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 ...

Catalytic Asymmetric Synthesis of Isoindolinones

“…However, another asymmetric arylation of imines in the presence of arylboroxines was reported in 2013. Nishimura and co‐workers disclosed the rhodium‐catalyzed asymmetric arylation of N ‐carbonyl ketimines, obtained by the dehydration of substrates 115 . Arylboroxines worked as dehydrating reagents to generate ketimines, and arylating reagents for the subsequent arylation (Scheme ).…”

A Palladium‐Catalyzed Enantioselective Addition of Arylboronic Acids to Cyclic Ketimines

“…[16] Thus, the alkyl-substituted ketimine 1 was chosen as the substrate for our palladium-catalyzed addition reaction. Subsequently, different chiral pyridine-oxazoline-type ligands were screened (entries [1][2][3][4][5][6][7][8]. Initial solvent screening showed that catalysis in MeOH provided the most promising result (entry 1; and see the Supporting Information).…”

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The construction of chiral quaternary stereocenters by asymmetric catalysis remains a challenging proposition for chemists. [2] Among reactions involving the construction of chiral a-tertiary amines, [3][4][5][6][7][8][9] asymmetric addition to ketimines is a powerful strategy. [2] Among reactions involving the construction of chiral a-tertiary amines, [3][4][5][6][7][8][9] asymmetric addition to ketimines is a powerful strategy.

…”

“…Organocatalytic and chiral Lewis acid catalyzed nucleophilic additions to ketimines have been reported for the synthesis of chiral a-tertiary amines. [2,[6][7][8][9] Several reports have described the copper-or zirconiumcatalyzed asymmetric addition of allylboronates or dialkylzinc reagents to ketimines. Despite the great advances in asymmetric transition metal catalyzed additions of organometallic reagents to imines, [10,11] the development of such reactions towards the construction of chiral a-tertiary amines has had limited success because of the steric and electronic factors.…”

Enantioselective, Copper-Catalyzed Alkynylation of Ketimines To Deliver Isoquinolines with α-Diaryl Tetrasubstituted Stereocenters

“…5,6,7 With an eye towards enantioselective addition of a versatile carbon nucleophile to cyclic diaryl ketimines, we envisioned enantioselective, copper-catalyzed alkynylation may provide a useful solution. Although enantioselective alkynylations of a variety of cyclic aldimines and aldiminium ions to deliver α-trisubstituted amines are known (Scheme 1, eq 1), 5a, 6, 8 only a single report of enantioselective alkynylation of a cyclic ketiminium ion exists. Maruoka has impressively shown that a Cu(Ph-PyBox)/Brønsted acid catalyst system enables alkynylation of alkyl-substituted isoquinolinium ions (Scheme 1, eq 2).…”