Rhodium-Catalyzed Ortho-Vinylation of 2-Arylpyridines and Its Application in the Total Synthesis of Palmatine

Abstract An efficient protocol by Rh-catalyzed direct C–H vinylation of 2-arylpyridines with a commercially available and air-stable potassium vinyl donor has been developed. This method affords the corresponding pyridinyl styrene derivative with moderate to excellent yields under mild conditions, which is extremely beneficial to the total synthesis of the natural product palmatine.


Introduction
In the past few decades, transition metal catalyzed C-H bond functionalization has witnessed significant progress as it avoids tedious and costly preactivation of starting materials and minimizes the formation of byproducts. [1][2][3] After decades of development, it has become a useful tool in the total synthesis of natural products. [4][5][6] A lot of research studies have proved that transition metal catalyzed C-H activation is a simpler and more time-saving methodology for the synthesis of natural products compared with traditional transformations. Here are just a few examples. Ellman's group 7 synthesized the natural product pancratistatin through an amide-directed C-H activation in 2017 (Scheme 1a), and Kazmaier's group 8 completed the synthesis of cyclopeptide alkaloids abyssenine A and mucronine E by C À H functionalization of N-methylated amino acids and peptides in 2018 (Scheme 1b). Meanwhile, our previous work 9 successfully synthesized the natural compound decumbenine B via Ru (III)-catalyzed ortho-hydroxymethylation (Scheme 1c).
Palmatine, an isoquinoline alkaloid isolated from Fibraurea recisa Pierre (Chinese name: Huangteng), has a wide range of pharmacological and biological activities, such as antibacterial, antifungal, and antiviral effects. 10,11 Clinically, palmatine has been used for the treatment of surgical infections, respira-tory and urinary tract infections, conjunctivitis, and gynecological inflammation. 12 Due to the wide range of applications and exact efficacy in clinic, the demand for palmatine in the pharmaceutical market is growing. However, palmatine is in short supply because of the long growth cycle of the medicinal plant, or long synthetic route with low yield, environmentally unfriendliness, and high cost, etc. 13,14 Therefore, developing a new and effective method to synthesize palmatine still has great practical significance. Based on structural analysis and our interest in C-H functionalization, 15-18 a retrosynthetic analysis route was proposed, as shown in Scheme 2. Through this route, palmatine could be synthesized in only four steps, and among this, the two-step C-H activation reactions are crucial. Fortunately, our group has completed the synthesis of intermediate B by a water-mediated C-H activation using primary amines and sulfoxonium ylides. 19 Therefore, the ortho-vinylation of isoquinoline B is our main research object.
As far as we know, there are no literatures on the direct C-H vinylation of 3-arylisoquinolines. Based on the similarity of physical and chemical properties between 2-arylpyridines and 3-arylisoquinolines, we decided to study the ortho-vinylation (Scheme 3a), but there remains some limitations, particularly with regard to high reaction temperature, toxic reactant, low yield, and using ligand additive. So it is of great value to explore a mild and efficient method to complete direct ortho-vinylation of 2-arylpyridines. Very recently, Zhou and coworkers reported an efficient Rh-catalyzed direct C2-alkenylation of indoles, 24 which is the first example for building a C2 block utilizing commercially available and air-stable potassium vinyltrifluoroborate as the vinyl source. We are interested in the practicability of this vinyl source in the C-H bond functionalization and wonder if it can be used in 2-arylpyridines. Considering all the above facts, herein, we developed Rhcatalyzed direct C-H vinylation of 2-arylpyridines with potassium vinyltrifluoroborate as the vinyl source under mild conditions (Scheme 3b), and further completed the total synthesis of palmatine.
Having the optimized conditions in hand, we then explored the practicality of this novel method by applying the procedure to the vinylation of a wide range of arenes (►Fig. 1).
Generally, 2-phenylpyridines with substituents at different positions of the aromatic ring all reacted smoothly with 2a, giving the corresponding products in moderate to good yields. For example, 2-phenylpyridines containing methyl substituents at the ortho-, metaand para-positions of the benzene ring afforded the desired products 3b, 3d, and 3h and 3h′ in 75, 90, and 55% yields, respectively. Both electron-donating and withdrawing groups were tolerated, as demonstrated by the isolation of 66% of 3e and 81% of 3g. Similarly, the reaction of chloro-substituted 2-phenylpyridine provided the corresponding product 3f in a lower yield. To our satisfaction, this method is compatible well with 3-phenylisoquinoline and gave the corresponding products 3i and 3i′ in moderate yield. When the aromatic ring without substitution at the orthoor meta-positions was used, divinylated products are obtained, such as 3h′ and 3i′. On the basis of these results, we decided to verify the synthetic applicability of the developed protocol for the synthesis of the natural isoquinoline alkaloid palmatine.   As shown in Scheme 4, palmatine was successfully synthesized from commercially available materials in only four steps, and the crucial two-step C-H activation reactions both were first reported by our group. First, intermediate B was obtained by Rh-catalyzed C-H activation/cyclization of primary amine A with sulfoxonium ylide according to our recent work. 15 Second, compound B reacted with potassium vinyltrifluoroborate under standard conditions, giving the key intermediate C (3j) in 70% yield. Finally, compound C was easily converted into palmatine through hydroboration oxidation and cyclization reactions. 25,26 Conclusions In summary, we have developed a mild and efficient protocol by Rh-catalyzed direct C-H ortho-vinylation of 2-arylpyridines using commercially available and air-stable potassium vinyltrifluoroborate as a vinyl source. The salient features of this protocol include using a low-toxicity solvent (EtOH) as reaction solution, mild reaction conditions, and moderate to excellent yields. More importantly, 3-arylisoquinolines, the skeleton of palmatine, were well tolerated in this process. Thus a short and efficient synthesis route of palmatine over four steps was developed with this methodology.

Conflict of Interest
The authors declare no conflicts of interest.