Palladium‐Catalyzed Branch‐ and Z‐Selective Allylic C−H Amination with Aromatic Amines
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Abstract Allylamines are important building blocks in the synthesis of bioactive compounds. The direct coupling of allylic C−H bonds and commonly available amines is a major synthetic challenge. An allylic C−H amination of 1,4‐dienes has been accomplished by palladium catalysis. With aromatic amines, branch‐selective allylic aminations are favored to generate thermodynamically unstable Z‐allylamines. In addition, more basic aliphatic cyclic amines can also engage in the reaction, but linear dienyl allylic amines are the major products.Allylic amination is a powerful tool for constructing
Reductive amination
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Allylic amination enables late-stage functionalization of natural products where allylic C–H bonds are abundant and introduction of nitrogen may alter biological profiles. Despite advances, intermolecular allylic amination remains a challenging problem due to reactivity and selectivity issues that often mandate excess substrate, furnish product mixtures, and render important classes of olefins (for example, functionalized cyclic) not viable substrates. Here we report that a sustainable manganese perchlorophthalocyanine catalyst, [MnIII(ClPc)], achieves selective, preparative intermolecular allylic C–H amination of 32 cyclic and linear compounds, including ones housing basic amines and competing sites for allylic, ethereal, and benzylic amination. Mechanistic studies support that the high selectivity of [MnIII(ClPc)] may be attributed to its electrophilic, bulky nature and stepwise amination mechanism. Late-stage amination is demonstrated on five distinct classes of natural products, generally with >20:1 site-, regio-, and diastereoselectivity.
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This system allows for highly stereoselective intramolecular allylic aminations and etherifications as well as intermolecular allylic amination followed by intramolecular cyclization (shown). Low catalyst loading (2 mol%), and fast reaction times make this a suitable system for the synthesis of various ring sized N-heterocycles.
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Abstract Allylamines are important building blocks in the synthesis of bioactive compounds. The direct coupling of allylic C−H bonds and commonly available amines is a major synthetic challenge. An allylic C−H amination of 1,4‐dienes has been accomplished by palladium catalysis. With aromatic amines, branch‐selective allylic aminations are favored to generate thermodynamically unstable Z‐allylamines. In addition, more basic aliphatic cyclic amines can also engage in the reaction, but linear dienyl allylic amines are the major products.
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The choice of the peroxycarbamate oxidant was important for producing either allylic oxidation products or allylic amination products. While the yields for this reaction were often very low, the interesting finding is that the nature of the oxidant plays a vital role in determining the reaction pathway. An enantioselectivity of 70% is encouraging for allylic amination, but the yield needs to be significantly increased (from 14%) for this reaction to become useful.
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A selective allylic C-H amination for the preparation of 1,3-amino alcohols is reported. The use of electron-deficient N-nosyl carbamate nucleophiles is crucial for the reaction to proceed under mild conditions. The method is highly chemoselective and tolerates a range of various functionalities. Remarkably, the allylic C-H bonds of terminal alkenes are preferentially aminated to those of internal olefins. The reaction proceeds diastereoselectively favoring the formation of the syn product.
Carbamate
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Key words allylic amination - dynamic kinetic asymmetric transformation - palladium
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Allylic oxidation of hydrocarbon substrates is the foundation of many industrial and fine-chemical production processes. Direct allylic oxidation of cycloalkenes (C5-8) has been widely discussed in the chemical literature. However, certain mechanistic details related to the presence of allylic free radicals have yet to be fully resolved. The corresponding copper-catalyzed allylic amination reaction has not been previously achieved. We report the first examples of this class of amination reaction using saccharin and bis-p-toluenesulfonamide as nitrogen sources and t-BuOOH and PhI(saccharinate)2 as oxidants. Kinetic studies on stoichiometric model reactions demonstrate that the oxidant is not involved in the RDS of the transformation, and studies with 3,3,6,6-tetradeuteriocyclohexene conclusively show a mechanistic dichotomy between the catalytic oxidation and amination reactions. Both oxidative processes involve η1-allyl intermediates, and regiochemical results are a consequence of discrete copper complexes. A mechanistic rationale involving allylic transpositions explains this mechanism dichotomy.
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Allylamines are important building blocks in the synthesis of bioactive compounds. The direct coupling of allylic C-H bonds and commonly available amines is a major synthetic challenge. An allylic C-H amination of 1,4-dienes has been accomplished by palladium catalysis. With aromatic amines, branch-selective allylic aminations are favored to generate thermodynamically unstable Z-allylamines. In addition, more basic aliphatic cyclic amines can also engage in the reaction, but linear dienyl allylic amines are the major products.
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