Catalytic Asymmetric [4+1] Spiroannulation of α-Bromo-β-Naphthols with Azoalkenes by an Electrophilic Dearomatization/S _RN 1-Debromination Approach

Abstract

Open AccessCCS ChemistryRESEARCH ARTICLE1 Mar 2022Catalytic Asymmetric [4+1] Spiroannulation of α-Bromo-β-Naphthols with Azoalkenes by an Electrophilic Dearomatization/SRN1-Debromination Approach Lu Bai†, Xin Luo†, Yicong Ge, Hui Wang, Jingjing Liu, Yaoyu Wang and Xinjun Luan Lu Bai† Key Laboratory of Synthetic and Natural Functional Molecule of the Ministry of Education, College of Chemistry & Materials Science, Northwest University, Xi'an 710127 , Xin Luo† Key Laboratory of Synthetic and Natural Functional Molecule of the Ministry of Education, College of Chemistry & Materials Science, Northwest University, Xi'an 710127 , Yicong Ge Key Laboratory of Synthetic and Natural Functional Molecule of the Ministry of Education, College of Chemistry & Materials Science, Northwest University, Xi'an 710127 , Hui Wang Key Laboratory of Synthetic and Natural Functional Molecule of the Ministry of Education, College of Chemistry & Materials Science, Northwest University, Xi'an 710127 , Jingjing Liu *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] Key Laboratory of Synthetic and Natural Functional Molecule of the Ministry of Education, College of Chemistry & Materials Science, Northwest University, Xi'an 710127 , Yaoyu Wang Key Laboratory of Synthetic and Natural Functional Molecule of the Ministry of Education, College of Chemistry & Materials Science, Northwest University, Xi'an 710127 and Xinjun Luan *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] Key Laboratory of Synthetic and Natural Functional Molecule of the Ministry of Education, College of Chemistry & Materials Science, Northwest University, Xi'an 710127 State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071 https://doi.org/10.31635/ccschem.021.202100831 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail An enantioselective [4+1] spiroannulation of α-bromo-β-naphthols with azoalkenes has been developed for the one-step construction of a new class of pyrazoline-based spirocyclic molecules. Using chiral Cu(II)/Box catalysts, asymmetric induction was achieved with high levels of enantioselectivity [up to 99:1 enantiomeric ratio (er)]. Notably, α-chloro- and α-iodo-substituted β-naphthols were also tolerated by this reaction. Mechanistic studies disclosed that this process was triggered by electrophile-facilitated dearomatization of α-bromo-β-naphthols and followed by the debromination via SRN1-subsitution with in situ-formed N-nucleophile. The chiral copper(II)-species, bound with azoalkene moiety, was assumed to control the enantio-discrimination over the naphthoxy C-radical that was generated from the debromination step. Moreover, the potential utility of this protocol was greatly amplified by the derivatization of spirocyclic products through oxidative dearomatization of the other aromatic ring in the naphthyl fragment, providing a rather attractive route for the rapid generation of synthetically more valuable doubly dearomatized architectures. Download figure Download PowerPoint Introduction Dearomatization of phenolic compounds, one of the most powerful strategies for accessing densely functionalized cyclohexadienones, has inspired the development of a wide range of fascinating and innovative synthetic methods.1–5 Given the putative biosynthetic routes for some phenol-rooted natural products,6,7 many early examples in this area relied on oxidative dearomatization processes involving attack of an "oxidant-activated" electrophilic phenol by a nucleophile.8–11 Although often effective, such processes sometimes met with the difficulties of more easily tolerating oxidizable functional groups. In this regard, the reverse strategy on the direct use of phenols as carbon nucleophiles has recently attracted considerable attention. As a result, elegant protocols such as dearomative alkylation,12–17 arylation,18–22 alkenylation,23–25 halogenation,26–29 amination,30–33 hydroxylation,34 and thiolation35 of phenolic compounds with a variety of stoichiometric or catalytically activated electrophiles have been successfully developed (Scheme 1a). Notably, carbon-substituent, which plays an important role in enhancing the C-nucleophilicty of substrates and maintaining the stability of products, is generally required for the dearomatized site of phenolic rings. In sharp contrast, the development of similar processes on the basis of electrophile-facilitated dearomatization at the heteroatom-substituted site of phenols,15,19,22 has dramatically lagged behind, yet remains highly desirable for enriching the application scope of this category of transformations. Scheme 1 | (a–c) Direct dearomatization of phenolic derivatives with electrophiles. Download figure Download PowerPoint In this context, we focused on the exploration of new reactions in this area. Special attention was drawn by an ancient process reported in 1888,36 demonstrating that electrophilic chlorinative dearomatization of β-naphthol can take place with α-chloro-β-naphthol (Scheme 1b, top). Subsequent studies disclosed that some halogenated phenolic compounds were able to attack hard halogen or nitronium electrophiles through the dearomatization at certain halo-sites (Scheme 1b, down).37–42 However, further attempts on making stable dearomatized products by involving soft C-electrophiles proved to be a big challenge,43,44 which might be due to the low C-nucleophilicity of such halogenated carbons, or the poor stability of dearomatized intermediate bearing a C(sp3)-center with a labile halogen leaving group.28,45,46 In consideration of the limitations of the state-of-the-art, we reasoned that the development of C−C bond-forming dearomatization processes by using halophenols as C-nucleophiles would represent a highly valuable advance. Given the metastable character of halogen-containing dearomatized species,46 we have recently developed a dearomatization/dehalogenation strategy, Facile SRN1-type of debromination can take place via a dearomatized intermediate being formed by the attack of C-electrophiles from the halo-site of halophenols, for the [4+1] spiroannulation of bromophenols with α,β-unsaturated imines.47 Notably, asymmetric control of this process was realized for α-bromo-β-naphthols by creating a chiral environment for the naphthoxyl species through direct binding with chiral Sc(III)-catalysts (Scheme 1c, top). Afterward, we set out to explore the catalytic asymmetric dearomatization (CADA)2 of α-bromo-β-naphthols by reversed asymmetric control over other types of reaction partners. Inspired by the good performance of azoalkenes in the [4+n] cycloadditions and the excellent asymmetric control by chiral copper catalyts,48–53 we herein present the successful development of an enantioselective Cu(II)/Box-catalyzed [4+1] spiroannulation of α-bromo-β-naphthols with azoalkenes (Scheme 1c, down) and offer a rapid avenue for chiral spirocyclic frameworks with pyrazolines54–56 that have been recognized as privileged scaffolds in drug discovery.57,58 Experimental Methods General procedure In a glovebox, a 10.0 mL vial equipped with a stir bar was charged with Cu(OTf)2 (7.2 mg, 0.02 mmol), L7 (14.4 mg, 0.024 mmol), and CH2Cl2 (4.0 mL). The reaction mixture was stirred at room temperature until a clear solution was formed. Next, α-halo N-benzoyl hydrazone 2 (0.2 mmol), Na3PO4 (78.7 mg, 0.48 mmol), and α-bromo-β-naphthols 1 (0.24 mmol) were sequentially added. After it was stirred at room temperature for 72 h, the reaction mixture was directly filtered and concentrated under reduced pressure. The residue was then subjected to a silica gel column to obtain the desired compound 3. The enantiopurity of the product was determined by chiral high-performance liquid chromatography (HPLC). More experimental details and characterization are presented in the Supporting Information. Results and Discussion Optimization of the reaction conditions The exploration was started by examining the reaction performance of α-bromo-β-naphthol ( 1a) with different C-electrophiles ( 2), and it was found that 1a was able to participate in two ways, through a typical O-alkylation or an unconventional dearomatizing C−C bond-forming pathway for the generation of 3 I and 3 II, respectively (Scheme 2). The experimental results indicated that C(sp3)- and C(sp)-electrophiles were prone to be attacked by the hydroxyl group of 1a, leading to the formation of etherification products 3 I-1– 3 I-5. In comparison, common C(sp2)-electrophiles such as electron-deficient olefins were inactive for the reactions with 1a. However, azoalkenes, which are typically generated from α-halo-hydrazones, participated well in the dearomatizing [4+1] spiroannulation with 1a, leading to the formation of spirocyclic products 3aa– 3ac in appreciable yields (up to 81%).a Presumably, this domino reaction was realized by the capture of a possible dearomatized intermediate 3 II with N-nucleophiles that were in situ generated from azoalkenes. Scheme 2 | Reaction exploration by combining α-bromo-β-naphthol (1a) with C-electrophiles (2). Download figure Download PowerPoint Intrigued by such a novel azaspirocyclic scaffold bearing a quaternary stereocenter, we further undertook the challenge of developing the asymmetric version of this new transformation. To prevent unwanted background reaction, we began the CADA studies of 1a with a less reactive 2c, using chiral Cu(II)-catalysts to accelerate the formation of 3ac (Table 1). Adapting the common conditions for the catalytic asymmetric reactions with azoalkenes,50–53 the results indicated that copper salt indeed enhanced the reactivity (entry 1 vs entry 2), and its combination with chiral BOX ligands L1– L8 was able to promote the reaction in an enantioselective manner (entries 3–10), with ligand L7 giving the better enantioselectivity [85∶15 enantiomeric ratio (er)] for the formation of 3ac (entry 9). Variations on the base indicated that Cs2CO3 and K2CO3 were less effective (entries 11 and 12), while Na3PO4 slightly improved the reaction in terms of both reactivity and selectivity (entry 13). At this stage, further improvement did not look promising. However, we were pleased to find that the use of substrate 1b, which possessed a double phenolic moiety, behaved very well under the current reactions conditions, affording the corresponding product 3bc in 78% yield with 95∶5 er (entry 14). Notably, compound 3bc offered a new opportunity for the further derivatization by the second dearomatization of its down naphthyl ring.22,26,31 Therefore, 1b was chosen as the standard substrate for exploring the reaction scope. Table 1 | Optimization of the Reaction Conditions Entry 1 [Cu] L Base 3 Yield (%)a erb 1 1a — — Na2CO3 3ac 10 — 2 1a Cu(OTf)2 — Na2CO3 3ac 54 — 3 1a Cu(OTf)2 L1 Na2CO3 3ac 28 50∶50 4 1a Cu(OTf)2 L2 Na2CO3 3ac 61 53∶47 5 1a Cu(OTf)2 L3 Na2CO3 3ac 68 56∶44 6 1a Cu(OTf)2 L4 Na2CO3 3ac 44 50∶50 7 1a Cu(OTf)2 L5 Na2CO3 3ac 49 56∶44 8 1a Cu(OTf)2 L6 Na2CO3 3ac 51 58∶42 9 1a Cu(OTf)2 L7 Na2CO3 3ac 73 85∶15 10 1a Cu(OTf)2 L8 Na2CO3 3ac 77 75∶25 11 1a Cu(OTf)2 L7 Cs2CO3 3ac 78 65∶35 12 1a Cu(OTf)2 L7 K2CO3 3ac 85 82∶18 13 1a Cu(OTf)2 L7 Na3PO4 3ac 81 86∶14 14 1b Cu(OTf)2 L7 Na3PO4 3bc 78 95∶5 aIsolated yield. bDetermined by HPLC analysis. Substrate scope Under the optimized reaction conditions, the substrate scope was first examined by taking a number of α-halo-N-benzoyl hydrazones ( 2c– 2u) as azoalkene precursors (Table 2). The results revealed that variations on the N-benzoyl group were well tolerated, affording the corresponding products 3bc– 3bh in moderate to good yields (56–87%) with excellent enantioselectivities (95:5 to 97:3 er) (entries 1–6). With regard to the aromatic group of hydrazones, it could be diversely substituted by the electron-donating methoxy group ( 2g), electron-neutral methyl group ( 2h), and electron-withdrawing groups such as fluoro ( 2i, 2p and 2r), chloro ( 2j and 2q), bromo ( 2k), trifluoromethyl ( 2l), trifluoromethoxy ( 2m), cyano ( 2n), and nitro ( 2o) groups. The spirocyclic products 3bg– 3br could be obtained in 53–92% yields with high levels of enantioselective control (entries 5–16). Moreover, fused aromatic 2-naphthyl-substitued hydrazone 2s was compatible as well (entry 17). In addition, less reactive substrate 2t with an alkyl group was also tolerated in the titled reaction, affording product 3bt in 82% yield with 77∶23 er. Notably, the attempt with a cyclic substrate 2u led to the formation of the anticipated product 3bu as a single diastereomera with good enantioselectivity (96:4 er), albeit in lower yield (35%) (entry 19). The absolute stereochemistry of product 3bh was unambiguously assigned to be R-configuration by X-ray crystal structure analysis.a Table 2 | Reaction Scope of α-Bromo-β-Naphthols Entry X′, R1, R2 3 Yield (%)a erb 1 Cl, Ph, Ph ( 2c) 3bc 78 95∶5 2 Cl, Ph, 4-MeO-C6H4 ( 2d) 3bd 73 97∶3 3 Cl, Ph, 3-MeO-C6H4 ( 2e) 3be 56 95∶5 4 Cl, Ph, 2-thienyl ( 2f) 3bf 84 97∶3 5 Cl, 4-MeO-C6H4, 2-thienyl ( 2g) 3bg 87 96∶4 6 Cl, 4-Me-C6H4, 2-thienyl ( 2h) 3bh 85 95∶5 7 Cl, 4-F-C6H4, Ph ( 2i) 3bi 86 97∶3 8 Cl, 4-Cl-C6H4, Ph ( 2j) 3bj 92 96∶4 9 Br, 4-Br-C6H4, Ph ( 2k) 3bk 76 94∶6 10c Br, 4-CF3-C6H4, Ph ( 2l) 3bl 91 92∶8 11 Cl, 4-F3CO-C6H4, Ph ( 2m) 3bm 81 93∶7 12 Br, 4-CN-C6H4, Ph ( 2n) 3bn 67 95∶5 13c Br, 4-NO2-C6H4, Ph ( 2o) 3bo 72 92∶8 14 Br, 3-F-C6H4, Ph ( 2p) 3bp 61 94∶6 15 Cl, 3-Cl-C6H4, Ph ( 2q) 3bq 77 93∶7 16 Br, 2-F-C6H4, Ph ( 2r) 3br 53 90∶10 17 Cl, 2-naphthyl, Ph ( 2s) 3bs 87 90∶10 18 Cl, Me, Ph( 2t) 3bt 82 77∶23 19 35 96∶4 aIsolated yield. bDetermined by HPLC analysis. c2.0 equiv of Ag3PO4 was added. Next, we continued to explore the generality of this [4+1] spiroannulation with respect to α-bromo-β-naphthols (Table 3). Satisfactorily, the intermolecular CADA reactions of 1b– 1s with 2i proceeded smoothly to deliver the desired products 3bi– 3si in 58–92% yields, with good to excellent enantioselectivities (up to 99:1 er). Overall, α-bromo-β-naphthol could be substituted with a variety of electron-donating groups ( 1b– 1e and 1o) (entries 1–4 and 14), aliphatic ( 1f), and aromatic ( 1g– 1i) groups (entries 5–8), and electron-withdrawing groups ( 1j– 1n and 1p– 1s) (entries 9–13 and 15–18), offering highly useful synthetic handles for the further transformations. Notably, the reaction with bulkier substrates ( 1b– 1n) led to better results for the enantioselectivity. Moreover, it should be mentioned that simple o-bromo-phenols and p-bromo-phenols (or naphthols) were not applicable for this [4+1] spiroannulation reaction under the currently examined conditions. Table 3 | Reaction Scope of α-Bromo-β-Naphthols Entry R 3 Yield (%)a erb 1 7-TBSO ( 1b) 3bi 86 97∶3 2 7-TIPSO ( 1c) 3ci 73 96∶4 3 7-MeO ( 1d) 3di 87 95∶5 4 7-BnO ( 1e) 3ei 84 96∶4 5 7-Me ( 1f) 3fi 91 97∶3 6 7-Ph ( 1g) 3gi 67 98∶2 7 7-(3′-furyl) ( 1h) 3hi 58 97∶3 8 7-(3′-thienyl) ( 1i) 3ii 72 96∶4 9 7-(E)-styryl ( 1j) 3ji 77 99∶1 10 7-phenylethynyl ( 1k) 3ki 73 96∶4 11 7-Cl ( 1l) 3li 89 92∶8 12 7-Br ( 1m) 3mi 65 93∶7 13 7-I ( 1n) 3ni 62 94∶6 14 6-MeO ( 1o) 3oi 90 85∶15 15 6-Cl ( 1p) 3pi 83 81∶19 16c 6-CHO ( 1q) 3qi 61 85∶15 17 6-Ac ( 1r) 3ri 64 81∶19 18d 3-Cl ( 1s) 3si 92 90∶10 aIsolated yield. bDetermined by HPLC analysis. c2.0 equiv of Ag3PO4 was added. dPerformed at 0 °C for 120 h. To our delight, α-chloro-β-naphthol 1t and α-iodo-β-naphthol 1u were found to be suitable for the titled [4+1] spiroannulation, affording product 3ji in 86% yield with 95∶5 er, and 62% yield with 93∶7 er, respectively (Scheme 3). Although lower enantioselectivities were obtained than the run with α-bromo-β-naphthol (99∶1 er), this work represented the second example of CADA of chlorinated and iodonated phenolic derivatives at their halogenated sites.47 Scheme 3 | CADA studies with α-chloro-β-naphthol (1t) and α-iodo-β-naphthol (1u). Download figure Download PowerPoint Mechanistic investigation Based on previous reports in the literature by our research group47 as well as others,50–53 a plausible pathway for the formation of 3 under catalyst-free conditions was proposed (Scheme 4a). It was postulated that the reaction was initiated by the electrophilic dearomatization of 1 with azoalkene to generate intermediate I, followed by the debromination with in situ formed N-nucleophile via a SRN1 mechanism, and was finally terminated by the cross-coupling of diradical species II to give product 3. Compared with our prior work,47 the major difference is the involvement of another type of N-nucleophile for the debromination step. Thereby, a diagnostic reaction between dearomatized 4 and nitrogen anion 5, which could be considered as two separated units of intermediate I, was carried out (Scheme 4b). The experimental results indicated that compound 4 could indeed be reduced by 5 through one-electron transfer (SRN1) to give the bromide and C-radical III, thus enabling the formation of radical-coupling product 6. Although the envisioned N-radical IV was not directly identified from the above reaction mixture, an N-radical capture reaction of 7 with 4 and 2,2,6,6-tetramethylpiperidinyloxy (TEMPO) successfully led to 8 in 38% yield,59 with the contaminant generation of product 6 by the coupling of radicals III and III′ (Scheme 4c). Notably, the control reaction between 7 and TEMPO did not produce 8 at all (Scheme 4d). These two experiments confirmed that the nitrogen anion 7 could clearly be oxidized by 4 to give the N-radical IV′, which was then captured by TEMPO after a 5-exo-trig cyclization. With regard to the better reaction performance by adding Cu(II)-source (entry 1 vs entry 2, in Table 2), it was believed that activation of azoalkene with such a Lewis acid accelerated the challenging intermolecular electrophilic dearomatization, which could be the rate-determining step for the titled domino reaction. Scheme 4 | (a–d) Mechanistic considerations. Download figure Download PowerPoint Studies on the enantiodiscrimination In consideration of the asymmetric control of the tilted reaction, the enantiodiscrimination with chiral Cu(II)-catalyst might take place at the step of either electrophilic dearomatization or radical coupling (Scheme 5a). Based on the above reaction mechanism, the former proposal should be excluded, since the chirality would be lost when the C-radical was formed at the stereocenter from I to II. Therefore, it was assumed that enantiocontrol took place at the radical coupling step. Much to our delight, this assumption was strongly supported by the probe run between 9 and 2a (Scheme 5b). Presumably, the reaction proceeded through a sequence of Michael addition to give intermediate I A, followed by the oxidation with Cu(II)-species to generate diradical II A. This eventually furnished the product 3bc with 94:6 er under the enantiocontrol with chiral Cu(II)-catalyst. Notably, the species II A′ should be identical with the plausible intermediate II for the reaction of 1b with 2c, in which almost the same enantioselectivity (95:5 er) was obtained. Based on the above experimental results, a stereochemical model for the formation of 3bc is proposed (Scheme 5c). Simple modeling reveals the formation of (R)- 3bc (Model A) is far more favorable than the generation of (S)- 3bc (Model B), which is consistent with the observed (R)-configuration of 3bc. Scheme 5 | (a–c) Postulated enantiocontrol with chiral Cu(II)-catalyst. Download figure Download PowerPoint Synthetic applications To showcase the synthetic value of this new method, we first carried out a scaled-up experiment, and gram-scale preparation of product 3bi (1.09 g) was achieved in 83% yield with 97:3 er (see Supporting Information). Next, several reactions for the further dearomatization of 3bi were performed (Scheme 6). After reduction and subsequent tert-butyldimethylsilyl-deprotection, 3bi was converted into a phenol-containing compound 10, which could then participate in two different types of dearomatizing transformations,60–62 affording products 11 and 12 in 63% and 68% yields, respectively. Notably, both reactions occurred on the less hindered side of the phenolic ring with excellent diastereoselectivity (<20∶1 dr), which were confirmed by X-ray crystallographic analysis of 11 and 12.a Moreover, a less electron-rich phenol 13, which was directly generated from 3bi, was also converted into a doubly dearomatized product 14 through an oxidative dearomatization approach.61,62 Scheme 6 | Derivatization of product 3bi by further dearomatization. Download figure Download PowerPoint Conclusion We have developed a novel example of Cu(II)-catalyzed asymmetric [4+1] spiroannulation reaction, wherein α-bromo-β-naphthols and azoalkenes were used to construct chiral azaspirocyclic scaffolds, by employing a dearomatization/dehalogenation approach. Remarkably, this new process, relying on matched reactivities of those two reaction components under very mild conditions, represents a rare example of CADA transformation of phenolic derivatives at their heteroatom-substituted positions. Footnote a CCDC 1891237 ( 3ac), 1891239 ( 3bu), 1891238 ( 3bh), 1891240 ( 11) and 1891241 ( 12) contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre. Supporting Information Supporting Information is available, including synthetic procedures, characterization data, additional spectra, and X-ray crystallographic data. Conflict of Interest There is no conflict of interest to report. Funding Information This work was financially supported by the National Natural Science Foundation of and the Key Science and of the Key Laboratory of Xi'an and the of and in the of Natural Asymmetric Dearomatization 3. Asymmetric Dearomatization of and Dearomatization An in the Dearomatization of 6. of Using a A. 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