Background and Originality Content
Palladium/norbornene (Pd/NBE) cooperative catalysis (namely, the Catellani reaction)[1,2] is widely recognized as a powerful strategy for expeditious synthesis of highly substituted arenes. Recently, asymmetric Catellani reaction[3-8] based on palladium/chiral norbornene cooperative catalysis has also been realized in desymmetrization,[5] kinetic resolution[4-6] and axial chirality construction.[7-8] However, current scope of this chemistry is mainly limited to (hetero)aromatic substrates, and its application to partially aromatic or non-aromatic scaffolds is rarely reported,[9] because the vinylic C–H bonds are generally more challenging to functionalize than (hetero)aryl C–H bond.[10] Owing to the efforts of Lautens,[9a] Yamamoto,[9b]Dong,[9c-d] and our group,[9e-f] alkenyl Catellani reaction has emerged as a new direction of this field (Figure 1A). For example, in 2018, the Yamamoto group uncovered a unique two-component alkenyl Catellani annulation for the assembly of benzofused polycyclic products, involving 4-iodo-2-quinolones and 4-iodo-coumarin as the substrates (Figure 1B).[9b] Later on, the Dong group revealed two elegant alkenyl Catellani reactions, utilizing alkenyl (pseudo)halides[9c] and alkenes with a directing group[9d] as the substrates, respectively. Nevertheless, the asymmetric alkenyl-type Catellani reaction hasn’t been realized for a long time. Until very recently, the Gong group reported the first asymmetric case for enantioselective construction of all-carbon brideged ring systems via Pd/NBE/chiral amino acid cooperative catalysis (Figure 1C).[9g]
Recently, we[7a-b] and the Song group[8a] independently reported de novo construction of C–C axial chirality via palladium/chiral norbornene cooperative catalysis. Later on, we extended this chemistry to atroposelective construction of C–N axial chirality.[7c] Inspired by these innovative studies, we envisaged to develop the asymmetric alkenyl Catellani reaction version for the construction of C–N axial chirality. As illustrated in Figure 1D, 4-iodo-2-quinolone or 4-iodo-2-pyridone1 is employed as the substrate and 2,6-disubstituted aryl bromide with a tethered amide group (2 ) is utilized as the arylating reagent as well as terminating reagent. Firstly, 1undergoes sequential oxidative addition with Pd0, chiral NBE* insertion and ortho -C–H activation to generate the chiral vinyl-NBE* palladacycle species A , which then undergoes oxidative addition by 2 . The resulting PdIVcomplex subsequently undergoes reductive elimination and β-carbon elimination to form axially chiral Pd complex B , which eventually leads to the final C–N axially chiral product 3via intermediate C . This step involves an intramolecular amidation alongside the chirality transfer from C–C axis (Band C ) to C–N axis (3 ). This asymmetric alkenyl Catellani reaction provides a promising strategy for constructing C–N axial chirality in a partially aromatic heterocycle setting, which is also a recognized challenging field due to the innate low configurational stability of C–N atropisomers[11]as compared to the well-developed C–C atropisomers.[12] Other potential features include readily available substrates (both 1 and 2 ) and step economy. Nevertheless, several challanges of this reaction are also foreseeable. First, the asymmetric alkenyl Catellani reaction based on palladium/chiral norbornene cooperative catalysis remains elusive since very limited cases have been reported to date.[9]Second, the final C–N axial chirality is originated from the preinstalled transient C–C axial chirality[6-8]through an intriguing but scarcely reported axial-to-axial chirality transfer process.[7c,13] Lastly, the reaction should be performed under mild conditions because of configurational vulnerability of the obtained C–N atropisomers.[11]
Results and Discussion
Our efforts commenced with a model reaction using readily available 1-benzyl-4-iodoquinolin-2(1H )-one (1a ) and 2-bromo-N-(2-(tert-butyl)phenyl)-3-methyl-benzamide (2a ) as the substrates (Table 1). After extensive survey of the reaction parameters, the optimal reaction conditions was identified to be: Pd(OAc)2 (5 mol%) as the catalyst, the ethyl (1S ,4R )-bicyclo[2.2.1]hept-2-ene-2-carboxylate (N1 , 50 mol%) as the chiral mediator,[5] K2CO3(2.5 equiv) as the base, heated THF (80 oC) as the solvent, wherein the desired product 3a was afforded in a good yield (83% NMR yield, 80% isolated yield) and excellent enantioselectivity (93% e.e. ) (entry 1). In order to understand the role of each component in this protocol, several control experiments were subsequently conducted. In the absence of either Pd catalyst orN1 , no 3a was formed, indicating the cirtical role they are taken (entries 2-3). The reaction efficiency increased at a higher reaction temperature (90 oC), however the enantioselectivity of the product was slightly declined (entry 4). On the contrary, enantioselectivity maintained excellent at a lower temperature (e.g., 70 oC), but the yield of3a dropped dramatically (entry 5). The reaction efficiency also decreased while shortening the reaction time (to 36 h, entry 6) or lowering the loading of N1 (to 25 mol%, entry 7). The methyl ester chiral mediator N2behaved similar to N1 but with a slightly diminished enantioselectivity. It is worthwhile mentioning that the chiral mediator N1 could be recovered in 84% yield without any erosion of the enantiopurity. Other details of the reaction conditions optimization regarding the solvent and ligand effects etc were listed in SI.
With the optimal reaction conditions in hand, we then investigated the scope of iodoheterocycles, with 2a as the reaction partner (Table 2). First, the reactivity of various substituted 4-iodo-2-quinolones were explored (Table 2A). Gratifyingly, whether it is electron-donating or -withdrawing groups on the 4-iodo-2-quinolones, all could be reacted smoothly and afforded the desired products (3a -3m ) in from good to excellent yields (76%-93%) and high enantioselectivities (88%-94% e.e.s ). Notably, the tricyclic 4-iodo-2-quinolone was also a suitable substrate to deliver the complex polycyclic product 3o in 76% yield and 90%e.e. . Importantly, the reaction showed good chemoselectivity, and a wide range of functional groups were tolerated, including alkyl (3b , 3i and 3n ), trifluoromethyl (3c ), ester (3d and 3j ), methoxy (3eand 3k ), and halogen atoms (3f-h and 3l-m ), providing handles for further manipulations. In addition, 4-iodo-coumarin was also a suitable substrate to afford the desired product 3p in 91% yield, however the enantioselectivity was declined to 76% e.e. . Moreover, the scope of iodoheterocycles can be extended to monocyclic 4-iodo-2-pyridones under slightly modified reaction conditions compared to standard conditions of Table 2A (see Table S5 of Supporting Information for details), which included the use of tri-2-furanylphosphine (TFP, 10 mol%) as the ligand and an increase of the reaction temperature to 90 °C. A series of substituted 4-iodo-2-pyridones were suitable substrates (Table 2B). For example, 4-iodo-5-methyl-2-pyridones with different 1-N substitution, eg,N -methyl (1q ), N -Bn (benzyl) (1r ),N -PMB (p- methoxybenzyl) (1s ), andN -mesityl (2,4,5-trimethylbenzyl) (1t ), reacted well with 2a to provide the desired products 3qtwith 73–89% yields and excellent enantioselectivities. Beside the methyl group, the C5 substituent of 4-iodo-2-pyridones could be switched to various functional groups, such as fluoro (3u ), chloro (3v ) and substituted methylene groups (3wz ). Interestingly, 3-methyl-4-iodo-2-pyridone (3aa ) showed a much higher reactivity than the aforementioned substrates, and its reaction with 2a took place at 60 °C to afford the desired product 3aa in 87% yield and 93%e.e. . Addtionally, 1,3-dibenzyl-6-iodo-uracil was a substrate with good reactivity to deliver the product 3ab in 84% yield, albeit with a poor enantioselectivity (21% e.e. ). Importanly, the absolute C–N axial configuration of product 3a was unambiguously determined to be (R ) by X-ray crystallographic analysis,[14] and those of other products were assigned by analogy.
Next, the scope of arylbromides 2 were investigated. The reaction of naphthyl bromide with 1a and 1q delivered the desired product 3aʹ and 3bʹ respectively with excellent yields and enantioselectivities. Then, we focused on examing aryl bromides 2 with different aniline moieties. We found modifications at the para position of the aniline moiety of2 were well tolerated, including the introuction of a bromo (3cʹ ), alkene (3dʹ ), alkyne (3eʹ ) group aldehyde (3fʹ ) or benzyl alcohol (3gʹ ). The corresponding products were obtained with excellent enantioselectivities (93–98% e.e. s). In addition, modifications at the orthoposition of the aniline moiety were also investigated. Switching one methyl of the ortho tert -butyl group to OTBS (tert -butyldimethylsilyloxy) (3hʹ ) or TBS-protected hydroxymethyl (3jʹ ) group produced the corresponding axially chiral benzo[c ][1,6]naphthyridinediones with excellent enantiocontrol (94–95% e.e. s). Notably, the free hydroxyl group of arylbromide was tolerated, and the corresponding product (3kʹ ) was obtained in 77% yield, albeit with a slightly dropped enantioselectivity (87% e.e. ). 3kʹ was facilely transformed into aldehyde 3lʹ and ester 3mʹ without any erosion of the enatioselectivity.[15] Overall, these results indicated that sterically bulky aniline moieties were required to ensure high fidelity of the axial-to-axial chirality transfer process. In addition, we performed both racemization experiments and DFT calculations to probe the thermal stability of the obtainded stereogenic C–N axis. For example, the rotation barrier of3a is experimentally measured as 31.9 kcal/mol (ΔG exp), which is well consistent with the DFT computational value (ΔG calc = 32.0 kcal/mol) (see SI for details), indicating excellent thermal stability.
Finally, we focused on illustrating the synthetic utility of the C–N atropisomers in Tables 2-3 (Scheme 1). For instance, N -Bn deprotection of 3a proceeded smoothly under the catalytic hydrogenation conditions (with 10 mol% Pd(OH)2 as the catalyst)[16] to deliver 4 in 90% yield, which could be readily transformed into a OTf-substituted chiral quinoline derivative 5 through an aromatization promoted by Tf2O and pyridine.[17]Furthermore, 5 underwent an intramolecular cyclization to generate a chiral polycyclic compoud 6 through a C(sp3)–H activation[18]promoted by Pd(PPh3)4 catalyst and K2CO3 with good efficieny. Interestingly, if the loading of Pd(OH)2 was increased to 30 mol%, together with prolonged reaction time (18 h), one aromatic ring of 3a could be partially hydrogenated during the debenzylation process, and the polycyclic product 7 with a newly generated chiral center was obtained as the sole product, indicating the excellent diastereoselectivity (dr > 20:1) of the hydrogenation step which was dictated by the remote C–N axial chirality through an axial-to-central diastereoinduction process.[13c-d]. Then, chiral quinoline derivative8 was generated in excellent yield following the same aromatization protocol. Similarly, complex chiral pyridine derivatives10 and 13 with an OTf substitution were efficiently assembled from product 3r through catalytic hydrogenation and aromatization. Moreover, 10 was transfermed to 3,4,5-tri-substituted chiral pyridine derivative 13 under a mild Pd-catalyzed reduction conditions.[19]Additionally, catalytic hydrogenation of the N -Me product3q was performed (with Pd/C as the catalyst) to deliever the dearomatization product 14 with excellent diastereoselectivity (dr > 20:1). The absolute configurations of14 are unambiguously determined to be (R , aR ) by X-ray crystallographic analysis.[14] It is worth mentioning that all these transformations proceeded without any erosion of the enantiopurity.
Conclusions
In summary, we have developed an asymmetric two-component alkenyl Catellani reaction for the construction of C–N axial chirality, which is based on a palladium/chiral norbornene cooperative catalysis and an axial-to-axial chirality transfer process. Various partially aromatic iodinated 2-pyridones, quinolones and coumarin substrates react with 2,6-disubstituted aryl bromides with a tethered amide group, to afford a wide variety of polycyclic C–N atropisomers with excellent enantioselectivities. The obtained C–N axial chirality is originated from the preformed transient C–C axial chirality with high fidelity. The synthetic utility of this chemistry is demonstrated by facile preparation of complex quinoline- and pyridine-based C–N atropisomers through a N-deprotection and aromatization sequence, and a remote axial-to-central diastereoinduction process dictated by C–N axial chirality is observed with excellent diastereocontrol.
Experimental
General procedure for the synthesis of enantioenriched compounds 3a-p and 3a’ :
Unless otherwise noted, in an argon-filled glove box, an oven-dried 4.0 mL vial equipped with a magnetic stir bar was charged with Pd(OAc)2 (0.005 mmol, 5.0 mol%),N1 (99% e.e. , 0.05 mmol, 0.5 equiv), K2CO3 (0.25 mmol, 2.5 equiv), iodoheterocycles 1a -p (0.1 mmol, 1.0 equiv), aryl bromide 2 (0.1 mmol, 1.0 equiv), and dry THF (0.5 mL). The vial was sealed with a cap and stirred at r.t. for about 5 min, and then the reaction mixture was heated at 80 oC for 48 h. After the reaction vessel was cooled to r.t., the mixture was filtered, and concentrated in vacuo . The residue was directly purified by column chromatography on silica gel or pre-TLC to yield the desired chiral products 3a -p and 3a’ .
General procedure for the synthesis of enantioenriched compounds 3q-ab and 3b’-3m’ :
Unless otherwise noted, in an argon-filled glove box, an oven-dried 4.0 mL vial equipped with a magnetic stir bar was charged with Pd(OAc)2 (0.005 mmol, 5.0 mol%), TFP (0.01 mmol, 10 mol%), N1 (99% e.e. , 0.05 mmol, 0.5 equiv), K2CO3 (0.25 mmol, 2.5 equiv), iodoheterocycles 1q -ab (0.1 mmol, 1.0 equiv), aryl bromide 2 (0.1 mmol, 1.0 equiv), and dry THF (0.5 mL). The vial was sealed with a cap and stirred at r.t. for about 5 min, and then the reaction mixture was heated at 90 oC for 48 h. After the reaction vessel was cooled to r.t., the mixture was filtered and concentrated in vacuo. The residue was directly purified by column chromatography on silica gel or pre-TLC to yield the desired chiral products 3q -ab and 3b’-3m’ .
Supporting Information
The supporting information for this article is available on the WWW under https://doi.org/10.1002/cjoc.2023xxxxx.
Acknowledgement
We are grateful to the start-up funding from Wuhan University for financial support. We thank Prof. Wen-Bo Liu for sharing the instruments.
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