Palladium/N-CD3-Xu-Phos-catalyzed enantioselective cascade Heck/remote C(sp2)−H alkylation reaction

doi:10.21203/rs.3.rs-155228/v1

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Palladium/N-CD3-Xu-Phos-catalyzed enantioselective cascade Heck/remote C(sp2)−H alkylation reaction

https://doi.org/10.21203/rs.3.rs-155228/v1

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posted 15 Jul, 2021

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Heck-type C-H bond activation of unactivated alkenes has emerged as a powerful strategy for the construction of synthetically valuable spirocycles over past 30 years, however, the development of asymmetric version has lagged largely behind. Herein we demonstrate a robust Heck-type reaction of a broad range of unactivated alkenes enabled by the first palladium/Xu-Phos-catalyzed tandem Heck/remote C−H bond alkylation. Moreover, the synthesis of both enantiomers of the product using the same enantiomer of a chiral ligand via a position of the phenyl ring-dependent enantiodivergent synthesis. The salient features of this methodology include operational simplicity, high chemo- and enantioselectivity, broad substrate scope. In addition, we first revealed that the C(sp²)-H activation, alkene insertion and C−I reductive elimination steps are reversible by experiments.

Catalysis

Synthetically Valuable Spirocycles

Phenyl Ring-dependent Enantiodivergent Synthesis

Alkene Insertion

C−I Reductive Elimination

Chiral spirocycles are key structural skeletons found in a wide of bioactive natural products^1-4, effective chiral ligands and catalysts^5-6. Owing to its unique three-dimensional orientation and conformational constraints, chiral spirocycles as privileged pharmacophores exist in many drug development programs⁷. Despite a plenty of methods have been developed for the preparation of spiro stereocenters^8-17, most existing methods need to elaborate a preconstructed monocycle^8-9. Therefore, it is highly desirable to explore novel protocols for the construction of two cycles along with a quaternary stereocenter in one operation.

Functionalizing C-H bonds selectively at various locations in molecules will ultimately afford synthetic chemists transformative tools to modify and construct molecular structures^18-23. C-H bonds that are remote from functional groups are widespread, and distinguishing these C-H bonds bearing little difference in electronic property is a formidable challenge in C-H activation. To date, much pioneering work utilized the intrinsic steric or electronic properties of the arenes^24-28, or the type of “U”-shaped directing group (DG)^29-30. Although a large number of brilliant achievements were made with the use of DG, there is one point that the DG needs to be installed on the substrate and removed after the reaction couldn’t be ignored. Instead of using a DG that is covalently bound to a substrate for site-selective C-H activation, an alternative approach that utilizing a transient DG can be generated in situ under the reaction conditions would open the door to new reactivities (Fig. 1a, 1b)^31-40. As a pioneering study, Grigg et al. successfully implemented this strategy in the Pd-catalyzed remote-C-H functionalization of the heteroaromatic tethered alkene moiety through carbopalladation of alkenes to form neopentyl-type σ-alkylpalladium intermediate as the DG³². This marks that the direct and selective functionalization of remote C-H alkylation of arenes has been successfully applied to the construction of spirocycles. Utilizing the same concept, Ruck et al. have accomplished the expansion of the C(sp²)-H scope to an unactivated aryl C-H bond³³. Subsequently, Zhu et al. demonstrated that the σ-alkylpalladium intermediate can activate the C(sp³)-H bond, thereby leading to the 5,6-spiroheterocycles³⁶. Notably, continued interest in this reaction has recently culminated with the highly strained spiro-fused benzocyclobutene derivatives by Lautens³⁹. Very recently, Beller’s group combines selective nucleophilic substitution (S_N2’), Pd-catalyzed Heck and C-H activation reaction in a cascade manner, affording the highly strained racemic 5,4-spiroheterocycles in good to high yields⁴⁰. In the classic domino Heck/intramolecular C-H alkylation reaction, the carbopalladation step is a chiral-determining step, but this step is reversible^31,33.

Nowadays much progress has been made in racemic domino Heck/intramolecular C-H alkylation reaction to construct complex molecular architectures. However, due to no solid experiment evidence, there remain some unresolved issues relating to the mechanism of this kind of reaction, such as: (1) whether the carbopalladation step is reversible; (2) whether the C(sp²)-H activation step is reversible; (3) whether the C−I reductive elimination is reversible. Moreover, the development of an enantioselective version remains extremely challenging, due to the following issues: (1) various competitive side reactions such as reductive Heck reaction, carboiodination reaction, 1,4-Pd migration/C(sp²)−H functionalization^41-43; (2) when having two different ortho-position C-H of aromatic ring, how to control the site-selectivity; (3) the high temperature was required in previous work^39-40, which easily lead to the ring-opening byproduct (Fig. 1a). Inspired by the good performance of

Xu-Phos in asymmetric Heck and related cascade reactions^44-53, we became very interested in addressing this long-standing unsolved asymmetric tandem Heck reaction/C-H alkylation, which, if successful, would provide an immediate access to synthetically-valuable optically active 5,4- and 5,5-spirocycle derivatives⁵⁴. Herein, we present a robust palladium/Xu-Phos catalyst system for asymmetric tandem Heck reaction/C-H alkylation via a palladacycle intermediate (Fig. 1c). Synthesis of both enantiomers of the product can be accomplished depending on the site of the substituent on the aromatic or heteroaromatic ring (Fig. 1d). Moreover, this reaction exhibits a broad scope of the unactivated aryl tethered alkene moiety while under operationally simple and mild reaction conditions.

We began our investigation by revisiting our previously developed catalytic system for enantioselective cascade Heck-type reactions of alkene-tethered aryl iodides^44-48. With the ortho-iodophenol-derived allyl ether 1a as the model substrate, we conducted a preliminary study in isopropyl ether (120 ^oC) for 24 h with Pd₂(dba)₃•CHCl₃ as the precatalyst, N-Me-Xu-Phos (N-Me-Xu3) as the chiral ligand and Cs₂CO₃ as the base (Table 1). Our initial efforts resulted in poor yield of the desired product 4a with moderate enantiomeric ratio (e.r.) (67% conversion, 22% yield with 88:12 e.r.) together with a series of byproducts 2, 3 and 5 (Table 1, entry 1), indicating that the synthesis of the highly strained chiral 5,4-spirocycles is indeed very challenging. Subsequently, further evaluation of the reaction conditions revealed that all of bases, additives, Pd salts, and temperature were the key factors to obtain a robust reaction.

Several points are noteworthy: (1) this reaction is very sensitive to the bases (Table 1, entries 2−6). For example, when PMP was chosen as the base, the byproduct 2 was given as the main product via carboiodination of alkene (Table 1, entry 3). Nevertheless, changing to CsOAc, a 1,4-Pd shift of palladacycle followed by ortho-C-H activation led to the fused polycycle 6 (Table 1, entry 4). (2) In Lauten’s work, 1a quickly converts to the target compound 4a in good yield by using the racemic ligand (P^tBu₃) at 100 ^oC for 1 hour (entry 9)³⁹. By a huge margin, the rate of reaction is greatly reduced under current conditions without P^tBu₃ (Table 1, entry 8). Even extending to 72 hours and warming up to 110 ^oC, the desired product 4a was obtained in only 48% yield (63% conversion). Indeed, adding the racemic ligand was beneficial to the conversion of the reaction (Table 1, entries 2 vs 3, and 7 vs 8). However, such a strong racemic background reaction poses a great challenge to the high enantioselectivity. (3) The potassium bases are beneficial to the enantioselectivity (Table 1, entries 5, 6 vs 2). (4) Reducing the temperature to 110 ^oC could inhibit the formation of the ring-opening by-product 5 (Table 1, entries 1−6 vs 7, 8). After an extensive evaluation of the reaction conditions, the current conditions were not satisfactory (Table 1, entry 7). Not only the desired product 4a was provided with 92.5:7.5 e.r., but also the conditions have poor universality (more detail see the supporting information, Table S1−S9).

Then, we focused our attention on screening of chiral ligands (Table S10−S12). Firstly, various commercially available chiral ligands such as biphosphines (L1−L7), monophosphine (L8), phosphoramidite (L9), ferrocene-derived P,N-ligands (L10−L11), bis(oxazoline) (L12) were tested occasionally together with the byproduct 7. The biphosphine ligands (L1−L4, L6, L7), ferrocene-derived P,N-ligands (L10−L11) failed to give the desired product 4a. Both a bulky biarylphosphine (L5) and monophosphine (L8) gave 4a in good yield without any enantioselectivity. Only the phosphoramidite (L9) delivered 4a but with low enantioselectivity. Subsequently, we examined the performance of a Sadphos kit (including Ming-Phos⁵⁵, Xu-Phos^44-48, Xiang-Phos⁵⁶, PC-Phos⁵⁷, Xiao-Phos⁵⁸, Wei-Phos⁵⁹ and TY-Phos⁶⁰ etc.). The dicyclohexyl phosphine ligands (Xu-Phos) remained the most effective for enantioselective induction. Inspired by these results, other Xu-Phos such as N-Me-Xu4 (Table 1, entry 11) and N-CD₃-Xu4 (Table 1, entry 10) were then examined under previous reaction conditions. Of which, the better results could be obtained by using the newly indentified N-CD₃-Xu4 as the chiral ligand. To the best of our knowledge, the introduction of deuterium atom in the chiral ligand to increase the enantioselectivity are rarely reported.

With the optimal reaction conditions established, we next examined the generality of this enantioselective tandem Heck reaction/C-H alkylation. First, the effect of allyl substituents was examined, and the results are shown in Table 2. A broad series of allyl substituted aryl iodides 1 including monosubstituted phenyl rings with electron-donating or -withdrawing groups at different positions (ortho, meta or para-), a disubstituted phenyl ring, worked smoothly to afford 4a–4l in 65–96% yields with 91:9–96.5:3.5 ers. The absolute configuration of the product was confirmed by the X-ray diffraction analysis of 4b. In addition, highly strained 5,4-spiro-fused 2,3-dihydrobenzofurans 4m–4n that contain medicinally relevant heterocycles, such as 9,9-dimethyl-9H-fluorene and 9-phenyl-9H-carbazol-1-yl were isolated in 70–71% yields with 95:5–96:4 ers. The effect of substituents on the benzene ring of the 2- iodophenoxy moiety was then investigated under the optimal reaction conditions. The desired products 4o–4ad were also obtained in 44–86% yields with 92.5:7.5–97:3 ers for the reactions with substrates bearing monosubstituted phenyl rings with either electron-rich or electron-deficient group at C4 or C5, a disubstituted phenyl ring and a naphthalene ring. When using N-Me-Xu4 as a chiral ligand, except in one particular case (4e), no better enantioselectivities were given. It is general phenomenon that the introduction of deuterium atom is beneficial to increase the enantioselectivity.

To gain deep insight into the reaction mechanism, several control experiments were carried out (Fig. 2). Although a series of byproducts had been inhibited under the standard conditions, a key mechanistic question is: how does the relative rate of σ-alkyl palladium compare reductive elimination with Sonogashira coupling, Suzuki coupling, reductive Heck and alkyne insertion? To probe this question, several competing reactions were performed (Fig. 2a). Note that no desired product 4a was detected with using PhB(OH)₂, cyclohexenylboronic acid or phenylacetylene as the second substrates. These results supported that the C(sp³)-C(sp)and C(sp³)-C(sp²) cross-coupling of the domino Heck/Suzuki or Sonogashira reaction is more favored than this present domino Heck/remote C-H alkylation reaction. However, the C(sp³)-C(sp³) cross-coupling is obviously unfavored. Subsequently, adding HCO₂Na or ethyl 3-phenylpropiolate to the reaction mixture, roughly the same amount of the reductive Heck product 3 or alkyne insertion⁶¹ product 9 with the spirocycle 4a were furnished, indicating that the rates of these reactions are similar. All these results further confirmed that the realization of domino Heck/remote C-H alkylation reaction is extremely challenging^{31, 39-40}, especially in an enantioselective manner. It's worth noting that er of 3, 8, 9, 12 and 13 are different, which might indicate that the transmetalation step taking place prior to the alkene insertion. Experiments with D₂O instead of H₂O were conducted under the optimal conditions by using 1a and 1g as the substrates (Fig. 2b), respectively. 75% D-labeled 4a was obtained in 85% yield with 94:6 er. Nevertheless, ortho-methyl aryl group derived 1g could not afford D-labeled 4g. Deuterium (D)-labeling experiments confirmed our assumption that the step of C-H bond activation is reversible. Moreover, the five-membered palladacycle of C(sp²)-H bond activation was favored comparing with the less-strained six-membered palladacycle of C(sp³)-H bond activation under the reaction conditions³⁵. Despite overcoming the high barriers was required to construct the highly strained 5,4-spirocycle, the C-C bond of 4a could be cleaved to give the ring-opening byproduct 5a at 120 ^oC (Fig. 2c). Nonlinear effect studies on the enantiomeric composition of the chiral ligand N-CD₃-Xu4 and product 4a indicated there is a clear first-order dependence was observed for the catalyst (Fig. 2d). These results are consistent with an active catalyst/ligand being of a monomeric nature and the reaction possessing a first-order dependence on catalyst. When carboiodination compound 2ae (5-exo) was subjected to the catalysis of Pd(dba)₂/QPhos or Pd₂(dba)₃•CHCl₃/N-Me-Xu3, 6-endo-products 16a and 16a' could be obtained, which indicates that the alkene insertion and carboiodination steps are reversible. Subsequently, we examined the progress of the reaction as a function of time and temperature with ortho-iodophenol-derived allyl ether 1ae as the model substrate (Fig. 2f). At 100 ^oC, the reaction proceeded smoothly and gave the 5-exo-product 2ae with 93% ee and 95:5 rr. With the increase of reaction time, the ratio of 5-exo-product and 6-endo-product, and ee value hardly changes. However, the proportion of 6-endo-product increased significantly with increasing of the temperature (120 ^oC and 150 ^oC). Meanwhile, the ee value of 5-exo-product decreased obviously.

Based on the results of the above experiment and previous works, a reasonable pathway for this palladium-catalyzed Heck/intramolecular C-H alkylation reaction is shown in Fig. 3. First, the arylpalladium species I was generated by oxidative addition of 1 or 14 with Pd(0) complex. Then, followed by an intramolecular 5-exo-Heck-type or 6-endo-Heck-type reactions form chiral σ-alkylpalladium species II or II’. Next, aryl (Ar²) C-H bond activation via the σ-alkylpalladium intermediate II deprotonation gave a spiropalladacycle III, which produces the corresponding product 4 or 15 and regenerates the Pd(0) catalyst to the next catalyzed cycle from reductive elimination. Nevertheless, σ-alkylpalladium species II through C-I elimination also afforded the iodide 2. The β-H elimination of 6-endo-cyclization σ-alkylpalladium species II’ could delivered the endo-products 16a and 16a'. Here, it is worth noting that the C(sp²)-H activation, the carbopalladation and the C−I reductive elimination steps are reversible.

Encouraged by these excellent results, we applied this method to the construction of the optically active 5,5-spirocycles. Both enantiomers of a chiral molecule are often required in organic synthesis, biological chemistry, and the medicinal and pharmaceutical industries. Generally, the synthesis of the enantiomer of a chiral molecule could be obtained by using the enantiomer of chiral ligands. Herein, we envisaged that the synthesis of a pair of enantiomers might be achieved by changing the position of the aromatic or heteratomic aromatic rings (Table 3). Using a variety of aryl iodides 14 bearing electron-donating/withdrawing groups at the para- and meta-positions of phenyl rings, both (R)- and (S)-enantiomers of the spiro-indane-dihydrobenzofuran products 15a–15f were obtained in high yields (80–99% for the (R)-enantiomers and 82–98% for the (S)-enantiomers) with excellent enantioselectivity (95:5–97:3 ers for the (R)-enantiomers and 95:5–97.5:2.5 ers for the (S)-enantiomers) under the standard condition, respectively. When the linker at C2 or C3 of heteratomic aromatic rings, such as thiophene, benzothiophene and furan, the corresponding 5,5-spirocycle products 15g–15n were also afforded with good results (93–99% yields with 95:5–98.5:1.5 ers for the (R)-enantiomers and 94–>99% yields with 95:5–98.5:1.5 ers for the (S)-enantiomers).

Then, we further extended the scope of alkene-tethered aryl iodides 14 (Table 4). In more than 40 examples, the desired products 15o–15bc were synthesized exclusively in good yields with excellent enantioselectivity (up to 98.5:1.5 er). Substrates bearing monosubstituted phenyl rings with electron-donating or -withdrawing groups at different positions (ortho or para), a disubstituted phenyl ring, a trisubstituted phenyl ring, a naphthalene, a pyrene and medicinally relevant heterocycles (dibenzo[b,d]thiophene, benzofuran, thiophene and indole) could be well tolerated. Notably, the present asymmetric catalytic system is applicable to BocN as a tether, delivering the indolines 15al–15am in good yields and with good ee values.

In summary, we have developed the first highly enantioselective palladium-catalyzed domino Heck/intramolecular C-H alkylation of alkenes with excellent chemo- and regioselectivities. The mothed not only constructs various chiral 5,4-and 5,5-spirocycles including one challenging all-carbon quaternary stereocenter, but also exhibits superior catalytic properties of Xu-Phos, which open up new avenues for the asymmetric domino Heck/intramolecular C-H activation reaction. Moreover, this work also provides an alternative solution that a position of the phenyl ring-dependent enantiodivergent synthesis, enabling the synthesis of both enantiomers of the product using the same enantiomer of a chiral catalyst. Moreover, this protocol works with a wide range of substrates and tolerates a series of functional groups under operationally simple and mild reaction conditions. In addition, the reversibility of the C(sp²)-H activation, alkene insertion and C−I reductive elimination steps was revealed by experiment. Further direction will focus on the development of asymmetric functionalization of palladacycles and will be reported in the due course.

General procedure for the 5,4-spirocycle derivatives (4). To a 10 mL oven-dried sealed tube was added substrate 1 (0.20 mmol, 1.0 equiv.), Pd-P^tBu₃-G3 (11.4 mg, 0.02 mmol, 10 mol%), N-CD₃-Xu4 (31 mg, 0.044 mmol, 22 mol%), Cs₂CO₃ (65.2 mg, 0.2 mmol, 1.0 equiv.), KOAc (19.6 mg, 0.2 mmol, 1.0 equiv.). The flask was evacuated and refilled with argon. Then, H₂O (36 mg, 2.0 mmol, 10.0 equiv.), MTBE (2 mL), and ⁱPr₂O (2 mL) was added to the tube, and stirred at room temperature for 1 h. Then the mixture was stirred at 110 °C for 12-24 h. After the reaction was complete (monitored by TLC), solvent was removed under reduced pressure. The crude product was then purified by flash column chromatography on silica gel to afford the desired product 4.

General procedure for the 5,5-spirocycle derivatives (15). To a sealed tube was added substrate 14 (0.2 mmol), Pd₂(dba)₃•CHCl₃ (0.01 mmol, 5 mol%), N-Me-Xu3

(0.04 mmol, 20 mol%) and Cs₂CO₃ (0.4 mmol). The flask was evacuated and refilled with argon. Then, MTBE (2 mL) was added to the tube, and stirred at room temperature for 1 h. Then the mixture was stirred at 90 °C for 12-24 h. After the reaction was complete (monitored by TLC), solvent was removed under reduced pressure. The crude product was then purified by flash column chromatography on silica gel to afford the desired product 15.

Data availability

The data supporting the findings of this study are available within the article and its Supplementary Information. Crystallographic data for the structures reported in this Article have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC 2058479. Copies of the data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif.

Acknowledgements

We gratefully acknowledge the funding support of NSFC (21672067, 21801078), 973 Program (2015CB856600), and the Program of Eastern Scholar at Shanghai Institutions of Higher Learning and the China Postdoctoral Science Foundation (2019M650071, 2019M661418).

Author contributions

X.B. and Z.-M.Z. carried out the experimental and data-analysis work. D.J., L.Z., and L.W. performed the synthesis of the chiral ligands and materials. Z.-M.Z. and J.Z. designed the reaction, directed the project and wrote the paper with the assistance of L.Y.

Competing interests

The authors declare no competing interests.

Additional information

Correspondence and requests for materials should be addressed to Z.-M.Z. and J.Z.

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Tables 1-4 are available in the Supplementary Files.

SupportingInformation.pdf
Palladium/Xu-Phos-catalyzed enantioselective cascade Heck/remote C(sp2)-H alkylation reaction
Table1.png
Table 1 | Reaction Conditions optimization.
Table2.png
Table 2 | Scope of the enantioselective construction of 5,4-spirocycle derivatives
Table3.png
Table 3 | Synthesis of the enantiomers by changing the position of the aromatic or heteroaromatic rings
Table4.png
Table 4 | Scope of the enantioselective construction of 5,5-spirocycle derivatives

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Palladium/N-CD3-Xu-Phos-catalyzed enantioselective cascade Heck/remote C(sp2)−H alkylation reaction

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Abstract

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