Synthesis Of Piperidines Research Articles

Metal free green protocol for the synthesis of bis-spiro piperidine and pyrimidine derivatives

A highly efficient one-pot three-component synthesis of bis-spiro piperidine and pyrimidine derivatives has been reported by performing the reaction of formaldehyde, aromatic aniline and 1,3-dicarbonyl compounds. This reaction was carried out at room temperature in 2,2,2-trifluoroethanol (TFE) as a recyclable reaction medium under the metal free condition. The strong hydrogen donor ability and acidic property of TFE plays a key role in accelerating the rate of reaction and initiates the reaction smoothly. The advantageous features of this method are a mild reaction condition, no column chromatographic purification, and high yield of products and recyclability of TFE.

Hajime Ito

Angewandte Chemie International EditionVolume 57, Issue 23 p. 6733-6733 Author ProfileFree Access Hajime Ito First published: 05 January 2018 https://doi.org/10.1002/anie.201712526AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Graphical Abstract “I can never resist the temptation of spicy food. The best advice I have ever been given is love what you do, and do your best ...” This and more about Hajime Ito can be found on page 6733. Hajime Ito The author presented on this page has recently published his 10th article in Angewandte Chemie in the last 10 years: “Synthesis of Acylborons by Ozonolysis of Alkenylboronates: Preparation of an Enantioenriched Amino Acid Acylboronate”: J. Taguchi, T. Ikeda, R. Takahashi, I. Sasaki, Y. Ogasawara, T. Dairi, N. Kato, Y. Yamamoto, J. W. Bode, H. Ito, Angew. Chem. Int. Ed. 2017, 56, 13847; Angew. Chem. 2017, 129, 14035. Date of birth: March 11, 1968 Position: Professor, Division of Applied Chemistry, Graduate School of Engineering, Hokkaido University E-mail: hajito@eng.hokudai.ac.jp Homepage: http://labs.eng.hokudai.ac.jp/labo/organoelement/?lang=en ORCID: 0000-0003-3852-6721 Education: 1991 BS (Eng) Kyoto University 1996 PhD with Prof. Yoshihiko Ito, Kyoto University 2001 Research Associate with Prof. Kim D. Janda, The Scripps Research Institute, La Jolla Awards: 2011 The President's Research Award, Hokkaido University; 2014 The Chemical Society of Japan Award for Creative Work; 2016 Fujifilm Corporation Award in Synthetic Organic Chemistry, Japan Current research interests: Development of new reactions for organic synthesis; design of molecular crystalline materials and their phase transitions; mechanoresponsive materials If I were not a scientist, I would be a historian. My favorite place on earth is my home, Sapporo. My top three films of all time are Gladiator, Castle in the Sky, and Seven Samurai. My favorite food is Tonkatsu (Japanese deep-fried pork cutlets). My favorite quote is “Do your best in your research. Do not think your students are bad when their research did not go well” (the late Professor Yoshihiko Ito). The most significant scientific advance of the last 100 years has been the development of semiconductors and computers. If I could have dinner with three famous scientists from history, they would be Archimedes, Alexander Fleming, and Michael Faraday. My best investment was when I was a student, I tried to maintain a broad sense of curiosity. I think that was an important investment that helps my current research. My worst nightmare was a dream in which I was chased by a horde of zombies who used to be my neighbors in my hometown. Guaranteed to make me happy is talking with students about their new findings and future ideas. My 5 top papers: 1“Boration of an α,β-enone using a diboron promoted by a copper(I)–phosphine mixture catalyst”: H. Ito, H. Yamanaka, J. Tateiwa, A. Hosomi, Tetrahedron Lett. 2000, 41, 6821. (The first reported copper(I)-catalyzed borylation, which later turned to be a very powerful tool in organoboron synthesis.) 2“Mechanical stimulation and solid seeding trigger single-crystal-to-single-crystal molecular domino transformations”: H. Ito, M. Muromoto, S. Kurenuma, S. Ishizaka, N. Kitamura, H. Sato, T. Seki, Nat. Commun. 2013, 4, 2009. (A small mechanical stress can induce an entire single-crystal phase change, as well as a variation in luminescent properties.) 3“Controlling Mechano- and Seeding-Triggered Single-Crystal-to-Single-Crystal Phase Transition: Molecular Domino with a Disconnection of Aurophilic Bonds”: T. Seki, K. Sakurada, H. Ito, Angew. Chem. Int. Ed. 2013, 52, 12828; Angew. Chem. 2013, 125, 13062. (Mechanical picking can induce a molecular-level structural change in a crystal.) 4“Synthesis of Optically Active Boron-Silicon Bifunctional Cyclopropane Derivatives through Enantioselective Copper(I)-Catalyzed Reaction of Allylic Carbonates with a Diboron Derivative”: H. Ito, Y. Kosaka, K. Nonoyama, Y. Sasaki, M. Sawamura, Angew. Chem. Int. Ed. 2008, 47, 7424; Angew. Chem. 2008, 120, 7534. (These borylative cyclization and carboborylation reactions provide access to cyclopropane structures, which are important for drug discovery.) 5“Enantioselective Synthesis of Chiral Piperidines via the Stepwise Dearomatization/Borylation of Pyridines”: K. Kubota, Y. Watanabe, K. Hayama, H. Ito, J. Am. Chem. Soc. 2016, 138, 4338. (This borylation reaction can be used to form many optically active boron compounds from readily available pyridine derivatives.) Volume57, Issue23June 4, 2018Pages 6733-6733 ReferencesRelatedInformation

Facile and Green Synthesis of Saturated Cyclic Amines

Single-nitrogen containing saturated cyclic amines are an important part of both natural and synthetic bioactive compounds. A number of methodologies have been developed for the synthesis of aziridines, azetidines, pyrrolidines, piperidines, azepanes and azocanes. This review highlights some facile and green synthetic routes for the synthesis of unsubstituted, multisubstituted and highly functionalized saturated cyclic amines including one-pot, microwave assisted, metal-free, solvent-free and in aqueous media.

Synthesis of 2-Unsubstituted Pyrrolidines and Piperidines from Donor-Acceptor Cyclopropanes and Cyclobutanes: 1,3,5-Triazinanes as Surrogates for Formylimines.

A synthetic procedure to access 2-unsubstituted pyrrolidines and piperidines is presented. In the presence of MgI2 as Lewis acid, donor-acceptor cyclopropanes or corresponding cyclobutanes were treated with 1,3,5-triazinanes, leading to the five- or six-membered ring systems under mild conditions in yields up to 93%. This protocol tolerates a great variety of functional groups and thus provides an efficient entry to this class of pyrrolidines and piperidines.

Stereoselective Synthesis of Piperidines by Iridium‐Catalyzed Cyclocondensation

AbstractAn iridium‐catalyzed cyclocondensation of amino alcohols and aldehydes is reported. Intramolecular allylic substitution by an enamine intermediate and subsequent in situ reduction furnishes 3,4‐disubstituted piperidines with high enantiospecificity and good diastereoselectivity. The modular approach and the broad functional group tolerance provide access to diverse piperidine derivatives, which were further functionalized to give a versatile set of products.

Stereoselective Synthesis of Piperidines by Iridium-Catalyzed Cyclocondensation.

An iridium-catalyzed cyclocondensation of amino alcohols and aldehydes is reported. Intramolecular allylic substitution by an enamine intermediate and subsequent in situ reduction furnishes 3,4-disubstituted piperidines with high enantiospecificity and good diastereoselectivity. The modular approach and the broad functional group tolerance provide access to diverse piperidine derivatives, which were further functionalized to give a versatile set of products.

Transaminase-Catalyzed Enantioselective Synthesis of Piperidines

Transaminase-Catalyzed Enantioselective Synthesis of Piperidines

A flexible method for the synthesis of 2-substituted 1,2,5,6-tetrahydropyridines and piperidines from chloro-containing propargylamines

A general approach for the stereoselective synthesis of 2-substituted 1,2,5,6-tetrahydropyridines and piperidines is described. The addition of 4-chloro-1-butyne to Ellman sulfinimines to produce chloro-containing propargylamines, reduction with Lindlar catalyst, and cyclization using LHMDS provides efficient, stereoselective access to diverse 2-substituted 1,2,5,6-tetrahydropyridines. For substrates incompatible with the LHMDS cyclization reaction conditions removal of the sulfinamide moiety and cyclization with Cs2CO3 allows the preparation of the corresponding 2-substituted 1,2,5,6-tetrahydropyridines. This method can be extended to the synthesis of 2-substituted piperidines through reduction of the chloro-containing propargylamine with PtO2.

Regio- and Stereoselective Alkylation of Pyridine-N-oxides: Synthesis of Substituted Piperidines and Pyridines.

Regio- and stereoselective addition of alkyl Grignard reagents to pyridine-N-oxides gave C2-alkylated N-hydroxy-1,2,5,6-tetrahydropyridines and trans-2,3-disubstituted N-hydroxy-1,2,5,6-tetrahydropyridines in good to excellent yields. These intermediates were aromatized or alternatively reduced in one-pot methodologies for efficient syntheses of alkylpyridines or piperidines, respectively. These reactions have a broad substrate scope and short reaction times.

Pd-Catalyzed Carboamination of Alkylidenecyclopropanes: Synthesis of Congested Pyrrolidines and Piperidines.

The synthesis of densely functionalized N-heterocycles is an ongoing challenge in chemical synthesis. Herein, we report an efficient method for the construction of pyrrolidine and piperidine scaffolds using a palladium-catalyzed carboamination of alkylidenecyclopropanes.

Site-Selective Alkenylation of δ-C(sp(3))-H Bonds with Alkynes via a Six-Membered Palladacycle.

Most chelation-assisted aliphatic C-H activation proceeds through a kinetically favored five-membered cyclometalated intermediate. Here, we report the first site-selective alkenylation of δ-C(sp(3))-H in the presence of more accessible γ-C(sp(3))-H bonds via a kinetically less favored six-membered palladacycle. A wide range of functional groups are tolerated, and the unique protocol can be applied to the synthesis of chiral piperidines. Moreover, mechanistic insights have been conducted to elucidate the origin of the unusual site-selectivity.

Synthesis of Pyrrolidines and Piperidines with Tin Amine Reagents

Synthesis of Pyrrolidines and Piperidines with Tin Amine Reagents

Frontispiece: Efficient Synthesis of Dimeric Oxazoles, Piperidines and Tetrahydroisoquinolines from N‐Substituted 2‐Oxazolones

Frontispiece: Efficient Synthesis of Dimeric Oxazoles, Piperidines and Tetrahydroisoquinolines from <i>N</i>‐Substituted 2‐Oxazolones

Enantioselective Synthesis of Piperidines from Pyridines

Enantioselective Synthesis of Piperidines from Pyridines

Efficient Synthesis of Dimeric Oxazoles, Piperidines and Tetrahydroisoquinolines from N-Substituted 2-Oxazolones.

A mild and practical method for the construction of heterocycles from N-substituted 2-oxazolones through cascade, BF3 ⋅Et2 O/H2 O-catalyzed reactions involving iminium ion generation and trapping by external or internal olefinic and aryl moieties is described. Mechanistic and computational studies revealed the strong protic acid HBF4 as the initiating catalyst for these cascade reactions. Providing access to novel molecular diversity, these processes may facilitate chemical biology studies, drug discovery efforts and natural products synthesis.

Enantioselective Synthesis of Chiral Piperidines via the Stepwise Dearomatization/Borylation of Pyridines.

We have developed a novel approach for the synthesis of enantioenriched 3-boryl-tetrahydropyridines via the Cu(I)-catalyzed regio-, diastereo-, and enantioselective protoborylation of 1,2-dihydropyridines, which were obtained by the partial reduction of the pyridine derivatives. This dearomatization/enantioselective borylation stepwise strategy provides facile access to chiral piperidines together with the stereospecific transformation of a stereogenic C-B bond from readily available starting materials. Furthermore, the utility of this method is demonstrated for the concise synthesis of the antidepressant drug (-)-paroxetine. A theoretical study of the reaction mechanism is also described.

A common approach to the total synthesis of l-1-deoxyallonojirimycin, l-homo-1-deoxyazaallose and triacetyl derivative of 5-epi hyacinthacine A5

A common strategy for the synthesis of polyhydroxylated piperidines l-1-deoxyallonojirimycin, l-homo-1-deoxyazaallose and triacetyl derivative of 5-epi hyacinthacine A5 from the readily available d-ribose as a starting material has been described.

Microwave Assisted Hydrogenation of Pyridinecarboxylates: a Convenient Access to Valuable Scaffolds for Diversity Oriented Synthesis

Hydrogenation of pyridine under Microwave (MW) dielectric heating is a valuable method for a rapid approach to piperidine synthesis. Starting from easily available pyridinecarboxylate derivatives, aminopipecolic scaffolds were prepared and further decorated with a procedure potentially useful for parallel synthesis. MW hydrogenation on PtO2 proceeded with high stereoselectivity and low catalyst loading under mild conditions (80°C and 850 MPa of H2 pressure). MWs were also effective to perform a Pinner reaction on 2-cyano-nitropyridines to obtain the corresponding methyl nitropyridine carboxylates. A general procedure to decorate the 3-, 4-, and 5-amino-pipecolic derivatives obtained from the pyridine hydrogenation has been also developed. Keywords: Amines, diversity oriented synthesis, heterocycles, heterogeneous catalysis, hydrogenation, pinner reaction.

Stereoselective synthesis of oxazolidinonyl-fused piperidines of interest as selective muscarinic (M1) receptor agonists: a novel M1 allosteric modulator.

Syntheses of (1RS,2SR,6SR)-2-alkoxymethyl-, 2-hetaryl-, and 2-(hetarylmethyl)-7-arylmethyl-4,7-diaza-9-oxabicyclo[4.3.0]nonan-8-ones, of interest as potential muscarinic M1 receptor agonists, are described. A key step in the synthesis of (1RS,2SR,6SR)-7-benzyl-6-cyclobutyl-2-methoxymethyl-4,7-diaza-9-oxabicyclo[4.3.0]nonan-8-one, was the addition of isopropenylmagnesium bromide to 2-benzyloxycarbonylamino-3-tert-butyldimethylsilyloxy-2-cyclobutylpropanal. This gave the 4-tert-butyldimethylsilyloxymethyl-4-cyclobutyl-5-isopropenyloxazolidinone with the 5-isopropenyl and 4-tert-butyldimethylsilyloxymethyl groups cis-disposed about the five-membered ring by chelation controlled addition and in situ cyclisation. This reaction was useful for a range of organometallic reagents. The hydroboration-oxidation of (4SR,5RS)-3-benzyl-4-(tert-butyldimethylsilyloxymethyl)-4-cyclobutyl-5-(1-methoxyprop-2-en-2-yl)-1,3-oxazolidin-2-one gave (4SR,5RS)-3-benzyl-4-(tert-butyldimethylsilyloxymethyl)-4-cyclobutyl-5-[(SR)-1-hydroxy-3-methoxyprop-2-yl]-1,3-oxazolidin-2-one stereoselectively. 4,7-Diaza-9-oxabicyclo[4.3.0]nonan-8-ones with substituents at C2 that could facilitate C2 deprotonation were unstable with respect to oxazolidinone ring-opening and this restricted both the synthetic approach and choice of 2-heteroaryl substituent. The bicyclic system with a 2-furyl substituent at C2 was therefore identified as an important target. The addition of 1-lithio-1-(2-furyl)ethene to 2-benzyloxycarbonylamino-3-tert-butyldimethylsilyloxy-2-cyclobutylpropanal gave (4SR,5RS)-4-tert-butyldimethylsilyloxymethyl-4-cyclobutyl-5-[1-(2-furyl)ethenyl]-1,3-oxazolidinone after chelation controlled addition and in situ cyclisation. Following oxazolidinone N-benzylation, hydroboration at 35 °C, since hydroboration at 0 °C was unexpectedly selective for the undesired isomer, followed by oxidation gave a mixture of side-chain epimeric alcohols that were separated after SEM-protection and selective desilylation. Conversion of the neopentylic alcohols into the corresponding primary amines by reductive amination, was followed by N-nosylation, removal of the SEM-groups and cyclisation using a Mitsunobu reaction. Denosylation then gave the 2-furyloxazolidinonyl-fused piperidines, the (1RS,2SR,6SR)-epimer showing an allosteric agonistic effect on M1 receptors. Further studies resulted in the synthesis of other 2-substituted 4,7-diaza-9-oxabicyclo[4.3.0]nonan-8-ones and an analogous tetrahydropyran.

Rhodium(I)-Catalyzed Asymmetric Synthesis of Piperidines

Rhodium(I)-Catalyzed Asymmetric Synthesis of Piperidines