Acid-catalyzed additions of amines to alkenes are generally unsuccessful due to the buffering effect of the amine substrate. 1 Friedel-Crafts alkylations of arylamines are hindered by coordination of the amine to the Lewis acid catalyst. 2 A recent communication by Hartwig et al. reports that several common Brønsted acids catalyze the intramolecular hydroamination of tosyl-protected amino olefins. 3 Beller and co-workers have reported that alkylations of electron-rich anilines with styrene are promoted with HBF 4 ·Et 2 O. 2b,4 Herein we report the first homogeneous 5 acid catalyst that promotes both hydroamination and hydroarylation reactions of anilines and alkenes, including simple cyclic alkenes and dienes. These transformations are air-and moisture-tolerant and can be controlled to favor either N-H or Ar-H addition products based on reaction conditions and aniline substitution pattern. The key to the activity of this system is that the acid counteranion has a dramatic effect on reaction efficiency.In the course of our studies on metal-catalyzed hydroamination reactions, 6 we found that Ph 3 CB(C 6 F 5 ) 4 (1) catalyzes the reaction of norbornene with aniline. Both hydroamination (2) and ortho-hydroarylation (3) products are formed using 5 mol % of 1 (eq 1). 7(1)
The identification of causal variants in sequencing studies remains a considerable challenge that can be partially addressed by new gene-specific knowledge. Here, we integrate measures of how essential a gene is to supporting life, as inferred from viability and phenotyping screens performed on knockout mice by the International Mouse Phenotyping Consortium and essentiality screens carried out on human cell lines. We propose a cross-species gene classification across the Full Spectrum of Intolerance to Loss-of-function (FUSIL) and demonstrate that genes in five mutually exclusive FUSIL categories have differing biological properties. Most notably, Mendelian disease genes, particularly those associated with developmental disorders, are highly overrepresented among genes non-essential for cell survival but required for organism development. After screening developmental disorder cases from three independent disease sequencing consortia, we identify potentially pathogenic variants in genes not previously associated with rare diseases. We therefore propose FUSIL as an efficient approach for disease gene discovery.
[reaction: see text] Several tantalum imido complexes have been synthesized and shown to efficiently catalyze the hydroamination of internal and terminal alkynes. An unusual hydroamination/hydroarylation reaction of norbornene catalyzed by a highly electrophilic cationic tantalum imido complex is also reported. Factors affecting catalyst activity and selectivity are discussed along with mechanistic insights gained from stoichiometric reactions.
The synthesis and reactivity of dibenzyl cationic tantalum imido complexes is described. The trialkyl tantalum imido compounds Bn(3)Ta=NCMe(3) (1) and Np(3)Ta=NCMe(3) (2) were synthesized as starting materials for the study of dialkyl cationic tantalum imido complexes. Compound 1 undergoes insertion reactions with diisopropylcarbodiimide and 2,6-dimethylphenylisocyanide to give (bisamidinate)imido complex 5 and (bisimino-acyl)imido complex 6, respectively. Treatment of compound 1 with B(C(6)F(5))(3) gives the zwitterionic tantalum complex [Bn(2)Ta=NCMe(3)][BnB(C(6)F(5))(3)] (7) which is stabilized by eta(6)-coordination of the benzyl triaryl borate anion. Coordination of the aryl anion can be displaced by three equivalents of pyridine to give the Lewis base complex 8. Treatment of compound 1 with [Ph(3)C][B(C(6)F(5))(4)] gives the cationic tantalum imido complex [Bn(2)Ta=NCMe(3)][B(C(6)F(5))(4)] (3). This salt forms insoluble aggregates unless trapped by THF coordination or an insertion reaction with an alkyne or an alkene. Cation 3 undergoes migratory insertion reactions with diphenylacetylene, phenylacetylene, norbornene, and cis-cyclooctene to give the corresponding alkenyl or modified alkyl imido complexes. The characterization of these products and the significance of these insertion reactions with respect to Ziegler-Natta polymerizations and hydroamination reactions are described.
A solvent-controlled cascade process has been identified for the dual purpose of the preparation of either dihydrocarbazoles or dihydropyridoindoles from identical N-aryl-α,β-unsaturated nitrones and electron-deficient allene starting materials. These reactions proceed smoothly under mild metal-free conditions affording a range of two types of skeletally distinct indole-based heterocycles in high yield and diastereoselectivity. These transformations demonstrate the use of a bifurcated cascade process that hinges on the ring-opening event of a benzazepine intermediate for the synthesis of skeletally diverse heterocyclic products and rapid access to biologically-significant, indole-based structures.
Although best known for their [3+ +2]-dipolar cycloaddition reactivity and use in the preparationo fi soxazolines and isoxazolidines,n itrones are versatile reagents that undergo av ariety of transformationsf or the synthesis of ad iverse array of heterocyclic compounds. Theb readth of heterocycle synthesis using nitrone reagentsi ncludes: 1) stepwise [3+ +3]-cycloaddition reactions of nitrones with vinyl diazoacetates, transition-metal-coordinated cycloisomerization intermediates, trimethylenem ethanes, and cyclopropane diesters to form dihydro-a nd tetrahydro-1,2-oxazines;2 )internal redox cyclization reactions of alkyne-tetheredn itrones to provide access to azabicyclooctanes,i soindoles, aminoindanones, and isoquinolones;3 )electrocyclizationso fi ns itu generated N-allenylnitrones to form pyridines and azetidine-N-oxides, as well as metal-catalyzed cyclizationsa nd rearrangements of nitrones to form azepine-N-oxides, spirocyclic isoxazolines, and a,b-epoxyimines;a nd 4) the use of [3+ +2]cycloaddition reactions of nitrones to trigger cascade reactions for the formationo ft etrahydrooxazepines, dihydrocarbazoles, and benzoindolizines. This Focus Review aims to highlight these diverse applicationso fn itrones for the synthesis of heterocyclest oe mphasize the broad utility of these reactive intermediates andt oi nspire their furtherd evelopment as important synthons beyond the scope of traditional [3+ +2]-dipolar cycloaddition reactions. Scheme1.[3+ +2]-Dipolar cycloadditions of nitrones and their application to the synthesis of naturalproducts and biologically active compounds:Diverse applicationsofn itrones for the synthesis of heterocyclic compounds.[a] Prof. Dr.L.L.A nderson 2. Formal [3+ +3]-Cycloadditions of Nitrones and [4+ +2]-Cycloadditions of N-Alkenylnitrones.Formal [3+ +3]-cycloadditions of nitrones have been investigated as alternative methods for the synthesis of dihydro-and tetrahydro-1,2-oxazines and offer new routes to these heterocycles that are unique from traditional [4+ +2]-cycloadditions of dienes and nitrosobenzenes. [8] The nitrone cycloaddition partners discussed below include vinyldiazoacetates, alkenyl gold complexes,m etal carbenoids generated through cycloisomerization processes, trimethylene methanes, and cyclopropane diesters (Scheme 3A). The synthesiso fN-alkenylnitrones has also prompted an investigation of these electron-deficient azadienesa si nverse-demand cycloaddition partners for the synthesis of six-membered-ring nitrones that are poised to undergo furtherf unctionalization (Scheme 3B). Prof. Laura L. Anderson receivedh er B.A. from Knox College in 2000 and moved to the University of California, Berkeley,f or her graduate studies where she worked with Prof. John Arnold and Prof. Robert G. Bergman developing new hydroamination catalystsa nd studying the reactivity of transition metal imido complexes. After obtaining her Ph.D. in 2005, Prof. Anderson movedt ot he Universityo f California, Irvine, wheres he completed aR uth L. Kirschstein NIH postdoctoral fellowship with Pr...
N-Vinyl nitrones derived from fluorenone have been prepared via a copper-mediated coupling between fluorenone oxime and vinyl boronic acids. These compounds undergo subsequent rearrangement and addition reactions that are distinct from the traditional [3 + 2] cycloaddition reactivity of nitrones. Thermal rearrangements of fluorenone N-vinyl nitrones give spiroisoxazolines, while treatment with alkynes provides fluorene-tethered isoxazoles. The scope and limitations of the preparation of fluorenone N-vinyl nitrones and their subsequent rearrangement and addition reactions are discussed.
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