Palladium-catalysed branch- and enantioselective allylic C–H alkylation of α-alkenes

Enantioselective functionalization of alkenes is an attractive and straightforward method to assemble molecular complexity from readily available chemical feedstocks. Although regio- and enantioselective transformations of the C=C bond of alkenes have been extensively studied, those of the allylic C–H bonds of unactivated alkenes are yet to be explored. Here we report a palladium-catalysed branch- and enantioselective allylic C–H alkylation that is capable of accommodating diverse types of α-alkenes, ranging from feedstocks annually manufactured on a million-tonne scale to olefins tethering a wide scope of appended functionalities, providing unconventional access to chiral γ,δ-unsaturated amides. Notably, mechanistic studies reveal that regioselectivity is not only governed by the coordination pattern of nucleophiles but also regulated by the ligational behaviours of ligands, highlighting the importance of the monoligation of chiral phosphoramidite ligands in provoking high levels of stereo- and branch-selectivity via a nucleophile coordination-enabled inner-sphere allylation pathway. The selective functionalization of C=C bonds of alkenes is well studied, however, regio- and enantioselective transformations of the allylic C–H bond of unactivated alkenes are relatively underexplored. Now, a palladium-catalysed branch-selective and enantioselective allylic C−H alkylation of α-alkenes is reported. The process tolerates a wide range of α-alkenes, from chemical feedstocks to bioactive α-alkenes

A lkenes are among the most abundant feedstock hydrocarbons. The unparalleled reactivity and diverse range of reaction modes workable in the C=C bond allocate the alkenes unique capacity to serve as versatile reagents in the realm of synthetic organic chemistry 1 . Indeed, the selective functionalization of alkenes based on the fundamental reactions working on the C=C bond has long been the linchpin of synthetic chemistry 2-4 , culminating in a huge number of synthetically important transformations, some of which have exerted historical impact on society and constitute the backbones of organic chemistry. On the other hand, from a viewpoint of synthetic organic chemistry, direct allylic C-H activation adds an extra dimension to complement the improvement in selective transformations of alkenes. Progress has been made over the past decades in transition metal-catalysed allylic C-H functionalization [5][6][7] , but the majority of protocols are non-stereoselective transformations and thus precise and concurrent control of both the regio-and stereoselectivities remain a challenging issue. Successful highly stereoselective allylic C-H functionalizations are so far rendered by several principally distinct transition metal catalyst systems. For example, chiral bioxazoline-copper complexes generally offer high levels of enantioselectivity for Kharasch-Sosnovsky-type reactions, but are seemingly only amenable for cyclic alkenes (Fig. 1a) 8 . Lin and Liu described a copper-catalysed site-specific asymmetric allylic C-H cyanation (Fig. 1a) 9 , however, this concept has not yet been expanded to other nucleophiles. Apart from the copper catalysis, chiral dirhodium carbenes are also efficient for regio-and stereoselective allylic C-H alkylation of internal alkenes (Fig. 1a) 10,11 . A planar-chiral rhodium indenyl complex was recently identified to enable a branch-and enantioselective allylic C-H amidation of α-alkenes (Fig. 1a) 12 , but seems to be only applicable to the C-N bond-forming events. Chiral palladium complex catalysis has been a robust alternative strategy to enable the asymmetric C-H functionalization of versatile α-alkenes 13 . White and co-workers identified that aryl sulfoxide-oxazoline (ArSOX) ligands can exhibit high enantioinduction for asymmetric allylic oxidation 14 , which allows the alkylation reaction to favourably give a linear selectivity 15 (Fig. 1b). Past works have shown that chiral phosphoramidite ligands 16 are able to facilitate the palladium-catalysed allylic C-H functionalization of α-alkenes (Fig. 1b) 17,18 , wherein the allylic C-H cleavage occurs via a concerted proton and two-electron transfer process (Fig. 1c) to generate π-allylpalladium complexes 19 , which prefer to undergo an outer-sphere addition at the less-hindered terminus (Fig. 1d); however, this does not apply to cases using prochiral nucleophiles, which lead to the formation of achiral linear products 20 . Although nucleophile coordination to the palladium centre impels the reaction to favour an inner-sphere pathway (Fig.  1d), allowing for the favourable formation of branched products 21,22 , α-alkene substrates remain restricted to alkenes that are relatively more reactive, such as allylarenes, 1,4-dienes and others 19,[23][24][25][26][27] . By sharp contrast, a branch-and enantioselective allylic C-H oxidative alkylation of unactivated α-alkenes has long been a formidable challenge [28][29][30] . A representative contribution from the Hartwig group describes a sequential conversion of allylic C-H bond into chiral tertiary carbon centre by merging the palladium-catalysed C-H oxidation and iridium-catalysed asymmetric substitution 31 , however, a direct asymmetric variant remains unknown and yet to be developed. Herein we report a chiral phosphoramidite-palladiumcatalysed branch-and enantioselective allylic C-H alkylation capable of accommodating diverse types of α-alkenes (Fig. 1b).

Results and discussion
Given that nucleophile coordination to the π-allylpalladium intermediate facilitates branch-selectivity 19,23 , our design plan was initiated with the evaluation of various carbon nucleophiles containing Lewis basic functionalities for the asymmetric allylic C-H alkylation of 1-octene 1 by using Pd 2 (dba) 3 and chiral phosphoramidite L1 as the catalyst, 2,5-dimethyl-p-benzoquinone (2,5-DMBQ) as an oxidant and Na 2 CO 3 as a base (Fig. 2a). Although glycine Schiff base 2, 2-acylimidazole 3 and α-quinolinylacetamide 4 were not able to undergo the desired reaction, α-benzothiazylacetamide 5 was reactive enough to participate and gave the branched product 7 in 78% yield with 24% e.e., 12:1 d.r. and 18:1 b/l. Extensive evaluation of

Palladium-catalysed branch-and enantioselective allylic C-H alkylation of α-alkenes
Zhong-Sheng Nong 1,3 , Ling Zhu 1,3 , Tian-Ci Wang 1 , Lian-Feng Fan 1 , Pu-Sheng Wang 1 ✉ and Liu-Zhu Gong 1,2 ✉ Enantioselective functionalization of alkenes is an attractive and straightforward method to assemble molecular complexity from readily available chemical feedstocks. Although regio-and enantioselective transformations of the C=C bond of alkenes have been extensively studied, those of the allylic C-H bonds of unactivated alkenes are yet to be explored. Here we report a palladium-catalysed branch-and enantioselective allylic C-H alkylation that is capable of accommodating diverse types of α-alkenes, ranging from feedstocks annually manufactured on a million-tonne scale to olefins tethering a wide scope of appended functionalities, providing unconventional access to chiral γ,δ-unsaturated amides. Notably, mechanistic studies reveal that regioselectivity is not only governed by the coordination pattern of nucleophiles but also regulated by the ligational behaviours of ligands, highlighting the importance of the monoligation of chiral phosphoramidite ligands in provoking high levels of stereo-and branch-selectivity via a nucleophile coordination-enabled inner-sphere allylation pathway. chiral ligands suggests that incorporation of a carbazole moiety and H 8 -BINOL skeleton into the chiral phosphoramidite (Fig. 2b) led to superior enantioinduction, albeit with a slight decrease in the diastereo-and regioselectivities (Fig. 2c, entry 1 versus 2). Fine-tuning of the aryl group on the H 8 -BINOL skeleton (entries 3-5) revealed that the installation of para-trifluoromethyl phenyl substituents at 3,3′-positions turned out to be most beneficial to the control of stereo-and regioselectivities. Furthermore, enhanced results of 96% yield, 90% e.e., >20:1 d.r. and >20:1 b/l were obtained by using piperidine-derived amide 6 as a nucleophile, NaOAc as a base and Ref. 8 Ref. 9 Ref. 12 Rh Pd R Nu * R Nu this work Refs. 10   1,4-dioxane as a solvent, and conducting the reaction at a higher concentration, a slightly lower temperature and with a prolonged time (entry 6).
With the optimized conditions, the scope of α-alkenes was initially evaluated for the asymmetric allylic C-H alkylation protocol (Table 1). Importantly, 1-butene-with millions of tonnes manufactured annually from the worldwide petroleum industry-participated in the reaction to provide the branch-selective alkylation product 9 with high levels of stereo-and regioselectivity, explicating the great potential of this protocol in practical applications. Moreover, easily available 1-hexene and allylcyclohexane were both suitable substrates to afford corresponding products 10 and 11 with excellent enantioselectivity and perfect branch-selectivity, but a moderate yield was observed for allylcyclohexane, which bears a bulkier substituent at the allylic position. Other unactivated α-alkenes bearing a γor β-aryl substituentor a C=C bond remote from the reaction site-were all tolerated well to give the desired products 12-14 in satisfactory outcomes. Furthermore, a broad scope of unactivated α-alkenes bearing appended functionalities such as C-C triple bond, halides, hydroxyl, aldehyde, silyl ether, ether, ester, sulfonamide, amide and nitro groups all underwent the reaction to provide the desired products 15-27 in moderate to excellent yields and with high levels of regio-and stereoselectivity. The introduction of homoallylic  Reaction conditions: α-alkene (0.15 mmol, 1.5 equiv.), 6 (0.10 mmol, 1.0 equiv.), Pd 2 (dba) 3 (2.5 µmol, 2.5 mol%), L6 (7.5 µmol, 7.5 mol%), 2,5-DMBQ (0.12 mmol, 1.2 equiv.), NaOAc (0.10 mmol, 1.0 equiv.) and 1,4-dioxane (0.5 ml, 0.2 M) under N 2 , 50 °C, 36 h. Isolated yield, values of d.r. and b/l were determined by 1 H NMR analysis; the e.e. was determined by HPLC analysis. The absolute configuration of 16 was assigned by X-ray crystallography, whereas the others were assigned by analogy. a 1-butene (10 equiv. ether, substituted phenol-derived ethers and heteroarylcarboxylic acid-derived esters to substrates was permitted to generate corresponding products 28-34 in moderate to high yields and with high levels of regio-and stereoselectivity. 1,4-dienes were also amenable to preferentially generate C3-branched products 35 and 36, however, a lower yield was delivered with the alkyl-substituted diene. As anticipated, allylbenzene was highly reactive under the standard conditions to furnish the alkylation product 37 in an excellent yield with >20:1 d.r. and >20:1 b/l, but with a moderate enantioselectivity. Moreover, allyl ketone, allyl ester and allyl ether all underwent the desired reaction to deliver the branched products 38-40 with synthetically acceptable results. Notably, 1,1-disubstituted α-alkenes bearing both primary and secondary allylic C-H bonds were more challenging substrates, but still underwent the highly branch-selective reaction on the secondary allylic carbon to furnish branched products 41-43 in moderate yields and stereoselectivities by prolonging the reaction time or elevating reaction temperature, highlighting the preference of concerted proton and two-electron transfer process towards the activation of secondary allylic C-H bonds.  The extension of the asymmetric allylic C-H alkylation protocol to the late-stage functionalization of alkene substrates derived from structurally complicated molecules seemed to be equally successful ( Table 2). For instance, α-alkenes tethered with coumarin, menthol, chiral vicinal diol, galactose, oestrone, cholesteryl and liquid crystal monomer were all reactive components to furnish the desired products 44-51 in moderate yields with good levels of regio-and stereoselectivity. More importantly, 1,11-dodecadiene was able to undergo double asymmetric allylic C-H alkylation reaction at two allylic positions, giving rise to a densely functionalized chiral diamide 52 with high levels of branch-and stereoselectivity.
Apart from the α-alkene substrates, the generality of the asymmetric allylic C-H alkylation reaction of 1-octene 1 for other carbon nucleophiles was also explored ( Table 2). The presence of either electron-donating or -withdrawing substituent at the 6-position of the benzothiazolyl moiety was allowed to cleanly undergo the branch-selective asymmetric reaction and gave the desired products 53-57 in high yields with excellent stereoselectivities and almost perfect regioselectivity. Unfortunately, the installation of a fluoride substituent at the 4-position of benzothiazolyl moiety led to the branched product 58 with a diminished enantioselectivity. Furthermore, the replacement of piperidine with morpholine on the amide moiety was allowed and the desired alkylation products 59 and 60 were produced with high levels of enantioselectivity. Remarkably, α-heteroaryl ketones were also capable of serving as coordinating nucleophiles to provide branched products. For example, α-benzothiazolyl ketone regiospecifically delivered product 61 in good yield and enantioselectivity but with a poor diastereoselectivity. Moreover, α-quinolinyl ketones smoothly generated the branched products 62-68 in moderate to good yields and enantioselectivities with perfect diastereo-and branch-selectivities. Unfortunately, although α-pyridinyl ketone and 2-tosylmethylbenzothiazole worked to give products 69-70, low levels of enantioselectivity were delivered.  stereoselectivities (Fig. 3a). Interestingly, the exposure of 60 to diisobutylaluminium hydride (DIBAL-H) in toluene at −78 °C generated an amine 71 with maintained enantioselectivity, whereas the treatment of 60 with LiAlH 4 in THF at room temperature resulted in a deamidated product 72 (Fig. 3b) 32 . Following a onepot reaction sequence that involved methylation of benzothiazole moiety with MeOTf, reduction of benzothiazolium with NaBH 4 and hydrolysis of benzothiazoline with AgNO 3 , 72 was converted to chiral aldehyde 73. Treatment of aldehyde 73 with various Grignard reagents such as n-butyl, phenyl, alkenyl and ethynyl magnesium, followed by oxidation of the resultant alcohols with Dess-Martin periodinane, afforded chiral ketones 74-77 in 87-92% yields. Notably, this protocol was also amenable to the efficient synthesis of valuable building blocks from readily available α-alkenes (Fig. 3c), streamlining the allylating agent manipulation in comparison with the previous synthetic approaches based on iridium-catalysed allylic alkylation 33,34 . For instance, Taniguchi lactone 80, a key chiral building block to access (+)-gelsefuranidine 35 and quninine 36 , could be prepared from 22 via easily operational transformations including deamidation, conversion of benzothiazole to aldehyde, aldehyde oxidation and debenzylation-lactonization. A similar reaction sequence smoothly converted 23 to an enantioenriched sixmembered lactone 83, a key intermediate en route to a (+)-preclavulone A methyl ester prepared in a past work by optical resolution 37 . Furthermore, chiral γ,δ-unsaturated amide 10, derived from simple 1-hexene, could be transformed into a chiral aldehyde 85 for manufacturing celery ketone 33 .

Mechanistic investigations.
A series of kinetic studies and control experiments were conducted to gain insights into the possible reaction mechanism. First, a non-negligible kinetic isotope effect (KIE, k H /k D = 2.6) was observed for the reaction of α-benzothiazylacetamide 6 and α-alkene 86(d 2 ), suggesting that the allylic C-H cleavage might be involved in the rate-limiting step (Fig. 4a). Second, the reaction of α-benzothiazylacetamide 6 and 1-octene 1 showed a linear correlation between the e.e. of ligand L6 and that of product 9 (Fig. 4b), implying that only one molecule of chiral ligand was involved in the enantio-determining event of nucleophilic addition to π-allylpalladium 38,39 . Third, the first-order dependence of the initial rate on the concentration of Pd-L6 catalyst, 1-octene 1 and 2,5-DMBQ was identified, but a slightly negative effect on the initial rate was observed as the concentration of   α-benzothiazylacetamide 6 increased (Fig. 4b). Given that the allylic C-H cleavage was identified as the most possible ratelimiting step via the KIE studies, these kinetic results were consistent with a concerted proton and two-electron transfer process to cleave the allylic C-H bond, wherein a 16-electron Pd(0) complex formed from a phosphoramidite ligand, a p-quinone and an α-alkene was hypothesized as the key intermediate 19 (Fig. 1c). In this context, elevating the concentration of Pd-L6 catalyst, 1-octene 1 or 2,5-DMBQ was able to accelerate the reaction by facilitating the formation of the catalytically active 16-electron Pd(0) complex. On the other hand, the inhibitory effect of the coordinating nucleophile 6 on the reaction rate was also in accordance with the concerted proton and two-electron transfer process, as the competitive coordination of 6 to Pd(0) would most probably be leveraged by increasing the concentration of 6, being detrimental to the formation of the active 16-electron Pd(0) complex. Furthermore, an unusual dependence of regioselectivity on the mole-ratio of ligand to Pd [L/Pd] was observed in the case using Tsuji-Trost allylation of α-benzothiazylacetamide 6 and allylic carbonate 87 as a model reaction (Fig. 4c). In the process using PPh 3 as ligand, an increase in the molar ratio of PPh 3 to palladium tended to gradually favour the formation of a linear product 88 (ref. 32 ). By contrast, the variation of the [L6/Pd] molar ratio did not exhibit obvious influence on the reaction performance, always smoothly leading to a branched product 10 in >90% yield with 90% e.e., >20:1 d.r. and >20:1 b/l. These results were almost identical to those obtained from the asymmetric allylic C−H alkylation protocol (Table 1, 10), indicating that these reactions might proceed via a similar C-C bond-forming transition state. The different performance of Ph 3 P and L6 in regioselective control might be attributed to the different complexation ability between PPh 3 and L6. In the case involving a palladium complex of monodentate ligand with a 1/1 ratio, a coordination-unsaturated [(π-allyl) Pd(L)] was preferentially formed, allowing the secondary coordination of the nucleophile to palladium to occur, and thereby enabled a branch-selectivity via an inner-sphere allylation pathway (Fig. 4c). However, as the ratio of [L/Pd] increased, the complexation of [(π-allyl)Pd(PPh 3 )] with excess amounts of PPh 3 might occur and tended to give a coordination-saturated [(π-allyl)Pd(PPh 3 ) 2 ], which had not vacant site for an additional nucleophile coordination and thus preferred an outer-sphere pathway to give linear selectivity (Fig. 4c). By sharp contrast, the chiral phosphoramidite L6 was relatively bulkier and less-coordinating than PPh 3 (refs. 16,40 ), it was therefore more difficult to form a coordination-saturated [(π-allyl)Pd(L6) 2 ] even with excess amounts of L6 (ref. 41 ). As a consequence, the coordination-unsaturated [(π-allyl)Pd(L6)] that had a vacant site open for the secondary coordination always existed preferentially and allowed the branch-selective bond-forming event to keep working. Moreover, bidentate phosphorus-containing ligands-which are commonly used in Tsuji-Trost allylation to form coordination-saturated π-allylpalladium complexes structurally analogous to [(π-allyl)Pd(PPh 3 ) 2 ]-preferred a linear selectivity as anticipated (Fig. 4c). Interestingly, DPPE and BINAP, bearing a relatively narrow bite angle ranging from 86° to 93°, preferentially delivered linear selectivity, presumably as these ligands were able to stabilize coordination-saturated π-allylpalladium intermediates by strong chelation 42,43 . By contrast, DPPF and Trost's ligand with wider bite-angle (>99°) led to low levels of regioselectivity, wherein the branch-selectivity probably resulted from the mono-P-ligational behaviour 44 of these wide bite-angle ligands to generate coordination-unsaturated π-allylpalladium intermediates that basically preferred an inner-sphere allylation pathway. Notably, chiral phosphinooxazoline ligand 45 also preferentially gave a linear selectivity, whereas the chiral ArSOX ligand, which was reported to be optimal for a linear-selective asymmetric C-H alkylation 15 , failed to facilitate the current allylic alkylation reaction. Overall, these results clearly indicate that the regioselectivity of palladium-catalysed allylic substitution with coordinating nucleophile was switchable by tuning the ligational behaviour of ligands to alter the bond-forming pathway.
To gain more insight into the molecular origin of stereoselectivity, the competing transition states of both the inner-and outer-sphere pathways are explored through density functional theory (DFT) calculations using α-benzothiazylacetamide 5 as a model nucleophile and chiral phosphoramidite L7 as a model ligand. The computational analysis of α-benzothiazylacetamide anion suggests that a syn-periplanar 1,5-O···S relationship is beneficial to fix the geometry of this anion 46 , making the rigidized planar conformation 89 more thermodynamically favourable than the other competing conformations (89 versus 90, 91) by at least 4.6 kcal mol -1 (Fig. 5a). With respect to the inner-sphere pathways (Fig. 5b), the nitrogen-coordinating transition states (TS-N, 0-4.7 kcal mol -1 ) are energetically more favourable than the oxygen-coordinating transition states (TS-O, 3.6-8.1 kcal mol -1 ), suggesting that the bond-forming event proceeding via the nitrogencoordinating mode is more feasible. The enantio-and diastereoselectivities are governed by four competing nitrogen-coordinating transition states. The transition state (R,S)-TS-N that leads to the formation of the observed enantiomer is at least 1.9 kcal mol -1 more favourable than the other three transition states. Both (R,R)-TS-N and (S,S)-TS-N-which adopt the partially overlapped conformation in the Newman projections-suffer from the steric repulsion between the amide group of α-benzothiazylacetamide and the methyl group on the allyl moiety to make the generation of diastereomers unfavourable. These results are consistent with the experimental findings in Fig. 2c, wherein the replacement of dimethylamine with a bulkier piperidine on the amide moiety (entry 5 versus 6) is able to enhance the diastereoselectivity. Moreover, the length of the S-O bond in α-benzothiazylacetamide exerts considerable effect on the preferential formation of the enantio-determining transition state. In comparison with the rigidized planar conformation 89, the favoured transition state (R,S)-TS-N has a very similar S-O bond length (2.77 Å versus 2.74 Å), whereas the S-O bond is greatly elongated (2.81 Å versus 2.74 Å) in (S,R)-TS-N; (R,S)-TS-N is thus favourably formed to generate the experimentally observed stereochemistry of the major alkylation product. The outer-sphere bond-forming pathways are also considered (see the Supplementary Information for details); however, the activation energy barriers of the outer-sphere pathways turn out to be much higher than those of the inner-sphere pathways, suggesting that the outer-sphere pathways are highly disfavoured.

Conclusion
In summary, we have established a chiral phosphoramiditepalladium complex-catalysed branch-and enantioselective allylic C-H alkylation of α-alkenes by using α-benzothiazylacetamides as the alkylating agents. This protocol tolerates an extremely wide spectrum of α-alkenes and α-heteroaryl carbonyl compounds, providing an unconventional approach to access enantioenriched γ,δunsaturated carbonyl compounds in moderate to excellent yields with high levels of regio-and stereoselectivity. Experimental and computational studies suggest that aside from the coordination pattern of the nucleophiles, the ligational behaviours of ligands can also regulate the regioselectivity, highlighting that the monoligation of chiral phosphoramidite ligand is the key factor to keep the preference for the branch-selectivity via an inner-sphere allylation pathway. We anticipate that this report will facilitate the future development of the precise control in the palladium-catalysed allylation reactions.

Data availability
All data generated or analysed during this study are included in this published 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 no. CCDC 2142298 (16). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/.