0. University of Wisconsin-Madison
Catalytic fujiwara-moritani reaction. Challenges in c-h activation and catalyst oxidation.
Laura Ruiz Espelt
Yoon Group
University of Wisconsin-Madison
Literature Seminar
April 7, 2011

1. • Discovered in 1968 independently by Mizoroki and Heck
• Attractive transformation for C-C bond formation
• Richard F. Heck obtained the Nobel Prize on 2010
• Intensively developed from synthetic and mechanistic point of view
Oestrich, M. The Mizoroki-Heck Reaction; John Wiley & Sons, 2009

2. Garg, N.K.; Caspi, D.D.; Stoltz, B.M. Synlett 2006, 18, 3081

3. Garg, N.K.; Caspi, D.D.; Stoltz, B.M. Synlett 2006, 18, 3081

4. Garg, N.K.; Caspi, D.D.; Stoltz, B.M. Synlett 2006, 18, 3081

5. Yields are based on palladium complex
They were studying the nucleophilic substitution of alkenes using Pd salts
Acetic acid demonstrated to be necessary for the reaction (rxn doesn’t work in absence of acetic acid and use of other acids such as HCl doesn’t work either) Acetate anion believed to be necessary. Hypothesis: after chloride anion is abstracted from PdCl2 by the metal cation, the Pd metal coordinates to acetate anoin which is weaker ligand than the chloride anion, thus increasing the ability of the Pd to coordinate to the arene
Large excess of arene vs alkene used to avoid oxidative coupling of olefins to give butadiene
Fact that arylation products are formed almost exclusively suggests that the reactivity of the aromatic compounds towards olefins is far higher than that of acetate anion, suggesting that aromatics are highly activated by Pd(II) salts forming arylpalladium saltsd
Moritani, I.; Fujiwara, Y. Tetrahedron Lett. 1967, 12, 1119
Fujiwara, Y.; Moritani, I.; Matsuda, M.; Teranishi, S. Tetrahedron Lett. 1968, 5, 633

6. Fujiwara, Y.;Asano, R.; Moritani, I.; Teranishi, S.
Observation 3: might be difficult to control number of additions in the reaction.
Obeservation 4: substitution pattern suggests EAS mechanism. Not very synthetically useful
Observation 5: EWG decrease reactivity but differences in rates very small so cant’ be a usual EAS. Authors suggest electrophilic attack of PdII to arene forming aryl-palladium complex
Fujiwara, Y.;Asano, R.; Moritani, I.; Teranishi, S. J. Org. Chem. 1976, 41, 1681
Fujiwara, Y.;Asano, R.; Moritani, I.; Teranishi, S.
J. Org. Chem. 1976, 41, 1681

7. Solvated arylpalladium species is formed from a homogeneous solution of an arene and palladium(II) salt in a polar solvent via an electrophilic aromatic substitution reaction
The alkene then coordinates to the unstable arylpalladium species, followed by an insertion into the aryl-palladium bond
The arylethyl-palladium intermediate rapidly undergoes b-hydride elimination to form the alkenylated arene and a palladium hydride species
The hydride presumably decomposes into an acid and free palladium metal
Formation of arylpalladium species proposed in the mechanism was confirmed by the isolation of diphenyltripalladium(II) complexes obtained by the c-h activation reaction of benzene with palladium acetate dialkylsulfide systems
Fujiwara, Y.; Moritani, I.; Danno, S.; Asano, R.; Teranishi, S. J. Am. Chem. Soc. 1969, 7166

8. Fujiwara, Y.; Moritani, I.; Danno, S.; Asano, R.; Teranishi, S.
Oestrich, M. The Mizoroki-Heck Reaction; John Wiley & Sons, 2009, p. 14
Fujiwara, Y.; Moritani, I.; Danno, S.; Asano, R.; Teranishi, S.
J. Am. Chem. Soc. 1969, 7166

9. Challenge 1: C-H Activation
Challenge 2: Pd(0) Oxidation

11. C-H bonds easier to activate
Complete ortho regioselectivity for symmetrical substrates

12. Satoh and Miura (2009) Shi (2007)
Umeda N.; Hirano, K.; Satoh, T.; Miura, M. J. Org. Chem. 2009, 74, 7094
Shi (2007)
N,N-dimethylaminomethyl DG challenging bc is a very good sigma donor, binding to the metal very tightly (occupying coordination positions and decreasing the electrophilic ability of the tm) and bc the acidic conditions usually employed in fujiwara moritani rxns protonate the amine, limiting its ability to coordinate to the metal center. They try neutral conditions but see no reactivity so start screening acidic conditions. AcOH need to be used in eq with respect to the amine, if not the yield decrease drastically probably due to a decrease in concentration of tertiary amine and a decrease in the electrophilicity of the metal. Stronger acids did not work. Advantage of this dg is that it can be easily trsnformed to other functionatilites such as methyl. Can even do both reactions in one pot. The role of AcOH is most likely to tune the concentration of free amine so that the amine protomtes Pd-catalzed C-H cleavage to realize this transformation.
Cai, G.; Fu, Y.; Li, Y.; Wan, X.; Shi, Z. J. Am. Chem. Soc. 2007, 129, 7666

13. Entry into phthalide core
Reaction catalyzed by [Pd] cyclizes after first vinylation
Reaction catalyzed by [Rh] suffers a second vinylation before the cyclization step
No mechanistic insight
Ueura, K.; Satho, T.; Miura, M. Org. Lett. 2007, 9,
Miura, M.; Tsuda, T.; Satoh, T.; Pivsa-Art, S.; Nomura, M. J. Org. Chem. 1998, 63,

14. Electrophilic palladation via Wheland intermediate
Electrophilic palladation via Wheland intermediate. Pd(II) coordinates to pi system of arene and arenium transfers proton to acetate to generate cyclopalladated product.
Dimer considered starting material for the reaction was observed in solution from NMR experiments
An inversed dependence on the rate of the reaction when increasing the concentration of the amine starting material suggests a dissociative mechanism in which an amine ligand dissociates from the palladium center to leave a vacant position for further coordination of the alkene and form a pseudo three coordinate intermediate
Three coordinate intermediate can be in equilibrium with a species in which all four coordination sites are occupied if AcO acts as bidentate ligand. Rupture of the palladium-oxygen bond cis to the coordinated amine can easily provide a vacant coordination site for arene coordination
Migration of vacant coordination sites in square planar complexes is known to proceed rapidly,
KIE suggests that C-H activation is the rate limiting step also a Hammet study shows that electron rich arenes undergo the reaction faster suggesting an electrophilic mechanism
Proposed transition state in which the leaving hydrogen is abstracted by acetate but not by external amine
Palladium acetate has a dual role of electrophilic activation of the arene and intramolecular base to deprotonate
Ryabov, A.D.; Sakodinskaya, I.K.; Yatsimirsky, A.K. J. Chem. Soc. Dalton Trans. 1985, 2629

15. BP86 / 6-31G**
1a is same as proposed by previous study but calculated to have a singly bounded acetate and a bidentate one
First step is displacement of one arm of the bidentate acetate by one of the ortho C-H bonds leading to agostic intermediate 2
2a has H-bonding interacion between acetate and C-H bond and is therefore ideally positioned for a H-transfer which occurs with a minimal activation barrier
In the product 3a the H-acceptor acetate twists away from the new Pd-C bond and donates the transferred hydrogen to the second acetate ligand
Davies, D.; Donald, S.M.A.; Macgregor, S.T. J. Am. Chem. Soc. 2005, 127, 13754

16. Short distance between Pd and H Elongated C-H bond
Transition state for the transformation: agostic cpd (Milstein reported isolation of agostic cpd in Rh chemistry with pyncer ligands, suggesting that this might be a possibility)
Exhibits short Pd-H contact (1.91) and elongated C-H distance (1.15) indicative of agostic cpd. Calculated natural charges
Short distance between Pd and H
Elongated C-H bond
No charge change in aromatic ring

17. Carboxylic acid can act as a unique removable directing group
Carboxylic acid can act as a unique removable directing group. Observed previously that for some Ir chemistry the final product had been decarboxylated
LiOAc improves yield more than any other alkaly salts and its role might be to provide acetate anions as ligands to prevent deactivation of Pd(0) to metallic species
Maehara, A.; Tsurugi, H.; Satoh, T.; Miura, M. Org. Lett. 2008, 10, 1159

18. Challenge of finding suitable ligands: common NHC and phosphine ligands used in Heck are too strong sigma donors and outcompete substrate molecule for binding to Pd(II) or render the metal center too electron rich for C-H activation. Also complicated to find conditions that facilitate controlled assembly of retransition state with one molecule of substrate and one molecule of ligand (they must have well matched coordinative affinity for Pd(II))
Very low converstion without ligand so decide to investigate effect of pyridine ligands (shown in literature to be very efficient in promoting the reoxidation of Pd(0) by oxygen)
Hypothesis: Pd species is not electronically suited to catalyze the transformation with high efficiency
More electron poor pyridines result in more electrophilic Pd that is therefore more reactive
If ligand is too electron poor then Pd black precipitates, indicating that is not well suited to stabilize the transient Pd hydride species (hampering Pd reoxidation)
Further optimization showed that polar solvents work better (by stabilizing the charged intermediates of the catalytic cycle) and AcOH as cosolvent increases the yield to 82%, probably inhibiting the decomposition of the sm by protonating C3 or by interacting with the catalyst
Ferreira, E.; Stoltz, B.M. J. Am. Chem. Soc. 2003, 125, 9578

19. Reaction performed with 20 eq of arene
Reaction performed with 20 eq of arene. Shown that using 5 eq of arene and EtOAc as solvent gives lower but still good yields
Electron defficient arenes were unreactive due to poor coordination with Pd. Think that use of pyridyl ligands might favor reaction.
Only pyr doesn’t improve reaction probably because displacement of the ligand by the electron defficient arene is energetically disfavored due to strength of Pd-N bond. Postulate that even upon prior loss of acetate, the Pd+ species won’t be electrophilic enough.
Think that substituting positions 2 and 6 might decrease the Pd-N bond strength. Did not work presumably because their binding strenght to Pd is relatively weak, as evidenced by the high level of Pd prepcipiation.
Then think that putting EWG on pyridine might also decrease Pd-N bond strength but ligand is ineffective (the one used by Stoltz)
Finally think about designing a ligand that binds in single fashion to the Pd to allow substrate binding. This could be achieved by substituting the pyridine with minimal steric hindrance around the N atom and with steric hindrance on the side chain carbon atoms. A given pair of ligands would sense significant mutual steric repulsion when both are coordinated to the Pd(II) center, causing only one ligand to bind and allowing substrate binding to take place.
Ac2O improves yield either by acting as drying agent or by helping in Pd(0) oxidation by regenerating Pd(Oac)2 from the peroxide species
Zhang, Y.; Shi, B.; Yu, J.Q. J. Am. Chem. Soc. 2009, 131, 5072

20. Origin of meta selectivity still unclear
0.05 Å
longer than
Pd(Pyr)2(OAc)2
One of the ligands dissociates in solution to form a new complex. This new complex has not been fully characterized but NMR experiments show that dimeric complex is probable (ratio of Oac and ligand is :2) This dimer is potentially responsible for the observed reactivity
Origin of meta selectivity still unclear
Zhang, Y.; Shi, B.; Yu, J.Q. J. Am. Chem. Soc. 2009, 131, 5072

21. First example in which ligand no only regulates catalyst activity, but also controls regioselective outcome of the reaction
Hypothesis: tuning steric properties of the metal center through the coordination of the ligand can provide site recognition
Positional selectivity can be enhanced by using the aa ligand and improved by varying the protective group on the N
Improvement is likely a result of catalyst’s recognition of the different steric and electronic environments created by the different ligands
Dependent on substrate and coupling partner, need to optimize for each of them
Provides evidence that ligand are coordinated to Pd(II) during C-H cleavage event and influcence the TS energies
Wang, D.; Engle, K.; Shi, B.; Yu, J.Q. Science. 2010, 327, 315

22. In previous investigations also discovered that aa ligands afforded reactions that didn’t happen in the absence of the ligand
Important to demonstrate whether the improved reactivity using amino acid ligands is a result of ligand induced acceleration (decrease activation energy) and whether the aa core structure can be further tuned to offer improved reactivity, reduced reaction times, and lower catalyst loading
Interested in knowing whether the improved yield was due to improved catalyst lifetime or increased initial reaction rate
Engle, K.M.; Wang, D.; Yu, J.Q. J. Am. Chem. Soc. 2010, 132, 14137

23. Substrates for competition studies selected because they are roughly isosteric to one another and don’t contain any chelating functional groups
Competition studies show Me reacts preferentially in the absence of ligand. WhenBoc is used, the two substrates react almost ath the same speed but when using Ace a reversal in the relative reactivity is observed and now the CF3 substrate reacted almost as twice as fast as the Me substrate
KIE studies show that in the absence of ligand the KIE of 6.1 means that C-H bond cleavage is the rate limiting step. In the presence of Boc C-H activation still seems to be the rls. With Ace the KIE decreases to 1.7, suggesting the rate of C-H increases to the point in which is probably not the rls anymore, this moderate value suggests that the C-H activation takes place before the rls
Engle, K.M.; Wang, D.; Yu, J.Q. J. Am. Chem. Soc. 2010, 132, 14137

24. Assuming that deprotonation is slow, the KIE agrees with an electrophilic aromatic substitution (usually have lower values bc deprotonation is assumed to be fast relative to formation of the arenium species)
Even though KIE is very different for both ligands, still think that they should undergo same mechanism (Boc suggests C-H cleavage is not rds and Ac suggests that C-H cleavage is rds) because they suspect they coordinate in an identical bidentate fashion and thus affect C-H cleavage similarly
Based on previous experiments, palladation is not believed to be the mechanism
All indicates that it might be proton abstraction mechanism, in which the amino acid ligand reversible bidentate coordination plays a crucial role in facilitating the initial agostic interaction between Pd and the C-H bond and then in shuttling the hydrogen atom to an internal or external base
Previous studies suggest that ligand is bidentately coordinated to Pd throughouth the C-H activation process, but is difficult to imagine bc Pd will be coordinatively saturated in the pretransition state. Therefore traditional proton abstraction mechanism is likely not in play and instead, deprotonation is likely to occur from an external base or by one of the basic groups from the ligand.
Future work: detailed analysis of how amino acid ligand affect the TS energies of the different processes, also finding out the precise role of the ligand (small changes in the structure lead to big changes in reativity), also what coordination mode the aa ligand adopts with Pd in the TS
Engle, K.M.; Wang, D.; Yu, J.Q. J. Am. Chem. Soc. 2010, 132, 14137

25. Many improvements achieved since Fujiwara’s initial observations
Two main tactics used to achieve regioselectivity:
1. Directing groups- site selective palladation
2. Ligands- not fully understood
More “synthetically appealing” directing groups design: traceless directing groups
Future of ligands to direct reactivity and selectivity

27. Fujiwara (1968)
Fujiwara, Y.; Moritani, I.; Matsuda, M.; Teranishi, S. Tetrahedron Lett. 1968, 35, 3863
Itahara (1983)
Itahara, T.; Ikeda, M.; Sakakibara, T. J. Chem. Soc. Perkin Trans , 1361

28. Pros: - Environmentally friendly - Lower cost
“Green Oxidants”: O2
Pros: - Environmentally friendly
- Lower cost
- Increase in atom efficiency
- Facilitate product isolation
Stahl, S. Angew. Chem. Int. Ed. 2004, 43, 3400

29. Cons: - O2 requires rigorous safety handling
“Green Oxidants”: O2
Cons: - O2 requires rigorous safety handling
- Slow electron transfer compared to
decomposition of the reduced metal
Solution: - Use of ligands to stabilize Pd0 so that is stable under oxidative conditions
- Use an electron-transfer mediator to carry the electrons from Pd0 to terminal
“green oxidant’
In the absence of redox cocatalyst the direct aerobic oxidation of palladium often cannot compete kinetically with aggregation of the catalyst into inactive bulk metal. Problem addressed by conducting reactions at elevated O2 pressures (20-50 atm) but this is less appealing (unsafe, explosion hazards)
Piera, J.; Backvall, J.E. Angew. Chem. Int. Ed. 2008, 47,

30. Yokota, T. ; Tani, M. ; Sakaguchi, S. Ishii, Y. J. Am. Chem. Soc
Want, J.; Yang, C.; Liu, L.; Guo, Q. Tet. Letters. 2007, 48, 5449

31. Shue, R.S. Chem. Commun. 1971, 1510
First report in 1971 by shue
In the case of Milstein the coupling happens in the presence of oxygen or in an inert atmosphere. In the absence of oxygen the olefin itself serves as the oxidant and a 1:1 ratio of cinnamate and propionate is obtained. No carbonylation is observed. The TON increases with increasing pressure of CO (believed to stabilize Pd0). Radical mechanism excluded by adding galvinoxyl (which doesn’t retard the reaction) and doing the reaction in the dark.
Dams, M.; De Vos, D.E.; Celen, S.; Jacobs, P.A. Angew. Chem. Int. Ed. 2003, 42, 3512

32. 2 equiv Ferreira, E.; Stoltz, B.M. J. Am. Chem. Soc. 2003, 125, 9578
Engle, K.M.; Wang, D.; Yu, J.Q. J. Am. Chem. Soc. 2010, 132, 14137

33. OXIDIZING DIRECTING GROUPS
Challenge: Use a Directing Group that acts also as the Oxidant:
OXIDIZING DIRECTING GROUPS

34. Rakshit, S. ; Grohmann, C. ; Besset, T. ; Glorius, F. J. Am. Chem. Soc

35. They try other solvents (DMSO, toluene) and adding additives (4A MS, PPh3, Ag2O) and all result in lower yield
Competition experiement similar to the one performed in the previous paper performed and it was demonstrated that the oxidant was internal
A plausible mechanism for this reaction: first, aryl-Pd complex is formed via coordination of the palladium atom to the N-oxide and subsequent electrophilic attack at the 2-position carbon atom. Next, coordination of Pd complex with alkene followed by syn insertion. Beta hydride elimination forms palladium hydride and intermediate. Oxidation of palladium hydride by the intermediate affords the product and palladium acetate
Wu,J.; Cui, X.; Chen, L.; Jiang, G.; Wu, Y. J. Am. Chem. Soc. 2009, 131, 13888

36. Rakshit, S. ; Grohmann, C. ; Besset, T. ; Glorius, F. J. Am. Chem. Soc
Wu,J.; Cui, X.; Chen, L.; Jiang, G.; Wu, Y. J. Am. Chem. Soc. 2009, 131, 13888

37. Emerging strategy, other groups have done similar transformations
Cho, S.H.; Hwang, S.J.; Chang, S.
J. Am. Chem. Soc. 2008, 130, 9254
Pauterau, F.W.; Besset, T.; Glorius, F.
Angew. Chem. Int. Ed. 2011, 50, 1064
Emerging strategy, other groups have done similar transformations
Examine if alkenylated product oxidizes Rh by an intramolecular redox reaction, competition experiment in which two substrates were added to michael acceptor under standard reaction conditions. Recovery of 93% of alkenylated sm demonstrates that Ome acts as a truly internal oxidant converting Rh(I) into Rh(III) completing therefore the catalytic cycle.
Wu,J.; Cui, X.; Chen, L.; Jiang, G.; Wu, Y.
J. Am. Chem. Soc. 2009, 131, 13888
Rakshit, S.; Grohmann, C.; Besset, T.; Glorius, F.
. Am. Chem. Soc. 2011, 133,

38. Two main tactics used to achieve regioselectivity:
1.Directing groups Ligands
Oxidation on catalyst achieved by:
1. Stoichiometric oxidants such as Cu(OAc)2
or AgOAc
2. Oxygen in the presence of electron-
transfer-mediators such as Cu(OAc)2 or
polyoxometallate acids
3. Oxygen as sole oxidant in the presence
of ligands to stabilize the metal
Oxidizing directing group opens new avenues for this chemistry
Advantages/ disadvantages have to be evaluated individually

39. Thank you! Professor Tehshik Yoon Kat Myhre The Yoon Group
Practice Talk Attendees:
Travis Blum Shishi Lin
Jamie Chen Zic Lu
Megan Cismesia Jon Parrish
Juana Du Derek Salter
Olga Dykhno Liz Tyson
Elliot Farney Kevin Williamson
Anna Hurtley Adam Weinstein