Intermolecular Diastereoselective Annulation of Azaarenes into Fused N-heterocycles by Ru(II) Reductive Catalysis

doi:10.21203/rs.3.rs-963422/v1

Download PDF

Article

Intermolecular Diastereoselective Annulation of Azaarenes into Fused N-heterocycles by Ru(II) Reductive Catalysis

https://doi.org/10.21203/rs.3.rs-963422/v1

This work is licensed under a CC BY 4.0 License

Journal Publication

published 02 May, 2022

Read the published version in Nature Communications →

Version 1

posted

You are reading this latest preprint version

Despite the important advances in azaaryl C−H activation/functionalization, reductive functionalization of ubiquitously distributed but weakly reactive azaarenes remains to date a challenge. Herein, by a strategy incorporating a tandem coupling sequence into the reduction of azaarenes, we present a dearomative annulation of azaarenes into promising fused syn-N-heterocycles by combination with a large variety of aniline derivatives and paraformaldehyde under ruthenium(II) reductive catalysis, proceeding with excellent selectivity, mild conditions, and broad substrate and functional group compatibility. Mechanistic studies reveal that the products are formed via hydride transfer-initiated β-aminomethylation and α-arylation of the pyridyl core in azaarenes, paraformaldehyde serves as both the C1-building block and reductant precursor, and the use of Mg(OMe)₂ base plays a critical role in determining the reaction chemo-selectivity by lowering the hydrogen transfer rate. The present work opens a door to further develop valuable reductive functionalization of unsaturated systems by taking profit of formaldehyde-endowed two functions.

Organic Chemistry

Catalysis

syn-N-heterocycles

azaarenes

paraformaldehyde

Azaarenes constitute a class of ubiquitously distributed substances applied in numerous fields of science and technology.^1–2 The development of new strategies enabling efficient and selective transformation of weakly reactive azaarenes into functional frameworks is of important significance, as they not only pave the avenues to access novel functional products, but also enrich the synthetic connotation of the azaarenes. To date, except the well-established electrophilic substitution utilizing azaarenes as the nucleophiles under harsh conditions,^3–4 the recently emerged C−H activation/functionalization has offered many desirable ways for structural modification of the azaarenes.^5–7 In comparison with these aromaticity-retaining transformations, only a handful examples focused on dearomative coupling of active indole derivatives,^8–11 whereas dearomative functionalization of inert pyridine-fused azaarenes (e.g., quinolines, isoquinolines, naphthyridines, phenanthroline, etc.)^12–14 has been scarcely explored.

In recent years, hydrogen transfer-mediated coupling reactions have emerged as appealing tools in the production of various functional products, since there is no need for high pressurized H₂ and elaborate experimental setups. For instance, in addition to the well-known reductive amination applied for amine syntheses,^15–16 several groups such as Beller,^17–18 Kempe,^19–20 Kirchner,^21–22 Liu,^23–25 and others^26–29 have applied borrowing-hydrogen strategy to alkylate amines and the α-site of carbonyl compounds with alcohols. Krische has demonstrated elegant contributions on the linkage of alcohols/carbonyls with unsaturated C−C bonds.^30–32 Bruneau et al have achieved β-C(sp³)−H alkylation of N-alkyl cyclic amines.^33–34 The Li group has converted phenols into synthetically useful amines.^35–36 Our group has reported a reductive quinolyl β-C−H alkylation with a low-active heterogeneous cobalt catalyst.³⁷ Later, Donohoe et al have demonstrated interesting examples on the β-functionalization of azaarenes.^38–40 Despite these important advances, the strategy incorporating a tandem coupling sequence into the reduction of azaarenes remains to date a challenge due to the difficulty in controlling the reaction selectivity: on one hand, the azaarenes tends to undergo direct hydrogenation to form non-coupled cyclic amines under catalytic reduction conditions, on the other hand, it is hard to selectively transfer hydrogen only to one specific sites among different substrates.

Here, we conceived that, through an initial pretreatment of azaarenes A’ with bromoalkanes to form azaarenium salts^41–42, it would offer a solution to achieve the desired synthetic purpose: (ⅰ) the combination of a suitable metal catalyst (M) and hydrogen donor (HD) forms reductive metal hydride species [HMⁿX] in-situ, which allows hydride transfer (TH) to the azaarenium salts A and generates allylic amine int-1 and its tautomer N-alkyl enamine int-2 (Fig. 1a). Such an enamine (int-2) has higher β-reactivity in trapping electrophiles than its -NH counterpart and lowers the formation of non-coupled cyclic amine A’’. (ⅱ) It is relatively difficult to reduce electron-rich enamine int-2 to the undesired cyclic amine A''. Based on such an idea, we wish herein to report, for the first time, a dearomative annulation reaction of azaarenium salts A with aniline derivatives B and paraformaldehyde (Fig. 1b) under ruthenium(II) reductive catalysis, which offers a general way for diastereoselective construction of fused syn-N-heterocycles C featuring promising structural motifs of teterahydroquinoline and hexahydro-1,6-naphthyridine that are frequently found in natural alkaloids^43–44 and biomedical molecules,^45–47 as exemplified by the leading anesthesia drug taripiprazole 1, active composition 2 used for treating EP1 receptor-mediated diseases,⁴⁵ PXR agonist 3,⁴⁶ and anticancer agents 4 (Fig. 1c)⁴⁷.

Investigation of reaction conditions. We commenced our studies by performing the reaction of N-benzyl quinolinium bromide A₁, N-ethyl aniline B₁, paraformaldehyde, and base in MeOH at 65 ^oC for 18 h by employing [RuCl₂ (p-cymene)]₂ as the catalyst. Among various bases tested, Mg(OMe)₂ exhibited the best chemo-selectivity since there is no formation of by-product N-benzyl tetrahydroquinoline A₁’’ (Table 1, entries 1-4). The absence of catalyst or base failed to yield product C₁ (entries 5-6), showing that both of them are indispensable for the product formation. Then, we screened several other metal catalysts applied frequently in hydrogen transfer reactions (see Table S1 in the Supplementary Information (SI)). The results showed that Ir(I) or Ir(III) catalysts were also applicable, but the base metal catalysts (Co, Fe, Mn, and Ni) were totally ineffective for the transformation(entries 7-8 and Table S1). Here, we chose the cost-effective [Ru(p-cymene)Cl₂]₂as the preferred catalyst to further evaluate the solvents and temperatures, it showed that methanol and 55 ^oC were more preferable (entries 9-10). Decrease of the base or (CH₂O)_n amount diminished the product yields (entries 11-12). Thus, the optimal yield of product C₁was obtained when the reaction in methanol was performed at 55 ^oC for 18 h by using the combination of [Ru(p-cymene)Cl₂]₂ and Mg(OMe)₂ (entry 10). Interestingly, the use of Mg(OMe)2 base always resulted in excellent selectivity in affording product C₁ (entries 3, and 7-12).

Substrate scope. With the availability of the optimal reaction conditions (Table 1, entry 10), we then assessed the substrate scope of the newly developed synthetic protocol. As shown in Fig. 2, various quinolinium salts A (A₁−A₂₁, see Scheme S1 for their structures) in combination with N-ethylaniline B₁ and paraformaldehyde were evaluated. Gratifyingly, all the reactions underwent smooth reductive annulation and furnished the desired fused N-heterocycles in reasonable to excellent isolated yields with excellent syn-diastereoselectivity (C₁−C_21,d.r. > 20 : 1). The structure of compound C₁ was confirmed by X-ray crystallography diffraction and NOESY spectrum (Fig. S1-Fig.S3). As expected, the application of 1,5-dibromopentane generated the alkyl-linked product C₂₁ in good yield. Noteworthy, a variety of functionalities (e.g., −Me, −OMe, −SPh, amido, −F, −Cl, −Br, ester, −CF₃, −NO₂, alkenyl, and alkyl) on the quinolinium salts were well tolerated, and their electronic properties affected the product formation to some extent. Interestingly, no reduction of the nitro and alkenyl groups was observed (C₁₇ and C₁₈), and the halo-substrates also did not undergo hydrodehalogenation, indicating that the reaction proceeds in a chemoselective manner. In general, quinolines bearing an electron-donating group (C₂−C₇, and C₁₃−C₁₄) afforded relatively higher product yields than those having an electron-withdrawing group (C₈−C_10, and C₁₂), presumably because the electron-rich quinolinium salts can result in more reactive enamine intermediates that are beneficial to the electrophilic coupling process (Fig. 1a). The retention of these functionalities offers the potential for post-functionalization of the obtained products.

Next, we turned our attention to the synthesis of structurally diversified products by variation of both azaarenes A' and anilines B. First, a series of N-alkyl anilines (B₂−B₁₈, see Scheme S2 for their structures) in combination with quinolinium salt A₁ were tested. As illustrated in Fig. 3, all the reactions efficiently afforded the desired product in moderate to excellent isolated yields with exclusive syn-selectivity (C₂₂−C₃₆, d.r. > 20 : 1). The electronic properties of the substituents on the benzene ring of the anilines significantly affected the product formation. Especially, anilines containing electron-donating groups (C₂₂−C₂₃,C₂₇andC₃₅) gave much higher yields than those with electron-withdrawing groups (C₂₄−C₂₅). This observation is attributed to electron-rich anilines favoring the electrophilic coupling process during the formation of the products. In addition to N-alkyl anilines, diarylamine B₁₆ also served as an effective coupling partner, affording the N-aryl product C₃₃in moderate yield. As expected, primary anilines were not applicable for the transformation, as they easily reacted with formaldehyde to form aminals. Interestingly, tetrahydroquinolines (B₈ and B₉) and 2,3,4,5-tetrahydro-1H-benzo[b]azepine (B₁₀), two specific aniline derivatives, also underwent efficient multicomponent annulation to afford the polycyclic products (C₃₄−C₃₆,C₃₈andC₄₁). In addition to quinolines, other azaarenes, such as 1,8-naphthyridines (A₂₂−A₂₅), thieno[3,2-b]pyridine A₂₆, 1,7-phenanthroline A₂₇, 1,10-phenanthroline A₂₈, 5-substituted isoquinolines, and more challenging pyridine were also amenable to the transformation, delivering the desired products in an efficient manner (C₃₇−C₅₀, d.r. > 20 ：1), these examples demonstrate the capability of the developed chemistry in the functionalization of pyridine-containing azaarenes including the N-bidentate ligands (C₃₇−C₄₂, C₄₇).

Noteworthy, 5-substituted isoquinolines afforded the desired annulation products (Fig. 3, C₄₈ and C₄₉), whereas 5-nonsubstituted isoquinolines generated structurally novel products D by installing an additional methyl group at the β-site of the N-heteroaryl reactants, and all the products are produced with exclusive syn-diastereoselectivity (d.r. > 20 :1, Fig. S4). As shown in Fig. 4, N-benzyl isoquinolinium salts were firstly employed to couple with paraformaldehyde and N-ethyl aniline B₁. All the reactions gave rise to the desired annulation products in moderate to excellent yields upon isolation (D₁−D₁₃). Then, the transformation of secondary anilines including the N-alkyl and N-aryl ones was evaluated. Gratifyingly, all these anilines smoothly coupled with N-benzyl quinolium salt A₁ and paraformaldehyde, delivering the annulation products in reasonable to high yields (D₁₄−D₂₆). Similar to the results described in Fig. 2 and 3, various functionalities on both isoquinolium salts and anilines are well tolerated (−Bn, −Et, −Me, −F, −Cl, −Br, boronic ester, −SO₂Me, −n-hexyl, −OMe, −CF₃, −CO₂Me, alkenyl, cyclohexyl, and i-propyl). The substituents on the aryl ring of the isoquinoline salts have little influence on the product formation, whereas the substituents of the anilines significantly affected the product yields. Generally, aniline bearing an electron-donating group afforded higher yields (e.g., D₁₄−D₁₆ and D₂₀−D₂₃) than those of anilines with an electron-withdrawing group (e.g., D₁₇−D₁₉ and D₂₄), suggesting that the reaction involves an electrophilic coupling process. Benzocyclic amines (1,2,3,4-tetrahydroquinoxaline, 1,2,3,4-tetrahydroquinoline, and 2,3,4,5-tetrahydro-1H-benzo[b]azepine) and N1-isopropyl-N4-phenylbenzene-1,4-diamine also served as effective coupling partners, affording the polycyclic products in moderate to high yields (D₂₇−D₃₀). These examples show the practicality of the developed chemistry in the construction of structurally complex polycyclic N-heterocycles.

Synthetic applications. Further, we explored the synthetic applications of the developed chemistry. As shown in Fig. 5a, 6-ester quinolinium salts, arising from initial esterification of 6-carboxylic quinoline and subsequent pretreatment with benzyl bromide, efficiently reacted with aniline B₁ and paraformaldehyde to afford products C₅₁and C₅₂, which are the analogues of analgesic⁴⁸ and the agents used for antioxidation and antiproliferation⁴⁹, respectively. Through successive amidation and formation of N-benzyl heteroarenium salt, 6-amino quinoline was efficiently transformed in combination with aniline B₁ into camphanic amide C₅₃(Fig. 5b), an agent capable of stereoisomeric separation.⁵⁰Further, the gram-scale synthesis of product D₁ was successfully achieved by scaling up the reactants to 10 mmol, which still gave a desirable yield (Fig. 5c). Interestingly, representative compounds C₂₉ and D₁ underwent efficient debenzylation to afford N-unmasked products C₅₄ and D₃₁ in the presence of a Pd/HCOONH₄ system in methanol (Fig. 5d), which demonstrates the practicality of the developed chemistry in further preparation of fused heterocycles containing a useful -NH motif.

Mechanistic investigations. To gain mechanistic insights into the reaction, we conducted several control experiments (Fig. 6). First, the model reaction was interrupted after 6 hours to analyze the product system. Except for the formation of product C₁ in 23% yield, a dihydroquinoline int-1 was isolated in 5% yield (Fig. 6a). Subjection of compound int-1 (Fig. 6a and Fig. S6) with aniline B₁ under the standard conditions resulted in product C₁ in high isolated yield (Fig. 6b), showing that int-1 is a key reaction intermediate. However, removal of Ru-catalyst from the standard conditions failed to produce C₁ and the α-arylated product C₁' (Fig. 6c), revealing that the reaction initiates with Ru-catalyzed hydrogen transfer, instead of nucleophilic arylation of substrate A₁ with aniline B₁. Further, the model reaction using deuterated methanol solvent yielded product C₁ without any D-incorporation (Fig. 6d). In sharp contrast, the same reaction by replacing paraformaldehyde with the fully deuterated one gave product C₁-d_n with 35% and 27% D-ratios at the α and γ-sites and more than 99% D-ratio at the newly formed aminomethyl group (Fig. 6e and Fig. S8). These two crucial experiments show that the formaldehyde serves as both the source of the reductant and C1-building block for the formation of the newly formed β-methylene group, and there is a tautomerism between int-1 and enamine int-2 (Fig. 1a). In parallel, we conducted the control experiments in terms of the generation of product D₁(Scheme S3). The results also support that dihydroquinoline int-6 (Scheme S3b) and β-methyl dihydroquinoline int-9 (Fig S7) are the reaction intermediates, and formaldehyde serves as the reductant source and C1-building block in the construction of the product (Scheme S3d, S3e and Fig. S9).

Based on the above findings, the plausible pathways toward the formation products C₁ and D₁ are depicted in Fig. 7. Initially, the metal hydride species [Ru^IIHX] is generated via Mg(OMe)₂ addition to formaldehyde (E₁) followed by transmetallation (E₂) with [Ru^IIX₂] and β-hydride elimination and release of formate ester (detected by GC-MS analysis, Fig. S5). Then, the hydride transfer from [Ru^IIHX] to quinolinium salt A₁ forms dihydroquinoline int-1 and its enamine tautomer int-2 along with regeneration of the catalyst precursor [Ru^IIX₂]. Meanwhile, the condensation between aniline B₁ and formaldehyde affords iminium B₁'. Then, the β-nucleophilic addition of int-2 to B₁' gives the β-aminoalkyl iminium int-3. Further, the electron-rich benzene ring of int-3 attacks the iminium motif from both the same (int-3b) and opposite (int-3a) sides of the H-atom at the β-site. In comparison, the form of int-3a (opposite side) is more favorable due to the less steric hindrance, thus affording product C₁ with syn-selectivity after deprotonation of the coupling adduct int-4 (path a of Fig 7b, namely electrophilic aryl C−H aminoalkylation). Alternatively, the [4+2] cycloaddition of int-2 and B₁'via endo or exo π-π stacking also rationalizes the formation of int-4 and product C₁ (path b of Fig. 7b, via int-5 and int -4). Similarly, the generation of product D₁ from isoquinoline is shown in Fig. 6c. The hydride transfer from [Ru^IIHX] to isoquinolinium salt A₃₂ initially forms enamine int-6 (Scheme S3a, S3b and Fig. S6). Then, the β-capture of formaldehyde by int-6 followed by based-facilitated dehydration of int-7 and hydride transfer to alkenyl iminium salt int-8 forms β-methyl enamine int-9 (Scheme S3a and Fig. S7). Subsequently, the β-capture of B1’ by int-9 followed by intramolecular attack of the electron-rich phenyl ring to the iminium motif of int-10 from the sterically less hindered back side of the methyl group, or the [4+2] cycloaddition of int-9 and B₁'via π-π stacking gives intermediate int-11. Finally, the deprotonation of int-11 generates product D₁ with syn-diastereoselectivity (Fig 7c).

To better reveal the product formation including the unique cis-selectivity, computational study was preformed using the density functional theory (see details in SI). First, the participation of Mg(OMe)₂, KOMe, and t-BuOK as the bases in the generation of [Ru^IIHCl] was calculated. The barrier for the transmetallation step with Mg(OMe)₂ (14 kcal·mol^-1, Fig. S10) is significantly higher than the other two bases (6.6 kcal·mol^-1for t-BuOK and 3.8 kcal·mol^-1for t-MeOK, Fig. S11 and Fig. 12) in the potential energy surfaces. This trend is in accordance with the fact that the higher charge of Mg²⁺ increases the stability of adduct E₁ (Scheme 7a) and makes the dissociation of -MgOMe and transmetallation more difficult, thus leading to a slow forming rate of [Ru^IIHCl]. Correspondingly, a slow generation of enamine int-2 via hydride transfer from [Ru^IIHCl] to the azaarenium salt A1 is beneficial to the capture of int-2 by B1', and effectively avoids the formation of undesired N-benzyl tetrahydroquinoline A’’ (table 1).

Then, the potential energy profile computed for the conversion of int-2 and B₁' to C₁ is shown in Fig. 8a, and all of the structures were optimized in CH₃OH solution. The formation of intermediate int-3 via β-nucleophilic addition of int-2 to B₁'has an energy barrier of 14.0 kcal mol^-1 (TS4), which represents an exergonic process, as int-3a is 6.3 kcal·mol^-1 higher than int-2. In comparison, the formation of int-3b has a similar energy barrier of 14.5 kcal mol^-1 (TS4'), the torsion of C3-N2 bond of int-3a to form int-3b has a barrier of 8.7 kcal mol^-1 (TS5). However, the attack of the aniline benzene ring to the iminium motif of int-3b from the same side of the pyridyl β-H is less favored, which is due to the high stereoscopic hindrance of the N-ethyl group and pyridyl β-H as well as the long distance (~5.7 Å) between the pyridyl α-carbon (C1) and aniline ortho-carbon (C5). Thus, int-3a becomes a favorable intermediate. Starting with int-3a, the attack of aryl C5-atom on the C1-atom to form int-4 with a barrier of 15.5 kcal mol^-1 (TS6) represents an exergonic reaction, as int-4 is 10.8 kcal mol^-1 higher than int-3a. Finally, the formation of product C₁, via deprotonative aromatization of the coupling adduct int-4 has no energy barrier, is favored from a thermodynamic point of view (ΔG = -54.1 kcal mol^-1). In terms of the [4+2] cycloaddition of B₁' and int-2, the manner of endo π-π stacking encountered commonly in the Diels–Alder reactions has a significant energy barrier of 39.0 kcal mol^-1 (TS7). So, this pathway is disfavored. Meanwhile, we also found that it is difficult to form the transition state of exo π-π stacking due to the higher steric hindrance and long interaction distance. Based on the computational studies, path a shown in Fig. 7b is believed to be a favorable way in generating product C₁.

As for the formation of requisite intermediate int-9, it involves four main steps (Fig. 8b): the β-addition of int-6 to HCHO (int-6 → int-6'), proton transfer from the methanol (int-6' → int-7), Mg(OMe)₂-induced proton abstraction and dissociation of OH^- (int-7 → int-7' → int-8), and hydride transfer (int-8 → int-9). Noteworthy, the formation of int-8 clearly proceeds under the assistance of Mg²⁺, and the hydride transfer (int-8 → int-9) by the [RuHCl] complex requires to overcome an energy barrier of 11.6 kcal·mol^-1 (TS11), and the reaction is endothermic by 6.1 kcal mol^-1. In comparison with this process, other parts can easily take place with a maximum barrier of 8.8 kcal mol^-1 (TS8). Once int-9 has formed, the formation of D₁ from int-9 undergoes a similar way of C₁ generation from int-3 (Fig. 8a): β-addition of int-9 to B₁', intramolecular cyclization via C1-C5 bond formation, and based-promoted deprotonation to yield product D₁. The calculations show that the steps from int-9 to D₁ have a slightly higher barrier than the corresponding transition state from int-3 to C₁ (17.5 kcal·mol^-1 for TS13 vs 15.5 kcal·mol^-1 for TS6).

In summary, by a strategy incorporating a tandem coupling sequence into the reduction of azaarenium salts, we have developed an unprecedented intermolecular syn-diastereoselective annulation reaction by reductive ruthenium(II) catalysis. A variety of azaarenes were efficiently transformed in combination with a large variety of aniline derivatives into fused N-heterocycles by employing paraformaldehyde as both a crucial agent to generate active ruthenium(II)-hydride species and a C1-building block, proceeding with readily available feedstocks, excellent selectivity, mild conditions, and broad substrate and functional group compatibility. The present work has established a practical platform for the transformation of ubiquitously distributed but weakly reactive azaarenes into functional organic frameworks that are difficult accessible with the existing approaches, and further discovery of bioactive and drug-relevant molecules due to the promising potentials of the obtained compounds featuring the teterahydroquinolyl and hexahydro-1,6-naphthyridyl motifs. Mechanistic studies reveal that the products are formed via hydride transfer-initiated β-aminomethylation and α-arylation of the azaarenium salts, and the use of Mg(OMe)₂ as a base plays a critical role in determining the reaction chemo-selectivity by lowering the hydrogen transfer rate. The work presented fills an important gap in the capabilities of utilizing azaarenes as the synthons, and opens a door to further develop valuable reductive functionalization of inert unsaturated systems by taking profit of formaldehyde-endowed two functions.

Typical procedure I for the synthesis of product C₁

Under N₂ atmosphere, [Ru(p-cymene)Cl₂]₂ (1 mol %), 1-benzylquinolin-1-ium bromide A₁ (0.2 mmol), N-ethylaniline B₁ (0.2 mmol), Mg(OMe)₂ (0.75 eq, 12.9 mg)，(CH₂O)_n (10.0 eq , 60 mg) and methanol (1 mL) were introduced in a Schlenk tube, successively. Then the Schlenk tube was closed and the resulting mixture was stirred at 55 ^oC for 18 h. After cooling down to room temperature, the mixture was extracted with ethyl acetate, washed with 5% Na₂CO₃ solution, dried with anhydrous sodium sulfate, and then concentrated by removing the solvent under vacuum. Finally, the residue was purified by preparative TLC on silica to give 12-benzyl-5-ethyl-5,6,6a,7,12,12a-hexahydrodibenzo[b,h][1,6]naphthyridine C₁.

Data availability

The authors declare that all relevant data supporting the findings of this study are available within the paper and its supplementary information files.

Taylor, R. D., MacCoss, M. & Lawson, A. D. G. Rings in drugs. J. Med. Chem. 57, 5845–5859 (2014).
Bunz, U. H. F. & Freudenberg, J. N‑heteroacenes and N-heteroarenes as N‑nanocarbon segments. Acc. Chem. Res. 52, 1575–1587 (2019).
Li, G., Lv, X., Guo, K., Wang, Y., Yang, S., Yu, L., Yu, Y. & Wang, J. Ruthenium-catalyzed meta-selective C-H sulfonation of azoarenes with arylsulfonyl chlorides. Org. Chem. Front. 4, 1145–1148 (2017).
Moors, S. L. C., Deraet, X., Van Assche, G., Geerlings, P. & De Proft, F. Aromatic sulfonation with sulfur trioxide: mechanism and kinetic model. Chem. Sci. 8, 680–688 (2017).
Gandeepan, P., Mueller, T., Zell, D.,Cera, G., Warratz, S. & Ackermann, L. 3d Transition Metals for C-H Activation. Chem. Rev. 119, 2192–2452 (2019).
Arockiam, P. B., Bruneau, C. & Dixneuf, P. H. Ruthenium(II)-Catalyzed C-H Bond Activation and Functionalization. Chem. Rev. 112, 5879–5918 (2012).
Proctor, R. S. J. & Phipps, R. J. Recent Advances in Minisci-Type Reactions. Angew. Chem. Int. Ed. 58, 13666–13699 (2019).
Zhou, W.-J., Wang, Z.-H., Liao, L.-L., Jiang, Y.-X., Cao, K.-G., Ju, T., Li, Y., Cao, G.-M. & Yu, D.-G. Reductive dearomative arylcarboxylation of indoles with CO₂ via visible-light photoredox catalysis. Nat. Commun. 11, DOI: 10.1038/s41467-020-17085-9 (2020).
Bai, L., Liu, J., Hu, W., Li, K., Wang, Y. & Luan, X. Palladium/Norbornene-Catalyzed C-H Alkylation/Alkyne Insertion/Indole Dearomatization Domino Reaction: Assembly of Spiroindolenine-Containing Pentacyclic Frameworks. Angew. Chem. Int. Ed. 57 , 5151–5155 (2018).
Xia, Z.-L., Zheng, C., Wang, S.-G. & You, S.-L. Catalytic Asymmetric Dearomatization of Indolyl Dihydropyridines through an Enamine Isomerization/Spirocyclization/Transfer Hydrogenation Sequence. Angew. Chem. Int. Ed. 57, 2653–2656 (2018).
Wang, Y., Zheng, C. & You, S. L. Iridium-Catalyzed Asymmetric Allylic Dearomatization by a Desymmetrization Strategy. Angew. Chem. Int. Ed. 54, 15093−15097 (2015).
Fernandez-Ibanez, M. A., Macia, B., Pizzuti, M. G., Minnaard, A. J. & Feringa, B. L. Catalytic Enantioselective Addition of Dialkylzinc Reagents to N-Acylpyridinium Salts. Angew. Chem. Int. Ed. 48, 9339−9341 (2009).
Kubota, K., Watanabe, Y., Hayama, K. & Ito, H. Enantioselective Synthesis of Chiral Piperidines via the Stepwise Dearomatization/Borylation of Pyridines. J. Am. Chem. Soc. 138, 4338−4341 (2016).
Gribble, M. W. Jr., Guo, S. & Buchwald, S. L. Asymmetric Cu-Catalyzed 1,4-Dearomatization of Pyridines and Pyridazines without Preactivation of the Heterocycle or Nucleophile. J. Am. Chem. Soc. 140, 5057−5060 (2018).
Afanasyev, O. I., Kuchuk, E., Usanov, D. L. & D. Chusov, Reductive Amination in the Synthesis of Pharmaceuticals. Chem. Rev. 119, 11857–11911 (2019).
Irrgang, T. & Kempe, R. Transition-Metal-Catalyzed Reductive Amination Employing Hydrogen. Chem. Rev. 120, 9583–9674 (2020).
Elangovan, S., Neumann, J., Sortais, J.-B., Junge, K., Darcel, C. & Beller, M. Efficient and selective N-alkylation of amines with alcohols catalysed by manganese pincer complexes. Nat. Commun. 7, 12641. (2016).
Pena-Lopez, M., Piehl, P., Elangovan, S., Neumann, H. & Beller, M. Manganese-Catalyzed Hydrogen-Autotransfer C-C Bond Formation: alpha-Alkylation of Ketones with Primary Alcohols. Angew. Chem. Int. Ed. 55, 14967–14971 (2016).
Deibl, N. & Kempe, R. General and mild cobalt-catalyzed C-alkylation of unactivated amides and esters with alcohols. J. Am. Chem. Soc. 138, 10786–10789 (2016).
Kallmeier, F., Fertig, R., Irrgang, T. & Kempe, R. Chromium-Catalyzed Alkylation of Amines by Alcohols. Angew. Chem. Int. Ed. 59, 11789–11793 (2020).
Mastalir, M., Glatz, M., Gorgas, N., Stöger, B., Pittenauer, E., Allmaier, G., Veiros, L. F. & Kirchner, K. Divergent Coupling of Alcohols and Amines Catalyzed by Isoelectronic Hydride Mn-I and Fe-II PNP Pincer Complexes. Chem. Eur. J. 22, 12316−12320 (2016).
Mastalir, M., Stöger, B., Pittenauer, E., Puchberger, M., Allmaier, G. & Kirchner, K. Air Stable Iron(II) PNP Pincer Complexes as Efficient Catalysts for the Selective Alkylation of Amines with Alcohols. Adv. Synth. Catal. 358, 3824−3831 (2016).
Wang, Y., Shao, Z., Zhang, K. & Liu, Q. Manganese-Catalyzed Dual-Deoxygenative Coupling of Primary Alcohols with 2-Arylethanols. Angew. Chem. Int. Ed. 57, 15143−15147 (2018).
Fu, S., Shao, Z., Wang, Y. & Liu, Q. Manganese-Catalyzed Upgrading of Ethanol into 1-Butanol. J. Am. Chem. Soc. 139, 11941−11948 (2017).
Liu, Y., Shao, Z., Wang, Y., Xu, L., Yu, Z. & Liu, Q. Manganese-Catalyzed Selective Upgrading of Ethanol with Methanol into Isobutanol. ChemSusChem 12, 3069–3072 (2019).
Huang, F., Liu, Z. & Yu, Z. C-Alkylation of Ketones and Related Compounds by Alcohols: Transition-Metal-Catalyzed Dehydrogenation. Angew. Chem. Int. Ed. 55, 862–875 (2016).
Xu, Z. J., Yu, X. L., Sang, X. X. & Wang, D. W. BINAP-copper supported by hydrotalcite as an efficient catalyst for the borrowing hydrogen reaction and dehydrogenation cyclization under water or solvent-free conditions. Green Chem. 2018, 20, 2571–2577.
Vellakkaran, M., Singh, K. & Banerjee, D. An Efficient and Selective Nickel-Catalyzed Direct N-Alkylation of Anilines with Alcohols. ACS Catal. 7, 8152–8158, (2017).
Wang, D. W., Zhao, K. Y., Xu, C. Y., Miao, H. Y. & Ding, Y. Q. Synthesis, Structures of Benzoxazolyl Iridium(III) Complexes, and Applications on C-C and C-N Bond Formation Reactions under Solvent-Free Conditions: Catalytic Activity Enhanced by Noncoordinating Anion without Silver Effect. ACS Catal. 4, 3910–3918 (2014).
Spielmann, K., Xiang, M., Schwartz, L. A. & Krische, M. J. Direct Conversion of Primary Alcohols to 1,2-Amino Alcohols: Enantioselective Iridium-Catalyzed Carbonyl Reductive Coupling of Phthalimido-Allene via Hydrogen Auto-Transfer. J. Am. Chem. Soc. 141, 14136–14141 (2019).
Swyka, R. A., Shuler, W. G., Spinello, B. J., Zhang, W., Lan, C. & Krische, M. J. Conversion of Aldehydes to Branched or Linear Ketones via Regiodivergent Rhodium-Catalyzed Vinyl Bromide Reductive Coupling-Redox Isomerization Mediated by Formate. J. Am. Chem. Soc. 141, 6864–6868 (2019).
Doerksen, R. S., Meyer, C. C. & Krische, M. J. Feedstock Reagents in Metal-Catalyzed Carbonyl Reductive Coupling: Minimizing Preactivation for Efficiency in Target-Oriented Synthesis. Angew. Chem. Int. Ed. 58, 14055–14064 (2019).
Yuan, K., Jiang, F., Sahli, Z., Achard, M., Roisnel, T. & Bruneau, C. Iridium-Catalyzed Oxidant-Free Dehydrogenative C-H Bond Functionalization: Selective Preparation of N-Arylpiperidines through Tandem Hydrogen Transfers. Angew. Chem. Int. Ed. 51, 8876–8880 (2012).
Sundararaju, B., Achard, M., Sharma, G. V. M. & Bruneau, C. sp(3) C-H Bond Activation with Ruthenium(II) Catalysts and C(3)-Alkylation of Cyclic Amines. J. Am. Chem. Soc. 133, 10340–10343 (2011).
Chen, Z., Zeng, H., Girard, S. A., Wang, F., Chen, N. & Li, C.-J. Formal Direct Cross-Coupling of Phenols with Amines. Angew. Chem. Int. Ed. 54, 14487–14491 (2015).
Chen, Z., Zeng, H., Gong, H., Wang, H. & Li, C.-J. Palladium-catalyzed reductive coupling of phenols with anilines and amines: efficient conversion of phenolic lignin model monomers and analogues to cyclohexylamines. Chem. Sci. 6, 4174–4178 (2015).
Xie, F., Xie, R., Zhang, J.-X., Jiang, H.-F., Du, L. & Zhang, M. Direct Reductive Quinolyl beta-C-H Alkylation by Multispherical Cavity Carbon-Supported Cobalt Oxide Nanocatalysts. ACS Catal. 7, 4780–4785 (2017).
Grozavu, A., Hepburn, H. B., Smith, P. J., Potukuchi, H. K., Lindsay-Scott, P. J. & Donohoe, T. J. The Reductive C3 Functionalization of Pyridinium and Quinolinium Salts through idium-Catalysed Interrupted Transfer Tydrogenation. Nat. Chem. 11, 242−247 (2019).
Reeves, B. M., Hepburn, H. B., Grozavu, A., Lindsay-Scott, P. J. & Donohoe, T. J. Transition-Metal-Free Reductive Hydroxymethylation of Isoquinolines. Angew. Chem. Int. Ed. 58, 15697−15701 (2019).
Grozavu, A., Hepburn, H. B., Bailey, E. P., Lindsay-Scott, P. J. & Donohoe, T. J. Rhodium Catalysed C-3/5 Methylation of Pyridines Using Temporary Tearomatisation. Chem. Sci. 11, 8595−8599 (2020).
Huang, W. X., Yu, C. B., Ji, Y., Liu, L. J. & Zhou, Y. G. Iridium-Catalyzed Asymmetric Hydrogenation of Heteroaromatics Bearing a Hydroxyl Group, 3-Hydroxypyridinium Salts. ACS Catal. 6, 2368–2371 (2016).
Ye, Z. S., Guo, R. N., Cai, X. F., Chen, M. W., Shi, L. & Zhou, Y. G. Enantioselective Iridium-Catalyzed Hydrogenation of 1-and 3-Substituted Isoquinolinium Salts. Angew. Chem. Int. Ed. 52, 3685–3689 (2013).
Muthukrishnan, I., Sridharan, V. & Carlos Menendez, J. Progress in the Chemistry of Tetrahydroquinolines. Chem. Rev. 119, 5057–5191 (2019).
Sridharan, V., Suryavanshi, P. A. & Carlos Menendez, J. Advances in the Chemistry of Tetrahydroquinolines. Chem. Rev. 111, 7157–7259 (2011).
Aguilar, N., Fernandez, J. C., Terricabras, E., Carceller G. E., Garcia, F. J. & Salas, S. J. Substituted Tricyclic Compounds with Activity two towards EP1 Receptors. WO 2013/149996 A1 (2013).
Cerra, B., Carotti, A., Passeri, D., Sardella, R., Moroni, G., Di Michele, A., Macchiarulo, A., Pellicciari, R. & Gioiello, A. Exploiting Chemical Toolboxes for the Expedited Generation of Tetracyclic Quinolines as a Novel Class of PXR Agonists. ACS. Med. Chem. Lett. 10, 677–681 (2019).
Martin-Encinas, E., Selas, A., Tesauro, C., Rubiales, G., Knudsen, B. R., Palacios, F. & Alonso, C. Synthesis of novel hybrid quinolino[4,3-b][1,5]naphthyridines and quinolino[4,3-b][1,5]naphthyridin-6(5H)-one derivatives and biological evaluation as topoisomerase I inhibitors and antiproliferatives. Eur. J. Med. Chem. 195, 112292 (2020).
Lee, W. H., Xu, Z. L., Ashpole, N. M., Hudmon, A., Kulkarni, P. M., Thakur, G. A., Lai, Y. Y. & Hohmann, A. G. Small molecule inhibitors of PSD95-nNOS protein-protein interactions as novel analgesics. Neuropharmacology 97, 464–475 (2015).
Klisuric, O. R., Szecsi, M., Djurendic, E. A., Nikoletta, S., Herman, B. E., Santa, S. S. J., Vujaskovic, S. V. D., Nikolic, A. R., Pavlovic, K. J., Ajdukovic, J. J., Okljesa, A. M., Petri, E. T., Kojic, V. V., Sakac, M. N. & Gasi, K. M. P. Structural analysis and biomedical potential of novel salicyloyloxy estrane derivatives synthesized by microwave irradiation. Struct. Chem. 27, 947–960 (2016).
Licea-Perez, H., Wang, S., Rodgers C., et al. Camphanic acid chloride: a powerful derivatization reagent for stereoisomeric separation and its DMPK applications. Bioanalysis, 7, 3005–3017 (2015).

Acknowledgements

We thank the National Natural Science Foundation of China (21971071, 22163007), Natural Science Foundation of Guangdong Province (2021A1515010155), the Fundamental Research Funds for the Central Universities (2020ZYGXZR075), and Guizhou Province Science Foundation ([2020]1Y050) for financial support.

Author contributions

M. Z. conceived the idea, analyzed the data, directed the project, and wrote the manuscript. H. Z. and Y. W. carried out all the catalytic experiments. H. Z. drew the structures of all the obtained compounds and analyzed the single crystal structures. C.-G. C. performed the DFT calculations. Z.-D. T. and J. Y. synthesized the raw material. L. C. carried out partial NMR tests. H.-F. J. and P. H. D. discussed the mechanistic aspects and revised the manuscript. All the authors have read the manuscript and agree with its content.

Competing interests

The authors declare no competing interests.

Additional information

Supplementary information The online version contains supplementary material available at http://www.nature.com/naturechemistry.

Reprints and permission information is available online at http://nature.com/reprints.

Table 1 is in the supplementary files section.

There is NO Competing Interest.

Table1.docx
Table 1
20211011SIData.docx
Supplementary Information-data
20211011SINMRspectra.docx
Supplementary Information-NMR spectra

Download PDF

Journal Publication

published 02 May, 2022

Read the published version in Nature Communications →

Version 1

posted

You are reading this latest preprint version

Intermolecular Diastereoselective Annulation of Azaarenes into Fused N-heterocycles by Ru(II) Reductive Catalysis

Status:

Journal Publication

Version 1

Abstract

Figures

Introduction

Results

Discussion

Methods

References

Declarations

Tables

Additional Declarations

Supplementary Files

Status:

Journal Publication

Version 1