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Synthesis of C(sp2)-P bonds by palladium-catalyzed reactions: Mechanistic investigations and synthetic studies
Stockholm University, Faculty of Science, Department of Organic Chemistry.
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis focuses on synthetic and mechanistic aspects of palladium-catalyzed C(sp2)-P bond-forming reactions, with the aim to develop mild and efficient methods for the synthesis of biologically active phosphorus compounds, e.g. DNA analogs.

The first part of the thesis is devoted to detailed mechanistic investigations of the palladium-catalyzed C-P cross-coupling reaction, in order to fully understand the underlying chemistry and by rational design of the reaction conditions, improve the overall efficiency of the process and broaden its applicability. In particular influence of palladium coordination by different anions on the rate of ligand substitution and reductive elimination steps of the reaction was studied. It was found that coordination of acetate ion results in unprecedented acceleration of both of the mechanistic steps, what leads to remarkable shortening of the overall reaction times. In-depth kinetic investigations enabled to ascribe the observed effects to ability of the acetate ion to act as a bidentate ligand for palladium. This causes considerable alternation of the reaction mechanism, comparing to the reaction involving halide-containing complexes, and results in significant rate increase.

Based on the above mechanistic studies an efficient method for the synthesis of arylphosphonates, using substoichiometric amounts of inorganic acetate additive and reduced amount of catalyst, was developed.

In the next part of the thesis, efforts to further enhance the palladium-catalyzed cross-coupling efficiency by using a microwave-assisted synthesis are described. These explorations resulted in a successful development of two protocols, one for a cross-coupling of H-phosphonates and the other for H,H-phosphinates, under the microwave heating conditions. Application of this energy source resulted in extremely short reaction times, measured in minutes.

The final chapter of this thesis deals with studies on palladium-catalyzed SN2’ propargylic substitution reaction with phosphorus nucleophiles, which leads to allene products. Efficient procedure for the synthesis of allenylphosphonates and related compounds was developed. The method enables full control of stereochemistry in the allene moiety and at the asymmetric phosphorus center. Some conclusions on the mechanism of the reaction were also drawn.

Place, publisher, year, edition, pages
Stockholm: Department of Organic Chemistry, Stockholm University , 2011. , 95 p.
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
URN: urn:nbn:se:su:diva-56467ISBN: 978-91-7447-298-1OAI: oai:DiVA.org:su-56467DiVA: diva2:411448
Public defence
2011-06-09, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 10:00 (English)
Opponent
Supervisors
Note
At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 7: In press.Available from: 2011-05-12 Created: 2011-04-18 Last updated: 2011-05-13Bibliographically approved
List of papers
1. Pd(0)-Catalyzed phosphorus-carbon bond formation: Mechanistic and synthetic studies on the role of the palladium sources and anionic additives
Open this publication in new window or tab >>Pd(0)-Catalyzed phosphorus-carbon bond formation: Mechanistic and synthetic studies on the role of the palladium sources and anionic additives
2007 (English)In: Organometallics, ISSN 0276-7333, E-ISSN 1520-6041, Vol. 26, no 24, 5840-5847 p.Article in journal (Refereed) Published
Abstract [en]

Pd(PPh3)4, Pd(dba)2, Pd(OAc)2, and PdCl2, have been evaluated as possible Pd(0) sources for the palladium-catalyzed P−C bond formation via a cross-coupling of aryl halides with H-phosphonate diesters. It was found that the most efficient catalytic system can be generated from Pd(OAc)2 with a key role being played by Pd(II) and Pd(0) species with coordinated acetate ions. The reactivity of differently ligated Pd(II) complexes was determined, and 31P NMR spectroscopy studies were carried out to provide mechanistic interpretations for the observed differences between the catalytic systems.

National Category
Chemical Sciences
Identifiers
urn:nbn:se:su:diva-19617 (URN)10.1021/om700797k (DOI)000250975200015 ()
Available from: 2008-01-04 Created: 2008-01-04 Last updated: 2011-05-13Bibliographically approved
2. Palladium-catalyzed C-P bond formation: Mechanistic studies on the ligand substitution and the reductive elimination. An intramolecular catalysis by the acetate group in PdII complexes
Open this publication in new window or tab >>Palladium-catalyzed C-P bond formation: Mechanistic studies on the ligand substitution and the reductive elimination. An intramolecular catalysis by the acetate group in PdII complexes
2008 (English)In: Organometallics, ISSN 0276-7333, E-ISSN 1520-6041, Vol. 27, no 22, 5876-5888 p.Article in journal (Refereed) Published
Abstract [en]

Ligand substitution and reductive elimination of the palladium-catalyzed C−P bond forming cross-coupling were investigated in depth. It was found that for PhPdII(PPh3)2X (X = I, Br, Cl) complexes, a step commonly referred to as ligand substitution commenced with coordination of an H-phosphonate diester, followed by its deprotonation to form an equilibrium mixture of penta- and tetracoordinate palladiumphosphonate intermediates, from which reductive elimination of the product (diethyl phenylphosphonate) occurred. For the acetate counterpart, PhPdII(PPh3)2(OAc), the incorporation of a phosphonate moiety to the complex was preceded by a rate-determining removal of the supporting phosphine ligand, facilitated by an intramolecular catalysis by the acetate group. Both the reaction steps, i.e., formation of palladiumphosphonate intermediates and reductive elimination, were significantly faster for the acetate versus halides containing PdII complexes investigated. Similar observations were found to be true also for bidentate ligand complexes [(dppp)PdII(Ph)X]; however, in this instance, a single palladiumphosphonate intermediate, (dppp)PdII(Ph)(PO(OEt)2), could be observed by 31P NMR spectroscopy. The synthetic and kinetic studies on the cross-coupling reaction of diethyl H-phosphonate with phenyl halides permitted us to elucidate a crucial catalytic role of an acetate group in PdII complexes and to propose two distinctive catalytic cycles, which complemented traditional Pd0/PdII schemes, for the palladium-mediated C−P bond formation.

National Category
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-17638 (URN)10.1021/om800641n (DOI)000260791400017 ()
Available from: 2009-01-19 Created: 2009-01-19 Last updated: 2011-05-13Bibliographically approved
3. Preparation of arylphosphonates by palladium(0)-catalyzed cross-coupling in the presence of acetate additives: Synthetic and mechanistic studies
Open this publication in new window or tab >>Preparation of arylphosphonates by palladium(0)-catalyzed cross-coupling in the presence of acetate additives: Synthetic and mechanistic studies
2009 (English)In: Advanced Synthesis and Catalysis, ISSN 1615-4150, E-ISSN 1615-4169, Vol. 351, no 18, 3207-3216 p.Article in journal (Refereed) Published
Abstract [en]

An efficient protocol for the synthesis of arylphosphonate diesters via a palladium-catalyzed cross-coupling of H-phosphonate diesters with aryl electrophiles, promoted by acetate ions, was developed. A significant shortening of the cross-coupling time in the presence of the added acetate ions was achieved for bidentate and monodentate supporting ligands, and for different aryl electrophiles (iodo, bromo and triflate derivatives). The reaction conditions were optimized in terms of amount of the catalyst, supporting ligands, and source of the acetate ion used. Various arylphosphonates, including those of potential biological significance, were synthesized using this newly developed protocol. Some mechanistic aspects of the investigated reactions are also discussed.

National Category
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-34992 (URN)10.1002/adsc.200900590 (DOI)000273394500028 ()
Available from: 2010-01-13 Created: 2010-01-13 Last updated: 2011-05-13Bibliographically approved
4. Microwave-assisted palladium-catalyzed cross-coupling of aryl and vinyl halides with H-phosphonate diesters
Open this publication in new window or tab >>Microwave-assisted palladium-catalyzed cross-coupling of aryl and vinyl halides with H-phosphonate diesters
2008 (English)In: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 10, no 20, 4637-4640 p.Article in journal (Refereed) Published
Abstract [en]

A general and efficient method for the microwave-assisted formation of the C−P bond was developed. Using a prevalent palladium catalyst, Pd(PPh3)4, a quantitative cross-coupling of various H-phosphonate diesters with aryl and vinyl halides was achieved in less than 10 min. The reactions occurred with retention of configuration at the phosphorus center and in the vinyl moiety. Using this protocol, several C-phosphonates, including those bearing nucleoside and cholesteryl moieties, were prepared in high yields.

National Category
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-17630 (URN)10.1021/ol801935r (DOI)000259940600062 ()
Available from: 2009-01-19 Created: 2009-01-19 Last updated: 2011-05-13Bibliographically approved
5. Efficient synthesis of mono-and diarylphosphinic acids: a microwave-assisted palladium-catalyzed cross-coupling of aryl halides with phosphinate
Open this publication in new window or tab >>Efficient synthesis of mono-and diarylphosphinic acids: a microwave-assisted palladium-catalyzed cross-coupling of aryl halides with phosphinate
2009 (English)In: Tetrahedron, ISSN 0040-4020, E-ISSN 1464-5416, Vol. 65, no 50, 10406-10412 p.Article in journal (Refereed) Published
Abstract [en]

A general, efficient method for the microwave-assisted synthesis of mono- and diarylphosphinic acids from anilinium phosphinate and aryl halides, using Pd(0) and Xantphos as a supporting ligand, was developed.

National Category
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-31380 (URN)10.1016/j.tet.2009.10.028 (DOI)000272089500016 ()
Available from: 2009-11-11 Created: 2009-11-11 Last updated: 2011-05-13Bibliographically approved
6. Palladium-catalyzed propargylic substitution with phosphorus nucleophiles: efficient, stereoselective synthesis of allenylphosphonates and related compounds
Open this publication in new window or tab >>Palladium-catalyzed propargylic substitution with phosphorus nucleophiles: efficient, stereoselective synthesis of allenylphosphonates and related compounds
2010 (English)In: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 12, no 20, 4702-4704 p.Article in journal (Refereed) Published
Abstract [en]

A new, efficient method is developed, based on a palladium(0)-catalyzed reaction of propargylic derivatives with various phosphorus nucleophiles, to produce allenylphosphonates and their analogues with defined stereochemistry in the allenic and the phosphonate moiety. 

National Category
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-49241 (URN)10.1021/ol102121j (DOI)000282604700070 ()
Funder
Swedish Research Council
Available from: 2010-12-13 Created: 2010-12-13 Last updated: 2011-12-01Bibliographically approved
7. Novel, stereoselective and stereospecific synthesis of allenylphosphonates and related compounds via palladium-catalyzed propargylic substitution
Open this publication in new window or tab >>Novel, stereoselective and stereospecific synthesis of allenylphosphonates and related compounds via palladium-catalyzed propargylic substitution
2011 (English)In: Advanced Synthesis and Catalysis, ISSN 1615-4150, E-ISSN 1615-4169, Vol. 353, no 10, 1741-1755 p.Article in journal (Refereed) Published
Abstract [en]

We have developed a novel method for the synthesis of allenylphosphonates and related compounds based on a palladium(0)-catalyzed reaction of propargylic derivatives with H-phosphonate,H-phosphonothioate, H-phosphonoselenoate, and H-phosphinateesters. The reaction is stereoselective and stereospecific, and provides a convenient entry to a vast array of allenylphosphonates and their analogues with diverse substitution patterns in the allenic moiety and at the phosphorus center. Some mechanistic aspects of this new reaction were also investigated.

Keyword
allenes, allenylphosphinates, allenylphosphonates, H-phosphonate diesters, palladium, propargylic substitution, SN2’ reactions
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-56470 (URN)10.1002/adsc.201100119 (DOI)000292939600014 ()
Funder
Swedish Research Council
Note
authorCount :2Available from: 2011-04-18 Created: 2011-04-18 Last updated: 2011-12-28Bibliographically approved

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