Solvent-Free Cross-Dehydrogenative Coupling Reactions under High Speed Ball-Milling Conditions Applied to the Synthesis of Functionalized Tetrahydroisoquinolines

Abstract

Solvent-free reaction using a high-speed ball milling technique has been first applied to cross-dehydrogenative coupling (CDC) reactions between tetrahydroisoquinolines and three types of pronucleophiles such as nitroalkanes, alkynes, and indoles. All coupling products were obtained in good yields at short reaction times (no more than 40 min). When alkynes and indoles were used as pronucleophile, the reactions can be catalyzed efficiently by recoverable copper balls without any additional metal catalyst.

Mechanically activated ring-opening reactions of N-acyl-1,2,3,4-tetrahydroisoquinolines derived from the synthesis of praziquantel intermediate

“…4 Our group had reported a 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)-promoted solvent-free CDC reaction under ball-milling conditions. 5 During the study of a novel synthesis of PZQ, we planned to extend this solvent-free coupling method to the synthesis of 1-aminomethyl tetrahydroquinoline, a key-intermediate of praziquantel, by reduction and deprotection of the CDC product. Unexpectedly, the reaction was also found to afford oxidative ring-opening products and acylated DDQ derivatives using different acyl protecting groups on tetrahydroisoquinoline.…”

Metal-catalyzed organic reactions using mechanochemistry

“…58 In 2011, Su and co-workers explored the mechanochemical CDC reaction between tetrahydroisoquinolines and nitroalkanes using steel milling equipment (Scheme 3). 59 After 30 min milling in the presence of 2,3-dichloro-5,6-dicyanoquinone (DDQ) oxidizing agent, the reaction afforded the sp 3 -sp 3 -CDC products in good yield, after column chromatography and without metal catalysts. 59 However, the replacement of nitroalkanes with indoles or alkynes required also the use of copper salts such as CuBr, Cu(OAc) 2 ·H 2 O or Cu(OTf) 2 as catalysts.…”

“…59 After 30 min milling in the presence of 2,3-dichloro-5,6-dicyanoquinone (DDQ) oxidizing agent, the reaction afforded the sp 3 -sp 3 -CDC products in good yield, after column chromatography and without metal catalysts. 59 However, the replacement of nitroalkanes with indoles or alkynes required also the use of copper salts such as CuBr, Cu(OAc) 2 ·H 2 O or Cu(OTf) 2 as catalysts. Moreover, copper powder, as well as copper milling balls, were effective catalysts for the formation of the sp 3 -sp 2 and sp 3 -sp CDC products (Scheme 3).…”

α‐Cyanation of Aromatic Tertiary Amines using Ferricyanide as a Non‐Toxic Cyanide Source

“…Alternatively,s toichiometric oxidants like DDQ, [16] PhI(OAc) 2 , [17] TEMPO [18] or anodic oxidations [19] can be employed to effect iminiumf ormation. However, all these procedures employ toxic cyanide sources such as KCN, TMSCN,m alononitrile or ethylc yanoformate.R ecently,O fial andc o-workers reported the remarkable KSCN/t-BuOOH systemf or the oxidative cyanation of awide variety of tertiary amines.T hisc yanide source andt he stoichiometric oxidant are,h owever, classifiedash armful and toxic, respectively.…”

“…Reduction of the amount of K 3 [Fe(CN) 6 ]s lowed down the reactionb ut af ull conversion could evenb ee ffected with as little as 20 mol% of the reagent by increasing the reactiont ime. If the amount was reducedt o1 0m ol%, the turnover was 53% after4 2hindicating that as much as 85% of the bound cyanide was productively released (entries [16][17][18][19][20]. When K 3 [Fe(CN) 6 ]w as replaced by KCN,amixture of amino nitrile and lactam was formed at al ower turnover rate (entry 21).…”