Org Prep Daily

August 26, 2007

One phosphine to rule them all

Filed under: lit highlights — milkshake @ 10:20 am

sauronphos.gif

Buchwald et al: Angew Chem Int Ed Eng 45(39) 6523-7 (2006) DOI 10.1002/anie.200601612

Buchwald group developed a number of biphenyl-based phosphine ligands useful for Pd(0)-catalyzed arylations. Descendants from BINAP, these ligands form 1:1 complexes with Pd(0) that are particularly active catalysts, allowing arylations with both poor electrophiles (unactivated aryl chlorides) and lazy nucleophiles (such as heterocycles with very acidic NH).

The reason why the bulky monodentate electrone rich 2-biphenyl phosphines are good is that they make Pd(0) more nucleophilic – which helps the Pd insertion into Ar-X – while the bulk promotes the fast migration/dissociation rates in the intermeditate complexes and the formation of PdL2 is supressed. [Even a very sterically hindered PdL complex is coordinationally less saturated and hence more reactive than a PdL2 complex with a less bulky ligand. PdL4 is worse still]. The pi-electrons of the second benzene ring donate to Pd and the ring shielding prevents PdL2 from happening.

One of the problems with aryl-based phosphines has been cyclometallation, the palladacycles (such as Hermann catalyst) are good for high temperature Heck reactions but are quite inert below their decomposition temperature. In this case the cyclometallation is prevented by the ortho isopropyl groups.

There are other good phosphine ligands useful for difficult arylations: Xanphos (1), tert-Bu3P (2) and Josiphos (3). The great advantage of Buchwald phosphine ligands is that they are perfectly air stable, highly crystalline solids, easy to make and the produced catalysts are pretty active and robust.

This newest ligand with isopropyls on the ring and tert-butyls on the phosphine is reported to be very good for arylation of poorly reactive N-nucleophiles, with Pd2(dba)3 as a Pd source and NaOtBu in toluene (at 80C) or Cs2CO3 in dioxane (at 100C) . And some functional groups can be even left unprotected, such as primary amide and phenol, without interfering with the arylation process.

I have tried this ligand with my substrates and aryl bromindes and nearly everything that I did worked on the first try with 2-5% of Pd loadings and NaOtBu in toluene at 80C. The only exception was arylation using aryl iodide, as an electrophile – I suspect that the generated iodide anion complexed to Pd and prevented the catalyst from turning over. But all my aryl bromides worked beautifully.

The ligand is available from Aldrich, 638080-5G, and it is not too cheap ($161/5g) – so it would be worth making your own ligand for large-scale experiments. The phosphine can be made in a one-pot reaction from commercial reactants.

Note 1: Cheap, but often needs high temperature and a high-boiling solvent like o-dichlorobenzene. Best to be used 1:1 with Pd(0) since Pd(xanphos)2 is inert
Note 2: Expensive. The free tBu3P is super air-sensitive and should be handled only in glove box – it likes to smolder on air. Use the air-stable tetrafluoroborate salt (tert-Bu3PH) BF4 instead, 2:1 with Pd(0)
Note 3: Josiphos is a chiral ligand, very expensive

11 Comments »

  1. Thanks for the prospective. Very interesting!

    Comment by Spiro — August 26, 2007 @ 2:20 pm

  2. To the land of CBC where the shadows lie.

    Comment by liquidcarbon — August 26, 2007 @ 7:39 pm

  3. Are you familiar with the DPEphos ligand and how this might compare in use to that? DPEphos is not as expensive and also easy to work with.

    Javaslinger

    Comment by Javaslinger — August 26, 2007 @ 9:39 pm

  4. I don’t know much about ligand/Pd chemistry. What are the ‘Bedford’ ligand/complexes like?

    Comment by TWYI — August 26, 2007 @ 11:15 pm

  5. I love phosphine ligands. The Buchwald ligands are really cool particularly for their air-stability, and he published a really interesting JACS comm recently about why biaryl phosphine ligands are air-stable.

    Comment by excimer — August 27, 2007 @ 4:22 pm

  6. The cost of this ligand (161$/5g) appears quite low.
    It will be difficult to do the synthesis more cheaply “at home”, I guess (just think of the dry solvents, the phosphine, and the aryl bormide; workup under Argon…).

    By the way: you did not give the reference for the synthesis of the ligand.
    It’s not in the Angew. paper. (Supporting info says: “Ligand was prepared according to the literature procedure”, without reference).

    Cheers.

    Comment by LH07 — August 28, 2007 @ 11:05 am

  7. I think the best references to check for the ligand synthesis would be

    Adv. Synth. Catal (2001), 343 (8) 789-794
    Org. Process R&D (2004), 8, 1065-71

    Comment by milkshake — August 28, 2007 @ 4:48 pm

  8. Wow! Thanks for linking me.

    I’ve not touched a lab bench for 10 years now – I don’t think I can work a rotavap anymore even if my life depended on it :) If anyone asked me to distill THF, I’d end up blowing up the lab.

    Cheers

    Comment by lunch is served — September 2, 2007 @ 8:31 pm

  9. but your photos of Singaporean dishes are absolutely lovely

    Comment by milkshake — September 3, 2007 @ 7:47 am

  10. do you know then how does the N(Me)2 version of buchwald’s ligands work?
    They have been reported to be useful for alpha-arylations… but i never seem to really understand the design of the ligands till i read your post. Very insightful!

    Comment by meow — November 23, 2009 @ 11:51 am

  11. I noticed that they typically use their hindered biaryl phosphine ligands on new arylation reactions empirically – they test maybe five different ligands and two or three different bases and two different solvents until they get some acceptable result. The problem with choosing the right ligand for Pd is that the complex has to perform several transitions one after another to turn over, and the rates of each step in the catalytic cycle can go wrong if the ligand substitution is not optimal – the actual influence of the phosphine substitution is hard to guess with untested system. So they start with some reasonable precedent and guess about what factors are important, and they go on by trial and error

    Comment by milkshake — November 23, 2009 @ 5:55 pm


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