Copper(I)-catalyzed asymmetric 1,6-conjugate allylation

Catalytic asymmetric conjugate allylation of unsaturated carbonyl compounds is usually difficult to achieve, as 1,2-addition proceeds dominantly and high asymmetric induction is a challenging task. Herein, we disclose a copper(I)-NHC complex catalyzed asymmetric 1,6-conjugate allylation of 2,2-dimethyl-6-alkenyl-4H-1,3-dioxin-4-ones. The phenolic hydroxyl group in NHC ligands is found to be pivotal to obtain the desired products. Both aryl group and alkyl group at δ-position are well tolerated with the corresponding products generated in moderate to high yields and high enantioselectivity. Moreover, both 2-substituted and 3-substituted allylboronates serve as acceptable allylation reagents. At last, the synthetic utility of the products is demonstrated in several transformations by means of the versatile terminal olefin and dioxinone groups.

C atalytic asymmetric conjugate addition of various metal reagents to unsaturated compounds is identified as one of the most important tools in the construction of carboncarbon bonds in organic synthesis [1][2][3] . Among the various carbonbased metal reagents, allyl metal reagents exhibit advantages over other alkyl metal reagents as the olefin moiety is more synthetically versatile. Non-enantioselective methods based on different allyl metal (such as, Si, B, Zn, and Sn) species have been disclosed in the past several decades 4 . However, the catalytic asymmetric conjugate addition with allyl metal reagents is still in its infancy as such a reaction is not easy to achieve due to the competitive 1,2-addition and the difficulty in the asymmetric induction.
The same group also succeeded in the catalytic enantioselective 1,6-conjugate allylation of α,β,γ,δ-unsaturated diesters with B 2 Pin 2 and allenes 30,31 . In 2011, the Feng group achieved an asymmetric conjugate allylation of activated unsaturated lactones with a bimetallic catalytic system 32 . In 2019, the same group reported a formal catalytic asymmetric 1,4-allylation of β,γ-unsaturated α-ketoesters 4 . In fact, the formal conjugate allylation was enabled by the allylation of the ketone group and the following oxy-Cope rearrangement. Unfortunately, alkyl was not well tolerated at the γ-position as only moderate enantioselectivity was observed. Moreover, Shibasaki and Kumagai uncovered a catalytic asymmetric conjugate allylation of α,β-unsaturated thioamides with allyl cyanide under protontransfer conditions 33 . In view of the above achievements, we are interested in developing a catalytic asymmetric conjugate 1,6allylation with more general substrate structure and broader substrate scope. Copper(I)-catalyzed asymmetric 1,6-addition with alkyl metal reagents (such as organozinc reagent and Grignard reagent) has been reported as a powerful tool to regioselectively construct carbon-carbon bonds [34][35][36][37][38][39][40][41][42][43][44][45][46] . Herein, we disclose an asymmetric 1,6-conjugate allylation of 2,2-dimethyl-6-alkenyl-4H-1,3-dioxin-4-one with a copper(I)-NHC catalyst (Fig. 1c). The 2,2-dimethyl-4H-1,3-dioxin-4-one moiety is an equivalent of the synthetically versatile β-keto-ester group and the product containing both an allyl group and a dioxinone group allows further structure elaboration. Furthermore, in view of the bulky steric hindrance around the carbonyl group and the relative stability of the lactone moiety, it is envisioned that the highly nucleophilic allylcopper(I) species would not touch the carbonyl group in the dioxinone and thus would attack the less hindered conjugate carbon-carbon double bond to give the desired 1,6-allylation.
Substrate scope. With the optimized reaction conditions in hand, the substrate scope of (E)-2,2-dimethyl-6-alkyl-4H-1,3-dioxin-4ones was studied (Fig. 2). Linear alkyls, including ethyl (3b), n propyl (3c), and n heptyl (3d), were well tolerated and the corresponding products were isolated in good yields with high enantioselectivity. β-Branched alkyl ( i butyl) (3e) was also accepted at the δ-position. The substrates bearing a α-branched alkyl with bigger steric hindrance (3f and 3g), afforded the allylated products in moderate yields and slightly decreased enantioselectivity. Then, substrates with an alkyl containing a functional group, such as benzyl (3a), terminal alkene (3h), internal alkyne (3i), alkyl chloride (3j), ester (3k), TBS-ether (3l), and N-Boc (3n) were examined. To our joy, the products were obtained in moderate to high yields and high enantioselectivity. Notably, alkyl chloride and ester group were not touched by the nucleophilic allylcopper-NHC species, demonstrating that allylcopper-NHC species was less nucleophilic than allylcopper-bisphosphine species. Unfortunately, the substrate containing a free alcohol (3m) was not tolerated. A substrate with a preexisting chiral center (3o) was also studied. The allylated product was generated in 72% yield with 91% de, indicating that the asymmetric induction was mainly controlled by the copper(I) catalyst. It should be noted that in some cases, the reaction temperature was increased to get good yields.
The reaction conditions were applied to the catalytic asymmetric allylation of (E)-2,2-dimethyl-6-aryl-4H-1,3-dioxin-4-ones with 4 equiv allylboronate (2) as 3 equiv 2 generally resulted in inferior yields (Fig. 3). The reaction was not very sensitive to the position of a substituent on the phenyl ring. As the allylated products containing a para-substituent, ortho-substituent, or meta-substituent were isolated in moderate to high yields with uniformly high enantioselectivity (5a-5o). It was noted that substrates with electron-withdrawing groups led to lower yields but with maintained enantioselectivity (5d-5f, 5 m, and 5o). Moreover, substrates with electron-donating groups served as competent substrates as the corresponding products were furnished in good yields with high enantioselectivity (5b-5c, 5h-5i, and 5k-5l).
The phenyl group at δ-position was successfully changed to 2-naphthyl group without affecting both yield and enantioselectivity significantly (5p). Moreover, several heteroaryl groups, including 3-pyridyl (5q), 2-furanyl (5r), 2benzofuranyl (5s), 3-benzothienyl (5t), and 3-N-Boc-indolyl (5u), were successfully tolerated at the δ-position. The corresponding products were furnished in moderate yields with uniformly high enantioselectivity. It should be pointed out that the reaction temperature varied in order to get good yields. The absolute configuration of 5a was determined to be S by its transformation to a known compound (for the details, see SI).
The absolute configurations of other products (3 and 5) were deduced by analogy.
Then, the 1,6-conjugate allylation with 2-substituted allylboronates (6-8) was investigated as shown in Fig. 4. Several aryl groups, including phenyl, 2-F-phenyl, and 3-methylphenyl, were well tolerated at the δ-position in the reaction with 6. The corresponding products (9a-9c) were obtained in 57%-63% yield with 93%-97% ee. An alkyl group, such as 2-phenyl-ethyl, was also acceptable at the δ-position (9d). 2-Methyl group in allylboronate 6 was successfully extended to 2-benzyl and n hexyl without eroding both yields and enantioselectivity (10)(11). Moreover, the reactions of both 3-methyl-(E)-allylboronate (12a) and 3-methyl-(Z)-allylboronate (12b) were studied as shown in Fig. 5. The diastereoselective allylation of 4j and 12a proceeded smoothly to afford 13 in moderate yield with moderate diastereoselectivity and excellent enantioselectivity. Surprisingly, the reaction with 12b also furnished 13 as the product in decreased yield and slightly decreased enantioselectivity. At this stage, it is difficult to understand such experimental results. However, it is speculated that the addition of the (Z)-allylcopper(I) is kinetically unfavored and the isomerization of (Z)-allylcopper (I) species to (E)-allylcopper(I) might occur through 1,3translocation in the present reaction conditions 53 . The absolute  configurations of 9, 10, and 11 were deduced analogically based on the stereochemical structure of 5a. Moreover, the absolute configurations of the two stereogenic carbon centers in 13 were determined by its transformation (For the details, see SI). In addition, the present catalytic system was extended to the asymmetric additions with PhMgBr and EtMgBr. However, only racemic products were obtained 54 .
Demonstration of the importance of the phenol group in NHC ligands. Several ligand variants of NHC-L4 were prepared to investigate the importance of the naphthol group (Fig. 6). The allylation with NHC-L6 containing a protected naphthol group did not afford the product 3a at all. Moreover, the reaction using NHC-L7 without the naphthol moiety was fruitless. Interestingly, NHC-L8 bearing a naphthol group and a protected naphthol group was found as a good ligand as product 3a was generated in 32% yield with 85% ee. These control experiments demonstrate that a free naphthol moiety is indispensable for this reaction to proceed. Furthermore, the steric hindrances on the both aryls are responsible for the asymmetric induction. Our finding of the essentiality of the free phenol or naphthol in this type of NHC ligands in asymmetric catalysis with copper(I) is in accordance with Sawamura's original findings [49][50][51][52] .

Discussion
In summary, a catalytic asymmetric 1,6-conjugate allylation was achieved in moderate to high yields with high enantioselectivity. NHC ligands containing a phenolic hydroxyl group were found to be indispensable to enable this reaction. Both 2,2-dimethyl-6-alkenyl-4H-1,3-dioxin-4-one and allylboronate   enjoyed broad substrate scopes. Several functional groups, especially alkyl halide and ester, were well tolerated in this reaction. The allyl group in the product allowed facile both hydroboration and olefin metathesis to give synthetically useful products. Moreover, the versatile dioxinone group was easily transformed to β-keto-ester moiety and α,β-unsaturated ester moiety, which generated a formal 1,4-conjugate allylation product of α,β-unsaturated ketone and a formal 1,6-conjugate allylation product of α,β,γ,δ-unsaturated ester. Detailed investigations of the mechanism are currently undertaken in our laboratory.

Methods
A general procedure for the catalytic asymmetric 1,6-conjugate allylation. A dried 25 ml Schlenk tube equipped with a magnetic stirring bar was charged with CuPF 6 (CH 3 CN) 4    (0.1 mmol, 1 equiv) was added to the reaction mixture. It was cooled down to the stated temperature before adding 2 (50.4 mg, 0.3 mmol, 3 equiv) by a syringe. This mixture was stirred for 12-36 h at that temperature. Then the reaction was quenched by adding silica gel and the mixture was purified by flash silica gel column chromatography to give product 3.