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Synthesis of morpholines

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A tandem sequential one-pot reaction employing both hydroamination and asymmetric transfer hydrogenation reactions enables an efficient and practical enantioselective synthesis of 3-substituted morpholines from aminoalkyne substrates. A wide range of functional groups is tolerated. Hydrogen-bonding interactions between the oxygen and the [(S,S)-Ts-DPEN] ligand of the Ru catalyst are crucial for obtaining high ee's.
Y. Y. Lau, H. Zhai, L. L. Schafer, J. Org. Chem., 2016, 81, 8696-8709.

A scalable, photocatalytic coupling of silicon amine protocol (SLAP) reagents and aldehydes provides substituted morpholines, oxazepanes, thiomorpholines, and thiazepanes under continuous flow conditions in the presence of an inexpensive organic photocatalyst (TPP) and a Lewis acid additive.
M. K. Jackl, L. Legnani, B. Morandi, J. W. Bode, Org. Lett., 2017, 19, 4696-4699.

Boron trifluoride etherate mediates an intramolecular hydroalkoxylation/hydrothioalkoxylation of nitrogen-tethered alkenes providing five-membered thiazolidine, six-membered 1,4-oxazines (morpholines) and tetrahydro-2H-1,4-thiazines (thiomorpholines), and seven-membered 1,4-oxazepanes in good yields.
M. J. Deka, K. Indukuri, S. Sultana, M. Borah, A. K. Saikia, J. Org. Chem., 2015, 80, 4349-4359.

The reaction of 1,2-amino alcohols or diamines with an α-phenylvinylsulfonium salt enables a concise synthesis of stereodefined C-substituted morpholines and piperazines in very good yields. Factors affecting regio- and diastereocontrol are discussed. Azepines and oxazepines can also be prepared in moderate yields.
J. V. Matlock, T. D. Svejstrup, P. Songara, S. Overington, E. M. McGarrigle, V. K. Aggarwal, Org. Lett., 2015, 17, 5044-5047.

Use of a base-free Pd(DMSO)2(TFA)2 catalyst enables the synthesis of six-membered nitrogen heterocycles via a Wacker-type aerobic oxidative cyclization of alkenes. Various heterocycles, including morpholines, piperidines, piperazines and piperazinones, are accessible by this method.
Z. Lu, S. S. Stahl, Org. Lett., 2012, 14, 1234-1237.

Iron(III) catalyzes a diastereoselective synthesis of 2,6- and 3,5-disubstituted morpholines from 1,2-amino ethers and 1,2-hydroxy amines substituted by an allylic alcohol. The morpholines were obtained either by C-O or C-N bond formation.
T. Aubineau, A. Dupas, T. Zeng, J. Cossy, J. An, Synlett, 2021, 32, 525-531.

A Pd(0)-catalyzed Tsuji-Trost reaction of vinyloxiranes with amino-alcohols followed in situ by a Fe(III)-catalyzed heterocyclization provides 2,6-, 2,5-, and 2,3-disubstituted as well as 2,5,6- and 2,3,5-trisubstituted morpholines in very good yields and diastereoselectivities.
T. Aubineau, J. Cossy, Org. Lett., 2018, 20, 7419-7423.

4-CN-pyridine is an effective cyanation reagent under catalyst-free, paired electrochemical reaction conditions. Mechanistic studies support a nucleophilic reaction pathway, and the cyanation protocol can be applied to diverse substrates including N,N-dialkyl anilines, indole derivatives and amino acids (via decarboxylative cyanation).
G. S. Kumar, P. S. Shinde, H. Chen, K. Muralirajan, R. Kancherla, M. Rueping, Org. Lett., 2022, 24, 6357-6363.