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• W3157858217 abstract "Open AccessCCS ChemistryRESEARCH ARTICLE1 Apr 2022Palladium-Catalyzed Asymmetric Allylic Alkylation/α-Iminol Rearrangement: A Facile Access to 2-Spirocyclic-Indoline Derivatives Xin Chang, Chao Che, Zuo-Fei Wang and Chun-Jiang Wang Xin Chang Engineering Research Center of Organosilicon Compounds and Materials, Ministry of Education, College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072, Hubei Google Scholar More articles by this author , Chao Che Engineering Research Center of Organosilicon Compounds and Materials, Ministry of Education, College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072, Hubei Google Scholar More articles by this author , Zuo-Fei Wang Engineering Research Center of Organosilicon Compounds and Materials, Ministry of Education, College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072, Hubei Google Scholar More articles by this author and Chun-Jiang Wang *Corresponding author: E-mail Address: [email protected] Engineering Research Center of Organosilicon Compounds and Materials, Ministry of Education, College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072, Hubei State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Shanghai 230021 Google Scholar More articles by this author https://doi.org/10.31635/ccschem.021.202100875 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail We report an unprecedented Pd-catalyzed asymmetric allylic alkylation of 1-(indol-2-yl)cyclobutanols followed by an α-iminol rearrangement. High yields with excellent chemo-, regio-, diastereo-, and enantioselectivities have been realized, affording a wide range of enantioenriched 2-spirocyclic-indolines bearing two contiguous stereocenters. The facial selectivity of the ensuing rearrangement is controlled by the subtle difference of the substituents on the all-carbon quaternary stereogenic center formed in the allylic alkylation step. Nonactivated racemic terminal allylic alcohols are utilized as efficient electrophiles via kinetic resolution pathways for the first time in Pd-catalyzed asymmetric allylic alkylation. The role of Et3B additive is pivotal to activating allylic alcohols toward the formation of π-allylpalladium species and suppressing N/O allylic alkylation of indole with enhanced C3-nucleophilicity. Electrospray ionization high-resolution mass spectrometry (ESI-HRMS) experiments provided strong evidence for the existence of the key nucleophilic boron anionic species, which fully accounts for the essential role of the Et3B additive. The study of the mechanism indicates that the real catalytically active species is an electronic π-cinnamyl-palladium complex coordinated by two phosphoramidite ligands, which is consistent with the observed nonlinear effect and control experiments and is further confirmed by X-ray structure analysis. Download figure Download PowerPoint Introduction The chiral polycyclic indoline ring represents a privileged core structure in a plethora of alkaloids and bioactive natural products.1–4 Among them, 2-/3-spirocyclic-indolines with marvelous molecular complexity and diversity display a broad range of medicinally relevant properties5–11 (Figure 1). For example, vindolinine, isolated from the medicinal plant Catharanthus roseus (periwinkle), exhibits strong activity against diabetes. The Kopsia alkaloids pauciflorine A and B are claimed to “selectively inhibit melanin synthesis of the B16 melanoma cell without any cytotoxicity toward the cultured cells.” Driven by their potential pharmaceutical value and inherent synthetic challenge, much attention has been paid to develop efficient methods to synthesize those skeletons.12,13 A general platform for the preparation of enantiopure indoline derivatives often lies in the utilization of the C3-nucleophilicity of 3-substituted indoles in catalytic asymmetric dearomatization (CADA) of indoles,14–21 in which 3-spiroindolines or 2,3-fused-indolines are predominately formed. In sharp contrast, the direct catalytic asymmetric construction of 2-spirocarbocyclic-indolines remains an elusive goal,22,23 which is mainly ascribed to the enormous steric congestion caused by the two consecutively generated tetrasubstituted stereogenic centers (Scheme 1a). Therefore, it is highly desirable to develop efficient methodologies for the construction of chiral 2-spirocarbocyclic-indoline skeletons bearing a unique C3-adjacent quaternary stereogenic center. Figure 1 | Bioactive molecules containing a 2-spirocyclic-indoline motif. Download figure Download PowerPoint Scheme 1 | (a and b) Different synthetic strategies for the construction of chiral polycyclic indolines. Download figure Download PowerPoint We envisioned that a rationally designed 3-substituted 1H-indole substrate tethered with a built-in cyclobutanol motif could serve as a potential C-nucleophile in Pd-catalyzed asymmetric C3-allylic alkylation24–26 to generate the intermediacy of α-hydroxyl imine, which affects the subsequent α-iminol rearrangement27–34 to form biologically important spiro[cyclopentane-1,2′-indolin]-2-one incorporating two adjacent C3 all-carbon quaternary and spiro N-quaternary stereogenic centers (Scheme 1b). However, several formidable challenges are associated with this novel design: (1) the competitive chemoselectivity or site selectivity in the initial allylic alkylation reaction given that three potential nucleophilic sites (C3/N/O) are embedded in the designed 3-substituted 1H-indole; (2) the feasibility of racemic branched allylic alcohols serving as the precursors for the key electronic π-allylpalladium species, which involves the activation of the inert hydroxyl group and the interaction of racemic allylic alcohol (a pair of enantiomers) with the chiral palladium complex; (3) the enantioselectivity control of the allylic alkylation with the prochiral nucleophile to generate a C3 all-carbon quaternary stereogenic center; (4) the great challenge of constructing highly stereoselective vicinal tetrasubstituted stereogenic centers, one all-carbon and one spiro N-quaternary stereogenic.35–37 Herein, we report our development, chemo-/diastereo-/enantioselectivity control, substrate scope, and synthetic applications of a novel asymmetric Pd-catalyzed C3-allylic alkylation of 3-substituted 1-(indol-2-yl)cyclobutanol with branched racemic allylic alcohols followed by a stereospecific α-iminol rearrangement. The current protocol provides expedient access to a wide range of enantioenriched 2-spirocyclic-indolin derivatives that incorporate two vicinal tetrasubstituted stereogenic centers in a highly chemo-, regio-, enantio- and diastereoselective manner. Experimental Methods To a 25 mL Schlenk tube were added (S,R,R)- L10 (16.2 mg, 0.032 mmol), [Pd(C3H5)Cl]2 (2.9 mg, 0.008 mmol), 3 Å molecular sieve (MS) (70 mg), and 1.0 mL CH3CN under nitrogen atmosphere. The mixture was stirred at room temperature for about 30 min. After the reaction temperature was dropped to 5 °C, 1-(indol-2-yl)cyclobutanol 2 (0.20 mmol), racemic allylic alcohol 7 (0.60 mmol), Et3B ([0.30 mmol, 1 M in tetrahydrofuran (THF), 0.30 mL], and K2CO3 (0.24 mmol) were added sequentially. Once 1-(indol-2-yl)cyclobutanol 2 was consumed [monitored by thin-layer chromatography (TLC)], the organic solvent was removed, and the residue was purified by flash column chromatography to give complex 8. To compound 8 in 1.0 mL of Et2O/EtOAc (1:1) was added trifluoroacetyl (TFA) (20 mol %), which was stirred at 20 °C for 48–72 h. Then, the organic solvent was removed, and the residue was purified by silica gel column chromatography to afford the desired product 4, which was then directly analyzed by chiral high-performance liquid chromatography (HPLC) to determine the enantiomeric excess. More experimental details and characterization are available in the Supporting Information. Results and Discussion Reaction development and optimization In light of our previous work38 in which 1,3-dialkyl substituted indoles exhibited higher reactivity than 3-alkyl 1H-indole in on C2/C3-difunctionalization of indoles and to obviate the unwanted N-allylation, we deliberately chose 1-(1,3-dimethylindol-2-yl) cyclobutanol 1 as the initially tested substrate in the Pd(PPh3)4-catalyzed allylic alkylation reaction with the activated methyl cinnamyl carbonate 3a as the π-allyl-Pd precursor. Despite intensive efforts, disappointingly, no desired C3-allylic alkylation occurred except the decomposition of methyl cinnamyl carbonate. Since the 3-substituted 1H-indoles are commonly used in Pd-/Ir-catalyzed asymmetric allylic alkylation reactions,39–48 1-(3-methylindol-2-yl)cyclobutanol 2a was then examined. The reaction did proceed smoothly with full conversion to afford the desired C3-allylation/α-iminol rearrangement product 4a in 35% yield; however, a sizeable proportion of N/O-allylation compounds 5a and 6a were also observed (Table 1, entry 1). Although the variation of allylic precursors and other reaction parameters could not effectively suppress N/O-allylation, one useful piece of information can be extracted from these experimental results, that is, the less active allyl precursor cinnamyl acetate 3d delivered better chemoselectivity toward the desired product 4a (Table 1, entry 4). Table 1 | Initial Studies on the Reaction Designa Entry PG 4a/5a/6ab Yield of 4ac 1 CO2Me ( 3a) 3/1/2 35 2 Boc ( 3b) 3/2/2 31 3 P(O)(OEt)2 ( 3c) 3/2/1 38 4 Ac ( 3d) 6/1/1 39 aAll reactions were carried out with 0.2 mmol 2a, 0.3 mmol 3, and 8 mol % catalyst in 1.0 mL of CH2Cl2 at room temperature for 24 h. bdr and chemoselectivity were determined by crude 1H NMR. cIsolated yield. The partial success of the preliminary attempts prompted us to further reduce the reactivity of the allyl precursor to alleviate the concern with chemoselectivity. It is well-known that allylic alcohols are less active precursors to form Pd-π-allyl species due to the poor leaving ability of the hydroxyl group.49–51 For example, Trost and Quancard39 and You et al.46 reported elegant asymmetric Pd- and Ir-catalyzed C3-allylic alkylations of 3-substituted 1H-indoles with prop-2-en-1-ol or linear allyl alcohols, which was activated by Lewis acid trialkyl borane or Fe(OTf)2, respectively. Hence, readily available racemic phenyl vinyl carbinol 7a was next examined in this design, and full conversion with clean reaction was observed with Et3B as the activator (Table 2, entry 1). To our surprise, an unexpected tetrahedral boron complex 8a being chelated by N and O atom, as revealed by nuclear magnetic resonance (NMR)/HRMS and further confirmed by X-ray analysis (vide infra),a was isolated in high yield through exclusive C3-allylic alkylation. The additive of Et3B is capable of performing up to three crucial roles within this transformation: Coordination with the hydroxyl of phenyl vinyl carbinol facilitates the ionization of the hydroxyl group toward the formation of the key π-allyl-Pd species52; being tightly bound to the N/O atom of the indole substrate not only suppresses the N/O allylic alkylation but also increases the C3-nucleophilicity of 1-(3-methylindol-2-yl)cyclobutanol.53–55 Subsequently, the desired 2-spirocyclic-indoline 4a could be obtained in good yield with excellent diastereoselectivity via an acid-triggered α-iminol rearrangement of the boron complex 8a. Evaluation of different Lewis acids showed that Et3B is the best choice for this process to suppress the undesired N/O allylic alkylation (see Supporting Information Table S1, for more details). Reducing Et3B to a substoichiometric amount retarded the allylic alkylation and led to a significantly lower yield (entries 2 and 3). Activated allylic precursors 3a–3d could also be employed in this reaction to generate compound 8a with similar results, which further confirmed one of the aforementioned key roles of Et3B additive, that is, suppressing the undesired N/O allylic alkylation of indole (entries 4–7). From the standpoint, of cost-efficiency and sustainability, the readily available racemic phenyl vinyl carbinol 7a is the preferred allyl precursor. Then, we focused our attention on developing an asymmetric variation of this sequential Pd-catalyzed allylic alkylation/α-iminol rearrangement. Using [Pd(C3H5)Cl]2 as the metal source, initial screening several types of privileged chiral ligands reported in Pd-catalyzed asymmetric allylic alkylations24,25 revealed that the performance of chiral phosphoramidite ligands was better than that of bisphosphine or P,N-ligands in terms of reactivity and enantioselectivity (see Supporting Information Table S2, for more details). With phosphoramidite ligand56 (Sa,S,S)- L1, the allylic alkylation/rearrangement process occurred smoothly, and the desired product 4a was obtained in 80% yield with 87% ee and >20:1 dr (Table 2, entry 8). Ligand (Sa,R,R)- L2 with the opposite central chirality was proved to be a mismatched one in this protocol, delivering the spiro heterocycle 4a in 75% yield with 50% ee (entry 9). Further structural variation to the amido moiety and bi-2-naphthol (BINOL) skeleton in the phosphoramidite ligand could not improve the results further (entries 10–15). Fortunately, the phosphoramidite ligand57 (S,R,R)- L10 with a unique 2,2′,3,3′-Tetrahydro-1,1′-spirobi[1H-indene]-7,7′-diol (SPINOL) backbone exhibited the best asymmetric induction and led to the desired product 4a in good yield with 92% ee (entry 17). Similarly, (S,S,S)- L9 with the opposite central chirality was also a mismatched ligand for this transformation (entry 16). Furthermore, the solvent effect was examined for the two sequential steps (entries 17–20; see Supporting Information Table S3, for more details), and the allylic alkylation reaction in CH3CN followed by acid-promoted rearrangement in mixed Et2O/EtOAc led to high yield with exclusive chemoselectivity and excellent enantio-/diastereoselectivity (82% yield, 96% ee, >20:1 dr). Without 3Å MS, a lower yield of 4a was obtained, albeit with the comparable level of enantioselectivity (entry 21). Linear cinnamyl alcohol 9 was also compatible in this catalytic system, affording the same product in similar reactivity albeit with much lower enantioselectivity (entry 22). Additionally, the effect of the ratio of ligand L10 to Pd on the reaction was also studied. When the in situ-formed catalyst in a 1∶1 ratio (Pd to L10) was employed in this model reaction, only a trace amount of nearly racemic product 4a was obtained (entry 23). The absolute configurations of boron complex 8a [using chiral ligand (Sa,S,S)- L1 in the Pd-catalyzed asymmetric allylic alkylation] and spiro heterocyclic product 4a [using chiral ligand (S,R,R)- L10 in the initial Pd-catalyzed asymmetric allylic alkylation, vide infra] were unambiguously determined as R and (1R,3′S), respectively, by X-ray diffraction analysis. Table 2 | Reaction Optimizationa Entry [Pd] L Solvent Yieldb ee (%)c 1 Pd1 7a — DCM 90 — 2d Pd1 7a — DCM 72 — 3e Pd1 7a — DCM 41 — 4 Pd1 3a — DCM 91 — 5 Pd1 3b — DCM 85 — 6 Pd1 3c — DCM 65 — 7 Pd1 3d — DCM 88 — 8 Pd2 7a (Sa,S,S)- L1 DCM 80 87 9 Pd2 7a (Sa,R,R)- L2 DCM 75 50 10 Pd2 7a (Sa,S,S)- L3 DCM 64 45 11 Pd2 7a (Sa,S,S)- L4 DCM NR — 12 Pd2 7a (Sa,S,S)- L5 DCM 46 56 13 Pd2 7a (Sa,S,S)- L6 DCM 27 36 14 Pd2 7a (Sa,S,S)- L7 DCM 26 35 15 Pd2 7a (Sa,S,S)- L8 DCM 65 76 16 Pd2 7a (S,S,S)- L9 DCM 78 −50 17 Pd2 7a (S,R,R)- L10 DCM 81 −92 18 Pd2 7a (S,R,R)- L10 PhMe 87 −92 19 Pd2 7a (S,R,R)- L10 DCE 83 −91 20 Pd2 7a (S,R,R)- L10 MeCN 82 −96 21f Pd2 7a (S,R,R)- L10 MeCN 70 −93 22 Pd2 9 (S,R,R)- L10 MeCN 73 −62 23g Pd2 7a (S,R,R)- L10 MeCN trace −5 Note: PG, protecting group; DCM, dichloromethane; DCE, 1,2-dichloroethane. aAll reactions were carried out with 0.6 mmol 7a, 0.2 mmol 2a, 8 mol % [ Pd1] or 4 mol % [ Pd2] and 16 mol % chiral ligand, 0.3 mmol Et3B, 70 mg activated 3 Å MS, and 0.24 mmol K2CO3 in 1.0 mL of solvent at 5 °C for 24–48 h. [ Pd1] = Pd(PPh3)4. [ Pd2] = [Pd(π-C3H5)Cl]2. bIsolated yield. cdr was determined by crude 1H NMR, and ee was determined by HPLC analysis. d0.2 mmol Et3B was used. e0.1 mmol Et3B was used. fWithout 3 Å MS. gThe in situ-formed Pd-catalyst in a 1:1 ratio (Pd to L10) was employed. Substrate scope With the optimized reaction conditions in hand, we next investigated the generality of this sequential-catalyzed asymmetric allylic alkylation/α-iminol rearrangement protocol (Table 3). A range of racemic aryl vinyl carbinols possessing different electron and steric properties were well tolerated under the standard reaction condition to afford the corresponding 2-spirocyclic-indoline derivates 4b–4k containing adjacent quaternary stereocenters in good yield with excellent enantioselectivity and exclusive diastereoselectivity (Table 3, entries 2–11). In addition, the fused aryl vinyl carbinols 7l and 7m and heteroaryl vinyl carbinols 7n and 7o were subject to this sequential reaction, providing desired product in good yield and a high level of enantioselectivity (entries 12–15). For the challenging carbinol 7p with a styrenyl substitution, the reaction could proceed smoothly to obtain satisfactory results without the issue of regioselectivity (entry 16). Delightedly, we found that methyl vinyl carbinol was also compatible with this system, affording the desired product 4q in acceptable yield with high diastereoselectivity and excellent enantioselectivity (entry 17). Table 3 | Substrate Scope of Branched Racemic Allylic Alcoholsa Entry R 4 drb Yieldc ee (%)d 1 Ph 4a >20∶1 82 96 2 p-F-C6H4 4b >20∶1 79 93 3 o-F-C6H4 4c >20∶1 63 84 4 m-F-C6H4 4d >20∶1 65 90 5 p-Cl-C6H4 4e >20∶1 85 95 6 p-Br-C6H4 4f >20∶1 84 97 7 p-MeO-C6H4 4g >20∶1 80 95 8 p-Me-C6H4 4h >20∶1 77 91 9 m-Me-C6H4 4i >20∶1 71 92 10 3,4-Cl2-C6H3 4j >20∶1 74 92 11 3,5-Me2-C6H3 4k >20∶1 72 95 12 1-Naphthyl 4l >20∶1 50 85 13 2-Naphthyl 4m >20∶1 73 94 14 2-Furyl 4n >20∶1 71 89 15 3-Thienyl 4o >20∶1 75 95 16 Styrenyl 4p >20∶1 74 99 17 Me 4q 18∶1 61 99 aAll reactions were carried out with 0.6 mmol 7, 0.2 mmol 2a, 4 mol % catalyst, 0.3 mmol Et3B, 70 mg activated 3 Å MS, and 0.24 mmol K2CO3 in 1.0 mL of MeCN at 5 °C for 24–48 h. bdr was determined by crude 1H NMR. cIsolated yield. dee was determined by HPLC analysis. Having estimated the scope of racemic branch allylic alcohols, we next further investigated the scope of 2,3-disubstituted indole derivatives. As shown in Table 4, with phenyl vinyl carbinol 7a as the reaction partner, the sequential reaction of various 2,3-disubstituted indole derivatives with an electron-donating ( 2b–2d), electron-withdrawing ( 2e–2g) group at a different position (C-4, -5, -6, and -7) of the indole core could proceed smoothly to provide the desired spiroindolines ( 4r–4w) in 63%–85% yield with >20:1 dr and 87–94% ee (Table 4, entries 1–6). For 4-methyl- and 4-fluoro-substituted indole cyclobutanols 2b and 2e, the level of enantioselectivity of the corresponding products 4r and 4u could be further improved from the original 85% ee to 92% ee and 94% ee, respectively, when (Sa,S,S)- L1 was employed as the chiral ligand. Notably, the substrates could be readily extended to indole cyclobutanols 2h– 2j, tethered with five- to seven-membered spirocyclic carbon rings (entries 7–9). For indole substrate 2k with a phenyl group at the three-position of the cyclobutanol moiety, the corresponding spiroindoline 4aa was obtained in 71% yield with exclusive diastereoselectivity and 93% ee (entry 10). Finally, the effect of the substituents at C3 of the indole was also examined. To our surprise, although good yield and high enantioselectivity could be achieved for the 3-ethyl- and 3-propyl-substituted indole cyclobutanols 2l and 2m; a diastereoselective ratio of only around 2:3 was observed for the generated spiro indolines 4ab and 4ac in favor of the opposite diastereomer. Fortunately, synthetically useful diastereoselectivity and excellent enantioselectivity could be readily obtained through switching the Brønsted acid in the rearrangement step from TFA (20 mol %) to chiral phosphoric acid58,59 (S)- 10 (10 mol %) (entries 11 and 12). The absolute configuration of spiro heterocyclic product 4ab was unambiguously determined as (1S,3′S) by X-ray diffraction analysis, which revealed that the allylic alkylation step of 3-ethyl- and 3-propyl-substituted substrates maintained the same facial selectivity with that of the 3-methyl-substituted one while the ensuing α-iminol rearrangement step underwent the opposite facial selectivity. It is believed that the different facial selectivity of rearrangement was caused by the molar volume increment of the ethyl and propyl group compared with that of the methyl group. The bulky 3-benzyl-substituted indole cyclobutanol 2n was well tolerated in this protocol. Employing chiral ligand (R,S,S)- L10 in the initial Pd-catalyzed asymmetric allylic alkylation of 2n and followed by TFA-mediated α-iminol rearrangement, the corresponding spiro heterocyclic product (1R,3′S)- 4ad was achieved in 67% yield with 6∶1 diastereoselectivity and 88% ee (entry 13), and the stereoselectivity control was further identified by the X-ray structure analysis. Indoles with a 3-phenyl group have been problematic and are thus rarely used in the dearomative asymmetric allylic alkylation reactions under Lewis or Bronsted acid catalysis.40 In our case, the bulkier 3-phenyl-substituted substrate 2o was still tolerated in the initial Pd-catalyzed allylic alkylation, albeit with comparably lower reactivity and unsatisfactory asymmetric induction. The subsequent α-iminol rearrangement proceeded stereospecifically in nearly fully reversed facial selectivity to generate spiro heterocyclic product (1S,3′R)- 4ae in an excellent diastereoselective fashion (13∶1 dr). This further confirmed that the facial selectivity of the ensuing rearrangement was controlled by the substituents on the generated all-carbon quaternary stereogenic center in the allylic alkylation step. Table 4 | Substrate Scope of 2,3-Disubstituted Indole Derivativesa aAll reactions were carried out with 0.6 mmol 7a, 0.2 mmol 2, 4 mol % [Pd(C3H5)Cl]2/[(S,R,R)- L10]4, 0.3 mmol Et3B, 70 mg activated 3 Å MS, and 0.24 mmol K2CO3 in 1.0 mL of MeCN at 5 °C for 24–48 h. Yields refer to the isolated products after chromatography. dr was determined by crude 1H NMR, and ee was determined by HPLC analysis. b(Sa,S,S)- L1 was used as the chiral ligand in the asymmetric allylic alkylation step. c10 mol % (S)-chiral phosphoric acid 10 was used in the α-iminol rearrangement. d(R,S,S)- L10 was used as the chiral ligand in asymmetric allylic alkylation. Gram-scale and synthetic applications To explore the synthetic utility and practicability of this allylic alkylation/α-iminol rearrangement, a gram-scale synthesis of 2-spiroclcylo indoline (1R,3′S)- 4a was carried out under the optimized condition, as shown in Scheme 2. The sequential reactions proceeded smoothly to afford the spirocyclic product 4a in good yield with exclusive diastereoselectivity and 96% ee. The enantioselectivity of 4a could be easily increased to over 99% ee after recrystallization. Bromination of 4a with N-bromosuccinimide (NBS) at the C5-position of the indoline skeleton afforded the enantioenriched compound 11 (Scheme 2, upside). Exposure of 4a to direct hydrogenation provided quantitative yield of the target compound 12 without loss of enantiomeric purity. Reduction of the C=O of 4a led to the amino alcohol 13 in a highly diastereoselective manner that maintained its enantioselectivity. Moreover, enantioenriched spirocyclic compound 15 could be obtained by double base-promoted allylic alkylation followed by ring-closing metathesis. In addition, by utilizing the nucleophilic addition of allylmagnesium bromide to compound 4a and subsequent olefin metathesis,60 a more complicated spirocyclic-indoline 17, bearing three consecutive tetrasubstituted stereogenic centers, could be formed in satisfactory yield with excellent stereoselectivity control (Scheme 2, middle side). Meanwhile, the important roles of the chiral spiro skeleton in asymmetric catalysis61–66 motivated us to further explore the feasibility of the spirocyclic-indoline backbone for chiral ligand synthesis. Chiral phosphine-olefin ligand 18 was readily synthesized through a one-step reaction from chiral amino alcohol 13. To our delight, this chiral ligand exhibited a good performance (92% yield and 97% ee) in Rh-catalyzed asymmetric 1,4-addition reaction of phenylboronic acid to cyclohex-2-en-1-one 19 with THF as the solvent (Scheme 2, downside).67 Scheme 2 | Gram-scale reaction and synthetic transformations. Download figure Download PowerPoint Mechanism explanations and control experiments Since the racemic branched allylic alcohols were employed as the precursor of the π-allylpalladium species, we wondered whether potential kinetic resolution or dynamic kinetic resolution could be involved in the current process. Accordingly, the reaction was performed with 0.4 mmol rac- 7a with 0.24 mmol 2a under the standard conditions, as shown in Scheme 3, 37% yield of (R)- 7a with 97% ee was obtained along with a 39% yield of (1R,3′S)- 4a with 92% ee (S = 101).68,b When the reaction was performed with 0.4 mmol rac- 7a with 0.4 mmol 2a, allylic alcohol (R)- 7a was recovered in 35% yield with 99% ee along with 91% ee of (1R,3′S)- 4a (S = 111). Therefore, kinetic resolution of racemic branched allylic alcohol was indeed involved in the Pd-catalyzed allylic alkylation reaction instead of dynamic kinetic resolution. To the best of our knowledge, this is the first example of Pd-catalyzed allylic alkylation reaction with racemic terminal branched allylic alcohols featured with kinetic resolution.69 Scheme 3 | Kinetic resolution studies. Download figure Download PowerPoint To gain some mechanistic insight into the nature of the possible catalytically active species formed in the Pd-catalyzed allylic alkylation reaction, the relationship between the ee values of spiro heterocyclic product 4a and the ee values of the chiral ligand (S,R,R)- L10 was studied. As shown in Figure 2 (see Supporting Information Table S4 and Figure S1, for more details), with L10 as the chiral ligand, we observed a small positive nonlinear effect (NLE).70,71 Combined with the experimental results listed in Table 2 (entries 20 and 23), the observed NLE indicates that the true catalytically active species might be the π-allyl-Pd( L10)2-type complex. Figure 2 | Nonlinear relationship between enantiopurity of (S,R,R)-L10 and 4a. Download figure Download PowerPoint To obtain more solid evidence, the corresponding π-cinnamyl-palladium complex was synthesized through the treatment of [PdII(cinnamyl)(COD)]BF4 and chiral Ligand L10 in a 1∶2 ratio, as shown in Scheme 4a. Fortunately, the single crystal of complex 21 ([PdII(cinnamyl)[(S,R,R)- L10]2]BF4) was obtained and determined by X-ray diffraction analysis (Scheme 4a). In control experiments, a comparable level of reactivity and stereoselectivity was observed for the reaction of 2a and 7a using a catalytic amount of the performed [PdII(cinnamyl) L102]BF4 complex and the in situ-formed [PdII(cinnamyl)(COD)]BF4/ L10 complex, indicating that π-cinnamylpalladium complex is indeed the catalytically active species (Schemes 4b and 4c). Furthermore, this conclusion is consistent with the stoichiometric reaction of 2a and the performed [PdII(cinnamyl) L102]BF4 complex 21 (Scheme 4d). Scheme 4 | (a–d) The X-ray structure of π-cinnamylpalladium 21 and control experiments to verify the real catalytically active species. Download figure Download PowerPoint Based on the experimental study and the absolute configurations of the products, the following plausible mechanism for this Pd-catalyzed asymmetric allylic alkylation/α-iminol rearrangement was proposed in Scheme 5. Under the optimal reaction conditions, in situ-formed [Pd0((S,R,R)- L10)2] species coordinates to the racemic allylic alcohol (±)- 7a·BEt3 complex A52 to generate the corresponding complexes [(S,R,R)/(R)]- B and [(S,R,R)/(S)]- B. With the aid of Et3B, the activated hydroxyl moiety of [(S,R,R)/(S)]- B more readily undergoes further oxidative addition to [Pd0((S,R,R)- L10)2] with inversion of configuration,72 which results in the formation of the active" @default.
• W3157858217 created "2021-05-10" @default.
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• W3157858217 date "2022-04-01" @default.
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• W3157858217 title "Palladium-Catalyzed Asymmetric Allylic Alkylation/α-Iminol Rearrangement: A Facile Access to 2-Spirocyclic-Indoline Derivatives" @default.
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