Stereoconvergent Amine-Directed Alkyl–Alkyl Suzuki Reactions of Unactivated Secondary Alkyl Chlorides

Lü, Zhe; Wilsily, Ashraf; Fu, Gregory C.

doi:10.1021/ja203560q

Cited by 184 publications

(69 citation statements)

References 27 publications

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“…Based on these experimental mechanistic studies as well as insights into conventional nickel-catalyzed cross-coupling reactions [12,16] we propose a working Table 2. Ligand effect on the nickel-catalyzed direct alkyla-…”

Section: A C H T U N G T R E N N U N G Glyme)nibr 2 ]mentioning

confidence: 99%

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User‐Friendly [(Diglyme)NiBr₂]‐Catalyzed Direct Alkylations of Heteroarenes with Unactivated Alkyl Halides through CH Bond Cleavages

2011

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A nitrogen and phosphorus ligand-free catalytic system derived from inexpensive [(di-A C H T U N G T R E N N U N G glyme)NiBr 2 ] allowed for efficient direct C À H bond alkylations of heteroarenes with unactivated b-hydrogen-containing alkyl halides under basic reaction conditions. Keywords: alkylation; azoles; C À H activation; heterocycles; mechanism; nickel Substituted heteroarenes are indispensable substructures of, among others, biologically active compounds and functional materials. [1][2][3] In particular, strategies relying on direct C À H bond functionalizations arguably constitute the most ecologically benign and economically attractive methods for their preparation. [4] In recent years, various transition metal catalysts were devised for versatile direct arylations, alkenylations or alkynylations of heteroarenes by cleavages of unreactive C À H bonds.[5] In contrast, direct alkylations of (hetero)arenes with unactivated alkyl halides under basic reaction conditions continue to be difficult, predominantly because these challenging electrophiles lead to undesired b-eliminations.[6] Remarkable recent progress was represented by efficient ruthenium [7] and palladium catalyzed [8] direct alkylations of (hetero)arenes.[6] On the contrary, direct alkylations with less expensive nickel catalysts [9] are scarce, and were thus far solely achieved with nickel complexes derived from tridentate nitrogen ligands. [8g,10-12] Thus, Hu and co-workers elegantly devised the nickel complex [( Me NN 2 )NiCl] bearing a tridentate pincer N 2 Nligand for direct functionalizations of heteroarenes with alkyl halides.[10] Unfortunately, the synthesis of this catalyst involves several reaction steps, which can limit its broader applications.[13] Moreover, four direct alkylations of benzothiazole were recently achieved with a nickel complex derived from the tridentate nitrogen ligand terpyridine.[8g] Within our research program directed towards the development of userfriendly and sustainable C À H bond functionalizations, [14] we developed a cost-effective nitrogen-and phosphorus ligand-free [15] free nickel catalyst for direct alkylations of heteroarenes, on which we wish to report herein.At the outset of our studies, we tested a diverse array of commercially available nickel precursors for the direct C À H bond functionalization of benzoxazole (1a) with alkyl iodide 2a as the electrophile, 2,2'-bipyridine (bpy, 4) as the ligand, and CuI [10] as cocatalyst (Table 1). Among different nickel sources, [(di- Table 1. Nickel precursors for the direct C À H bond alkyla-A C H T U N G T R E N N U N G tion.[a] Entry[Ni] 3aaA C H T U N G T R E N N U N G [(diglyme)NiBr 2 ] 61%[a] Reaction conditions: 1a (1.0 mmol), 2a (1.5 mmol), [Ni] (5.0 mol%), CuI (7.5 mol%), 4 (6.0 mol%), t-BuOLi (2.0 mmol), 1,4-dioxane (3.0 mL), 140 8C, 16 h; isolated yields.

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Section: A C H T U N G T R E N N U N G Glyme)nibr 2 ]mentioning

confidence: 99%

“…[8g, [10][11][12] Thus, Hu and co-workers elegantly devised the nickel complex [( Me NN 2 )NiCl] bearing a tridentate pincer N 2 Nligand for direct functionalizations of heteroarenes with alkyl halides. [10] Unfortunately, the synthesis of this catalyst involves several reaction steps, which can limit its broader applications.…”

mentioning

confidence: 99%

User‐Friendly [(Diglyme)NiBr₂]‐Catalyzed Direct Alkylations of Heteroarenes with Unactivated Alkyl Halides through CH Bond Cleavages

2011

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“…When using chiral secondary alkylboron intermediates, these issues are compounded by the challenge of stereocontrol (control of the configuration of a stereogenic carbon). Indeed, although some progress has been realized in recent years [7][8][9][10][11][12][13][14][15][16][17][18][19][20] , control of stereoselectivity is viewed as one of the final frontiers in the Suzuki Miyaura reaction (Fig. 1b) 21 .…”

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confidence: 99%

Synthesis of chiral heterocycles by ligand-controlled regiodivergent and enantiospecific Suzuki Miyaura cross-coupling

2014

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Non-aromatic nitrogen-and oxygen-containing heterocycles such as piperidines and pyrans are prevalent components of natural products and pharmaceutical drugs. Although it has been a workhorse as a synthetic method for assembling unsaturated sp 2 -hybridized substrates, transition metal-catalysed cross-coupling chemistry is traditionally not a suitable approach to prepare chiral non-aromatic heterocycles. Several mechanistic issues hamper the coupling of stereogenic secondary sp 3 -hybridized carbon-metal centres. Moreover, use of unsymmetrical allylic boronates in the Suzuki Miyaura cross-coupling is further complicated by the possibility of forming two regioisomeric products. Here we address this two-pronged problem and demonstrate that chiral enantiomerically enriched heterocyclic allylic boronates can be coupled with high stereochemical retention with a wide variety of aryl and alkenyl halides to independently afford both regioisomeric 2-and 4-substituted dihydropyrans and dehydropiperidines in high selectivity. A divergent mechanism is proposed where regiochemistry is governed by the nature of the ligands on the palladium catalyst. This scalable method is applied to the efficient preparation of the neuroactive alkaloid anabasine and the antidepressant drug paroxetine.

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“…Fu and co-workers speculated that these observations could be due to coordination of the ether oxygen to the Ni catalyst and that this finding could be exploited to develop a method for the cross-coupling of oxygenated unactivated electrophiles 94 (Scheme 21c) [95]. Over the years, the same group has developed a number of methods for the coupling of unactivated electrophiles employing a variety of coordinating groups, including nitrogen [96], amides [97] and carbamates [98]. The scope of these processes has also been expanded to include secondary alkyl chlorides as well as aryl boranes, aryl boronates and secondary alkyl boranes.…”

Section: Stereoselective Couplings Of Alkyl Boranes With Alkyl Halidesmentioning

confidence: 99%

At the Forefront of the Suzuki–Miyaura Reaction: Advances in Stereoselective Cross-Couplings

Sun

Hall

2015

Topics in Organometallic Chemistry

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Stereoconvergent Amine-Directed Alkyl–Alkyl Suzuki Reactions of Unactivated Secondary Alkyl Chlorides

Cited by 184 publications

References 27 publications

User‐Friendly [(Diglyme)NiBr₂]‐Catalyzed Direct Alkylations of Heteroarenes with Unactivated Alkyl Halides through CH Bond Cleavages

User‐Friendly [(Diglyme)NiBr₂]‐Catalyzed Direct Alkylations of Heteroarenes with Unactivated Alkyl Halides through CH Bond Cleavages

Synthesis of chiral heterocycles by ligand-controlled regiodivergent and enantiospecific Suzuki Miyaura cross-coupling

At the Forefront of the Suzuki–Miyaura Reaction: Advances in Stereoselective Cross-Couplings

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Stereoconvergent Amine-Directed Alkyl–Alkyl Suzuki Reactions of Unactivated Secondary Alkyl Chlorides

Cited by 184 publications

References 27 publications

User‐Friendly [(Diglyme)NiBr2]‐Catalyzed Direct Alkylations of Heteroarenes with Unactivated Alkyl Halides through CH Bond Cleavages

User‐Friendly [(Diglyme)NiBr2]‐Catalyzed Direct Alkylations of Heteroarenes with Unactivated Alkyl Halides through CH Bond Cleavages

Synthesis of chiral heterocycles by ligand-controlled regiodivergent and enantiospecific Suzuki Miyaura cross-coupling

At the Forefront of the Suzuki–Miyaura Reaction: Advances in Stereoselective Cross-Couplings

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Resources

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User‐Friendly [(Diglyme)NiBr₂]‐Catalyzed Direct Alkylations of Heteroarenes with Unactivated Alkyl Halides through CH Bond Cleavages

User‐Friendly [(Diglyme)NiBr₂]‐Catalyzed Direct Alkylations of Heteroarenes with Unactivated Alkyl Halides through CH Bond Cleavages