Hydroxorhodium/Chiral Diene Complexes as Effective Catalysts for the Asymmetric Arylation of 3‐Aryl‐3‐hydroxyisoindolin‐1‐ones

Abstract

The transition-metal-catalyzed enantioselective alkylation and arylation of imines is a versatile means of accessing a-chiral amines, which are important structural components of a number of biologically active compounds, and there have been many reports of the successful catalytic enantioselective addition of organometallic reagents to imines derived from aldehydes. [1] In contrast, the asymmetric addition of organometallic reagents to ketimines, which provides chiral a-tertiary amines, remains less developed. [2][3][4] In this context, we have reported that rhodium/chiral diene complexes efficiently catalyze the asymmetric addition of arylboron reagents to N-sulfonyl ketimines with high enantioselectivity. [5,6] Herein, we report the rhodium-catalyzed asymmetric arylation of cyclic N-carbonyl ketimines, which are generated in situ by the dehydration of 3-aryl-3-hydroxyisoindolin-1ones with arylboroxines, resulting in isoindolin-1-ones bearing a triaryl-substituted stereogenic carbon center.The stability of imines towards hydrolysis depends on the substituent on the imine nitrogen. For example, N-sulfonyl imines are sufficiently stable to be isolated and they are often used in the addition of organometallic reagents. On the other hand, when the imines are highly sensitive to hydrolysis, benzotriazole [7] or sulfinic acid imine adducts, [8] or hemiaminals [9b] have been often used as stable imine precursors. We focused on the use of 3-aryl-3-hydroxyisoindolin-1-ones [9] 1 as stable precursors for the generation of cyclic N-carbonyl ketimines bearing a diaryl-substituted azomethine moiety, which can be used in the rhodium-catalyzed asymmetric arylation reaction to produce chiral isoindolin-1-ones, which are structurally important core unit found in many biologically active compounds and natural products (Scheme 1). [10,11] We also decided to use arylboroxines 2, which are dehydrated analogues of arylboronic acids, because they would be expected to work as dehydrating reagents to generate ketimine A, as well as arylating reagents for a subsequent arylation by a rhodium catalyst.It was found that a hydroxorhodium complex was effective in catalyzing the arylation of 3-phenyl-3-hydroxyisoindolin-1-one (1 a) with arylboroxines 2 (Table 1). Thus, treatment of hemiaminal 1 a with p-tolylboroxine (2 m; 2 equiv of B) in the presence of a hydroxorhodium complex [{Rh(OH)(cod)} 2 ] (5 mol % of Rh; cod = 1,5-cyclooctadiene) at 80 8C for 12 h gave 3-phenyl-3-(p-tolyl)isoindolin-1-one (3 am) in 87 % yield (entry 1). The arylating reagent p-tolylboronate 2 m' is also effective, giving 3 am in 85 % Scheme 1. Asymmetric arylation of isoindolin-1-ones 1. Table 1: Rhodium-catalyzed asymmetric arylation of 3-hydroxyisoindolin-1-one 1 a. [a] Entry Catalyst p-tol[B] Yield [%] [b] ee [%] [b] 1 [{Rh(OH)(cod)} 2 ] 2 m 87 -2 [{Rh(OH)(cod)} 2 ] 2 m' 85 -3 [{Rh(OH)(cod)} 2 ] 2 m'' 7 -4 [c] [{RhCl(cod)} 2 ]/KOH (aq) 2 m 0 -5 [d] [{RhCl(cod)} 2 ]/K 3 PO 4 2 m 7 -6 [{Rh(OH)[(R,R)-Bn-tfb*]} 2 ] 2 m 50 33 7 [{Rh(OH)[(R,R)-Ph-tfb*]} 2 ] 2 m 79 87 ...

Solvent‐Dependent Asymmetric Synthesis of Alkynyl and Monofluoroalkenyl Isoindolinones by CpRhIII‐Catalyzed C−H Activation

“…As to the enantioselective construction of chiral 3,3disubstituted isoindolin-1-ones,m any elegant methods have been developed based on either organocatalysis [4] or transition-metal catalysis. [5] However,t he substrates were mainly limited to 3-hydroxyisoindolinones,a lkenyl benzamides,a nd N-halobenzoyl indoles.W hereas transition-metal-catalyzed CÀHa ctivation has shown great potential [6] in terms of expanding the structural diversity of available isoindolinone motifs,asymmetric variants remain extremely rare and highly challenging. [7] In 2013, Nishimura and co-workers developed an iridium/diene-catalyzed [3+ +2] annulation by C À Ha ctivation that afforded spiroisoindolinones from 3-aryl-3-hydroxyisoindolinones and 1,3-dienes.…”

High Performance of a Palladium Phosphinooxazoline Catalyst in the Asymmetric Arylation of Cyclic N‐Sulfonyl Ketimines

“…The cyclic N-sulfonyl imines used as the arylation substrates are classified into aldimines and ketimines, of which the former are in general more reactive than the latter and some of the ketimines substituted with electron-withdrawing groups such as ester and CF 3 are as reactive as aldimines. [3][4][5][6] During our studies on the catalytic asymmetric addition of organoboron reagents to carbon-carbon and carbon-heteroatom double bonds, [8,9] we found that a cationic palladium complex containing a chiral phosphine-oxazoline ligand showed high catalytic activity and high enantioselectivity in the asymmetric addition of arylboronic acids to cyclic Nsulfonyl ketimines 1 (R = alkyl, aryl), giving high yields of the corresponding chiral cyclic sulfonamides, which bear a tetrasubstituted stereogenic center. Although the five-membered ring imines are highly reactive, giving the corresponding sultams upon arylation even for ketimines, the ring cleavage giving the corresponding chiral methylamines without loss of enantiomeric purity is not trivial.…”

Enantioselective Addition of Enamides to Cyclic Ketimines: Access to Chiral 3,3‐Disubstituted Isoindolin‐1‐Ones

“…[2] As a result, their asymmetric synthesis has attracted increasing attention in recent years. Among the established methods for the synthesis of chiral 3,3-disubstituted isoindolinones, [3][4][5][6][7][8][9] a particularly straightforward approach is the catalytic enantioselective addition of nucleophilic partners to cyclic Ncarbonyl ketimines, which were generated in situ by dehydration of 3-hydroxyisoindolinones (Scheme 1b). Followed this concept, the research groups of Zhou [4a] and Gredičak [4b] reported the asymmetric addition of indoles to 3-hydroxyisoindolinone-derived cyclic Ncarbonyl ketimines.…”

“…Followed this concept, the research groups of Zhou [4a] and Gredičak [4b] reported the asymmetric addition of indoles to 3-hydroxyisoindolinone-derived cyclic Ncarbonyl ketimines. Hayashi and co-workers [5] developed a rhodium-catalyzed asymmetric arylation of 3hydroxyisoindolinones by employing arylboroxines as nucleophiles. Both research groups of Hu [6] and Singh [7] described the asymmetric alkylation of 3hydroxyisoindolinones with oxonium ylides or α-diazo esters.…”