one day symposium on catalytic c-h functionalization · marcos university of leicester...
TRANSCRIPT
One Day Symposium on Catalytic C-H
Functionalization
Friday 23rd
January 2015
University of Leicester
Sponsors
Programme 10:30 - 11:00 Coffee and registration Chemistry Foyer
11:00 - 11:10 Welcome message (Prof. Dai Davies) Lecture Theatre A
11:10 - 11:55 Prof. Igor Larrosa, University of Manchester
Pd, Ag, and Au in C-H activation: reactivity and
selectivity control
11:55 - 12:15 Alan Reay, University of York
Development of mild and selective Pd-mediated
C2-arylations of tryptophans and tryptophan-
containing peptides
12:15 - 12:35 Michelle Montgomery, University of Bristol
Direct Arylation of Pyrazolo[1,5-a]pyrimidines with
Complete and Switchable Regiocontrol
12:35 - 13:55 Lunch and poster browsing MML Room
13:55 - 14:40 Prof. Hon W. Lam, University of Nottingham
Carbon-Carbon Bond Formation by Catalytic 1,4-
Metal Migration
Lecture Theatre A
14:40 - 15:25 Prof. Stuart Macgregor, Heriot-Watt University
Rh-Catalysed Heterocycle Formation: Competing
C-N and C-C Bond Forming Processes
15:25 - 15:50 Coffee break Chemistry Foyer
15:50 - 16:50 Prof. Lutz Ackermann, Georg-August-University
Göttingen
Ruthenium-Catalyzed C-H Functionalization and
Beyond
16:50 - 17:00 Closing remarks and poster prizes
(Prof. Dai Davies)
17:00 - 18:00 Wine reception MML Room
Participants
Prof. Lutz Ackermann Georg-August-University
Goettingen [email protected]
Dr Boris Aillard University of Leicester [email protected]
Mona Alhalafi University of Leicester [email protected]
Raed Alharis University of Leicester [email protected]
Afaq Al-Najm University of Leciester [email protected]
Rhiann Andrew University of Warwick [email protected]
James Ayres Nottingham Trent University [email protected]
Dr Laure Benhamou University College London [email protected]
Joshua Bray University of York [email protected]
Lucy Brown University of York [email protected]
Dr Alan Burns Sygnature Discovery
Dr David Burns University of Nottingham [email protected]
Michael Callingham University of Nottingham [email protected]
Kevin Carr Heriot-Watt University [email protected]
Lal Cheema RSC Member [email protected]
Dr Suresh Reddy
Chidipudi University of Nottingham [email protected]
Chris Clarke University of Nottingham [email protected]
Dr Alex Cresswell University of Edinburgh [email protected]
Giacomo Crisenza University of Bristol [email protected]
Dr Warren Cross Nottingham Trent University [email protected]
Prof. Dai Davies University of Leicester [email protected]
Dr Zhenting Du University of Cambridge [email protected]
Dr Charles Ellul University of Leicester [email protected]
Kieren Evans University of York [email protected]
Prof. Ian Fairlamb University of York [email protected]
Marta Fernandez-
Gimenez University of Liverpool [email protected]
Gregory Forrest University of Leicester [email protected]
Lewis Hall University of York [email protected]
Anders Hammarback University of York [email protected]
Jordan Holmes University of Leeds [email protected]
Prof. Eric Hope University of Leicester [email protected]
Dr Greg Iacobini Sygnature Discovery
Dr Celia Incerti-Pradillos University of Nottingham [email protected]
Amina Isbilir University of Leicester [email protected]
Mary Paymwa Kagoro University of York [email protected]
Imtiaz Khan University of Nottingham [email protected]
Raysa Khan University of Sussex [email protected]
Dr Paul Koovits University of Bristol [email protected]
Stamatis Korkis University of Nottingham [email protected]
Prof. Hon Wai Lam University of Nottingham [email protected]
Prof. Igor Larrosa University of Manchester [email protected]
Lyndsay Ledingham University of York [email protected]
Jamie Leitch University of Bath [email protected]
Dr Gabriel Lenagh-Snow Nottingham University gabriel.lenagh-
Dr Po Man Liu Sygnature Discovery
Dr Yunfei Luo University of Nottingham [email protected]
Dr Jason Lynam University of York [email protected]
Prof. Stuart Macgregor Heriot-Watt University [email protected]
Dr Claire McMullin Heriot-Watt University [email protected]
Jessica Milani University of York [email protected]
Lucy Milner University of York [email protected]
Michelle Montgomery University of Bristol [email protected]
Mahrukh Mukhtar Nottingham Trent University [email protected]
Marie-Therese Nolan University College Cork [email protected]
Daniel Oliver Nottingham Trent University [email protected]
Dr Nicholas Palmer Astex Pharmaceuticals [email protected]
Dr Leticia Pardo University College Cork [email protected]
Dr Ben Partridge University of Nottingham [email protected]
Ruth Patchett University of Warwick [email protected]
Andrew Paterson University of Bath [email protected]
Raissa Patia University of Leicester [email protected]
María Pin-Nó University of Liverpool [email protected]
George Platt University of York [email protected]
Aisling Prendergast University College Cork [email protected]
Abdul Quddus Sygnature Discovery
Nicholas Race University of Bristol [email protected]
Alan Reay University of York [email protected]
Tom Ronson University of York [email protected]
Paul Shaw University of Warwick [email protected]
Rena Simayi University of Leicester [email protected]
Frances Singer University of York [email protected]
Amandeep Singh University of Leicester [email protected]
Dr John Slattery University of York [email protected]
Joshua Smith University of Nottingham [email protected]
Dr Martin Smith Loughborough University [email protected]
Dr Gregory Solan University of Leicester [email protected]
Dr Brett Stevenson Sygnature Discovery
Dr Tom Storr University of Nottingham [email protected]
Kyle Toyne Nottingham Trent University [email protected]
Khai-Nghi Truong University of York [email protected]
Asuman Unal University of Leicester [email protected]
Martyna Urbonaite University of Leicester [email protected]
Dr Barbara Villa Marcos University of Leicester [email protected]
Martin Voelkel University of York [email protected]
Joe Walker University of Leicester [email protected]
Bowen Wang University of York [email protected]
Andrew Warner University of Manchester [email protected]
Michael Watt University of Bristol [email protected]
Dr Charlotte Willans University of Leeds [email protected]
Dr Tom Williams University of Manchester [email protected]
Ben Wilsher University of Leicester [email protected]
Luka Wright University of Leicester [email protected]
Poster Presentations
Title Presenter Institution
Study of Electronic Effect on the C-H Activation
of Substituted 1-Phenylpyrazole with Ru, Ir and
Rh
Raed Alharis University of Leicester
C(sp3)–H Activation without a Directing Group:
Regioselective Synthesis of N-Ylide or N-
Heterocyclic Carbene Complexes Controlled by
the Choice of Metal and Ligand
James Ayres Nottingham Trent
University
On the mechanism of C-X bond formation with
Palladium complexes: interactions of Pd(II)
dimeric complexes with halide additives, an
NMR and electrochemical study.
Dr Laure Benhamou University College
London
A Rh(III) sp2 to sp
3 1,4-Migration Enabling One-
Carbon C-H Oxidative Annulations Dr David Burns
University of
Nottingham
5- vs. 6-Membered Ring Formation in the Rh-
Catalysed Coupling of Imines with Alkynes Kevin Carr Heriot-Watt University
Branch Selective Ir-Catalyzed Hydroarylation of
Monosubstituted Alkenes via a Cooperative
Destabilization Strategy
Giacomo Crisenza University of Bristol
Understand Product Selectivity in Rhodium-
Catalysed Oxidative Coupling Dr Charles Ellul University of Leicester
Electrophilic Fluorination of Organometallic
Fragments Lewis Hall University of York
Palladium-catalysed intramolecular direct
arylation reactions affording phenanthridinones:
a mechanistic examination
Lyndsay Ledingham University of York
Mechanistic Investigations of C-H
Functionalisation of Pyrazoles with Alkynes Dr Claire McMullin Heriot-Watt University
Investigating the Mechanism of Ru(II)-Catalysed
Direct Arylation with DFT
Dr Claire McMullin /
Kevin Carr Heriot-Watt University
C–H functionalization of fluoroaromatics at Pd Jessica Milani University of York
Outer Sphere Electrophilic Fluorination (OSEF)
of Organometallic Fragments Lucy Milner University of York
Synthesis of Biologically Important 2-Pyrones, 2-
Coumarins, 2-Pyridinones and 2-Quinolones
Marie-Therese
Nolan
University College
Cork
The Direct Arylation of 2-pyrones, 2-pyridones
and 2-coumarins
Dr Leticia Pardo /
Aisling Prendergast
University College
Cork
Iridium-Catalysed Arylative Cyclisation of
Alkynones via 1,4-Iridium Migration Dr Ben Partridge
University of
Nottingham
Mechanism of Direct Arylation Reactions of
Fluoroaromatics George Platt University of York
Copper-catalysed Heck-like cyclisations of
oxime esters Nicholas Race University of Bristol
Development of mild and selective Pd-mediated
C2-arylations of tryptophans and tryptophan-
containing peptides
Alan Reay University of York
Reactivity of 5 Coordinate Pt(IV) Complexes Paul Shaw University of Warwick
Cross-Dehydrogenative-Coupling (CDC) of
1,3,5-Trialkoxybenzenes with Simple Aromatic
Hydrocarbons
Dr Tom Storr University of
Nottingham
Controlling Selectivity of C(sp2)-H Activation: An
Experimental and Computational Study
Dr Barbara Villa
Marcos University of Leicester
Electrophilic Cyclisation Using Boron Lewis
Acids Andrew Warner
University of
Manchester
Palladium-Catalysed C-H Activation Cascades
in the Synthesis of Polycyclic Heterocycles Michael Watt University of Bristol
1
Study of the Electronic Effect on the C-H Activation of Substituted 1-Phenylpyrazole with Ru, Ir and Rh
Raed Alharis,a* Jonathan Shiers,a David Richardson,b Stuart A. Macgregor,b
David L. Daviesa
aDepartment of Chemistry, University of Leicester, Leicester, LE1 7RH, UK
bInstitute of Chemical Sciences, Heriot-Watt University, Edinburgh, EH14 4AS, UK
In traditional Pd-catalysed cross-coupling reactions at least one of the starting materials contains a C-X (X= Cl, Br, I) bond leading to stoichiometric salts as waste.1 C-H functionalisation is an atom-economical alternative process for the synthesis of new C-Y (Y = C, O, N) bonds directly by C-H activation, without the need for pre-functionalisation.2 Recently, Ambiphilic Metal Ligand Activation (AMLA) / Concerted Metallation Deprotonation (CMD) has been put forward as a mechanism for C-H activation. This involves a two component agostic C-H interaction between a Lewis acidic metal and hydrogen bonding to a Lewis basic ligand (acetate). It has been shown to provide a low-energy pathway to C-H activation.3 This mechanism has been utilised to great success in various catalytic C-H functionalisation reactions such as amidations, aminations and acylations.4-6 Having a good understanding of the C-H activation process will enable the development of more efficient catalysts. This poster will highlight the electronic effects on C-H activation. A range of cyclometallated half-sandwich complexes have been synthesised by reaction of [RuCl2(p-cymene)]2, [RhCl2Cp*]2 or [IrCl2Cp*]2 with different para and meta substituted phenylprazole ligands (Me, OMe, NO2, and CF3) by acetate-assisted C-H activation (Scheme 1).
Scheme 1; Synthesis of half-sandwich complexes
1. a) T. Satoh and M. Miura, Chem. Lett., 2007, 36, 200; b) D. R. Stuart and K. Fagnou, Science, 2007, 316, 1172.
2. a) M. Lersch and M. Tilset, Chem. Rev. 2005, 105, 2471; b) D. Alberico, M. E. Scott and M. Lautens, Chem. Rev., 2007, 107, 174.
3. Y. Boutadla, D. L. Davies, S. A. Macgregor and A. I. Poblador-Bahamonde, Dalton Trans., 2009, 5820.
4. V. S. Thirunavukkarasu, K. Raghuvanshi and L. Ackermann, Org. Lett., 2013, 15, 3286. 5. C. Grohmann, H. Wang and F. Glorius, Org. Lett., 2012, 14, 656. 6. J. Weng, Z. Yu, X. Liu and G. Zhang, Tetrahedron Lett., 2013, 54, 1205.
2
C(sp3)-H activation without a directing group: regioselective synthesis of N-ylide or N-heterocyclic carbene complexes
controlled by the choice of metal and ligand
James Ayres,a Sunnah Razak,b Kuldip Singh,b Andrew J. Warner,b Warren Cross,*a
aSchool of Science and Technology, Nottingham Trent University, Nottingham,
NG11 8NS, UK bDepartment of Chemistry, University of Leicester, Leicester, LE1 7RH, UK
Over the past decade a number of highly-efficient synthetic strategies have been developed that involve the activation of C-H bonds by a transition metal catalyst. The overwhelming majority of reactions of this type involve the activation of C(sp2)–H bonds and, in contrast, C(sp3)–H activation has received much less attention.1 Performing C(sp3)-H activation in the presence of usually more reactive C(sp2)–H bonds has been achieved by using an appropriate directing group. However, the use of a chelating directing group introduces an intrinsic limitation to the reaction and strategies are required that avoid a directing group to functionalize alternative C–H bonds. Examples of C(sp3)-H activation without a directing group are relatively uncommon and most undirected C(sp3)-H activations occur at either allylic or benzylic C–H bonds.2,3 These undirected reactions rely on the innate reactivity of the C–H bond with the metal complex, yet there is almost no information on the factors that influence this reactivity. In this poster, we report the undirected C(sp3)-H activation of α-pyridinium and α-imidazolium carbonyl compounds by [Cp*IrCl2]2 and NaOAc, for example Figure 1.4 For the C-H activation of α-imidazolium esters, we demonstrate that the regioselectivity can be controlled by the choice of the metal and ligand and report the results of DFT calculations that rationalise this selectivity.
Figure 1; regioselective C–H activation of an α-imidazolium ester.
1. O. Baudoin, Chem. Soc. Rev. 2011, 40, 4902. 2. For example: a) C. Engelin, T. Jensen, S. Rodriguez-Rodriguez, P. Fristrup, ACS Catal. 2013,
3, 294; b) S. Rakshit, F. W. Patureau, F. Glorius, J. Am. Chem. Soc. 2010, 132, 9585. 3. For example: a) B. Qian, S. Guo, J. Shao, Q. Zhu, L. Yang, C. Xia, H. Huang, J. Am. Chem.
Soc. 2010, 132, 3650; c) L.-C. Campeau, D. Schipper, K. Fagnou, J. Am. Chem. Soc. 2008, 130, 3266.
4. W. B. Cross, S. Razak, K. Singh, A. J. Warner, Chem. Eur. J. 2014, 20, 13203.
3
On the mechanism of C-X bond formation with Palladium complexes: interactions of Pd(II) dimeric complexes with
halide additives, an NMR and electrochemical study.
L. Benhamou, M. Haque, E.Gascoigne, A. Aliev, K. Holt and T. D. Sheppard
Department of Chemistry, University College London, London, WC1H 0AJ
Recently, substantial improvements have been made in palladium catalysed C-H functionalization reactions to form new C-X bonds.1 To have a better insight into the mechanism of these reactions and for future improvement of these transformations, many theoretical and experimental studies (stoichiometric and catalytic) have already been reported. Gray et al. have recently reported the first evidence of a binuclear palladacycle oxidised via electrocatalysis in the presence of chloride.2 Following these results we were interested in the interaction of halide additives and dimeric PdII complexes and their effect on the oxidation potential of the Pd centres. Our study was focused on the NMR and electrochemical behaviour of two different dinuclear Pd(II) palladacycles in the presence of halides. The experiments showed that halide additives have a significant effect on the initial complex resulting in the formation of several new anionic species with considerably lower oxidation potential than the parent complexes. This poster describes the possible structures of the compounds formed in solution and their electrochemical properties. These observations provide an insight into the possible role of anions in Pd-catalysed CH activation reactions, and could lead to more efficient catalytic systems and the use of milder oxidants.
Effect of halide additive on dimeric benzo[h]quinoline palladacycle
1. T. W. Lyons, M. Sanford, Chem. Rev. 2010, 110, 1147. 2. A. C. Durell, M. N. Jackson, N. Hazari, H. B. Gray, Eur. J. Inorg. Chem. 2013, 1134.
4
A Rh(III) sp2 to sp3 1,4-Migration Enabling One-Carbon C−H Oxidative Annulations
Dr David J. Burns, Prof. Hon Wai Lam
School of Chemistry, University of Nottingham, Nottingham, NG7 2RD
Conventionally, alkynes and 1,3-enynes undergo two-carbon annulations. However, during our studies towards oxidative-annulations of 1,3-enynes we found that 1,3-enynes containing cis-allylic hydrogens underwent a one-carbon oxidative annulation reaction (Figure 1).1 Mechanistic experiments, including deuterium labelling studies, indicated that the reaction most likely involved a direct migration of a vinyl rhodium species to the cis-allylic position. This is thought to occur via a non-concerted sp3 activation mechanism to form a rhodacycle, which on protonation would give access to an electrophilic, allyl rhodium species capable of a one carbon annulation reaction (Figure 2).
Figure 1; one-carbon oxidative additions.
Figure 2; proposed mechanism of 1,4-migration.
1. Burns, D. J.; Lam, H. W. Angew. Chem., Int. Ed. 2014, 53, 9931−9935.
5
5- vs. 6-Membered Ring Formation in the Rh-Catalysed Coupling of Imines with Alkynes
Kevin J. T. Carr,a Barbara Villa-Marcos,b Stuart A. Macgregor,a and David L.
Daviesb
a Institute of Chemical Sciences, Heriot-Watt University, Edinburgh, EH14 4AS, UK
b Department of Chemistry, University of Leicester, Leicester, LE1 7RH, UK
1-phenyl-N-R-methanimines (R = iPr, p-tolyl) can undergo Rh-catalysed C-H Activation to give cyclometalated intermediates (e.g. I → IV, Figure 1) which react on with alkynes to yield heterocycles in the presence of acetic acid. With R = iPr migratory insertion (IV → VI) followed by C-N bond coupling yields a pyridinium cation, B, featuring a 6-membered ring. However, when R = p-tolyl a 5-membered indenamine product A was obtained through C-C bond formation. This result is similar to a previous observations by Miura,2 who obtained a related 5-membered indenimine product, C under similar reaction conditions, but using Cu(OAc)2 as reoxidant in place of acetic acid.
Figure 1. Possible organic products and experimental conditions for Rh-catalysed heterocycle
formation.
The mechanism of the formation of these different heterocycles was investigated by DFT calculations in conjunction with experimental studies. The most accessible reaction pathway proceeded with C-C bond formation via imine insertion into the Rh-C bond to form 5-membered heterocycles. In acetic acid protonation then leads to the indenamine A, whereas with Cu(OAc)2 a second acetate-assisted C-H activation gives indenimine C. C-N bond formation to yield B is disfavoured for R = p-Tol.
1. Carr, K. J. T.; Davies, D. L.; Macgregor, S. A.; Singh, K.; Villa-Marcos, B., Chem. Sci. 2014, 5,
2340-2346 2. Fukutani, T.; Umeda, N.; Hirano, K.; Satoh, T.; Miura, M., Chem. Commun. 2009, 5131-5143
6
Branch Selective Ir-Catalyzed Hydroarylation of Monosubstituted Alkenes via a Cooperative Destabilization
Strategy
Giacomo E. M. Crisenza, Dr. John F. Bower
School of Chemistry, University of Bristol, Cantock’s Close, Bristol, BS8 1TS, UK
In the last decades, C-H functionalization has emerged as a straightforward and powerful tool for the development of atom economical methodologies. In particular, Murai and co-workers demonstrated that Ru-catalyzed alkene hydroarylation can be achieved by carbonyl directed aryl C-H activation, providing access to linear hydroarylation products.1 Following this discovery, a wide range of transition metal catalyzed directed π-bond insertion procedures have been reported.2 For cases involving mono-substituted alkenes linear selectivity dominates and branched products are not usually accessible. Brach selectivity would provide direct and potentially enantioselective access to products that are difficult to obtain using conventional cross-coupling chemistry.3 However, to date, a protocol enabling carbonyl-directed branch selective hydroarylation remains elusive. We have developed a highly branch selective carbonyl directed hydroarylations of monosubstituted alkenes. The chemistry relies upon a cationic iridium(I)-catalyst modified with a wide bite angle and electron deficient bisphosphine ligand.4 This methodology provides for the first time a regioisomeric alternative to the Murai hydroarylation protocol.
Figure 1; Ir-catalyzed branch-selective hydroarylation.
1. S. Murai, F. Kakiuchi, S. Sekine, Y. Tanaka, A. Kamatani, M. Sonoda, N. Chatani, Nature 1993, 366, 529.
2. Selected recent reviews: (a) D. A. Colby, A. S. Tsai, R. G. Bergman, J. A. Ellman, Acc. Chem. Res. 2012, 45, 814; (b) P. B. Arockiam, C. Bruneau, P. H. Dixneuf, Chem. Rev. 2012, 112, 5879; (c) Q.-Z. Zheng, N. Jiao, Tetrahedron Lett. 2014, 55, 1121.
3. Selected recent examples: (a) S. D. Dreher, P. G. Dormer, D. L. Sandrock, G. A. Molander, J. Am. Chem. Soc. 2008, 130, 9257; (b) D. Imao, B. W. Glasspoole, V. S. Laberge, C. M. Crudden, J. Am. Chem. Soc. 2009, 131, 5024; (c) S. M. Podhajsky, Y. Iwai, A. Cook-Sneathen, M. S. Sigman, Tetrahedron 2011, 67, 4435; (d) H. M. Wisniewska, E. C. Swift, E. R. Jarvo, J. Am. Chem. Soc. 2013, 135, 9083.
4. G. E. M. Crisenza, N. G. McCreanor, J. F. Bower, J. Am. Chem. Soc. 2014, 136, 10258.
7
Understanding Product Selectivity in Rhodium-Catalysed Oxidative Coupling
Charles Ellul,a Claire McMullin,b Stuart Macgregor,b David Daviesa
aDepartment of Chemistry, University of Leicester, Leicester, LE1 7RH, UK
bInstitute of Chemical Sciences, Heriot-Watt University, Edinburgh, EH14 4AS, UK
Directed C-H functionalization catalysed by [Cp*RhCl2]2 and related
derivatives has recently attracted a large amount of interest as a convenient, atom economical route to new C-Y bonds (Y = C, N, O).1 For example, 1-phenylpyrazole has been shown to be a versatile substrate for oxidative coupling with internal alkynes forming carbocycles (1, 2) or heterocycles (3) via C,C coupling (Scheme 1).2
Scheme 1; Product scope of 1-phenylpyrazole in oxidative coupling with internal alkynes.
Additionally, we will demonstrate that C,N coupling is also facile (4, 5). Furthermore, we will highlight that combined experimental and computational studies can led to the elucidation of the mechanism thus enabling the identification of key steps within the catalytic cycle which control product selectivity. Our results suggest that product selectivity is dependent on anion coordination and reductive elimination, enabling rational control over product selectivity by altering the nature of the alkyne and reaction conditions.
1 a) G. Song, F. Wang, X. Li, Chem. Soc. Rev. 2012, 41, 3651; b) T. Satoh, M. Miura, Chem. Eur. J. 2010, 16, 11212. 2 N. Umeda, K. Hirano, T. Satoh, N. Shibata, H. Sato, M. Miura, J. Org. Chem. 2010, 76, 13.
8
Electrophilic Fluorination of Organometallic Fragments
Lewis M. Hall, Jason M. Lynam, John M. Slattery
Department of Chemistry, University of York, Heslington, York, YO10 5DD
The importance of fluorine has become ever more apparent despite its near absence
in biological systems. Incorporation of fluorine has become a powerful tool in the
pharmaceutical and agrochemical sectors, with the non-natural isotope, fluorine-18,
making an excellent radionuclide for positron emission tomography (PET).
Nevertheless regio- and stereo-selective incorporation of fluorine into organic
compounds still remains challenging, with a clear deficiency in research focusing on
the formation of Csp-F, non-aromatic Csp2-F, and Csp3-F bonds.1
The Lynam-Slattery group has demonstrated that through [1] (Scheme 1a), the
fluorinated vinylidene complex, [2]+, can be synthesised rapidly under mild conditions
via the first known example of Outer Sphere Electrophilic Fluorination (OSEF). To the
best of our knowledge most metal-mediated fluorination reactions proceed through
the formation of a metal-fluoride complex, with reductive elimination from the metal
centre forming the C-F bond, or via radicals.1 In the work presented here, fluorination
appears to proceed by direct attack of the ligand by the fluorenium ion source.
When the method was applied to the unsubstituted acetylide, [3], fluorination
significantly altered the reactivity of [4]+, such that it was not possible to isolate the
desired vinylidene complex. Instead [4]+, once formed, rapidly reacted with an
equivalent of [3] to form [5]+ (Scheme 1b). Changing the capping ligand from
cyclopentadienyl to 1,2,3,4,5-pentamethylcylopentadienyl prevented dimerization and
allowed for the isolation of the fluorinated vinylidene, [7]+. The addition of fluoride
resulted in phosphine activation forming a mixture of E- and Z- [8]+ (Scheme 1c).
Scheme 1; a) Fluorination of [1] to [2]
+; b) Fluorination of [3] to [5]
+; c) Fluorination of [6] to [7]
+, followed
by phosphine activation to E-[8]+ and Z-[8]
+ through addition of fluoride.
1. M. G. Campbell and T. Ritter, Chem. Rev. 2014, Article ASAP. DOI: 10.1021/cr500366b
9
Palladium-catalysed intramolecular direct arylation reactions affording phenanthridinones: a mechanistic examination
Lyndsay A. Ledingham, Rebecca Campbell, Alexander Pagett, Ian J. S.
Fairlamb
Department of Chemistry, University of York, Heslington, YO10 5DD
Phenanthridinones are important compounds in the pharmaceutical industry as they have immunosuppressant properties and can be used in cancer treatment.1 6-(5H)-Phenanthridinone (1, Figure 1) is a poly ADP ribose polymerase inhibitor, which can affect the cytotoxic processes of cells. This compound has been synthesised by several Pd-catalysed processes, including traditional Suzuki cross-couplings2 and, more interestingly from a sustainable chemistry perspective, direct C–H bond functionalisation reactions.3
N
O
NH
O
Pd precatalyst
(5 mol%),
dppe, K2CO3
DMF, 80-130 °C
0.5-4 hBr
NH
O
12 3
Figure 1. Synthesis of phenanthridinone via a Pd-catalysed direct C–H functionalisation reaction.
In this work, we present a mechanistic investigation into the reaction (2 → 3) shown in
Figure 1. Interestingly, this reaction requires two equivalents of starting material 2 to produce one equivalent of product 3. One equivalent of starting material donates one aromatic ring to the nitrogen centre. An X-ray structure of the unusual product 3 is shown in Figure 2.
An investigation into the catalytically active Pd species, via examination of a variety of Pd precursors and ligands, and a study into the effect of air on the reaction, has been carried out. A catalytic cycle can be proposed based on the observations made. A kinetic study by HRGC shows the presence of an induction period which is dependent on the pre-activation temperature of the PdII precatalyst.
1. D. Weltin, V. Picard, K. Aupeix, M. Varin, D.Oth, J. Marchal, P. Dufour and P.Bischoff, Int. J.
Immunopharmacol. 1995, 17, 265-271 2. K. Tanimoto, N. Nakagawa, K. Takeda, M. Kirihata and S. Tanimori, Tetrahedron Lett., 2013,
54, 3712-3714. 3. R. Bernini, S. Cacchi, G. Fabrizi and A. Sferrazza, Synthesis, 2008, 5, 729-738.
Figure 2. X-ray structure of
a single crystal of 3.
10
Mechanistic Investigations of C—H Functionalisation of Pyrazoles with Alkynes
Claire L. McMullin,a Andrés G. Algarra,a Qudsia Khamker,b Stuart A.
Macgregor,a David L. Davies,b
aInstitute of Chemical Sciences, Heriot-Watt University, Edinburgh, EH14 4AS, UK
bDepartment of Chemistry, University of Leicester, Leicester, LE1 7RH, UK
Catalytic C—H functionalisation has shown potential as a new route to many desired synthetic compounds by forming new C—C and C—Y bonds (Y = O, N). However, current understanding of the mechanisms involved in such reactions is limited - yet key to a rational basis for developing efficient and selective catalytic systems. Previously, we have shown that C—H activation can occur by a bound acetate group to a metal centre (M = Pd, Ru, Rh and Ir) via an ambiphilic metal ligand assisted (AMLA) process.1 This intramolecular step is now well established for a range of substrates with heteroatom directing groups (DG), leading to the synthesis of heterocycles or carbocycles (Scheme 1), depending on the nature of the DG and insertion partner.
Scheme 1; C—H Functionalisation reaction pathway for a phenyl substituted directing group substrate
and an alkyne (RC≡CR) with a [Cp*M] complex
In conjunction with experimental studies from the Davies group, DFT calculations are used to further elucidate the key steps within the catalytic cycle and reproduce observed mechanistic data, including kinetic isotope effects. The focus of work presented will be on phenyl-substituted pyrazole DG substrates coupling with an alkyne insertion partner (RC≡CR) to form new C—C bonds, using [Cp*M(OAc)(1)] when M = Rh or Ru. Whilst C—H activation is often thought to be rate limiting, our results suggest it is the migratory insertion and reductive elimination steps that can determine product selectivity and reaction viability. Methodology testing has also highlighted clear differences between hybrid and pure functionals in capturing the same reaction landscape structurally and energetically, as well as the significant impact of including a correction for dispersion effects.
1. a) Y. Boutadla, D. L. Davies, S. A. Macgregor, A. I. Poblador-Bahamonde, Dalton Trans. 2009,
5820 b) D. L. Davies, S. M. A. Donald, O. Al-Duaij, S. A. Macgregor, M. Pölleth, J. Am. Chem. Soc. 2006, 128, 4210
11
Investigating the Mechanism of Ru(II)-Catalysed Direct Arylation with DFT
Claire L. McMullin, Kevin J. T. Carr and Stuart A. Macgregor
Institute of Chemical Sciences, Heriot-Watt University, Edinburgh, EH14 4AS, UK
C-C bond formation via cross-coupling based on initial C-H activation is termed “direct” aryl- or alkylation and recent reviews have shown the wide scope of such reactions, in particular where Ru(II) catalysts are employed.1-2 An example is the coupling of 2-phenylpyridine with phenyl iodide to give the direct arylation product shown in Scheme 1.
Scheme 1; direct arylation reaction of 2-phenylpyridine and PhI with a Ru(II) catalyst
Despite these synthetic advances, kinetic and mechanistic data are sparse on these catalytic systems, leading to speculation as to the precise order of the reaction steps. For example, is the C-H activation followed by oxidative addition of the aryl halide (as in Scheme 2a)3 or is C-H activation preceded by oxidative addition4 (Scheme 2b)?
Scheme 2; two possible mechanisms for the direct arylation of ArX with RH with a Ru(II) catalyst
We have used DFT calculations to study these processes, using a model catalyst, [(C6H6)Ru(OAc)2], for the reaction of 2-phenylpyridine with phenyl iodide in o-xylene. We have also extended this study to the bromide and chloride congeners.
The low polarity of the o-xylene solvent indicated that incorporating ion-pairs into the model was essential in order to produce viable energetics for the key bond activation steps in the catalytic cycle. The presence of acetate in the outer coordination sphere also led us to propose a novel acetate-assisted process for C-I bond activation. Accordingly, we are able to discriminate between the two mechanisms shown in Scheme 2 and identify mechanism (a) as the more likely catalytic cycle.
1. L. Ackermann, Angew. Chem. Int. Ed. 2009, 48, 9792-9826 2. P. B. Arockiam, C. Bruneau, P. H. Dixneuf, Chem. Rev. 2012, 112, 5879-5918 3. H. H. Al Mamari, E. Diers, L. Ackermann, Chem. Eur. J. 2014, 20, 9739-9743 4. N. Dastbaravardeh, M. Schnürch, M. D. Mihovilovic, Org. Lett. 2012, 14, 3792-3795
(a) (b)
12
C–H functionalization of fluoroaromatics at Pd
Jessica Milani, Ian J. S. Fairlamb, Robin N. Perutz
Department of Chemistry, University of York, York, YO10 5DD.
jm1192york.ac.uk
The cyclometallation of benzylamines at Pd is known to proceed via a Concerted Metallation Deprotonation (CMD) mechanism, also known as Ambiphilic Metal Ligand Activation (AMLA) (Figure 1).1 C–H functionalization of fluoroaromatics is favoured ortho to the fluorine atom in intermolecular direct arylation reactions with phosphine ligands that proceed via CMD, as has been shown by experiment2 and rationalised by computation.3
Here we present a study on directed intramolecular reactions,
specifically examining the effect of fluorine substituents (Figure 2) on Heck4 (Scheme 1) and Cope5 cyclometallation reactions (Scheme 2).
Scheme 1. Heck cyclometallation.
Scheme 2. Cope cyclometallation.
1H-NMR, 19F-NMR and crystallographic studies of the products show no regioselectivity in substrates A and B (Figure 2) in the case of Heck’s reaction, and selectivity against ortho-fluorine in Cope’s reactions. A regioselective transmetallation6 reaction of fluoroaromatics (e.g. for C) is also presented (Figure 3).
Scheme 3. Pfeffer transmetallation.
(1) Davies, D. L.; Donald, S. M. A.; Macgregor, S. A. J. Am. Chem. Soc. 2005, 127, 13754. (2) Lafrance, M.; Rowley, C. N.; Woo, T. K.; Fagnou, K. J. Am. Chem. Soc. 2006, 128, 8754. (3) Guihaume, J.; Clot, E.; Eisenstein, O.; Perutz, R. N. Dalton Trans. 2010, 39, 10510. (4) Thompson, J. M.; Heck, R. F. J. Org. Chem. 1975, 40, 2667. (5) Cope, A. C.; Friedrich E. C. J. Am. Chem. Soc. 1968, 90, 909. (6) Lohner, P.; Pfeffer M., de Cian, A.; Fisher, J. C. R. Acad. Sci. Paris, 1998, 199, 615
Figure 2.
Figure 3.
13
Outer Sphere Electrophilic Fluorination (OSEF) of Organometallic Fragments
Lucy M Milner, Jason M Lynam, John M Slattery
Department of Chemistry, University of York, Heslington, York, YO10 5DD, UK
[email protected], [email protected], [email protected]
The incorporation of fluorine into biological molecules can dramatically alter physical properties including lipophilicity, metabolic stability and bioavailability, and as such, approximately 25 % of drugs and 30 % of agrochemicals contain fluorine.1 However, the regio- and stereoselective incorporation of fluorine into organic fragments remains challenging. In particular, new methodologies to form C(sp2)-F alkenyl or C(sp3)-F chiral centres that are selective and functional-group tolerant are desirable.
We have recently demonstrated the electrophilic fluorination of both a ruthenium acetylide complex (1) and a ruthenium pyridylidene species (2). Both reactions occur with 100 % regio- and diastereoselectivity, operate at room temperature and achieve quantitative conversion (by NMR spectroscopy) within minutes. Using this methodology, we have synthesised the first example of a mononuclear fluorinated vinylidene (3) and are currently exploring its reactivity. The incorporation of fluorine into these structures presents a novel synthetic route to fluorinated organometallic species that are currently difficult or impossible to access and which may have significant potential as intermediates in catalysis.
Scheme 1; General scheme of fluorination of ruthenium acetylide (1) and pyridylidene (2) complexes
Metal-mediated fluorination reactions typically involve either a metal-fluoride intermediate, where subsequent reductive elimination creates the new C-F bond, or the use of a Lewis acidic metal to increase the reactivity of a substrate.2 In the case of the chemistry in Scheme 1, mechanistic investigations suggest that fluorination takes place via an unprecedented mechanism which we have termed outer-sphere electrophilic fluorination (OSEF). In this mechanism, the ligand is fluorinated directly without the intermediate formation of a metal-fluoride complex.
1. M. G. Campbell, T. Ritter, Chem. Rev., 2014, Article ASAP. 2. T. Liang, C. N. Neumann, T. Ritter, Angew. Chem. Int. Ed., 2013, 52, 8214 – 8264
14
Synthesis of biologically important 2-pyrones, 2-coumarins, 2-pyridinones and 2-quinolones
Dr. Gerard McGlacken and Marie-Therese Nolan
Analytical and Biological Research Facility (ABCRF),
Department of Chemistry, University College Cork, Ireland
2-Pyrones are important biologically active molecules, highly abundant in bacteria, microbial, plant, insect and animal systems.1 Related to the 2-pyrone motif in both structure and biological diversity are 2-coumarins, 2-pyridinones and 2-quinolones. Traditional methods of biaryl formation such as Suzuki-Miyaura reactions require prefunctionalisation of both coupling partners. A more atom economic approach is “Direct Arylation” which requires preactivation of only one coupling partner and produces less waste.2,3
The aim of this project is to synthesise substituted 2-pyrones, 2-coumarins, 2- pyridinones and 2-quinolones via intramolecular direct arylation reactions. Intramolecular cross-coupled products have been successfully obtained on an array of substrates with preferred regioselectivity occurring at C-3.4 Synthesis of these substrates was carried out using Jeffrey’s conditions, via a Heck-type reaction which facilitate this type of transformation.
Intermolecular direct arylation and double C-H activation methodologies were also targeted, extending to the more robust 2-coumarin motif. A good substrate scope is tolerated.
1. G. P. McGlacken, I. J. S. Fairlamb, Nat. Prod. Rep., 2005, 22, 369-385
2. G. P. McGlacken, L. M. Bateman, Chem. Soc. Rev., 2009, 38, 2447-2464
3. K. Fagnou, D. Lapointe, M. Lafrance, Tetrahedron, 2008, 64, 6015-6020
4. M.-T. Nolan, J. T. W. Bray, K. Eccles, M. S. Cheung, Z. Lin, S. E. Lawrence, A. C. Whitwood, I.
J. S. Fairlamb, G. P. McGlacken, Tetrahedron, 2014, 70, 7120-7127
15
The Direct Arylation of 2-Pyrones, 2-Pyridones and 2-Coumarins
Leticia M. Pardo, Marie-Therese Nolan, Aisling Prendergast and Gerard P.
McGlacken
Department of Chemistry and Analytical and Biological Research Facility (ABCRF), University College Cork, Cork, Ireland
Compounds containing the 2-pyridone, 2-coumarin and particularly the 2-pyrone moiety1 exhibit remarkable biological activity as antibacterial, antifungal and anticancer agents and as potential therapeutics for HIV and Alzheimer’s disease. Traditional synthetic routes to arylated heteroaryl compounds of this sort include the Suzuki-Miyaura reaction.2 Arylation is often catalysed by transition metals and requires prefunctionalisation of both coupling partners. Direct Arylation is a more economic and atom efficient approach as it requires the preactivation of only coupling partner or on occasion, neither coupling partner.3 In this regard, we are interested in developing a novel Direct Arylation methodology towards the preparation of arylated heterocyclic frameworks. We report a new route to arylated pyrone and coumarin derivatives, employing a novel catalytic C-H activation reaction. Reactions conditions and mechanistic considerations are provided.
1. a) G. P. McGlacken, I. J. S. Fairlamb, Nat. Prod. Rep. 2005, 22, 369.
2. a) G. Collins, M. Schmidt, C. O’Dwyer, J. D. Holmes, G. P. McGlacken, Angew. Chem. Int. Ed.,
2014, 53, 4142; b) J. Hassan, M. Sevignon, C. Gozzi, E. Schultz, M. Lemaire, Chem. Rev.
2002, 102, 1359; c) P. Stanforth, Tetrahedron 1998, 54, 263; d) L. Anastasia, N. Negishi,
Handbook of Organopalladium Chemistry for Organic Synthesis, Wiley, New York, 2002, pp
311-334.
3. G. P. McGlacken, L. M. Bateman, Chem. Soc. Rev. 2009, 38, 2447.
16
Iridium-Catalysed Arylative Cyclisation of Alkynones via 1,4-Iridium Migration
Dr Benjamin M. Partridge, Jorge Solana González, and Prof. Hon Wai Lam
School of Chemistry, University Park, Nottingham, NG7 2RD
The functionalisation of C-H bonds by transition-metal catalysts has shown much promise towards making organic chemistry more sustainable and environmentally friendly. Such bonds are generally unreactive under standard conditions, and so a direct C-H functionalisation may lead to a desired product in fewer steps (using less solvent) or may lead to new structures which are inaccessible by traditional methodologies. The 1,4-metal migration is one method for the functionalisation of remote C-H bonds and, in particular, enables the introduction of metal centers at positions that would otherwise be difficult to metallate. To date, reactions involving the 1,4-migration of palladium, rhodium, platinum, nickel, and cobalt have been achieved. Demonstration of the ability of other metals to undergo 1,4-migration would be valuable as their distinct properties may offer new opportunities for the development of useful synthetic methods. Herein, we describe the preparation of highly functionalised polycycles by the iridium-catalyzed arylative cyclization of alkynones. One of the key steps in this transformation is a 1,4-iridium migration which, to our knowledge, had not been described previously.1
Figure 1; Arylative Cyclisation of Alkynones via 1,4-Iridium Migration
1. B. M. Partridge, J. Solana González, and H. W. Lam, Angew. Chem., Int. Ed. 2014, 53, 6523.
17
Mechanism of Direct Arylation Reactions of Fluoroaromatics
George M. H. Platt, Ian J. S. Fairlamb, Robin N. Perutz
Department of Chemistry, University of York, Heslington, York YO10 5DD, UK
Direct C-H functionalization of fluoroarenes allows access to fluorinated compounds widely seen in drug molecules and functional materials (Figure 1).1 Computational calculations using DFT methods have previously been used to propose a reaction mechanism involving a concerted metalation-deprotonation (CMD), also referred to as ambiphilic metal ligand activation [AMLA(6)].2, 3
Figure 1; Direct arylation reaction of pentafluorobenzene 1 with p-iodotoluene 2 to give 3.
Figure 2; a) Trend in the IR absorbance of 1 + 2 −> 3 (monitored by ReactIRTM
).
b) 3D representation of the in situ IR spectra.
Results from a selected model reaction system indicate a first-order dependence on pentafluorobenzene 1 and a half-order dependence on the Pd catalyst generated in situ (Fig. 2). IR spectroscopic analysis allowed the kinetic isotope effect and the activation parameters to be determined. The electronic effects of the substituents on starting materials 1 and 2 were understood by using a Hammett analysis. Our observations are in agreement with the literature and suggests AMLA(6) as the rate-determining state of the reaction presented in Fig. 1.
1. F. Chen, Q. Q. Min and X. Zhang, J. Org. Chem. 2012, 77, 2992–2998. 2. Y. Boutadla, D. L. Davies, S. A. Macgregor and A. I. Poblador-Bahamonde, Dalton Trans.
2009, 5887–5893. 3. S. I. Gorelsky, D. Lapointe and K. Fagnou, J. Org. Chem. 2012, 77, 658–668.
a b
1
3
2
A. U. = arbitrary units
18
Copper-catalysed Heck-like cyclisations of oxime esters
Nicholas J. Race, Adele Faulkner, John F. Bower
School of Chemistry, University of Bristol, Cantock’s Close, Bristol BS8 1TS
The palladium-catalysed cyclisation of oxime esters onto pendant alkenes to generate heteroaromatic compounds, such as pyrroles and imidazoles, is known as the Narasaka-Heck reaction.1 Work within the Bower group is interested in extending the reaction manifold toward the synthesis of chiral, N-heterocycles.2-4
Previous work has described the palladium-catalyzed aza-Heck cyclisation of
oxime esters onto 1,2-disubstituted alkenes.3 Here, product selectivity issues arose from the direction of β-hydride elimination in the key intermediate shown. Substrate- and catalyst-controlled methods were developed to provide chiral dihydropyrroles
through selective β-hydride elimination via Hb (Scheme 1).
Scheme 1; Palladium-catalysed aza-Heck cyclisations for synthesis of chiral, N-heterocycles
After the completion of this work, alternate catalyst systems were investigated in an attempt to improve the low reaction selectivity of some substrates in the process above. The work presented will describe a new copper-catalysed Heck-like reaction that has been developed (Scheme 2).4 Here, the reaction proceeds with complete selectivity for the chiral product and provides complementary reactivity to the established palladium-catalysed process. Mechanistic studies will be presented that provide evidence for a cyclisation that is highly radical in nature.
Scheme 2; Copper-catalysed Heck-like cyclisations of oxime esters
1. Tsutsui, H.; Narasaka, K. Chem. Lett. 1999, 28, 45. 2a. Faulkner, A.; Bower, J. F. Angew. Chem. Int.
Ed. 2012, 51, 1675. b. Faulkner, A; Scott, J. S.; Bower J. F. Chem. Commun. 2013, 49, 1521. 3. Race,
N. J.; Bower, J. F. Org Lett. 2013, 15, 4616. 4. Faulkner, A*; Race, N. J.*; Scott, J. S.; Bower, J. F.
Chem. Sci., 2014, 5, 2416 (*these authors contributed equally).
19
Development of mild and selective Pd-mediated C2-arylations of tryptophans and tryptophan-containing peptides
Alan J. Reay, Thomas J. Williams, L. Anders Hammarback, Adrian C. Whitwood, Ian J. S. Fairlamb*
University of York, Heslington, York, YO10 5DD
Metal-mediated direct C–H bond functionalisations present great utility in the selective modification of complex molecular systems, such as natural products1 or biomolecules.2 In this work we have explored the Pd-mediated direct arylation of tryptophan; this hydrophobic, indole-containing amino acid alters the structure of proteins and is a fluorescent marker;3 2-aryl tryptophans and their analogues can be accessed via Pd-mediated cross-couplings4 or C-H bond functionalisations.5 Several Pd-mediated C–H bond functionalisation protocols for the direct C2-arylation of protected tryptophan and tryptophan-containing peptides have been developed, allowing for a number of complementary synthetic approaches to this class of compounds (see Figure 1).
Figure 1; Complementary mild and selective approaches to C2-arylated tryptophan.
Our previous work demonstrated the use of both a boronic acid/iodobenzene diacetate system (Conditions A) as well as conditions utilising Cu(II) as a co-catalyst (Conditions B).6 The use of a Cu(II) salt is incompatible with certain peptidic motifs however, so we have expanded upon this methodology through the use of pre-synthesised asymmetric diaryl iodonium salts (Conditions C) and aryl diazonium salts (Conditions D). This has resulted in complementary synthetic approaches which can be used to produce a wide range of functionalised products; the mildest conditions provide C2-phenyl tryptophan quantitatively under air at room temperature, without the need for column chromatography. In conclusion, we have developed several useful methods to selectively functionalise tryptophan units, even when incorporated within a peptide. The conditions developed are complementary to one another in the motifs that can be installed and their synthetic utility, allowing access to a wide range of modified C2-arylated tryptophans under very mild and selective conditions.
1. Yamaguchi, J.; Yamaguchi, A. D.; Itami, K. Angew. Chem. Int. Ed. 2012, 51, 8960-9009. 2. Noisier, A. F. M.; Brimble, M. A.; Chem. Rev. 2014, 114, 8775-8806. 3. Vivian, J. T.; Callis, P. R.; Biophys. J. 2001, 80, 2093-2109. 4. Kolundzic, F.; Noshi, M. N.; Tjandra, M.; Movassaghi, M.; Miller, S. J. J. Am. Chem. Soc. 2011,
133, 9104-9111. 5. (a) Ruiz-Rodríguez, J.; Albericio, F.; Lavilla, R. Chem. Eur. J. 2010, 16, 1124-1127; (b)
Preciado, S.; Mendive-Tapia, L.; Albericio, F.; Lavilla, R. J. Org. Chem. 2013, 78, 8129-8135. 6. Williams, T. J.; Reay, A. J.; Whitwood, A. C.; Fairlamb, I. J. S. Chem. Commun. 2014, 50,
3052-3054.
20
Reactivity of 5 Coordinate Pt(IV) Complexes
Paul Shaw, Dr Jonathan P. Rourke
University of Warwick, Coventry, CV4 7AL
Coordinatively unsaturated intermediates are seen regularly in organometallic reactions such as oxidative addition and reductive elimination. The presence of these intermediates is often fleeting, or not seen at all. Being able to study these intermediates (their reactivity, including selectivity) is of academic and industrial interest. A simple oxidation of a Pt(II)C^N^C complex with PhICl2 at -60 oC gives the dichloro- cis and trans complexes which are stable at room temperature. By changing the phosphine ligand, we have seen some more interesting results. When the ligand is triphenylphosphine, the initial product is a 5-coordinate Pt(IV) complex, which stays around for hours at room temperature, eventually giving the trans complex, later isomerizing to a cis complex. Phosphines with long enough carbon chains (e.g. PnPr3 or PnBu3) give cyclometallated products as well as the trans (figure 1).
Figure 1; alkyl phosphine reaction scheme
21
Cross-Dehydrogenative-Coupling (CDC) of 1,3,5-Trialkoxybenznese with Simple Aromatic Hydrocarbons
Thomas E. Storr, Faridah Namata, Michael F. Greaney
School of Chemistry, University of Manchester, Manchester, M13 9PL, UK
The ubiquity of biaryls in bioactive molecules has prompted the development of a wide variety of transition metal catalysed reactions to promote the coupling of two aryl components (cross-coupling). Over the past decade, significant efforts have been directed towards the development of C–H variants of cross-coupling reactions in order to improve atom economy and to broaden the substrate scope.1 Within the arena of C–H coupling methodology, cross-dehydrogenative-coupling (CDC) has attracted significant interest due to the inherent elegance and atom economy of coupling two disparate C-H components.2 Despite significant progress in the field, the CDC of two aromatic components has only been achieved using: 1) directed approaches, 2) electron deficient arene substrates, 3) polyfluorobenzene substrates, and 4) naphthalene substrates.3 Herein, we report an addition to these relatively rare processes; a novel cross-dehydrogenative coupling of 1,3,5-trialkoxybenzenes with simple aromatic hydrocarbons. This methodology enables two aromatic C–H coupling partners to be coupled together to generate multi-ortho-substituted biaryls.
Figure 1; General scheme for the CDC of 1,3,5-trialkoxybenznese with simple aromatic hydrocarbons
1. J.-Q. Yu and Z.-J. Shi Top. Curr. Chem.: C-H Activation Springer, Heidelberg, 2010, Vol. 292. 2. a) Y. Wu, J. Wang, F. Mao and F. Y. Kwong Chem. Asian J. 2014, 9, 26-47. b) C.-J. Li Acc.
Chem. Res. 2009, 42, 335-344. 3. a) C. S. Yeung, X. Zhao, N. Borduas and V. M. Dong Chem. Sci. 2010, 1, 331-336; b) L. Zhou
and W. Lu Organometallics 2012, 31, 2124-2127; c) Y. Wei and W. Su J. Am. Chem. Soc. 2010, 132, 16377-16379; d) R. Li, L. Jiang and W. Lu Organometallics 2006, 25, 5973-5975.
22
Controlling Selectivity of C(sp2)-H Activation: An Experimental and Computational Study
Kevin Carr,a David L. Davies,b Stuart A. Macgregor,a Barbara Villa-Marcosb
aInstitute of Chemical Sciences, Heriot-Watt University, Edinburgh, EH14 4AS, UK
bDepartment of Chemistry, University of Leicester, Leicester, LE1 7RH, UK
Catalytic C-C bond formation by functionalisation of C-H bonds is a step-economical approach for the synthesis of complex organic molecules. An understanding of the kinetic and thermodynamic selectivity of the C-H activation will facilitate the rational design of more efficient and selective catalysts in the future. Herein, we present a combination of experimental and computational studies on the relative reactivity towards acetate-assisted C(sp2)–H activation in a series of imines featuring heterocyclic, vinyl and phenyl substituents at iridium and rhodium. H/D exchange experiments suggest that the selectivity of C–H activation at Ir is determined by kinetic factors while that at Rh is determined by the product thermodynamic stability, leading to a different order of selectivity depending on the metal used. The different reactivity of these substrates with Ir and Rh is well supported by the computational studies. This work provides the foundation for the development of a computational methodology for the design of selective catalysts that involve an AMLA/CMD1 C-H activation process.2
1. AMLA: Ambiphilic Metal-Ligand Assistance; CMD: Concerted Metalation-Deprotonation. 2. K. Carr, D. L. Davies, S. A. Macgregor, K. Singh and B. Villa-Marcos, Chem. Sci., 2014, 5,
2340
23
Electrophilic Cyclisation Using Boron Lewis Acids
Andrew J. Warner, James R. Lawson, Michael J. Ingleson
School of Chemistry, University of Manchester, U.K
The electrophilic cyclisation of internal alkynes has been previously investigated using a wide array of electrophiles, for example, aromatic electrophiles generated from iodonium reagents.1 However, related cyclisations using boron electrophiles are extremely limited,2 yet they offer an attractive route to cyclic systems possessing a boronic ester moiety (Figure 1). Such cyclic systems include the dihydronaphthalene framework, which can be found in many biologically active compounds including the anti-cancer drug, Nafoxidine. Boronic esters have been exploited by synthetic chemists for decades as they provide synthetically important intermediates that can be used to build and functionalise complex molecules (Figure 2)3.
Figure 1. General scheme for the electrophilic cyclisation of internal alkynes using boron electrophiles.
Figure 2. A variety of functionalisations via the use of boronic esters.
1. Walkinshaw, A. J., Xu, W., Suero, M. G., Gaunt, M. J. J. Am. Chem. Soc. 2013, 135, 12532. 2. Voss, T. C., C., Kehr, G., Nauha, E., Erker, G., Stephan, D. W. Chem.-Eur. J. 2010, 16, 3005. 3. Structure, Properties, and Preparation of Boronic Acid Derivatives. (ed D. G. Hall), 2005, Wiley-
VCH Verlag GmbH & Co. KGaA, Weinheim.
24
Palladium-Catalysed C-H Activation Cascades in the Synthesis of Polycyclic Heterocycles
Michael S. Watt, Kevin I. Booker-Milburn
School of Chemistry, University of Bristol, Cantock’s Close, Bristol, BS8 1TS, U.K.
The direct functionalization of C-H bonds in organic synthesis represents a
convenient, atom-economic transformation in the construction of new C-X bonds.
Nitrogen-containing heterocycles such as indole are found in a wide range of
compounds of interest to the pharmaceutical and agrochemical industries1 and are
also a common moiety in natural products.2 Thus the functionalization of such
heterocycles via C-H activation is a desirable goal in organic synthesis.
Within the Booker-Milburn group, the use of π-allyl intermediates has been
previously explored in the carbo-amination of dienes.3 Herein we report a palladium-
catalysed C-H activation/π-allyl trapping cascade reaction which produces products
such as 3 in good yield as single diastereoisomers, forming two new stereo-centres
in one step. It is proposed that an initial oxidative-Heck type reaction with the
tethered diene leads to proposed π-allyl intermediate 2, followed by ring closure via
attack of an internal nucleophile. Substrates such as 1 are readily prepared from
commercially available indoles, which enables rapid access to libraries of highly
functionalised N-heterocyclic compounds. Reaction optimisation and the ongoing
exploration of substrate scope will be discussed.
Scheme 1; Palladium-catalysed cascade reaction to produce polycyclic heterocycles
1. N. Kaushik; P. Attri; N. Kumar; C. Kim; A. Verma; E. Choi, Molecules, 2013, 18, 6620-6662 2. M. Ishikura; K. Yamada; T. Abe, Natural Product Reports, 2010, 27, 1630-1680
3. C. E. Houlden; C. D. Bailey; G. J. Ford ; M. R. Gagné; H. C. Lloyd-Jones; K. I. Booker-Milburn, J. Am. Chem. Soc, 2008, 130, 10066-10067
Notes
Notes
Notes
Notes
Notes
Notes