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Catalytic Amide Reductions under Hydrosilylation Conditions
Stockholm University, Faculty of Science, Department of Organic Chemistry. (Prof. Adolfsson)
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis covers the development of catalytic methodologies for the mild and chemoselective reductions of amides. The first part of the thesis describes the use of a Fe(II)/NHC catalyst for the deoxygenation of aromatic tertiary amides to corresponding amines. The protocol is characterized by low catalyst loading, mild reaction conditions and the use of air and moisture stable polymethylhydrosilaxane (PMHS) as the hydride source.

The second part concerns the development of a protocol for the room temperature deoxygenation of a wide range of tertiary amides to amines using catalytic amounts of Et2Zn and LiCl together with PMHS. The system displayed high levels of chemoselectivity tolerating various reducible groups such as nitro, nitrile, and olefin functionalities, and was shown to be applicable for the reduction of aromatic, heteroaromatic and aliphatic tertiary amides.

The attempts to expand the scope of the Fe-based protocol to accommodate benzylic tertiary amides led to the development of a transition metal-free catalytic system based on KOtBu for the formation of enamines. The final products constitute an important class of precursors for a wide range of valuable compounds in organic chemistry. Moreover, avoiding the use of transition metals in the protocol allowed the desired products to be obtained without the hazardous metal contaminants.

The last chapter of the thesis describes the Mo(CO)6-catalyzed hydrosilylation of amides. The Mo-based catalyst was proven to mediate the deoxygenation of α,β-unsaturated tertiary and secondary amides to the corresponding allylamines without reduction of the olefinic bonds. Further development of the catalytic system revealed an unprecedented chemoselectivity in the hydrosilylation of aromatic and certain aliphatic tertiary amides in the presence of a variety of reducible groups along with aldehydes and imines that were tolerated for the first time. Moreover, it was possible to control the reaction outcome by variation of the reaction temperature to obtain either amines or aldehydes as the major products. The synthetic utility of the developed Mo(CO)6-catalyzed protocols was further demonstrated in the synthesis of the pharmaceuticals Naftifine and Donepezil.

Place, publisher, year, edition, pages
Stockholm: Department of Organic Chemistry, Stockholm University , 2016. , 71 p.
Keyword [en]
Hydrosilylation, amides, reduction, chemoselectivity
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
URN: urn:nbn:se:su:diva-129028ISBN: 978-91-7649-406-6 (print)OAI: oai:DiVA.org:su-129028DiVA: diva2:919091
Public defence
2016-06-03, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 13:00 (English)
Opponent
Supervisors
Available from: 2016-05-11 Created: 2016-04-13 Last updated: 2017-02-24Bibliographically approved
List of papers
1. Direct Hydrosilylation of Tertiary Amides to Amines by an In Situ Formed Iron/N-Heterocyclic Carbene Catalyst
Open this publication in new window or tab >>Direct Hydrosilylation of Tertiary Amides to Amines by an In Situ Formed Iron/N-Heterocyclic Carbene Catalyst
2013 (English)In: European Journal of Organic Chemistry, ISSN 1434-193X, E-ISSN 1099-0690, no 11, 2066-2070 p.Article in journal (Refereed) Published
Abstract [en]

Tertiary amides were efficiently reduced to their corresponding tertiary amines in high isolated yields by using the commercially available and inexpensive polymeric silane polymethylhydrosiloxane (PMHS) as the reducing agent. The reaction is efficiently catalyzed by an in situ generated iron/N-heterocyclic carbene complex (1 mol-%) obtained from iron(II) acetate and 1-(2-hydroxy-2-phenylethyl)-3-methylimidazolium triflate ([PhHEMIM][OTF]). A catalytic amount of lithium chloride (1 mol-%) present in the reaction mixture significantly reduced the reaction time and increased the chemoselectivity of the reduction process.

Keyword
Hydrosilylation, Iron, Carbenes, Amides, Amines
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-89868 (URN)10.1002/ejoc.201300010 (DOI)000317132900005 ()
Funder
Swedish Research CouncilKnut and Alice Wallenberg Foundation
Note

AuthorCount:3;

Available from: 2013-05-14 Created: 2013-05-14 Last updated: 2017-12-06Bibliographically approved
2. Mild and Selective Et2Zn-Catalyzed Reduction of Tertiary Amides under Hydrosilylation Conditions
Open this publication in new window or tab >>Mild and Selective Et2Zn-Catalyzed Reduction of Tertiary Amides under Hydrosilylation Conditions
2015 (English)In: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 17, no 3, 446-449 p.Article in journal (Refereed) Published
Abstract [en]

Diethylzinc (Et2Zn) can be used as an efficient and chemoselective catalyst for the reduction of tertiary amides under mild reaction conditions employing cost-effective polymeric silane (PMHS) as the hydride source. Crucial for the catalytic activity was the addition of a substoichiometric amount of lithium chloride to the reaction mixture. A series of amides containing different additional functional groups were reduced to their corresponding amines, and the products were isolated in good-to-excellent yields.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2015
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-115688 (URN)10.1021/ol503430t (DOI)000349274200014 ()25587664 (PubMedID)
Funder
Swedish Research CouncilKnut and Alice Wallenberg Foundation
Note

AuthorCount:3;

Available from: 2015-03-31 Created: 2015-03-27 Last updated: 2017-12-04Bibliographically approved
3. Catalytic Reductive Dehydration of Tertiary Amides to Enamines under Hydrosilylation Conditions
Open this publication in new window or tab >>Catalytic Reductive Dehydration of Tertiary Amides to Enamines under Hydrosilylation Conditions
2014 (English)In: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 16, no 3, 680-683 p.Article in journal (Refereed) Published
Abstract [en]

Tertiary amides are efficiently reduced to their corresponding enamines under hydrosilylation conditions, using a transition-metal-free catalytic protocol based on t-BuOK (5 mol %) and (MeO)(3)SiH or (EtO)(3)SiH as the reducing agent. The enamines were formed with high selectivity in good-to-excellent yields.

National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-102074 (URN)10.1021/ol403302g (DOI)000331163900010 ()
Funder
Swedish Research CouncilKnut and Alice Wallenberg Foundation
Note

AuthorCount:3;

Available from: 2014-03-28 Created: 2014-03-26 Last updated: 2017-12-05Bibliographically approved
4. Mo(CO)6 catalysed chemoselective hydrosilylation of alpha,beta-unsaturated amides for the formation of allylamines
Open this publication in new window or tab >>Mo(CO)6 catalysed chemoselective hydrosilylation of alpha,beta-unsaturated amides for the formation of allylamines
Show others...
2014 (English)In: Chemical Communications, ISSN 1359-7345, E-ISSN 1364-548X, Vol. 50, no 93, 14508-14511 p.Article in journal (Refereed) Published
Abstract [en]

Molybdenum hexacarbonyl (Mo(CO)(6)) was used as an efficient catalyst for the chemoselective reduction of the amide functionality in alpha,beta-unsaturated compounds, under hydrosilylation conditions using 1,1,3,3-tetramethyldisiloxane (TMDS) as the hydride source.

National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-110773 (URN)10.1039/c4cc07150f (DOI)000344459400006 ()
Funder
Knut and Alice Wallenberg FoundationSwedish Research Council
Note

AuthorCount:5;

Available from: 2014-12-17 Created: 2014-12-17 Last updated: 2017-12-05Bibliographically approved
5. Chemoselective Reduction of Tertiary Amides under Thermal Control: Formation of either Aldehydes or Amines
Open this publication in new window or tab >>Chemoselective Reduction of Tertiary Amides under Thermal Control: Formation of either Aldehydes or Amines
2016 (English)In: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 55, no 14, 4562-4566 p.Article in journal (Refereed) Published
Abstract [en]

The chemoselective reduction of amides in the presence of other more reactive reducible functional groups is a highly challenging transformation, and successful examples thereof are most valuable in synthetic organic chemistry. Only a limited number of systems have demonstrated the chemoselective reduction of amides over ketones. Until now, the aldehyde functionality has not been shown to be compatible in any catalytic reduction protocol. Described herein is a [Mo(CO)6]-catalyzed protocol with an unprecedented chemoselectivity and allows for the reduction of amides in the presence of aldehydes and imines. Furthermore, the system proved to be tunable by variation of the temperature, which enabled for either C−O or C−N bond cleavage that ultimately led to the isolation of both amines and aldehydes, respectively, in high chemical yields.

Keyword
amides, chemoselectivity, molybdenum, reduction, silanes
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-128695 (URN)10.1002/anie.201600097 (DOI)000373133000027 ()
Funder
Knut and Alice Wallenberg FoundationSwedish Research Council
Available from: 2016-03-31 Created: 2016-03-31 Last updated: 2017-09-08Bibliographically approved

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