Catalytic Asymmetric Functionalization of Aromatic CH Bonds by Electrophilic Trapping of Metal‐Carbene‐Induced Zwitterionic Intermediates

Abstract

Asymmetric functionalization of aromatic C À H bonds of N,N-disubstituted anilines with diazo compounds and imines is reported for the efficient construction of a,a-diaryl benzylic quaternary stereocenters in good yields with high diastereoselectivities and excellent enantioselectivities. This Rh II /chiral phosphoric acid cocatalyzed transformation is proposed to proceed through a metal-carbene-induced zwitterionic intermediate which undergoes electrophilic trapping. To the best of our knowledge, this is the first asymmetric example of metal carbene-induced intermolecular functionalization of aryl CÀH bonds.Carbene-induced C À H functionalization by transitionmetal-catalyzed decomposition of diazo compounds is among the most efficient and reliable synthetic tools for the construction of CÀC bonds.[1] Within this context, by taking advantage of a broad selection of transition-metal catalysts, both non-asymmetric and asymmetric functionalizations of C(sp 3 ) À H bonds have been extensively studied over the past several decades.[1b-e] However, while non-asymmetric functionalization of aromatic C(sp 2 )ÀH bonds have also been developed to some extent, [2][3][4][5] the asymmetric version of metal-carbene-induced functionalization of aromatic C(sp 2 )À H bonds remains unexplored except for intramolecular examples [6] or those starting from heteroarenes. [7] Unlike the carbene-induced C(sp 3 ) À H functionalization in which efficient asymmetric control could be achieved by chiral transition-metal catalysts via a concerted nonsynchronous transition state, [1b,d, 8] the functionalization of aromatic CÀH bonds is generally considered to proceed through the formation of a zwitterionic intermediate from electrophilic addition of a metal carbene to the aromatic ring and a subsequent rapid proton transfer (Scheme 1, path a). [1b] This stepwise mechanism makes it very challenging to achieve efficient enantioselective control by means of chiral transition-metal catalysts, [9] probably owing to the difficulty in controlling enantioselectivity during the asymmetric protonation step.[10] As part of our continuous research efforts in exploring new transformations based on asymmetric electrophilic trapping of active intermediates generated from metal carbenes, [11,12] we became interested in developing catalytic asymmetric functionalization of aromatic C À H bonds with a similar strategy. We envisioned that the proposed metalcarbene-induced zwitterionic intermediate could be intercepted by electrophiles such as active imines prior to 1,2-proton transfer to give formal CÀH insertion products (Scheme 1, path b). With such a strategy, asymmetric control could be realized during the trapping process by introducing chiral cocatalyst such as chiral phosphoric acid (PPA; Scheme 1, path b).[13] Herein, we report the successful development of a catalytic asymmetric functionalization of aromatic CÀH bonds from a novel three-component reaction of arenes, diazo compounds, and imines in the presence of a rhodium(II)/chiral PPA cat...

Modern Organic Synthesis with α-Diazocarbonyl Compounds

“…The densely substituted β-aminoester products were formed with high enantio-and diastereoselectivities in most cases (Scheme 139). 324 The three-component approach has also been used by the Hu group to effect C−H alkylation of several indoles and oxindoles, again using imines as the electrophilic trap in a highly efficient, integrated rhodium/chiral Bronsted acidcocatalyzed approach. 351 For the oxindole synthesis, the fivemembered heterocyclic component was constructed in situ from N,N-disubstituted diazoacetamides via a rhodium(II)-catalyzed intramolecular C−H functionalization leading to a zwitterion intermediate which in the presence of the cocatalystactivated imine proceeded to the ultimate product.…”

Acyclic Quaternary Carbon Stereocenters via Enantioselective Transition Metal Catalysis

“…This reactivity pattern was successfully deployed using related π-nucleophiles, pyrroles and anilines (not shown). 138, 139 …”

Rhodium(II)‐Catalyzed Formal [4+1]‐Cycloaddition of Pyridotriazoles and Propargyl Alcohols: Synthesis of 2,5‐Dihydrofurans

“…[1] A variety of metal catalysts have been reported to mediate these reactions with diazo compounds as the carbene precursor, including rhodium, [2] copper, [3] palladium, [4] gold, [5] silver, [6] iron, [7] etc. Recently, combined with other co-catalysts, asymmetric rhodium (II)/chiral phosphoric acid cooperatively catalyzed multicomponent reactions through the trapping of ylide/zwitterionic intermediates; this has been extensively studied by us [9] and others. Recently, combined with other co-catalysts, asymmetric rhodium (II)/chiral phosphoric acid cooperatively catalyzed multicomponent reactions through the trapping of ylide/zwitterionic intermediates; this has been extensively studied by us [9] and others.…”

“…[15] In the last decade, Gevorgyan and others have reported a variety of cycloaddition reactions with pyridotriazole as a-pyridyl carbene precursor. [21] Inspired by these advances, and in continuation of our interest in catalytic metal carbene transformations, [9,14] we envisioned that a formal [4 + 1]-cycloaddition of pyridotriazoles and aryl propargyl alcohols in the presence of a compatible dirhodium catalyst could be realized for the synthesis of 2-pyridyl 2,5-dihydrofuran. [20] However, no cyclization reaction with this species as a "one-C" building block has been disclosed.…”

“…Other transitionmetal catalysts such as Ag, Pd and Cu were also examined, but poor results were obtained (entries [4][5][6][7][8]. Reaction in other solvents (entries [9][10][11] or in the absence of 4 Å molecular sieves (entry 13) led to inferior results, and the best results were obtained in DCE at 25 8C in the presence of Rh 2 (esp) 2 to give 3 a in 75% isolated yield (entry 12). Although high yields were obtained in the analogous [4 + 1]-cycloaddition of aryl diazoacetates with aryl propargyl alcohols in the presence of [PdCl(C 3 H 5 )] 2 , [14] the reaction gave complex mixture when promoted by the same catalyst.…”