Metal‐Free, One‐Pot Oxidative Triple Functionalization of Azaarenes with Methyl Arenes Mediated by Molecular Iodine/TBHP: Synthesis of N‐Benzylated Iodo(iso)quinolinones

Abstract

An efficient metal-free one-pot triple functionalization of azaarenes has been developed via a successive regioselective iodination, N-benzylation and amidation by using readily available methylarenes in presence of molecular iodine and TBHP. This method avoids the use of expensive noble metal catalysts and multi-step conversions. Moreover, we have shown the synthetic utility of the iodo functionality with traditional cross-coupling reactions (like Suzuki, Heck and Sonogashira) and the corresponding products were obtained in good yields.

Iodination/Amidation of the N-Alkyl (Iso)quinolinium Salts

“…Hence, our developed method is not suitable for N-benzyl quinolinium salts and complementary to Yang and Reddy's system, wherein the reaction occurred between (iso)quinolines and methyl arenes via a sequential iodination/benzylation/amidation process and limited to the N-benzyl quinolones formation. 11,12 In addition, the primary amides substituent on the N-alkyl group was not compatible with our system and led to complex mixtures. Finally, the attempt to achieve the chlorination and bromination by adopting quinolinium chloride salt or bromide salt under the developed procedure failed.…”

“…In 2019, Wang et al reported an elegant dirhodium (II)-catalyzed 1,4-bisfunctionalization reaction of the isoquinolinium salts with IBA-OAc as an oxidant by which 4-iodoisoquinolin-1(2H)ones were easily accessible from the readily available isoquinolinium iodides, 10 whereas no example of iodoquino-lone was demonstrated. In the same year, Yang 11 and Reddy 12 groups independently developed an I 2 /TBHP-mediated sequential iodination/N-benzylation/amidation reaction between (iso)quinolines and methyl arenes. These metal-free, one-pot reactions provided promising methodology for the synthesis of N-benzyl-substituted iodo-(iso)quinolinones.…”

I2/TBHP Reagent System: A Modern Paradigm for Organic Transformations**

“…Further, the reaction was optimized with different iodinated sources (KI, TBAI and NIS) and oxidants (O 2 , Na 2 S 2 O 8 , (NH 4 ) 2 S 2 O 8 , C 6 H 5 I(OAc) 2 , C 6 H 5 I-(OCOCF 3 ) 2 ) revealing iodine/TBHP as an effective system for this transformation (Scheme 13). [71] Electron donating and withdrawing groups on all types of substrates were found compatible to Scheme 10. Synthesis of 2-azolylindoles from indoles and azoles.…”

p-Toluenesulfonic acid-catalyzed regioselective C4–H iodination of isoquinolin-1(2H)-ones

“…In 2019, Wang and co-workers disclosed a dirhodium( ii ) complex-catalyzed 1,4-bisfunctionalization reaction of isoquinoline iodide salts with IBA-OAc as an oxidant to produce 4-iodoisoquinolinones (Scheme 1a). 11 Soon after, Yang 12 and Reddy 13 groups independently developed a metal-free, one-pot procedure for the synthesis of N -benzyl-substituted iodo-isoquinolinones via I 2 /TBHP-mediated sequential iodination/ N -benzylation/amidation reactions between isoquinolines and methyl arenes (Scheme 1b). Next, Song's group described visible-light-promoted aerobic oxidation of N -alkyl isoquinolinium salts to access 4-iodoisoquinolones in the presence of I 2 /Cs 2 CO 3 (Scheme 1c).…”