Efficient synthesis of new 3-heteroaryl-1-functionalized 1H-indazoles

Solution to the C3–Arylation of Indazoles: Development of a Scalable Method

“…After carrying out the reactions at room temperature for 15 h, it was found that 5 mol % of G2-XPhos, RuPhos, and XantPhos precatalysts provided high conversions to product (85% by HPLC), while other G2-precatalysts (e.g., SPhos, t BuXantPhos, P(o-Tol) 3 , t Bu 3 P) resulted in low conversions (∼10%). Interestingly, reactions catalyzed by Pd(PPh 3 ) 4 proceeded in 60% conversion after 15 h. 11 Other palladium sources such as Pd(PPh 3 ) 2 Cl 2 and Pd(dppf)Cl 2 proved ineffective at catalyzing the cross-coupling reaction at room temperature (<10% conversion by HPLC). Additionally, the coupling reaction performed poorly in the presence of Pd(OAc) 2 (5 mol %) and XPhos (10 mol %) (entry 12).…”

“…We hypothesized that a less active Pd-catalyst could provide the desired selectivity, and we turned our attention to Pd(PPh 3 ) 4 , which had exhibited only modest reactivity in our original catalyst screening. Indeed, when the cross-coupling reaction was carried out with 1.1 equiv of 4,6-dichloropyrimidine (4a) in the presence of 5 mol % Pd(PPh 3 ) 4 at room temperature, the desired product 5a was isolated in 70% yield (Scheme 4).…”

“…The examples follow the expected reactivity trend whereby the coupling occurs preferentially at the more reactive halogen, and the less reactive carbon−halogen bond remains intact. Reactions with aryl iodides 4b and 4c afforded 5b and 5c in 78% and 93% yields when using Pd(PPh 3 ) 4 . 12 Given the collective results presented here, it is clear that this new protocol has broad applications for accessing chemical entities that are difficult to access by previous methods.…”

“…This method exhibits high functional group tolerance and is operationally simple. While the use of the highly active G2-XPhos precatalyst provides convenient access to 3-arylindazoles within 1 h, the judicious choice of the less active Pd(PPh 3 ) 4 at room temperature provides access to halogenated indazole adducts in which the remaining halogen can be subjected to late-stage derivatization. Additionally, the successful coupling of aryl chlorides under these conditions provides a unique choice of coupling partners not previously demonstrated.…”

Regioselective zincation of indazoles using TMP2Zn and Negishi cross-coupling with aryl and heteroaryl iodides

“…Also the direct arylation 8 of 2H-indazoles as well as the use of 3-iodoindazoles in Suzuki- 9 or Stille 10 cross-couplings is known. However, the direct metalation and transition metal catalyzed arylation of 1H-indazoles has not been reported.…”