Recent progress in the synthesis of morpholines

Palchykov, Vitalii A.; Чебанов, Валентин А.

doi:10.1007/s10593-019-02461-1

Cited by 28 publications

(6 citation statements)

References 46 publications

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“…, chelonin A) and pharmaceuticals such as aprepitant (EMEND) and L-742,694, both of which are neurokinin-1 (NK-1) receptor antagonists (Scheme a). They are also important building blocks and useful chiral auxiliaries. , The chiral-pool-based approach has been widely adopted to access this important family of chiral N,O-heterocycles, − but it relies heavily on the availability of the chiral building blocks. Catalytic enantioselective syntheses of chiral C-substituted morpholines remain surprisingly rare, − and to the best of our knowledge, there are only two reports dealing with the de novo construction of chiral morpholines from two achiral linear compounds: Hayashi et al reported a synthesis of 2-vinyl morpholine (61% ee ) via a Pd-catalyzed double allylic substitution reaction (Scheme b), while Bode and co-workers applied their SnAP methodology to access 2,3-disubstituted morpholine (60% ee ) (Scheme c) …”

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Catalytic Enantioselective Synthesis of Morpholinones Enabled by Aza-Benzilic Ester Rearrangement

Wang

2021

J. Am. Chem. Soc.

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Chiral morpholinone is an important building block in organic synthesis and a pharmacophore in medicinal chemistry. However, catalytic enantioselective methods for the construction of this N,O-heterocycle remain scarce. We report herein a chiral phosphoric acid-catalyzed enantioselective synthesis of C3-substituted morpholinones from aryl/alkylglyoxals and 2-(arylamino)ethan-1-ols. The reaction proceeds through a domino [4 + 2] heteroannulation followed by a 1,2-aryl/alkyl shift of the resulting cyclic α-iminium hemiacetals. It represents formally an unprecedented asymmetric aza-benzilic ester rearrangement reaction. A concise synthesis of L-742,694, a neurokinin-1 receptor antagonist, featuring this reaction is documented.

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Catalytic Enantioselective Synthesis of Morpholinones Enabled by Aza-Benzilic Ester Rearrangement

Wang

2021

J. Am. Chem. Soc.

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“…Consequently, efficient access to these structural targets have been in great demand. Thus far, there have been a number of methods for the synthesis of C-functionalized morpholines or morpholinones 6 – 8 benefiting from metal-catalyzed cyclization reactions 9 – 14 , allylic alkylation 15 , hydrogenations 16 , 17 or other multi-step transformations 18 – 20 . On the contrary, approaches for the catalytic preparation of C3-disubstituted morpholines/morpholin-2-ones are far less developed, which is due probably to the steric hindrance effect of the incoming aza-quaternary carbon and availability of the corresponding branched starting materials 21 – 23 .…”

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confidence: 99%

Zinc chloride-catalyzed cyclizative 1,2-rearrangement enables facile access to morpholinones bearing aza-quaternary carbons

Li,

He,

2023

Commun Chem

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Morpholines and morpholinones are important building blocks in organic synthesis and pharmacophores in medicinal chemistry, however, C3-disubstituted morpholines/morpholinones are extremely difficult to access. Here we show the ZnCl2-catalyzed cyclizative 1,2-rearrangement for the efficient synthesis of morpholinones bearing aza-quaternary stereocenters. A series of structurally diverse C3-disubstituted morpholin-2-ones which are difficultly accessible by existing methods were efficiently constructed from readily available two achiral linear compounds. Notably, mechanistic studies reveal that this reaction proceeds via an unusual sequence of direct formal [4 + 2] heteroannulation regioselectively delivering specific α-iminium/imine hemiacetals followed by a 1,2-esters or amides shift process, which is different from the reported mechanism of the aza-benzilic ester rearrangements.

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“…Morpholine is considered a favored scaffold for medicinal chemistry [1][2][3][4][5][6]. Synthetic and natural molecules bearing a morpholine substituent have multiple biological activities, as well as improved pharmacokinetic and metabolic profiles, which have placed morpholine as one of the most promising compounds evaluated in structure-activity relationship studies (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Morpholine Radical in the Electrochemical Reaction with Quinoline N-Oxide

Dolengovski,

Gryaznova,

Sinyashin

et al. 2023

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An electrochemical reaction between quinoline N-oxides and morpholine was developed by using Cu(OAc)2 as a catalyst, generating products of 4-aminoquinoline N-oxides in CH2Cl2 or 2-aminoquinoline N-oxides in CH3CN in good yields. With an increase in the amount of electricity passed, the product deoxygenates with the formation of aminoquinolines. The advantages of the reaction are mild conditions, room temperature, the use of morpholine rather than its derivatives, and the ability to control the process when the electrolysis conditions change. Bisubstituted quinoline has also been obtained. The redox properties of both individual participants of C–H/N–H cross-coupling and multicomponent systems were established by voltammetry and EPR methods. For the first time, the EPR spectrum of the morpholine radical was recorded at room temperature, and its magnetic resonance parameters were determined in CH2Cl2. Mechanisms for the catalytic reaction have been proposed. This is a simple and easy-to-perform method for introducing a morpholine substituent, important in medicinal chemistry and other fields, by C–H/N–H cross-coupling.

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Recent progress in the synthesis of morpholines

Cited by 28 publications

References 46 publications

Catalytic Enantioselective Synthesis of Morpholinones Enabled by Aza-Benzilic Ester Rearrangement

Catalytic Enantioselective Synthesis of Morpholinones Enabled by Aza-Benzilic Ester Rearrangement

Zinc chloride-catalyzed cyclizative 1,2-rearrangement enables facile access to morpholinones bearing aza-quaternary carbons

Morpholine Radical in the Electrochemical Reaction with Quinoline N-Oxide

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