Catalytic Synthesis of N‐Unprotected Piperazines, Morpholines, and Thiomorpholines from Aldehydes and SnAP Reagents

Luescher, Michael U.; Bode, Jeffrey W.

doi:10.1002/anie.201505167

Cited by 70 publications

(49 citation statements)

References 48 publications

(27 reference statements)

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“…In subsequent publications of the same group, catalytic variants of the SnAP protocol were also reported, in addition to the previously reported stoichiometric ones, where a catalytic amount of Cu II is used in conjunction with a ligand, or an iridium catalyst along with irradiation in a continuous flow reaction (Figure D) …”

Section: Medicinal Chemistry Of Morpholine Derivativesmentioning

confidence: 96%

Morpholine as a privileged structure: A review on the medicinal chemistry and pharmacological activity of morpholine containing bioactive molecules

Kourounakis

Xanthopoulos

Tzara

2019

Medicinal Research Reviews

172

114

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Morpholine is a heterocycle featured in numerous approved and experimental drugs as well as bioactive molecules. It is often employed in the field of medicinal chemistry for its advantageous physicochemical, biological, and metabolic properties, as well as its facile synthetic routes. The morpholine ring is a versatile and readily accessible synthetic building block, it is easily introduced as an amine reagent or can be built according to a variety of available synthetic methodologies. This versatile scaffold, appropriately substituted, possesses a wide range of biological activities. There are many examples of molecular targets of morpholine bioactive in which the significant contribution of the morpholine moiety has been demonstrated; it is an integral component of the pharmacophore for certain enzyme active‐site inhibitors whereas it bestows selective affinity for a wide range of receptors. A large body of in vivo studies has demonstrated morpholine's potential to not only increase potency but also provide compounds with desirable drug‐like properties and improved pharamacokinetics. In this review we describe the medicinal chemistry/pharmacological activity of morpholine derivatives on various therapeutically related molecular targets, attempting to highlight the importance of the morpholine ring in drug design and development as well as to justify its classification as a privileged structure.

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Section: Medicinal Chemistry Of Morpholine Derivativesmentioning

confidence: 96%

Morpholine as a privileged structure: A review on the medicinal chemistry and pharmacological activity of morpholine containing bioactive molecules

Kourounakis

Xanthopoulos

Tzara

2019

Medicinal Research Reviews

172

114

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“…[53] (MS: molecular sieves, OTf: triflate, HFIP: hexafluoroisopropanol). [56] c) Ir[dF(CF 3 )ppy] 2 (dtbbpy)PF 6 (2.5 mol %), MeCN/TFE 1 : 1, blue light (overall yield: 33-57 %). [57] (PhBox: phenyl-bis(oxazoline), TFE: 2,2,2-trifluoroethanol).…”

Section: Methodsmentioning

confidence: 99%

“… Catalytic variants of the SnAP protocol. Reagents and conditions : a) 4 Å MS, DCM, 2–12 h, rt; b) Cu(OTf) 2 (5–20 mol %), (±)‐PhBox (5–20 mol %), HFIP, rt, 20 h, (overall yield: 32–82 %); c) Ir[dF(CF 3 )ppy] 2 (dtbbpy)PF 6 (2.5 mol %), MeCN/TFE 1 : 1, blue light (overall yield: 33–57 %) . (PhBox: phenyl‐bis(oxazoline), TFE: 2,2,2‐trifluoroethanol).…”

Section: Synthesis Of Morpholinesmentioning

confidence: 99%

Morpholine As a Scaffold in Medicinal Chemistry: An Update on Synthetic Strategies

2020

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Morpholine is a frequently used heterocycle in medicinal chemistry and a privileged structural component of bioactive molecules. This is mainly due to its contribution to a plethora of biological activities as well as to an improved pharmacokinetic profile of such bioactive molecules. The synthesis of morpholines is a subject of much study due to their biological and pharmacological importance, with the last such review being published in 2013. Here, an overview of the main approaches toward morpholine synthesis or functionalization is presented, emphasizing on novel work which has not been reviewed so far. This review is an update on synthetic strategies leading to easily accessible libraries of bioactives which are of interest for drug discovery projects.

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“…At the outset, assisted by the hydrogen bond involved double-activation model, the nucleophilic addition adduct 83 was generated. Then, the benzyl alcohol species 83 underwent dehydration and dearomatization to furnish ortho-quinone methides (o-QMs) 84, [49] which engaged in the following o-QMs triggered [1,5]-hydride transfer to afford the rearomatic intermediate 85. The subsequent nucleophilic dearomatization afforded the dearomative cyclohexaketenes as final products.…”

Section: P E R S O N a L A C C O U N T T H E C H E M I C A L R E C O R Dmentioning

confidence: 99%

“…[2] Owing to the strong electron-withdrawing property of fluoroalkyl groups, the fluorinated alcohols possess some unique properties: (1) Generally, there are two versions of reactions participated by fluorinated alcohols: the reactions catalyzed by additional promoters with fluorinated alcohols as solvents and the reactions performed without any catalysts. In the former version, numerous notable works have been achieved, in which transition metal complexes (Co, [3] Fe, [4] Cu, [5] Pd, [6] Ru, [7] Ir, [8] ), Brønsted acids, [9] hypervalent iodines [10] and electrochemical activation [11] have been applied as catalysts, additives or novel driving-force. With the assistance of fluorinated alcohols' unique properties, reactive intermediates of the above reactions can be stabilized by the distinctive solvent microstructure.…”

Section: Introductionmentioning

confidence: 99%

Fluorinated Alcohols: Magic Reaction Medium and Promoters for Organic Synthesis

Xiao

2019

The Chemical Record

110

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Fluorinated alcohols have been widely used in the synthetic organic chemistry over the past decades. The unique properties such as the strong hydrogen‐bonding donor ability and low nucleophilicity allow them to promote organic reactions in the absence of any catalyst. These approaches have distinct advantages in terms of operational simplicity, practicability and environmental friendliness. Reactions promoted by fluorinated alcohols, including nucleophilic substitution reactions, annulation reactions, electrophilic reactions, dearomatization reactions, functionalization of multiple bond, epoxidation reactions and miscellaneous reactions have been summarized in this account.

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Catalytic Synthesis of N‐Unprotected Piperazines, Morpholines, and Thiomorpholines from Aldehydes and SnAP Reagents

Cited by 70 publications

References 48 publications

Morpholine as a privileged structure: A review on the medicinal chemistry and pharmacological activity of morpholine containing bioactive molecules

Morpholine as a privileged structure: A review on the medicinal chemistry and pharmacological activity of morpholine containing bioactive molecules

Morpholine As a Scaffold in Medicinal Chemistry: An Update on Synthetic Strategies

Fluorinated Alcohols: Magic Reaction Medium and Promoters for Organic Synthesis

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