C6.
Scheme 9. Nucleophiles screening in the dearomatization of quinolinium salts catalyzed by chiral oligotriazole C6.
Catalysts 11 01249 sch009
Scheme 10. Addition of silyl ketene thioacetal 22a to quinolinium salts catalyzed by chiral oligotriazole C6.
Scheme 10. Addition of silyl ketene thioacetal 22a to quinolinium salts catalyzed by chiral oligotriazole C6.
Catalysts 11 01249 sch010
Scheme 11. Addition of N,N-hydrazones 27 to quinolinium salts catalyzed by chiral oligotriazole C8.
Scheme 11. Addition of N,N-hydrazones 27 to quinolinium salts catalyzed by chiral oligotriazole C8.
Catalysts 11 01249 sch011
Scheme 12. Addition of boronic acids 36 to quinolinium salts catalyzed by bifunctional catalyst C9.
Scheme 12. Addition of boronic acids 36 to quinolinium salts catalyzed by bifunctional catalyst C9.
Catalysts 11 01249 sch012
Scheme 13. Addition of ketene silyl acetal 2a to pyridinium salts catalyzed by chiral oligotriazole C6.
Scheme 13. Addition of ketene silyl acetal 2a to pyridinium salts catalyzed by chiral oligotriazole C6.
Catalysts 11 01249 sch013
Scheme 14. Addition of silyl phosphites 5 to pyridines derivatives catalyzed by chiral oligotriazole C6.
Scheme 14. Addition of silyl phosphites 5 to pyridines derivatives catalyzed by chiral oligotriazole C6.
Catalysts 11 01249 sch014
Scheme 15. Addition of indoles to N-alkylpyridinium salts 47 catalyzed by chiral thiourea C10.
Scheme 15. Addition of indoles to N-alkylpyridinium salts 47 catalyzed by chiral thiourea C10.
Catalysts 11 01249 sch015
Scheme 16. Addition of silyl ketene acetal 2a to diazaarenium salts by chiral oligotriazole C6.
Scheme 16. Addition of silyl ketene acetal 2a to diazaarenium salts by chiral oligotriazole C6.
Catalysts 11 01249 sch016
Scheme 17. Vinylogous-Mukaiyama-type addition of silyl dienol ethers derivatives 56 to (dia)zarenium salts by chiral oligotriazole C6 or C8.
Scheme 17. Vinylogous-Mukaiyama-type addition of silyl dienol ethers derivatives 56 to (dia)zarenium salts by chiral oligotriazole C6 or C8.
Catalysts 11 01249 sch017
Figure 3. General considerations for enantioselective dearomatization of azaareniums salts by aminocatalysis. * refers to either a stereogenic center or a chiral catalyst.
Figure 3. General considerations for enantioselective dearomatization of azaareniums salts by aminocatalysis. * refers to either a stereogenic center or a chiral catalyst.
Catalysts 11 01249 g003
Scheme 18. Diastereo- and enantioselective annulation reaction for the dearomatization of isoquinolininium salts 62 catalyzed by aminocatalyst C11.
Scheme 18. Diastereo- and enantioselective annulation reaction for the dearomatization of isoquinolininium salts 62 catalyzed by aminocatalyst C11.
Catalysts 11 01249 sch018
Scheme 19. Diastereo- and enantioselective dearomatization of isoquinolines 1 catalyzed by Hayashi–Jørgensen catalyst C12.
Scheme 19. Diastereo- and enantioselective dearomatization of isoquinolines 1 catalyzed by Hayashi–Jørgensen catalyst C12.
Catalysts 11 01249 sch019
Scheme 20. Diastereo- and enantioselective dearomatization of in situ-formed quinolinium salt 72 via synergistic TsOH/chiral secondary amine catalyst ent-C12.
Scheme 20. Diastereo- and enantioselective dearomatization of in situ-formed quinolinium salt 72 via synergistic TsOH/chiral secondary amine catalyst ent-C12.
Catalysts 11 01249 sch020
Scheme 21. Diastereo- and enantioselective dearomatization of in situ formed quinolinium salts 70 via synergistic Cu(OTf)2/chiral secondary amine catalyst C14.
Scheme 21. Diastereo- and enantioselective dearomatization of in situ formed quinolinium salts 70 via synergistic Cu(OTf)2/chiral secondary amine catalyst C14.
Catalysts 11 01249 sch021
Scheme 22. Diastereo- and enantioselective dearomatization of in situ formed quinolinium salts 70 via synergistic In(OTf)3/chiral secondary amine catalyst C13.
Scheme 22. Diastereo- and enantioselective dearomatization of in situ formed quinolinium salts 70 via synergistic In(OTf)3/chiral secondary amine catalyst C13.
Catalysts 11 01249 sch022
Scheme 23. Diastereo- and enantioselective dearomatization of quinoline 16 catalyzed by C12.
Scheme 23. Diastereo- and enantioselective dearomatization of quinoline 16 catalyzed by C12.
Catalysts 11 01249 sch023
Scheme 24. Asymmetric dearomative cascade multiple functionalization of quinolinium salts 79 catalyzed by C15.
Scheme 24. Asymmetric dearomative cascade multiple functionalization of quinolinium salts 79 catalyzed by C15.
Catalysts 11 01249 sch024
Scheme 25. Asymmetric dearomative cascade multiple functionalization of pyridinium salts 47 catalyzed by C16.
Scheme 25. Asymmetric dearomative cascade multiple functionalization of pyridinium salts 47 catalyzed by C16.
Catalysts 11 01249 sch025
Scheme 26. Asymmetric nucleophilic dearomatization of pyridinium salts 47 catalyzed by C17.
Scheme 26. Asymmetric nucleophilic dearomatization of pyridinium salts 47 catalyzed by C17.
Catalysts 11 01249 sch026
Scheme 27. Asymmetric dearomative formal [4 + 2] cycloaddition of 4-alkyl-substituted N-alkyl pyridinium salts 47 to enones 80.
Scheme 27. Asymmetric dearomative formal [4 + 2] cycloaddition of 4-alkyl-substituted N-alkyl pyridinium salts 47 to enones 80.
Catalysts 11 01249 sch027
Scheme 28. Asymmetric dearomatization of acridinium salt 91a catalyzed by ent-C14·CF3CO2H.
Scheme 28. Asymmetric dearomatization of acridinium salt 91a catalyzed by ent-C14·CF3CO2H.
Catalysts 11 01249 sch028
Scheme 29. Asymmetric dearomatization of acridinium salt 91 catalyzed by ent-C12.
Scheme 29. Asymmetric dearomatization of acridinium salt 91 catalyzed by ent-C12.
Catalysts 11 01249 sch029
Scheme 30. Asymmetric dearomatization of acridinium salt formed in situ from 95 catalyzed by C13·CF3CO2H.
Scheme 30. Asymmetric dearomatization of acridinium salt formed in situ from 95 catalyzed by C13·CF3CO2H.
Catalysts 11 01249 sch030
Figure 4. Dearomatization by nucleophilic catalysis: an Overview.
Figure 4. Dearomatization by nucleophilic catalysis: an Overview.
Catalysts 11 01249 g004
Scheme 31. (3 + 3) cycloaddition to azomethine imines 97 catalyzed by NHC.
Scheme 31. (3 + 3) cycloaddition to azomethine imines 97 catalyzed by NHC.
Catalysts 11 01249 sch031
Scheme 32. (3 + 2) cycloaddition to azomethine imines 97 catalyzed by NHC.
Scheme 32. (3 + 2) cycloaddition to azomethine imines 97 catalyzed by NHC.
Catalysts 11 01249 sch032
Scheme 33. (3 + 2) cycloaddition of unsaturated carboxylic esters 105 to azomethine imines 97 catalyzed by NHC.
Scheme 33. (3 + 2) cycloaddition of unsaturated carboxylic esters 105 to azomethine imines 97 catalyzed by NHC.
Catalysts 11 01249 sch033
Scheme 34. Double Mannich reaction to isoquinolinium salts 109 catalyzed by NHC.
Scheme 34. Double Mannich reaction to isoquinolinium salts 109 catalyzed by NHC.
Catalysts 11 01249 sch034
Scheme 35. C4-selective addition of 98 to pyridinium salts 47 catalyzed by NHC.
Scheme 35. C4-selective addition of 98 to pyridinium salts 47 catalyzed by NHC.
Catalysts 11 01249 sch035
Scheme 36. Highly selective C4-acylation of pyridinium salts 47 catalyzed by NHC.
Scheme 36. Highly selective C4-acylation of pyridinium salts 47 catalyzed by NHC.
Catalysts 11 01249 sch036
Scheme 37. C4-addition of aryl esters 105 to N-alkyl pyridinium salts 47 catalyzed by NHC.
Scheme 37. C4-addition of aryl esters 105 to N-alkyl pyridinium salts 47 catalyzed by NHC.
Catalysts 11 01249 sch037
Scheme 38. (4 + 3) cycloaddition between azomethine imines derivatives 121 and allenoates 122 catalyzed by NHC.
Scheme 38. (4 + 3) cycloaddition between azomethine imines derivatives 121 and allenoates 122 catalyzed by NHC.
Catalysts 11 01249 sch038
Scheme 39. Asymmetric reductive coupling of isoquinolines 1 catalyzed by chiral diboron C27.
Scheme 39. Asymmetric reductive coupling of isoquinolines 1 catalyzed by chiral diboron C27.
Catalysts 11 01249 sch039
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Segovia, C.; Nocquet, P.-A.; Levacher, V.; Brière, J.-F.; Oudeyer, S. Organocatalysis: A Tool of Choice for the Enantioselective Nucleophilic Dearomatization of Electron-Deficient Six-Membered Ring Azaarenium Salts. Catalysts 2021, 11, 1249. https://0-doi-org.brum.beds.ac.uk/10.3390/catal11101249

AMA Style

Segovia C, Nocquet P-A, Levacher V, Brière J-F, Oudeyer S. Organocatalysis: A Tool of Choice for the Enantioselective Nucleophilic Dearomatization of Electron-Deficient Six-Membered Ring Azaarenium Salts. Catalysts. 2021; 11(10):1249. https://0-doi-org.brum.beds.ac.uk/10.3390/catal11101249

Chicago/Turabian Style

Segovia, Claire, Pierre-Antoine Nocquet, Vincent Levacher, Jean-François Brière, and Sylvain Oudeyer. 2021. "Organocatalysis: A Tool of Choice for the Enantioselective Nucleophilic Dearomatization of Electron-Deficient Six-Membered Ring Azaarenium Salts" Catalysts 11, no. 10: 1249. https://0-doi-org.brum.beds.ac.uk/10.3390/catal11101249

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