Rhodium(I)-Catalyzed Defluorinative Bisarylation of Monofluorodienes with Boronic Acids

We herein describe a Rh(I)-catalyzed bisarylation reaction of monofluorodienes using arylboronic acids. Two aryl groups are installed in the trisubstituted (E)-alkene products in one step with excellent diastereoselectivities. An intriguing reaction sequence of Rh(I)-catalyzed 1,6-addition followed by defluorinative coupling is proposed for product formation.

R hodium(I)-catalyzed addition reaction of organometallic reagents to alkenes is a powerful strategy for the construction of carbon−carbon bonds. 1 The use of organoboron reagents, especially boronic acids, 2 is highly attractive in such transformations due to their commercial availability, stability, and low toxicity.It has been well-established that α,βunsaturated carbonyl compounds and styrene derivatives can undergo Rh(I)-catalyzed conjugate addition with organoboron reagents. 3On the other hand, much less is known about the reactions of f luoroalkenes under Rh(I) conditions. 4e have recently reported stereoselective Rh(I)-catalyzed arylation reactions of β-fluoroacrylate derivatives with arylboronic acids. 5For instance, Rh(I)-catalyzed defluorinative coupling of (E)-monofluoroalkenes could generate trisubstituted (Z)-alkene products with inversion of double bond geometry (Scheme 1a).5a Also, Rh(I)-catalyzed C−F bond arylation of gem-difluoroalkenes could give access to tetrasubstituted (E)-monofluoroalkene products (Scheme 1b).5b In this work, we describe an unprecedented Rh(I)catalyzed defluorinative bisarylation reaction of (E)-monofluorodienes 1, which led to the synthesis of a new class of trisubstituted (E)-alkene products 2 with the cleavage of a C− F bond and formation of two C−C bonds (Scheme 1c).
During the optimization studies, the 1,6-addition product 3a was found to be a side product in the reaction (cf.Table 1). 10e subsequently learned that using the catalyst [Rh(COD)-(OH)] 2 without BINAP at 25 °C could generate 3a (80% iso.yield) exclusively from 1a (Scheme 3a).Other boronic acids were also effective in the 1,6-addition providing products 3b−e in good yields.However, the diastereoselectivities of 3 were rather low, ranging from ∼1:1 to 7:1.Intriguingly, by resubmitting 3a (dr = 1.2:1) to the standard conditions, the bisarylated product 2a was obtained in >99:1 dr (Scheme 3b), which indicated that the 1,6-addition product was a potential intermediate for the bisarylation product.
Based on this observation, we devised a modular synthesis of a triaryl compound 5 where each aryl substituent group was different (Scheme 3c).Monofluorodiene 1d containing a 4fluorobenzene unit was reacted with 4-(trifluoromethyl)phenylboronic acid in Rh(I)-catalyzed 1,6-addition to give intermediate 4 (dr = 2.3:1).Arylation of 4 using 4methoxyphenylboronic acid under the standard conditions gave the final product (E)-5 in excellent dr (>99:1).Thus, each of the three aromatic rings of 5 could be tuned for desirable electronic and steric properties, which should be attractive to medicinal chemists for lead compound screening.
The bisarylation reaction was not limited to dienoate esters.Monofluorodiene 6 containing an amide moiety was prepared and subjected to the standard conditions (eq 1).The bisarylated product (E)-7 could be isolated in excellent dr (>99:1).Further experiments were conducted to understand the reaction mechanisms (Scheme 4).Monofluorodiene 8 without the ester group or 9 without the terminal alkene did not react under the standard conditions (Scheme 4a).Using a chiral ligand (R)-BINAP gave the product (E)-2a in 24% ee (Scheme 4b).We have also screened a variety of other chiral ligands under the standard conditions, the highest ee (34%) was obtained from (R)-DTBM-SEGPHOS. 10 Moreover, switching the substrate to (Z)-1a under identical conditions provided the same product (E)-2a in excellent dr (>99:1) and yield, with 15% ee (Scheme 4c).Thus, the E/Z configuration of monofluorodiene 1 does not influence the diastereomeric outcome of product 2.By subjecting the 1,6-addition product 3a as a diastereomeric mixture (dr = 1.4:1) to the Rh-catalyzed conditions without the boronic acid, we observed an isomerization process favoring the (Z)-product in excellent dr (>99:1) (Scheme 4d).The same trend was also observed for analogues 3b−e.Resubmitting (Z)-3a to the standard conditions led to the bisphenylated product (E)-2a in good yield and excellent dr (>99:1) (Scheme 4e).
Based on the above studies and known literature reports, we proposed the following plausible reaction mechanism for the stereoselective Rh(I)-catalyzed defluorinative bisarylation of monofluorodiene 1 (Scheme 5).Transmetalation between the Rh(I) catalyst and arylboronic acid generates the Rh(I)-Ar species. 1 Regioselective migratory insertion of Rh(I)-Ar to the terminal double bond of 1 gives the alkyl-Rh(I) intermediate A. Isomerization of A leads to the oxo-π-pentadienyl-Rh(I) complex B. 9 Protonolysis of B with water forms the 1,6addition product 3 and regenerates the Rh(I) catalyst. 11 are two possibilities for the outcome of the alkene geometry of 3.
(1) The isomerization of B favors (Z)-3 at 75 °C. 12(2) Both (E)-and (Z)-3 were formed; however, under the reaction conditions (E)-3 can isomerize to (Z)-3.We have experimental evidence for such isomerization (cf.Scheme 4d) although the exact mechanism is unclear at the moment.The acidic α-proton under the basic reaction conditions likely facilitates the isomerization.Monofluoroalkene (Z)-3 undergoes migratory insertion with another 1 equiv of Rh(I)-Ar to generate alkyl-Rh(I) C. Bond rotation leads to conformer D, which is set up for syn-β-F elimination.Final product 2 is therefore formed in the E-alkene configuration, and Rh(I)-F is eliminated to re-enter the catalytic cycle.Control experiment showed (Z)-3a can generate (E)-2a in good yield and excellent dr (cf.Scheme 4e).Overall, there is an inversion of alkene geometry from (Z)-3 to (E)-2, which is consistent with our previous Rh(I)catalyzed defluorinative coupling of monofluoroalkenes.5a This could be a situation of dynamic kinetic resolution (DKR) in the case where both (E)-and (Z)-3 are present but only (Z)-3 continues to react and (E)-3 isomerizes to (Z)-3. 13This explains why the E/Z mixtures of monofluoroalkenes 3/4 only gave the (E)-products (cf.Scheme 3b-c).Also, substrates (E)and (Z)-1a can give the same product (E)-2a (cf.Scheme 4bc) because they converge to the same intermediate (Z)-3a.
In conclusion, we have discovered a novel Rh(I)-catalyzed bisarylation reaction of monofluorodienes 1 using arylboronic acids.The method allowed the synthesis of an array of trisubstituted alkene products (E)-2 containing two newly installed aryl groups with excellent diastereoselectivities.The reaction mechanism presumably involves the combination of two Rh(I)-catalyzed sequences: (1) 1,6-addition of monofluorodiene 1 to generate the monofluoroalkene 3; (2) defluorinative arylation of monofluoroalkene 3 to form product 2.The enantioselective version of this reaction is ongoing in our laboratories.