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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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March 15, 2007

Lousy Reactions: Reader's Choice

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Posted by Derek

Here's a quick synthetic question for the lab jockeys in the audience: is there a name reaction that has never, ever worked well for you? The Skraup synthesis has a bad reputation, for example - I've never had the pleasure, but I've heard many stories of splattering dark crud and 20% yields.

I suppose we should distinguish between reactions that are supposed to work well and don't, and reactions that no one has ever claimed are nice (like the Skraup). There's a whole category of reactions that will give you 40 per cent yields when other methods will give you 90, but will also give you 40 per cent when everything else gives you zero. I can't say anything bad about those; they are what they are.

On the other hand, even more most reliable transformations can turn on you. I once had a primary alcohol that I just could not protect with a TBDMS group, a difficulty that made me feel like a complete hack until a disgusted colleague or two had to try it on the same substrate and I was vindicated. But silyl groups are usually pretty friendly. For now, let's take nominations for Least Reliable/Most Overrated Reaction. I'm curious to see what makes the list. . .

Comments (73) + TrackBacks (0) | Category: Life in the Drug Labs


COMMENTS

1. phenolic on March 15, 2007 3:20 PM writes...

Grignard...I remember doing a fail-safe one in an undergrad lab...and have tried about a half dozen different ones in my current research (i mean six different substrates) with no luck at all. I tried THF, Et2O, wet, dry, magnesium turnings, chunks, powder, I2, MgI2, different halides...

Now, I don't even bother. I just do lithium halogen exchange.

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2. Chemist of Sorts on March 15, 2007 3:44 PM writes...

The DIBAL-H low temp reduction of an ester to an aldehyde has certainly been blacklisted in my book. Good example of textbook Ochem reaction that just doesn't work well in practice. Nearly every time I tried it, I get mixtures of aldehyde and alcohol. So much easier (and better yield) to take the ester to the alcohol and back up to the aldehyde.

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3. Hap on March 15, 2007 4:32 PM writes...

Has anyone had experience with ring-closing (alkene) metatheses? They appear to work under a variety of conditions with substrates that are likely to be hard, but I've also read about isomerization problems with some substrates (diallylamines?).

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4. Mark M on March 15, 2007 4:40 PM writes...

I can think of many! Permanganate oxidation of a toluene-like molecule to the acid is no fun at all

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5. PK on March 15, 2007 4:46 PM writes...

We've blacklisted the Shapiro reaction... no one I know of has gotten it to work in anything but the simplest of model systems.

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6. Ψ*Ψ on March 15, 2007 4:48 PM writes...

I've managed to get nice results from Grignards, but I still prefer Li to Mg.
The Swern oxidation seems to work beautifully for everyone else in my lab but refuses to run when I do it.

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7. Handles on March 15, 2007 4:53 PM writes...

Does anyone else get a little over-reduction under Birch conditions, no matter what you do? Only a few percent, but really difficult to separate, and it carries through the next couple of steps. I like the pretty blue colour though..

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8. A-non-y-mous on March 15, 2007 5:27 PM writes...

I'll second the Swern oxidation. Tried it once or twice on the simplest of compounds as a grad student. it may have worked to some degree, but I was in no mood to purify so I tossed it. But for the record, most people I know have no problem with it.

It's not a name reaction, but how about named reagents? Lawesson's reagent: most hyped reagent ever! I wanted this to work in the worst way, and all I got was tar. Since I'd done a lot of pyrrole chemistry, I was used to the black stuff, but it was disappointing nonetheless.

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9. Jose on March 15, 2007 6:16 PM writes...

IBX!! The oxidation of unactivated benzylic positions does not work at all. (JACS 2001, 3183-3185). period. No SciFinder hits aside from the original publication. Tried toluene, with IBX from Aldrich and even made a fresh batch (NMR spot on), and got 0% conversion by TLC, GC and NMR. That paper should be blacklisted!

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10. Tot. Syn. on March 15, 2007 6:30 PM writes...

First of - nice topic, Derek!

Swern - no problem - done it on four substrates, and has no trouble. However, keeping it at the correct temperature is sooo essential!

DiBAL Ester to aldehyde - I've done that too on a few substrates, and it's the same deal. -30C seems to be the perfect temperature for my work, but all systems are different. LAH has been a bane of our lives in my lab - every sodding batch behaves differently. And the Mitsunobu is a b**tard.

However, my protecting groups never stay on - ever heard of TBDPSO cleavage by catechol borane?!!
And the McMurry coupling is rubbish - I've never known anyone to get that to work well.

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11. carbazole on March 15, 2007 6:49 PM writes...

I'll second the Shapiro reaction. I've tried, as well as two others in my group, and we can't get the darned thing to go. Swerns run pretty smoothly, and as long as you have bleach around for the smell, we've had no problems with them.

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12. Hap on March 15, 2007 6:56 PM writes...

Azide hydrogenolysis gave me 15% yields when I tried it, with most of the product ending up as secondary amine (which got someone a TL paper a year after I left grad school). I don't know if those are typically bad, or just me.

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13. d_orbital on March 15, 2007 7:02 PM writes...

The Sandmeyer kind of sucks. I always get a brownish-red goo. Products there, just never as much (or clean) as you'd like.

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14. rhodium on March 15, 2007 7:08 PM writes...

While I have had good luck with the Skraup (as long as I get to throw the flask away) I have never gotten a reductive amination with sodium cyanoborohydride to work. I've also heard tell the textbook Rosemund reduction does not work, not that anyone would do that anymore. Catalytic hydrogenations are always a black art, sometimes they dont work and the next time the substrate has the phenyl rings turned into cyclohexanes.

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15. Jim on March 15, 2007 7:46 PM writes...

Anything involving MnO2 is an absolute nightmare. This has a lot to do, I think, with the multitude's of forms (and activities) that the stuff can have. But even with careful formation of Gamma-MnO2, reproducible results are hard to come by and for most substrates (ie 5 out of 6 tried) I got Complex Residues And Products.

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16. Derek Lowe on March 15, 2007 7:48 PM writes...

Oh, it pains me to see nasty things said about Grignards. Although I have to admit that there are times that they just don't work, they've saved me more than once, and I just love to see 'em get going. As long as they don't get going right out of the flask, that is.

As for the Swern, it's been very reliable for me, producing the smell of success (dimethyl sulfide) almost every time. No complaints there.

DIBAL reduction to aldehydes deserves some of its bad press, though. I've always had some over-reduction; it's very picky about temperature; and the aluminum salts at the end can be messy, tartrate or no tartrate.

The only times I've done azide hydrogenolysis it's worked perfectly, ditto for the reduction with triphenylphosphine. Azides and I go way back. Cyanoborohydride should be an antique by now, replaced by triacetoxyborohydride for almost every application I can think of. I view its reign as an anomaly of the timing of discovery.

And, interestingly, the only time I ever tried a Shapiro reaction (a good twenty-three years ago, damn it all), it didn't work.

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17. Philip on March 15, 2007 8:39 PM writes...

Swern's work OK but I've pretty much replaced the Swern oxidation with the TEMPO oxidation for most simple alcohol to aldehyde oxidations.

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18. Tex on March 15, 2007 8:40 PM writes...

Semi-reductions with DIBAL for sure. My group has tried over the last ten years a couple of dozen of these, and only one ever worked. Now of course this could be due to the type of substrates (methyl benzoates) that we looked at most of the time.

Grignards - love 'em. Particularly use Knochel-type exchange reactions, they are sweet.

Done tons of azide reductions (Pd-H2 or PPh3/H2O or NaBH4), also no problems.

Swern - watch that temperature.

Tex

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19. Grizzley on March 15, 2007 8:53 PM writes...

Ullman couplings with heteroaromtic systems. Sometimes they work great, most of the time they royally suck. Thats probably why there is still so much research going on in the field. Yes, Buchwald has made vast improvements and most Med. Chemists love using his chemistry. Problem comes around when it needs to be scaled up by the process team. Two of the last three projects I've had the displeasure of trying to fix were primarily due to management not wanting to tread into an area which is covered by Buchwalds tenuous IP positions. Having spent a few years as a Med. chemist I always point out that maybe we should just roll the dice and challenge his patents or do like Med. Chem. and break his patents.

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20. Fat Old Man on March 15, 2007 8:56 PM writes...

1st, my vote for an unreliable reaction is the Barbier. Never worked for me. Seems odd to include carbonyl substrate in the same pot as the Grignard formation. I was prompted to write by the comment about the McMurry coupling. When I spent a few years at a sweatshop CRO I knew a guy who scaled up a McMurry coupling into 6 72L flasks at a time. One side of the alkene was adamantyl. Just to humble all of you, this guy started at the company as a janitor and worked his way to pilot plant manager. Never took a chemistry class. I know it sounds incredible. I switched from process chem to to project management a while ago but I sure enjoy reading this site

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21. movies on March 15, 2007 9:38 PM writes...

I'm glad to see the Shapiro made the list here. No one has had success with that in our lab either.

I have to admit I hadn't successfully put a TBDMS on an alcohol until my third year in grad school. I didn't try too many times, but I had bad luck every time I did.

I did an MnO2 oxidation a couple weeks back and I was bracing for a terrible result based on the reputation, but it worked absolutely flawlessly. A pleasant surprise!

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22. TNC on March 15, 2007 10:52 PM writes...

The trick with MnO2 is making it yourself.

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23. ZAL on March 16, 2007 2:59 AM writes...

I'll second the Mitsunobu reaction. Tried it three or four times and never worked well; I was a bit afraid about writing this, because it seems to work so well for so many people, but with the backing of a pro like Tot. Syn. I feel safe!

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24. Petros on March 16, 2007 4:38 AM writes...

Some silylations are incredibly sluggish. I recall trying to silylate a secondary alcohol, following a Tet Letts prep, and finding no silylation apparent. On enquiring of the author (at Merck) I was told that the reaction ahd been run for 14 days!

I always found the Mitsunobu to be OK but some Wittig recations to be a pain becuase of the problems of removing triphenylphosphine oxide.

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25. Milo on March 16, 2007 5:52 AM writes...

I needed to use the Corey-Fuchs once, and man it was horrific! Granted, my substrate was a little more complicated than PhCHO, however. For some reason, the I kept seeing yields in the lit for this reaction in the high 80s to low 90s. All I got was crap.

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26. LNT on March 16, 2007 6:41 AM writes...

A couple people mentioned reduction of azides with PPh3 ("Staudinger Reaction"). Like others, I've had mixed results with this seamingly easy reaction. I always seems to get significant amounts of the phorphoramide (conjugate of the reduced amine to the triphenylphosphine oxide). I don't know where it comes from and I don't see any reports of it in the literature! This always makes my yields moderate and purification tricky.

Mitsunobu's have decidedly mixed results for me as well. I've done a couple that work great, but numerous ones have failed for no apparent reason.

DIBAH reductions of a nitrile to an aldehyde has failed me every time I've tried.

Grubbs RCM works amazingly well -- I think that's why it's caught on so quickly. It seems very reliable.

Any sort of reaction involving polyphosphoric acids seems to be problematic. Occassionally it's worked well for me, but the vast majority of the time I get a black goo that doesn't dissolve in even hot DMSO.

I've also had very mixed results with Buchwald aminations. Sometimes they've worked great, but they frequently fail for no good reason. Ditto copper promoted amidations.

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27. estronaut on March 16, 2007 8:34 AM writes...

Why do a Swern when you can do a Parikh-Doering instead, just as stinky but the temp is nothing tricky, just an ice bath.

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28. Thomas McEntee on March 16, 2007 8:34 AM writes...

Next time anyone takes an Aleve dose, thank Victor Grignard and my lab colleagues at the Syntex Boulder plant. They developed the industrial-scale Grignard coupling process for naproxen and eventually ran 4000-gal batches around the clock virtually every day of the year. But in the beginning, even given our experience with Grignard reagents, yields were poor. But the prospects of a world-scale drug led to years of work on optimizing the Grignard formation and coupling reactions.

The folks in Bob Shapiro's group at Colorado who discovered what became known as the Shapiro reaction were not total synthesis guys and my recollections don't include their having pushed towards establishing the generality of this technique.

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29. Harry on March 16, 2007 9:37 AM writes...

Wow- I've had so many things flop that its hard to pick out the worst offender.

Love Grignards- I've done enough of them that I can usually get them going with a little tweaking.

Never had much problems with Skraups, the few times I've run them, aside from being incredibly messy and low-yielding.

LAH reductions have been hit-or-miss. Lots of literature yields have proven unattainable in my hands.

I'd have to say the one that I hate running most would be the Fischer Indole Synthesis, most especially those that require polyphosphoric acid. They are messy and mix poorly unless you're running them in a Waring blender and when they do run they tend to foam all over the place.

My $0.02. YMMV

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30. rk on March 16, 2007 10:24 AM writes...

Your comments on the Skraup reaction reminded me of a grad student classmate. He tried many Skraup reactions and never had much success. He finally changed the name of the reaction from "the Skraup reaction" to "the Screw-up reaction."

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31. pc on March 16, 2007 11:02 AM writes...

Cyclization of, for example, aromatic acids with polyphosphoric acid sometimes worked wonder when other conventional conditions failed. A recent project called for such a transformation and conditions such as conc. sulfuric acid or thionyl chloride refused to get things going. Eventually PPA saved the day to give yields around 80%. The only major inconvenience about this thing is it's very viscous and often times one has to heat it to, say 150 degree, before adding the substrate.

On another note Derek, it looks like for the same transformation though obviously with different substrates, folks could have different, sometimes dramatically, results. So how about a post with imput from the audience with regard to the tricks that can get these thing work?

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32. agogmagog on March 16, 2007 11:19 AM writes...


Commercial MnO2 can be activated by refluxing in Benzene or toluene, then distilling off most of the solvent. Store under the dry solvent until needed.

Love Grignards and Lithiations. Work well and pose enough dangers to keep life interesting.

Have struggled with DIBAL reductions. Some good, some bad.

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33. Erik on March 16, 2007 11:46 AM writes...

Oh boy, I second the Parikh-Doering for Swern replacement. It's been like magic for me in some tricky oxidations.

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34. SLCNJ on March 16, 2007 11:59 AM writes...

TEX---
DIBAL half reductions don't work ever on a.b unsaturated or aromatic aldehydes. Over-reduction in alipahtic systems is primarily a temperature phonomenon. Addition of DIBAL solution via syringe pump down the side of the flask at -78 C or better yet -90 C is your best bet. Often the overrduction occurs upon quenching so quench with xs methanol slowly in the same matter at the same temp.

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35. badjeannot on March 16, 2007 1:54 PM writes...

Yep, the Parikh-Doering oxidation is the way to go, I've never done a swern since I discovered it.

Radical deoxygenations using tin hydride and AIBN have always given very random results in my hands, although sometime it works OK.

For the birch reduction, using sodium benzoate to quench the reaction can avoid side reactions.

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36. one in tenthousand on March 16, 2007 1:58 PM writes...

Mitsunobu reaction...
The never discussed problem with this reaction is that it requires excess reacgents. Someone find an example in the literature where someone was using only 1 equivalent of reagent and/or nucleophile....And don't get me started about having to get rid of triphenylphosphine oxide and hydrazide byproducts.

You could also fill a book with examples where the reaction doesn't work or gave an alternative product.

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37. milkshake on March 16, 2007 4:48 PM writes...

Derek - as you can see, I totally stole the subject from your today's post.

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38. Art on March 16, 2007 6:25 PM writes...

There's also the of Corrolary of Inverse Mechanistic Complexity(TM) to consider. The more complex the mechanism, the easier it is in practice to run. I've built incredibly complex ring systems in a single step by throwing two things haphazardly together and having the products crash out in perfect yield 30 seconds later, whereas something like a simple damn SN2 reaction on a primary substrate goes to shit. Then when I go redfaced to the boss he talks about the Goldilocks Principle, which is always the preamble to an incredibly tedious, soul-sucking search in temperature, solvent, and pH parameter space for the right conditions to get the simple fucking reaction to work, for which no laud, honor or glory awaits your completion.

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39. CET on March 16, 2007 7:14 PM writes...

And here I thought that was just me . . .

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40. bitter pill on March 17, 2007 5:48 AM writes...

Anything involving allylic oxidations is my vote. Either SeO2 or Cr species always gave me fits.

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41. Processator on March 17, 2007 9:08 AM writes...

This is very cool information. I am going to save some of the tricks to handle MnO2 and do DIBAl-H reductions for future reference.

Remember that when you buy LiAlH4 it is not the only chemical that comes into the bottle. There are a bunck of other stuff depending on how long it has been standing ...

I am a process chemist so most of the times I do not only need reactions that are reliable and reproduceble but that they amenable for scale-up.

Never had much luck with Nicolaou's IBX oxidation chemistry in the past (now in Process I stay away from explosive compunds!).

Great post Derek!

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42. CET on March 17, 2007 9:55 AM writes...

Minor point: I'm pretty sure IBX is only explosive if you make it the old way - rumor has it that one of the side products tended to do a fast exotherm with the IBX.

I've never had any problems with the stuff produced using oxone - and I've had undergrads make 50g batches of it. I will grant you that IBX oxidations can flop unexpectedly. The mechanistic disagreements don't help either.

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43. MTK on March 17, 2007 10:13 AM writes...

To be honest I've never had that much trouble with most of the reactions mentioned, especially the Swern. I hate the smell and it does take some babysitting, so it's usually my oxidation of last resort, but it seems to bail me out nearly every time. I then kick myself for not trying it from the beginning.

Grignards always work for me, but since they're actually pretty lousy at SN2 reactions, I limit their use to carbonyl additions. I always form them by slow dropwise addition of a dilute solution of the halide with 0.5 equiv of DBE to a stirred suspension of 5 equiv of Mg turnings. Guarenteed to initiate everytime and minimizes Wurtz coupling. BTW, worse feeling in the world is when you've got a good size Grignard forming and you've realized it hasn't initiated properly, but that once it does, it's gonna blow.

Of the ones mentioned, the Mitsunobu is probably the most capricious. The darn thing seems to be so dependent on the order of addition and there doesn't seem to be a good rationale behind when to add what first. Oh yeah, and if your acid has a pKa higher than about 12, you're really pushing it.

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44. TNC on March 17, 2007 3:13 PM writes...

What is it about SN2 or alkyl halide coupling that Grignards can't do? Is it just the electronics of the situation?

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45. Chemist of Sorts on March 17, 2007 6:33 PM writes...

Alkylation is just not chemistry that grignards do well. Now add some catalytic Cu salt, and its a different story.

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46. PMP on March 18, 2007 10:21 AM writes...

DIBAL-H reduction of esters to aldehydes requires a stable tetrahedral intermediate - as such it works only with aliphatics and requires extremely cold temperatures, apolar solvents (toluene, hexanes) etc. The problem is that the reaction is very exothermic. As such cooling becomes a problem if you want to scale up your reaction - I recommend that anyone doing the reduction at > 10 mmol scale should
1) monitor the internal temperature AND, especially at > 50 mmol,
2) use mechanical stirring! This greatly improves heat transfer, reducing the overall reaction time, and improves selectivity (allows less time for the intermediate to decompose). Use a good, robust cooling bath - EtOAc/N2 or i-PrOH/N2.

There is always some overreduction, however, DIBAL-H saves an extra step and sometimes it is worth it - especially with substrates prone to epimerization.

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47. petr on March 18, 2007 10:43 AM writes...

I regularly use red-al for reduction of a crowdy ethyl ester to aldehyde on 1 mol scale with less than 10% overreduction. Rx is stirred like hell with mechanical stirrer, cooled to -80°C, with hydride being added dropwise. Excess of reductant is quenched with methanol at -80°C as well. On the other hand, methyl ester gives more than 50 % of alcohol under same conditions.

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48. eugene on March 18, 2007 12:27 PM writes...

"What is it about SN2 or alkyl halide coupling that Grignards can't do? Is it just the electronics of the situation?"

Chemist of sorts in #46 is very right. The copper salt protocol I find works best is 10 mol% of CuI. Add at -30 degrees Celsius and keep the temperature at -23 for an hour or two (this is very important), and most couplings with Grignards will work for me. Of course, then you have a lot of copper salts in your workup mixture that you have to dissolve with strong base.

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49. kiwi on March 18, 2007 5:14 PM writes...

Swern is one of the better oxidations around, keeping two key words in mind: cold and dry. but the thought of travelling back in time to run over victor grignards cat has occured to me more than once. i remember seeing it summed up somewhere: "grignard reaction(n): a completely fictional reaction that exists only in organic chemistry exam papers..."

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50. AMD on March 19, 2007 2:23 AM writes...

Re: TEMPO osidation. I have never had it work once. Always overoxidises benzyl or PMB protecting groups or has been sitting around for yonks and doesnt do anything at all. Minding the horrid smell, give me a swern any day

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51. tom bartlett on March 19, 2007 8:43 AM writes...

"DIBAL half reductions don't work ever on a.b unsaturated or aromatic aldehydes"

I've had luck with aromatics.

"Addition of DIBAL solution via syringe pump down the side of the flask at -78 C or better yet -90 C is your best bet. Often the overrduction occurs upon quenching so quench with xs methanol slowly in the same matter at the same temp."

The quench is key-- gotta kill excess reducing species. I like acetaldehyde over methanol.

Bad reactions: I've had poor luck in general with 3+2's, and with epoxidation of things like styrene.

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52. Copper on March 19, 2007 9:42 AM writes...

I've had bad luck with the dissolving metal reduction to remove tosyl groups - mostly I think because tosyl is junk. But amines need protection and since I switched to 2-nosyl groups it's been peachy ever since.

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53. eugene on March 19, 2007 11:27 AM writes...

I didn't think I had anything to contribute (due to poor memory of name reactions), but thanks to AMD for reminding me of the TEMPO oxidation. I just did it (tried to) twice. Didn't work at all and from what others told me it only works for the simple substrates in the original article.

I think it should be blacklisted as a general method due to the grief it has given others... since I have only a two-time experience.

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54. Phlogiston on March 19, 2007 1:09 PM writes...

The TEMPO oxidation is wonderful if you use a buffered bleach system with controlled addition of NaBr and careful pH control. If you control pH with a buffer, then TEMPO will not over oxidize to the acid.

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55. Michael on March 19, 2007 1:21 PM writes...

I have never been able to match literature yield on the conversion of 1,3,5-triacetylbenzene to 1,3,5-benzenetriacetic acid, using the Kindler modified Willgerodt reaction.
http://pubs3.acs.org/acs/journals/doilookup?in_doi=10.1021/ja01652a102

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56. MTK on March 19, 2007 1:31 PM writes...

TNC,

I'm not sure that I have a real good reason why Grignards are not very good at SN2 alkylations. (But that's not going to stop me from trying.) One could argue that the addition of copper points to some sort of "hard-soft" rationale for the reactivity.

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57. CR on March 19, 2007 2:25 PM writes...

I've since filed away the Shapiro in the "fun on paper, impractical in the lab" folder. I've never been able to make them work with anything but sec-BuLi (though I'm not entirely sure why) and always in very modest yields. What really turned me off was the material loss from the trisylhydrazone. In small molecule synthesis that thing is a huge.

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58. TheEdge on March 19, 2007 4:36 PM writes...

Re:Dibal-H quench, I like using EtOAc. It generally doesn't exotherm much, and it's a liquid year round (unlike acetaldehyde). As far as exotherming reactions go, you really ought to have a temperature probe in anything you can realistically put a probe into (>30-50 mL). Especially if it's > 0.1 M.
I've never liked the Prasad reduction or anything using Zinc borohydride. Too many problems getting rid of the boronate crap stuck to my product.

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59. richard blaine on March 19, 2007 9:53 PM writes...

I nominate BBr3 cleavage of methyl-aryl ethers to phenols. Completely capricious with varying substrates in my hands. Sometimes gives 80% yields with no effort, other times gives boatloads of green-brown gunk from which (after lotsa chromatography, thank FSM for Isco!), I can extract maybe 20% yield. Variations of time/temperature/equivalents have rarely helped. For example, recently with one fairly simple substrate I got gunk at room T and no reaction (!) at -78C.

I know there are alternative reagents for this task, but BBr3/DCM always seems irresistible in its simplicity on paper.

Tips will be gratefully received!

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60. marklar on March 20, 2007 12:16 AM writes...

One rxn that recently topped my list of ugly reactions, although not very common, was the decarboxylation of an indole-2-carboxylic acid using CuO in quinoline at 225 oC. Fortunately acid-base workup minimized the hassle, but the amount of waste generated is crazy.

I did a number of Dibal reductions in grad school going from lactone-->lactol without much problem. I agree with comments 34 and 51. I would use the next size larger rbf than I would normally use and submerge it in dry ice/acetone to the neck to allow for a larger cooling surface for the Dibal that was SLOWLY introduced along the inside wall of the flask. A co-worker had a good quench procedure of slowly adding a saturated Et2O soln of oxalic acid (not much oxalic acid dissolves in Et2O!!) followed by a sat. aq. oxalic acid soln to sequester the aluminum salts. It's a pretty good workup...I seem to remember having 2 'clear' layers and no pptd aluminum salts to filter--it's been awhile.

Another headache was working up a reductive-Nef reaction using a buffered aq. TiCl3 soln on an acid-sensitive substrate. It was a mess trying to separate the Ti-snot formed in the rxn.

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61. Jose on March 20, 2007 9:35 AM writes...

Richard- BBr3 can capricious, and *very* substrate specific. Best bet is to add 1.1 Eq at -78 C, warm to -30 C, get a TLC; if no rx warm to zero deg, TLC. If still no rx after a couple hours, warm to rt overnight. My experience is that you either get 90% yield, or it all goes to baseline, depending on substrate. 9-I-9-BBN (Aldrich) works very well, as does refluxing HI if your structure can take it.

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62. Anonymous on March 20, 2007 11:12 AM writes...

I had a lot of success with BBR3 in DCM. I always was able to add the crude reaction to water and filter off clean product in good yields

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63. soapchemist on March 20, 2007 12:41 PM writes...

Ok where to start:

Grignards - never had any problems with them... I have had some real slow starting reactions though and while I never tried the Cu addition trick, I have been able to get them going by sonication.

Reductive aminations - I have found that with some of the substrates I have worked with, sodium cyanoborohydride worked where sodium triacetoxyborohydride did not.

Ar-O-Me cleavage with BBr3 - I have never gotten this to work.

And on a different note, wrt DIBAL-H v. Parikh-Doering reactions: perhaps I am very wrong, but is this a comparison of oranges and grapefruits? I mean, both get you that vitamin C, but... So DIBAL-H reduces an acid to either the aldehyde or the alcohol (aldehyde desired), whereas the Parikh-Doering reaction starts from the alcohol. Isn't comparing them like comparing the above fruit... just plain wrong? (no offence to oranges or grapefruit; all analogies are, by their inherent nature, false)

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64. richard blaine on March 20, 2007 10:28 PM writes...

Jose: Thanks for the advice on BBr3 cleavage of ArOMe - very logical and sensible. I haven't tried 9-I-9-BBN, worth a shot. HI (and also AlCl3) tend to chew up my substrates. LiI/DMF has never worked for me. I have had some luck with substrates bearing an ortho-CHO by using the relatively weird Me-piperazine/BuLi procedure.

Anonymous+soapchemist re BBr3: My point exactly.

Anyone used Ph2PLi for this conversion?

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65. milkshake on March 20, 2007 11:45 PM writes...

There is also pyridinium hydrochloride melting at 140-150C. It is not as brutal as many people think. Py.HCl is somewhat acidic so you have to watch out for amide and sulfonamide hydrolysis but this problem is usualy just few% with the right temperature/time.

AlCl3 works lot better as a 2:1 complex AlCl3-Me3N.HCl. You add a good grade AlCl3 (solid) 2 equivs to vacuum-dried Me3N.HCl solid in a large flask. A crazy exothermic liqufaction occurs. When the resulting liqud mix cooled down, you dilute it with anhydrous 1,2-dichloroethane to 0.5-1M soln of AlCl3 and let the cloudiness to settle. You use it at 0C to RT, few equivs of AlCl3 per ArOMe. The used AlCl3 should be a good grade because Fe(III) traces tend to cause discoloration with phenols.

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66. Harry on March 21, 2007 7:10 AM writes...

Re: decarboxylation of Indole-2-carboxylic acids. Some of them can be carboxylated pretty readily by simply heating them in 2% acetic acid to 220C in an autoclave for a couple of hours (this gives you about 425 psig). The nice thing here it that any unreacted carboxylic acid is simply filtered out and recycled to the autoclave. Throughput stinks, but in general I've had better luck with this than the Quinoline/Copper oxide route.

Oh yeah- sometimes you can substitute N-methyl pyrrolidinone or N,N-Dimethylacetamide for quinoline.

My $0.02, YMMV

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67. Justin on September 20, 2007 3:25 PM writes...

I've had a lot of problems brominating the benzylic position on 2-methyl quinoline. The published procedures claim 40-50%, but I find myself getting closer to 5-10%. I usually end up with a lot of starting material and a lot of the dibrominated compound. My current solution to this problem is making an undergraduate run the reaction on a 30g scale once a week.

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68. Nick K on October 6, 2007 12:32 PM writes...

A few years ago we were faced with the oxidation of a Boc-aminoalcohol to the aldehyde by Swern. Yields were highly variable and usually terrible until we discovered that the freshness of the oxalyl chloride was critical. Merely redistilling it just before the reaction gave 90% yields consistently.

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69. dhanraj on November 4, 2007 9:45 AM writes...

dear sir
as a researcher in pharma r&d,i am facing the problem regarding the cyclization process in the processing of desloratadine intermidiate.past procesess reveals the usage of triflic acid and sulfuric acid+boric acid as a cyclization reagent.however use of triflic acid makes the product, cost more.in case of sul+boric acid the cost is not a problem, but the work up and the yield.with triflic acid yield is 70 per.and with other it is 85 per. reported,but i never crossed 55 per.does i have to change the work up condition-pls suggest me
thanking u
dhanraj

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70. subhendu on October 15, 2008 5:51 AM writes...

reduction of α,β-unsaturated ester to allylic alcohol in presence of an acid group at ortho position.selectively reduce the ester not the acid group. is it possible? which reagent i should use? please help

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71. Cda on July 7, 2009 11:27 AM writes...

Personally, I love the Swern, it always seems to work (except this last time, tried it on a 15 chain alcohol - nothing.)

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72. glinkst on December 11, 2009 4:29 PM writes...

I had plenty of problems with TCrap (aka TPAP) when it first became commercially available. I have been told it has improved considerably since then (early 90's).

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73. narasimharao on February 4, 2010 2:24 AM writes...

how to quench DIBAL H

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