Tuesday, February 12, 2013

Blog Syn #002: Pd-Catalyzed C-3 Selective C-H Olefination of Pyridines

(Disclaimer: The following experiments do not constitute rigorous peer review, but rather illustrate typical yields obtained and observations gleaned by trained synthetic chemists attempting to reproduce literature procedures. We've taken efforts to stay close to the original procedure, using similar glassware, equipment, and reagents wherever possible. Images have been cropped and scaled to fit in the allotted space, but have not been digitally altered otherwise.)

Updated: 2/20/13 - Added Yu rxn pictures

Ref: Ye, M.; Gao, G.-L.; Yu, J.-Q. J. Am. Chem. Soc. 2011, 133, 6964-6967. doi: 10.1021/ja2021075.
Experimenters: Two - See Arr Oh (Somewhere, U.S.A.), Organometallica (IL)

Recommendation: Pending Blog Syn repeat
Initial - Moderately reproducible - yields/conversion lower than reported; reactivity / regioselectivity mostly consistent with literature. May require optimization.

General scheme:


Context: This reaction comes from a 2011 paper (dx.doi.org/10.1021/ja2021075) by Jin-Quan Yu's group at the Scripps Research Institute titled "Ligand-Promoted C-3 Selective C- H Olefination of Pyridines with Pd Catalysts." See Arr Oh proposed this reaction, noting its potential to be "operationally simple...with few variables to goof up, and wide substrate availability." Synthetically, C-H activation appeals to synthetic chemists due to its high atom efficiency (less waste) and simplicity (no need to pre-functionalize a reaction center).

The procedure employs a Pd catalyst to 'activate' the pyridyl C-3 carbon-hydrogen bond. A bidentate pyridyl ligand, phenanthroline (phen), presumably enhances ligand exchange via the trans-effect (to counteract the strong coordination of the pyridine substrate to the metal center). The reaction is run with a Ag(I) co-catalyst under air, which serves as the terminal oxidant.

The authors highlight the important of 3-alkenyl pyridine derivatives in chemistry, citing numerous natural products and pharmaceuticals exhibiting this motif. They claim the first instance of C-3 selective pyridine olefination (a number of examples with more limited substrate scope and different site selectivity are given). Just how C-3 selective? Yu and coworkers report C-3/C-2/C-4 site selectivity ranging from 7/1/1 to 30/1/1. 

According to Web of Science, the article has been cited 45 times as of February 2013 (including 4 reviews). A cursory SciFinder search didn't find any examples with direct usage of this chemistry; an extension to arylation is found in a 2011 synthesis of preclamol by Yu's group.
Update(2-17): A related reaction for C-2 olefination of pyridines was reported in Adv. Synth. Cat. 2012, 354, 2135. We apologize for this omission.

Experimental


Trial 1 - See Arr Oh

Scale: 0.5 mmol (same as researchers)
Entry: Compound 3a, Table 2 from JACS 2011, 6964.

Reaction in 75 mL
sealed pressure tube.
Reagents: ACROS Ethyl acrylate [140-88-5], 99.5%; Alfa silver carbonate [534-16-7], 99.5%; ALD anhydrous pyridine [110-86-1], 99.8%; STREM Pd(OAc)[3375-31-3], 99%; ALD 1,10-phen [66-71-7], Aldrich DMF, anh. 99.8%

Glassware: Pressure tube (75 mL, Teflon bushing) oven-dried o/n. All dry reagents weighed out in air.

Observations: First 5 mins: yellow pasty suspension. At temp (141.3 deg, sand bath) - deep orange-brown. After 16 h - deep brown, almost homogeneous, silvery Ag(0) / Pd(0) sheen around top of flask. Diluted with EtOAc, filtered over 1/2" Celite plug (2 x 5mL wash), then column chromatography (3 x 1 cm, silica, 1:4 - 1:1 EA / Hept).

Pale yellow oil, 7/1/1 meta / ortho / para, 27% yield overall (38 mg isol'd: 24 mg pdt + 14 mg DMF by NMR integration)

Advice: Crude product an orange gum, tough to handle / redissolve. I would re-load onto silica, and incorporate a water wash to eliminate DMF.

Supplementary images (click to enlarge):


1H NMR spectrum, post-chromatography.
Reaction setup, before heating.
TLC: left, ethyl acrylate
center, co-spot
right, reaction mixture
Filter.
Reagents employed.
Measured reagents.


Trials 2 and 3 - Organometallica

Scale: 0.5 mmol, as per SI conditions.
Entry: Compound 3a, Table 2 from JACS 2011, 6964.

Reagents: Palladium acetate [3375-31-3] (Strem, fresh bottle stored in glovebox), 1,10-phenanthroline [66-71-7] (Sigma-Aldrich, age unknown), Silver Carbonate [534-16-7] (Strem, ~2 mos old, stored in freezer in amber bottle within glovebox), ethyl acrylate [140-88-5] (Sigma, age unknown-purity >99% by NMR), Pyridine [110-86-1] (ACROS 99.8%), and DMF [68-12-2] (from solvent still, source unknown, see Advice for comments on this reagent).

Glassware: Pressure tube (75 mL).

Trial 3; reaction setup.
Observations: NOTE: This reaction was attempted multiple times. In all cases, the reaction was set up on the bench without precautions against preventing air contamination. Reagents were added neat to 75 mL pressure vessel in the order Pd(OAc)2, 1,10-phenanthroline, Ag2CO3, pyridine, ethyl acrylate, followed by DMF, then sealed and heated at 140˚C for 12 hrs.

For Trial 2, DMF used directly from solvent still, for Trial 3, air was bubbled through DMF for 1 hour prior to use. Trial 2: Reaction darkens, remains heterogeneous. Trial 3 (Pictured): Turns pasty yellow, still some solid left in the flask.

Analysis: 1H NMR: Trial 2: no conversion observed. Trial 3: ~40% conversion.

Advice: When I first ran this reaction (Trial 2), I panicked. There was absolutely no product; nothing by TLC, nothing by NMR, nothing by GC-MS. However, one of my friends who work on Pd-catalyzed C-H activation remarked that reactions run under air are particularly sensitive to solvent O2 concentration, so much so that he saturates solvents with O2 before use. Thinking this might be what plagued me, I aerated my solvent (Trial 3), which seemed to kick off the reaction. This may be the first time I've ever had a reaction fail for having my reagents be too clean!

Supplementary images (click to enlarge):
1H NMR spectrum, full

1H NMR spectrum, expanded to show
aromatic region

Results and Discussion


Author* response: Corresponding author Jin-Quan Yu (Scripps) was kind enough to respond with some helpful advice (Bold highlights are mine).
1. As what you have observed, the oxygen concentration is very important to this reaction. So the tube volume is also very important. We used the 50-mL tube, which is the total volume of the tube (from the bottom to the cap). For smaller one, the air is not enough. For bigger one, the pyridine will volatilize too much outside the solution. 
2. Heating and stirring is another important thing. Prior to starting experiments, turn on the hot plate and set the oil bath to 140°C first. To make the oil temperature is stable, you can put a paper clip into the oil, which will help to stir the oil. Put the reaction tube in the middle of hot plate to obtain a stable stirring (500 rpm is enough). Don't let the solid adhere to the tube wall. And make sure the surface of reaction solution is lower than oil surface. 
3. Another thing I should mention is that the quality of Ag2CO3 and Phen may ruin this reaction. We found that these chemicals from Strem Chemicals are good quality and there is no risk for this reaction.
Roundup: The reaction certainly works, though certain variables essential to its success are under-emphasized in the original paper (see Author response) and were unfortunately omitted from the SI. Notably, conversion depends on the presence of oxygen in solution (see Organometallica's trials). Even solvent aeration produced substantially lower conversion than the authors report (40% vs. 73% isolated yield). See Arr Oh did, however, observe similar regioselectivity (7/1/1 vs. 12/1/1).

Since both yields and observed regioselectivities fall within the low end of those reported, we classify this procedure as moderately reproducible.

Thanks to See Arr Oh and Organometallica for experiments, and thanks to Prof. Yu for providing feedback. Readers: if you have experience with this reaction or suggestions for future investigations, please feel free to comment.

*Addendum (Feb 20, 2013): After an exchange of emails, Prof. Yu felt it best to have a new postdoc (not an original paper author) repeat the experiment, and sent over pictures of the reaction setup, along with a crude NMR.





The ratio I get from these integrations is 12.7 / 1.5 / 1 (m/o/p), which agrees with the original publication.

Update (2/20/13): Prof. Yu indicates that integration of the crude against 0.5 equiv. of CH2Br2 (4.94 ppm, above) gives an NMR yield of meta-olefination product matching the literature (76%).

Of note, the reagents are quite different - he's using a higher grade of both (1,10-phen) and pyridine, but we don't have information on the acrylate used or the Pd source. Also of note, the 50 mL long, cylindrical tube volume clearly benefits the reaction, as alluded to in Prof. Yu's original email.

We thank Prof. Yu for sending along some clarification. Perhaps this signifies a change in the way reactions are reported; if everyone had to send along photo evidence, would there be so many reproducibility issues in the modern literature?

-SAO

12 comments:

  1. I really like the Mythbusters-style approach of first doing the reaction under standard procedures, then if/when it fails repeating things under stringent conditions until you see something close to the reported results.

    The comparison really highlights essential steps and conditions that may otherwise not be mentioned in the paper.

    ReplyDelete
    Replies
    1. Thanks! It was one of those scenarios where I wasn't ready to accept that the reaction just didn't work, and I figured it was important to try and understand "why," especially since I guarantee someone else would eventually make the same or similar mistake at some point. I think everyone at Blog Syn agrees that this isn't a literature witch hunt, but rather a guide to understanding the practical aspects of a reaction. Barring falsification, which I don't think Yu et al would ever consider, reactions in the literature should work to some degree, and so consider Blog Syn an attempt to bridge the gap between SI and users' hands.

      Delete
  2. Brilliant blog, guys, and a wonderful reminder of the sharp end of organic synthesis for those of us who haven't run a column in anger for over a decade (alas, limited scope for this on Wall Street...). With time, this could become a powerful endorsement for new synthetic methods.

    Two points

    1. See Arr Oh- nothing wrong with your technique, save for an apparent difficulty in drawing straight baselines on TLC plates. My approach was always to run my second finger along the bottom edge while holding the pencil, ensuring you always get a perfectly straight line! The sight of a permanganate-stained plate got this old chemist all dewy-eyed with nostalgia...

    2. It's probably not in the positive spirit of the blog, but I'd love you to tackle a reaction from an HC Brown paper. Any of them;)

    Keep up the great work!

    ReplyDelete
    Replies
    1. Anon - Good tip, I'll have to try it sometime.
      Luckily, I've never let my wonky baselines hinder setting up that next reaction : )

      Delete
  3. About TLC plates:
    1. Order some 6B pencils from Amazon. Super soft for writing on TLC plates without scraping off the silica.
    2. Carry a 6 inch ruler in your lab coat to draw the nice straight baseline with your new soft as a baby butt pencil.
    3. Get a flatbed scanner for the lab and scan your TLC plates for posterity. Faster than drawing and captures all the colors of development.

    ReplyDelete
    Replies
    1. With smartphones so readily available, it's easy to take a picture of your TLC plates, which can be easily uploaded into your electronic notebook

      Delete
  4. When the follow up paper you mentioned (10.1021/ja209510q) on C3 direct arylation came out, I was so shocked that I went to the lab and set one of the entries up to see if it would really work. I ran it on gram scale in a sealed vessel over a weekend, and given my bad technique, there must have been enough oxygen in there for it to give product.
    I did get the correct product, although both my ratios and yields were poorer than reported. I didn't see any reason to be concerned because I've published methodology and know first hand that sometimes even a detailed SI isn't enough because the authors have run the reaction so many times that they are well practiced. That being said, since they have run it so many times, they know what is important for success and therefore all the subtleties need to be mentioned.
    I think if this blog keeps going, it might force people to be more careful (or even honest if it applys) for fear of getting blogged about.

    ReplyDelete
  5. You're all getting an excellent insight into the world of process chemistry via this particular blog entry - mixing issues from a heterogeneous reaction, non-obvious but significant variable like headspace volume, and purity of reagents impacting reaction outcome.

    Definitely second the flatbed scanner for TLC plates. We had one back in grad school in the late 90's. Time you save versus drawing your TLC's adds up over the course of time.

    ReplyDelete
  6. This is a great blog!

    ReplyDelete
  7. Alluded to? He specified it.

    ReplyDelete
    Replies
    1. The allusion refers to the specific shape and dimensions of the tube in question. If you've shopped for pressure vessels, you know there's multiple shapes and sizes (rb, short, squared, external threaded, etc) for a 50 mL tube. In this case, the long cylindrical tube performs better than the short, squat tubes we used for our runs.

      Delete