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Development and Applications of Molybdenum-Catalyzed Chemoselective Amide Reduction
Stockholm University, Faculty of Science, Department of Organic Chemistry.ORCID iD: 0000-0003-2013-8093
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis covers the development of catalytic methodologies for the mild and chemoselective hydrosilylation of amides. The first part describes the investigation of the Mo(CO)6-catalyzed reduction of carboxamides. It was found that the reduction could be controlled by tuning the reaction temperature and either amines or aldehydes could be obtained selectively. The system showed an unprecedented chemoselectivity and the amide reduction could take place in the presence of other reducible functional groups such as ketones, aldehydes, and imines. Moreover, the transformation could be performed on a preparative scale and was further employed in the synthesis of Donepezil, a pharmaceutical drug used in the treatment of Alzheimer´s disease.

The third chapter concerns the development of the Mo(CO)6-mediated hydrosilylation protocol for the reduction of carboxamides containing acidic α-hydrogens. In this case, enamines were formed and a high level of chemoselectivity was observed. Enamines containing sensitive functional groups such as ketones, aldehydes and imines were generated. The enamines were not isolated but used in subsequent catalytic reductive functionalization of amides, which is described in the last part of the thesis (Chapters 4 – 7). The in situ formed enamines were reacted with a wide variety of electrophiles, generating heterocyclic compounds as triazolines, triazoles, 4,5-dihydroisoxazoles and pyrimidinediones. N-sulfonylformamidines as well as thioacrylamides could also be prepared with this approach. The protocols for the synthesis of triazolines, triazoles and N-sulfonylformamidines could additionally be performed on a preparative scale, showing the practicality of the methodology.

Place, publisher, year, edition, pages
Stockholm: Department of Organic Chemistry, Stockholm University , 2017. , 92 p.
Keyword [en]
hydrosilylation, reduction, reductive functionalization, catalysis, amides, enamines, chemoselective
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
URN: urn:nbn:se:su:diva-145560ISBN: 978-91-7649-911-5 (print)ISBN: 978-91-7649-912-2 (electronic)OAI: oai:DiVA.org:su-145560DiVA: diva2:1139676
Public defence
2017-11-17, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 10:00 (English)
Opponent
Supervisors
Available from: 2017-10-25 Created: 2017-09-08 Last updated: 2017-10-04Bibliographically approved
List of papers
1. 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
2. Transformation of Amides into Highly Functionalized Triazolines
Open this publication in new window or tab >>Transformation of Amides into Highly Functionalized Triazolines
Show others...
2017 (English)In: ACS Catalysis, ISSN 2155-5435, E-ISSN 2155-5435, Vol. 7, no 3, 1771-1775 p.Article in journal (Refereed) Published
Abstract [en]

Triazoles and triazolines are important classes of heterocyclic compounds known to exhibit biological activity. Significant focus has been given to the development of synthetic approaches for the preparation of triazoles, and they are today easily obtainable through a large variety of protocols. The number of synthetic procedures for the formation of triazolines, on the other hand, is limited and further research in this field is required. The protocol presented here gives access to a broad scope of 1,4,5-substituted 1,2,3-triazolines through a one-pot transformation of carboxamides. The two-step procedure involves a Mo(CO)6-catalyzed reduction of tertiary amides to afford the corresponding enamines, followed by in situ cycloaddition of organic azides to form triazolines. The amide reduction is chemoselective and allows for a wide variety of functional groups such as esters, ketones, aldehydes, and imines to be tolerated. Furthermore, a modification of this one-pot procedure gives access to the corresponding triazoles. The chemically stable amide functionality is demonstrated to be an efficient synthetic handle for the formation of highly substituted triazolines or triazoles.

Keyword
triazolines, amides, enamines, chemoselective reduction, azides
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-142486 (URN)10.1021/acscatal.7b00095 (DOI)000395726500033 ()
Available from: 2017-05-16 Created: 2017-05-16 Last updated: 2017-09-27Bibliographically approved
3. Mild Reductive Functionalization of Amides into N-Sulfonylformamidines
Open this publication in new window or tab >>Mild Reductive Functionalization of Amides into N-Sulfonylformamidines
2017 (English)In: ChemistryOpen, ISSN 2191-1363, Vol. 6, 484-487 p.Article in journal (Refereed) Published
Abstract [en]

The development of a protocol for the reductive functionalization of amides into N-sulfonylformamidines is reported. The one-pot procedure is based on a mild catalytic reduction of tertiary amides into the corresponding enamines by the use of Mo(CO)6 (molybdenum hexacarbonyl) and TMDS (1,1,3,3-tetramethyldisiloxane). The formed enamines were allowed to react with sulfonyl azides to give the target compounds in moderate to good yields.

National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-145556 (URN)10.1002/open.201700087 (DOI)000407167100006 ()
Available from: 2017-08-09 Created: 2017-08-09 Last updated: 2017-09-18Bibliographically approved
4. An Efficient One-pot Procedure for the Direct Preparation of 4,5-Dihydroisoxazoles from Amides
Open this publication in new window or tab >>An Efficient One-pot Procedure for the Direct Preparation of 4,5-Dihydroisoxazoles from Amides
2017 (English)In: Advanced Synthesis and Catalysis, ISSN 1615-4150, E-ISSN 1615-4169, Vol. 359, no 11, 1990-1995 p.Article in journal (Refereed) Published
Abstract [en]

A Mo(CO)(6) (molybdenumhexacarbonyl) catalyzed reductive functionalization of amides to afford 5-amino substituted 4,5-dihydroisoxazoles is presented. The reduction of amides generates reactive enamines, which upon the addition of hydroximinoyl chlorides and base undergoes a 1,3-dipolar cycloaddition reaction that gives access to the desired heterocyclic compounds. The transformation of amides is highly chemoselective and tolerates functional groups such as nitro, nitriles, esters, and ketones. Furthermore, a versatile scope of 4,5-dihydroisoxazoles derived from a variety of hydroximinoyl chlorides and amides is demonstrated.

Keyword
4, 5-dihydroisoxazole, Amides, Reductive functionalization, Chemoselectivity, Enamines
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-144789 (URN)10.1002/adsc.201700154 (DOI)000402839300027 ()
Available from: 2017-07-14 Created: 2017-07-14 Last updated: 2017-09-27Bibliographically approved
5. Facile preparation of pyrimidinediones and thioacrylamides via reductive functionalization of amides
Open this publication in new window or tab >>Facile preparation of pyrimidinediones and thioacrylamides via reductive functionalization of amides
2017 (English)In: Chemical Communications, ISSN 1359-7345, E-ISSN 1364-548X, Vol. 53, no 65, 9159-9162 p.Article in journal (Refereed) Published
Abstract [en]

The development of an efficient protocol for the reductive functionalization of amides into pyrimidinediones and amino-substituted thioacrylamides is presented. Enamines are generated in a highly chemoselective amide hydrosilylation reaction catalyzed by molybdenum hexacarbonyl in combination with 1,1,3,3-tetramethyldisiloxane. The direct addition of either isocyanate or isothiocyanate generates the corresponding pyrimidinediones and 3-aminothioacrylamides in high yields.

National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-145558 (URN)10.1039/c7cc04170e (DOI)000407333400029 ()
Available from: 2017-08-10 Created: 2017-08-10 Last updated: 2017-09-18Bibliographically approved

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