Palladium/Norbornene-Catalyzed Direct Vicinal Di-Carbo-Functionalization of Indoles: Reaction Development and Mechanistic Study.

Methods that can simultaneously install multiple different functional groups to heteroarenes via C-H functionalizations are valuable for complex molecule synthesis, which, however, remain challenging to realize. Here we report the development of vicinal di-carbo-functionalization of indoles in a site- and regioselective manner, enabled by the palladium/norbornene (Pd/NBE) cooperative catalysis. The reaction is initiated by the Pd(II)-mediated C3-metalation and specifically promoted by the C1-substituted NBEs. The mild, scalable, and robust reaction conditions allow for a good substrate scope and excellent functional group tolerance. The resulting C2-arylated C3-alkenylated indoles can be converted to diverse synthetically useful scaffolds. The combined experimental and computational mechanistic study reveals the unique role of the C1-substituted NBE in accelerating the turnover-limiting oxidative addition step.

Redox-Neutral Vicinal Difunctionalization of Five-Membered Heteroarenes with Dual Electrophiles.

A new reaction mode of palladium/norbornene (Pd/NBE) cooperative catalysis is reported involving the selective coupling of two different carbon-based electrophiles for vicinal double C-H functionalization of five-membered heteroarenes in a site-selective and redox-neutral manner. The key is to use alkynyl bromides as the second electrophile, which allows vicinal difunctionalization of a wide range of heteroarenes including pyrroles, thiophenes and furans at their C4 and C5 positions. One- or two-step tetrafunctionalizations of simple pyrrole and thiophene have also been realized. The C2-substituted NBEs prove most effective in these reactions, and the mechanistic exploration discloses the origin of the high selectivity of this transformation. Synthetic utility of this method has been exemplified in the concise preparations of thiophene-containing organic materials and a protein kinase inhibitor analogue. Preliminary success has also been achieved in a direct annulation event, using a tethered ketone as the second electrophile.

Structurally Modified Norbornenes: A Key Factor to Modulate Reaction Selectivity in the Palladium/Norbornene Cooperative Catalysis.

Palladium/norbornene (Pd/NBE) cooperative catalysis has received enormous attention and found numerous synthetic applications in the past two decades. Considering the critical roles that NBE plays in the catalytic cycle, the use of structurally modified NBEs (smNBEs), starting from 2015, has become an important approach to address limitations and modulate reaction selectivity in Pd/NBE catalysis. This Perspective highlights the development of three types of smNBEs: C1-substituted, C2-substituted, and C5-substituted or C5,C6-disubstituted NBEs, as well as their synthetic applications toward site-selective C-H functionalization. A focus is on the structure-activity relationship of smNBEs in these reactions, and rationales for using smNBEs in many cases have also been provided.

Direct Vicinal Difunctionalization of Thiophenes Enabled by the Palladium/Norbornene Cooperative Catalysis.

Herein we report a direct vicinal difunctionalization of thiophenes via the palladium/norbornene (Pd/NBE) cooperative catalysis. A series of mono- and disubstituted thiophenes can be difunctionalized site-selectively and regioselectively at the C4 and C5 positions in good yields, enabled by an arsine ligand and a unique amide-based NBE. The synthetic utility has been shown in derivatizations of complex bioactive compounds and an open-flask gram-scale preparation. Preliminary results have been obtained in the difunctionalization of furans and a direct C4-selective arylation of 2-substituted thiophenes.

Redox-Neutral ortho Functionalization of Aryl Boroxines via Palladium/Norbornene Cooperative Catalysis.

Palladium/norbornene (Pd/NBE) cooperative catalysis, also known as the Catellani reaction, has become an increasingly useful method for site-selective arene functionalization; however, certain constraints still exist due to its intrinsic mechanistic pathway. Herein we report a redox-neutral ortho functionalization of aryl boroxines via Pd/NBE catalysis. An electrophile, such as carboxylic acid anhydrides or O-benzoyl hydroxylamines, is coupled at the boroxine ortho position, and a proton as the second electrophile is introduced at the ipso position. This reaction does not require extra oxidants or reductants, and avoids stoichiometric bases or acids, thereby tolerating a wide range of functional groups. In particular, orthogonal chemoselectivity between aryl iodide and boroxine moieties is demonstrated, which could be used to control reaction sequences. Finally, a deuterium labelling study supports the ipso-protonation pathway. This unique mechanistic feature could inspire the development of a new class of Pd/NBE-catalyzed transformations.

Sulfenamide-enabled ortho thiolation of aryl iodides via palladium/norbornene cooperative catalysis.

Poly-substituted aromatic sulfur compounds are widely found in pharmaceuticals, agrochemicals and organic materials. However, the position that a sulfur moiety can be introduced to is largely restricted to a pre-functionalized site; otherwise, use of electronically biased substrates or auxiliary groups that direct catalysis is required. Here we report a general ortho thiolation of common aryl and heteroaryl iodides via palladium-norbornene cooperative catalysis. Using this approach, an aryl or alky sulfur moiety can be site-selectively introduced at the arene ortho position without using sterically or electronically biased substrates. The arene ipso functionalization is simultaneously achieved through Heck, Suzuki or Sonogashira termination. The reaction is enabled by a unique class of electrophiles in palladium-norbornene cooperative catalysis, which are sulfenamides derived from seven-membered lactams. The broad substrates scope and high chemoselectivity could make this method attractive for synthesis of complex sulfur-containing aromatic compounds.

Complementary site-selectivity in arene functionalization enabled by overcoming the ortho constraint in palladium/norbornene catalysis.

Achieving site-selectivity in arene functionalization that is complementary to the site-selectivity from electrophilic aromatic substitution reactions has been a long-standing quest in organic synthesis. Palladium/norbornene cooperative catalysis potentially offers a unique approach to this problem, but its use has been hampered by the ortho constraint, which is the requirement of an ortho substituent for mono ortho functionalization of haloarenes. Here, we show that such a challenge could be addressed using a new class of bridgehead-modified norbornenes, thereby enabling a broadly useful strategy for arene functionalization with complementary site-selectivity. A range of ortho-unsubstituted aryl iodides, previously problematic substrates, can now be employed to provide mono ortho-functionalized products effectively. This method is applicable for late-stage functionalization of complex bioactive molecules at positions that are difficult to reach by conventional approaches.

Palladium-catalyzed asymmetric annulation between aryl iodides and racemic epoxides using a chiral norbornene cocatalyst.

Herein, we describe our initial development of an asymmetric Pd-catalyzed annulation between aryl iodides and racemic epoxides for synthesis of 2,3-dihydrobenzofurans using a chiral norbornene cocatalyst. A series of enantiopure ester-, amide- and imide-substituted norbornenes have been prepared with a reliable synthetic route. Promising enantioselectivity (42-45% ee) has been observed using the isopropyl ester-substituted norbornene (N1*) and the amide-substituted norbornene (N7*).

Direct Annulation between Aryl Iodides and Epoxides through Palladium/Norbornene Cooperative Catalysis.

Herein we report a direct annulation between aryl iodides and epoxides through palladium/norbornene (Pd/NBE) cooperative catalysis. An iso-propyl ester substituted NBE was found to be most efficient to suppress the formation of multiple-NBE-insertion byproducts and affords the desired 2,3-dihydrobenzofuran derivatives in 44-99 % yields. The reaction is scalable and tolerates a range of functional groups. Asymmetric synthesis is realized using an enantiopure epoxide. Application of this method into a concise synthesis of insecticide fufenozide is demonstrated.

Rhodium(III)-catalyzed intermolecular amidation with azides via C(sp³)-H functionalization.

The amidation reactions of 8-methylquinolines with azides catalyzed by a cationic rhodium(III) complex proceed efficiently to give quinolin-8-ylmethanamine derivatives in good yields via C(sp(3))-H bond activation under external oxidant-free conditions. A catalytically competent five-membered rhodacycle has been isolated and characterized, revealing a key intermediate in the catalytic cycle.

[Repair of old injury of knee medial collateral ligament by a combination of dynamic and static stability].

OBJECTIVE: To observe the effectiveness of the combination of dynamic and static stability in the treatment of old knee medial collateral ligament injury. METHODS: Between March 2004 and June 2008, 26 cases of old knee medial collateral ligament injury were treated, including 19 males and 7 females with a mean age of 38 years (range, 21-48 years). Injury was caused by traffic accident in 6 cases, by sprains in 12 cases, by falling from height in 8 cases. The location was left knee in 15 cases and right knee in 11 cases. Of them, 24 patients showed the positive result of knee valgus test, 2 cases showed slightly relaxed knee tendon. The knee X-ray films of valgus stress position showed that the medial joint space differences between both knees were 3-5 mm in 2 cases and 5-12 mm in 24 cases. The injuries included avulsion of the medial femoral condyle starting point in 19 cases, central laceration in 6 cases, and tibial point laceration concomitant meniscus injury in 1 case. The time from injury to hospitalization was 3-14 months (mean, 6.4 months). Gracilis muscle was used to repair knee medial collateral ligament and the sartorius muscle transfer to reconstruct the medial rotation of knee stability function. RESULTS: All incisions healed by first intention. No joint infection, deep vein thrombosis, or other postoperative complications occurred. Twenty-six cases were followed up 12-58 months with an average of 30 months. The results of knee valgus stress test were negative with no joint tenderness. At 3 months after operation, the knee X-ray films of valgus stress position showed the medial joint space differences between both knees were less than 1 mm. According to the modified Lysholm-Scale score, the results were excellent in 18 cases, good in 7 cases, and fair in 1 case with an excellent and good rate of 96% at last follow-up. CONCLUSION: A combination of dynamic and static stability in repairing old knee medial collateral ligament injury is easy-to-operate and has the advantages to perform the operation in the same incision, so it can avoid the shortcomings of single repair method and achieve better effectiveness.