Ruthenium‐Catalyzed Cycloisomerization of Aromatic Homo‐ and Bis‐Homopropargylic Amines/Amides: Formation of Indoles, Dihydroisoquinolines and Dihydroquinolines

Abstract

Ruthenium-catalyzed cycloisomerizations of aromatic homo-and bis-homopropargylic amines/amides efficiently afford indoles, dihydroisoquinolines and dihydroquinolines. These processes were regioselective (5-and 6-endo cyclizations) on using key Ru vinylidene intermediates. The presence of an amine/ammonium base-acid pair increased the rate of cyclization and facilitated the catalytic turnover.Keywords: alkynylamines; azaheterocycles; cyclo-A C H T U N G T R E N N U N G isomerization; ruthenium; vinylidenes Nitrogen heterocycles like indole, isoquinoline and quinoline are prominent structural units in a variety of biologically active natural products and in synthetic organic materials.[1] In recent years, a plethora of synthetic methods to obtain these benzoheterocycles has been developed [2] and transition metal-catalyzed intramolecular cyclizations of aromatic alkynylamines and derivatives are particularly successful.[3] Typically, in the case of internal alkynes, heterocyclization is initiated by p-activation of the alkyne by coordination with transition metals. This favors the formation of electrophilic species that immediately undergo nucleophilic attack. This strategy has been used to prepare efficiently many types of heterocycles including indoles, isoquinolines and quinolines (Scheme 1).In the case of terminal alkynes, the use of metal vinylidenes as electrophilic species represents an attracScheme 1. Metal-catalyzed synthesis of indoles, isoquinolines and quinolines.

Formation of Indoles, Dihydroisoquinolines, and Dihydroquinolines by Ruthenium-Catalyzed Heterocyclizations

“…Upon completion (24 h) and workup, the residue was purified by flash column chromatography through silica gel using a 1:1 mixture of EtOAc-hexanes as eluent to afford 3e (0.18 g, 18%) as a brown solid; mp 104-106 °C. 13 …”

“…The residue was purified by flash column chromatography through silica gel using a 1:4 mixture of EtOAc-hexanes as eluent to give N-(2-bromobenzyl)-4-methylbenzenesulfonamide (2.85g, 75%) as a white solid; mp 72-74 °C. 13 …”

“…Since the pioneer work of McDonald using molybdenum catalysts, 10 modern syntheses of indoles by heterocylization of substituted (2-ethynyl)anilines have been also described by Trost and Grotjahn groups using rhodium 11 and ruthenium catalysts. 12 Herein, we wish to report typical practical procedures, not only for the ruthenium-catalyzed synthesis of indoles, but also to the six-membered 1,2-dihydroisoquinolines and 1,4-dihydroquinolines by heterocyclization of aromatic homo-and bis-homopropargyl amines/amides using commercial ruthenium catalysts 13 (Scheme 1).…”

Efficient synthesis of indoles from 2-alkynylaniline derivatives in water using a recyclable copper catalyst system

“…As a result, a large number of methods, especially, various cyclizations, have been well developed after the first practical indole synthesis was reported by Fischer and Jourdan in 1883. 1,[4][5][6][7][8][9][10][11][12][13][14][15][16][17][18] In particular, the introduction of transition metal reagents as catalysts (such as palladium, [19][20][21][22][23][24] gold, 5,10,14,25-28 rhodium, [29][30][31][32] ruthenium, 27,31,[33][34][35][36] platinum, 37 copper 6,18,22,[38][39][40][41][42][43][44][45][46][47][48] ) has deeply improved on the synthesis of indole and its derivatives. Among them, the ring closing of 2-ethynylaniline derivatives or their precursors (such as 2-bromo-anilines), 5,[49][50][51...…”

“…Henceforth, copper 18,22,[40][41][42][43][44][46][47][48]53,54 and many other inexpensive catalysts (metal or nonmetal, such as Hg [55][56][57] , Zn 58-61 and I 62 ) have received much attention for use in functionalized indole synthesis, although noble metals are necessary for some special purposes. 14,28,30,34,63 Water is the most environmentally benign and inexpensive medium, and its use often leads to the observation of unique reactivity and a simplified separation process. Furthermore, organic reactions in water are of high practical value due to their potential to reduce the amount of waste resulted from the use of organic solvents in the chemical industry.…”