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Iridium-Catalyzed Asymmetric Hydrogenation of Fluorinated Olefins Using N,P-Ligands: A struggle with hydrogenolysis and selectivity
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry. (PGA)
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry. (PGA)
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry. (PGA)
2007 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 129, no 15, 4536-4537 p.Article in journal (Refereed) Published
Abstract [en]

To broaden the substrate scope of asymmetric iridium-catalyzed hydrogenation, fluorine-functionalized olefins were synthesized and hydrogenated with iridium complexes. Preliminary results showed high levels of fluorine elimination together with low selectivity. The loss of vinylic fluorine at first seemed difficult to handle, but further studies revealed that a catalyst with an azanorbornyl scaffold in the ligand gave more promising results. With this in mind, a new ligand was developed. This gave among the best results published to date for fluorine asymmetric hydrogenation, yielding high conversion and very high ee's with very little fluorine elimination. Further increasing the selectivity, the trials also revealed that tetrasubstituted fluorine-containing olefins can be hydrogenated with high ee's, despite that this class of compounds has usually shown low reactivity in this reaction type.

Place, publisher, year, edition, pages
2007. Vol. 129, no 15, 4536-4537 p.
National Category
Chemical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-97352DOI: 10.1021/ja0686763ISI: 000245739700016PubMedID: 17375924OAI: oai:DiVA.org:uu-97352DiVA: diva2:172253
Available from: 2008-05-13 Created: 2008-05-13 Last updated: 2012-08-01Bibliographically approved
In thesis
1. Asymmetric Hydrogenations of Imines, Vinyl Fluorides, Enol Phosphinates and Other Alkenes Using N,P-Ligated Iridium Complexes
Open this publication in new window or tab >>Asymmetric Hydrogenations of Imines, Vinyl Fluorides, Enol Phosphinates and Other Alkenes Using N,P-Ligated Iridium Complexes
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The research described in this thesis is directed toward the efficient, enantioselective synthesis of chiral products that have useful functionality. This goal was pursued through catalytic asymmetric hydrogenation, a reaction class that selectively introduces one or two stereocenters into a molecule in an atom-efficient step. This reaction uses a small amount (often <1 mol%) of a chiral catalyst to impart stereoselectivity to the product formed. Though catalytic asymmetric hydrogenation is not a new reaction type, there remain many substrate classes for which it is ineffective. The present thesis describes efforts to extend the reaction to some of these substrates classes. Some of the products synthesized in these studies may eventually find use as building blocks for the production of chiral pharmaceuticals, agrochemicals, or flavouring or colouring agents. However, the primary and immediate aim of this thesis was to develop and demonstrate new catalysts that are rapid and effective in the asymmetric hydrogenation of a broad range of compounds.

Paper I describes the design and construction of two new, related chiral iridium compounds that are catalysts for asymmetric hydrogenation. They each contain an N,P-donating phosphinooxazoline ligand that is held together by a rigid bicyclic unit. One of these iridium compounds catalyzed the asymmetric hydrogenation of acyclic aryl imines, often with very good enantioselectivities. This is particularly notable because acyclic imines are difficult to reduce with useful enantioselectivity. The second catalyst was useful for the asymmetric hydrogenation of two aryl olefins. In Paper II, the class of catalysts introduced into Paper I is expanded to include many more related compounds, and these are also applied to the asymmetric hydrogenation of prochiral imines and olefins. By studying a range of related catalysts that differ in a single attribute, we were able to probe how different parts of the catalyst affect the yield and selectivity of the hydrogenation reactions.

Whereas iridium catalysts had been applied to the asymmetric hydrogenation of imines and largely unfunctionalized olefins prior to this work (with varied degrees of success), they had not been used to reduce fluoroolefins. Their hydrogenation, which is discussed in Paper III, was complicated by concomitant defluorination to yield non-halogenated alkanes. To combat this problem, several iridium-based hydrogenation catalysts were applied to the reaction. Two catalysts stood out for their ability to produce chiral fluoroalkanes in good enantioselectivity while minimizing the defluorination reaction, and one of these bore a phosphinooxazoline ligand of the type described in Papers I and II.

Enol phosphinates are another class of olefins that had not previously been subjected to iridium-catalyzed asymmetric hydrogenation. They do, however, constitute an attractive substrate class, because the product chiral alkyl phosphinates can be transformed into chiral alcohols or chiral phosphines with no erosion of enantiopurity. Iridium complexes of the phosphinooxazoline ligands described in Papers I and II were extremely effective catalysts for the asymmetric hydrogenation of enol phosphinates. They produced alkyl phosphinates from di- and trisubstituted enol phosphinate, β-ketoester-derived enol phosphinates, and even purely alkyl-substituted enol phopshinates, in very high yields and enantioselectivities.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2008. 64 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 447
Keyword
Organic chemistry, Catalysis, Asymmetric, Hydrogenations, Reductions, Alkenes, Imines, Vinyl fluorides, Enolphosphinates, Transition metal, Complexes, Iridium, Organisk kemi
National Category
Other Basic Medicine
Identifiers
urn:nbn:se:uu:diva-8971 (URN)978-91-554-7236-8 (ISBN)
Public defence
2008-06-03, B21, BMC, Husargatan 3, Uppsala, 10:15 (English)
Opponent
Supervisors
Available from: 2008-05-13 Created: 2008-05-13 Last updated: 2009-06-26Bibliographically approved
2. Chemo- and Enantioselective Hydrogenations: The Struggle of Expanding the Substrate Scope of Iridium Catalyzed Asymmetric Hydrogenations of Olefins
Open this publication in new window or tab >>Chemo- and Enantioselective Hydrogenations: The Struggle of Expanding the Substrate Scope of Iridium Catalyzed Asymmetric Hydrogenations of Olefins
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The asymmetric hydrogenation of olefins is a facile and popular method of reaching chiral products. Whereas ruthenium- and rhodium-catalyzed asymmetric hydrogenations have a long history, the use of iridium in this area is new but fast-growing. Since the first chiral N,P-ligated iridium catalyst was created in the late 1990s, the growing pool of N,P ligands has filled up rapidly, but most have been tested with a limited range of standard olefins. To extract the full potential of these complexes, new methods using substrates having many possible applications must be developed. This thesis focuses on the iridium-catalyzed asymmetric hydrogenation of three different new substrate classes to yield very high conversions and enantiomeric excesses (ee's). As the use of fluorine has recently become common in many different fields of chemistry, the asymmetric reduction of fluoroolefins to reach chiral products having fluorine at the stereogenic centers is highly interesting. We studied this reaction and eventually obtained very high ee values and lower degree of defluorination (Paper I and Paper II). The hydrogenations of trifluoromethylated olefins to reach products useful in applications reaching from pharmaceuticals to additives in liquid crystal displays (LCDs) were also challenging, but fruitful (Paper III). As asymmetric hydrogenation usually demands differences in the substituents of the double bond, the highly selective reduction of 1,1-diaryl olefins having similar aryls give a new perspective on the broad scope of substrates that N,P-ligated iridium complexes can reduce selectively (paper IV).

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2009. 70 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 624
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-99808 (URN)978-91-554-7471-3 (ISBN)
Public defence
2009-05-16, BMC, C2:301, Husargatan 3, Uppsala, 10:15 (English)
Opponent
Supervisors
Available from: 2009-04-24 Created: 2009-03-20 Last updated: 2010-03-04Bibliographically approved
3. Asymmetric Hydrogenations using N, P - Ligated Iridium Complexes
Open this publication in new window or tab >>Asymmetric Hydrogenations using N, P - Ligated Iridium Complexes
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The research described in this thesis focuses on the catalytic asymmetric hydrogenation of prochiral olefins using N, P – chelated iridium catalysts. This catalytic system is tolerant to a wide range of substrates and performs better than the well-known ruthenium- and rhodium-catalytic systems for substrates devoid of coordinating groups in proximity of the olefin. Low catalytic loadings (often <1 %) and the high atom efficiency of this reaction make it a synthetically useful method of chiral molecule synthesis. The primary aim of this thesis was to develop new catalysts that rapidly and efficiently hydrogenate a broad range of alkenes asymmetrically. Papers I and II describe the synthesis and evaluation of new, highly efficient, chiral N, P – ligated iridium complexes. These catalysts were obtained in relatively few steps, while leaving open possibilities to modify and fine-tune their structure. Their versatility is ideally suited to both industrial uses and to equip any catalyst box. Paper III deals with a common problem of defluorination of vinylic fluorides during the hydrogenation. The catalyst designed in that work performs well for several substrates giving very low defluorination rates making it a good starting point for further improvements to cover a broader scope of vinyl fluorides. The structures of the catalysts from papers I and III also offers an easy approach to attach the catalyst ligands to a solid support. Paper IV explores hydrogenation of vinyl boronates, which gives synthetically interesting borane compounds with high enantioselectivities. Taking into account the rich chemistry of organic boranes, these compounds are very important. Paper V deals with hydrogenation of diphenylvinylphosphine oxides and vinyl phosphonates, another important classes of substrates that give chiral phosphorous containing compounds of interest in many fields of chemistry: such as medicinal chemistry and organocatalysis. In papers VI and VII we explore the Birch reaction as a source of prochiral olefins. By combining asymmetric hydrogenation with it, we obtain a powerful method to create chiral compounds with excellent enantioselectivities that are next to impossible to make by other routes. The products of the asymmetric hydrogenation are further modified by other well-known transformation to create other induced stereogenic centres.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. 61 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 939
Keyword
asymmetric hydrogenation, iridium, birch, boronates, fluorine
National Category
Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-173459 (URN)978-91-554-8380-7 (ISBN)
Public defence
2012-06-08, B41, Husargatan 3, BMC, Uppsala, 10:15 (English)
Opponent
Supervisors
Available from: 2012-05-15 Created: 2012-04-24 Last updated: 2012-08-01Bibliographically approved

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