Lately I’ve been stuck in synthetic limbo, a single transformation consuming months of work. With ample time to think I’ve tried to optimize my workflow, and the broad strokes are outlined below. I’d be (very) interested to hear from anyone who’s found a different way through.
Fail early, fail often
An implicit assumption in this plan is that the bulk of what I do is wasted effort. Almost all of the reactions are going to fail, while the few that succeed may be low yielding or give products that rapidly decompose, even in the reaction vessel. Depending on the compound common analytical techniques like mass spec. and NMR may be unreliable or exceedingly difficult to interpret. In short, it’s going to be a bumpy ride.
Mentally, the key for me has been to dissociate the ego from the chemistry. It’s easy to get excited when something works and sad when it doesn’t, but the only way out involve a lot of bad news. Since failure can’t be avoided it has little bearing on your skill as a chemist–you aren’t the first to go through a bit of a rough patch and won’t be the last.
What’s a win, anyway?
Let’s start by defining success. The goal is compound XXX, but the various reaction vials aren’t going to shout out their contents. Purifying each and subjecting the contents to full NMR/MS analysis is incredibly time consuming, and if each run requires a column you’re going to have plenty of time to memorize the treaty of Westphalia.
So ideally we’ll look for the compound of interest in the crude, after either the workup or quench. If you’re lucky enough to have a standard of the material you need to make (and it’s stable), TLC is simple, fast, and informative. I have a preference for multi-coloured stains like anisaldehyde or vanillin, which discriminate spots based on structure as well as Rf.
Crude NMR also sits in the “simple, but powerful” bracket. While I generally don’t run crude NMRs during routine synthesis, a quick scan of the proton spectra will reveal the presence or absence of key peaks, again saving you the time and effort of a tedius workup/purification. This works best for reactions that give >5% yield, as otherwise the peaks of interest tend to be buried in the baseline (longer scans will reduce throughput, which may or may not be a concern).
If you don’t already have a sample of your compound of interest, a different approach is required. Mass spectrometry is the easiest way of spotting a single compound of interest among dozens of byproducts, and nearly every lab has access to at least a basic instrument. GC(-MS) and LC(-MS) both go one step further, giving information on the yield and removing contaminants which might otherwise quench the MS signal. The ideal system may be an automated LC-MS, which is more useful than TLC .
Measure twice, cut once
Once you can definitely say if a reaction is successful, it’s time to find a few dozen to try. As the project goes on expect to spend significant amounts of time on Scifinder/Reaxys digging up obscure 1970’s protocols, looking for new conditions and reagents. Don’t worry about trying the obscure and implausible, as presumeably you’ve already tried the conditions most likely to work .
Once you have 5-20 papers picked out, start setting up reactions. I’m a big fan of vial chemistry at this stage, for the simple fact that multiple round bottomed flasks don’t fit on stir plates very well. Your starting material is likely precious, so restrict quantities to the smallest amount needed for analysis .
Take the time to do things properly. Work only with pre-dried glassware, maintain an inert environment, control the temperature, add reagents slowly, and mix well. Every reaction is new, and it’s hard to know in advance which require special care to work properly. The only thing worse than running 100 reactions without success is running 200 because one that should have worked failed due to a temp. fluctuation or math error.
Most reagents will fail to react, while the broad remainder will decompose the starting material. Double your reaction load and try to make every reagent do both, by chilling the reactions that decomposed and heating/forcing those that did nothing at all. If you don’t see product under both gentle and forcing conditions, move on. In the absence of a confirmed hit (ie. a good NMR or LC-MS spectra) I haven’t found it useful to try a full suite of conditions for each reagent, but exploring the limits on either end gives information quickly and cleanly.
Learn from your successes
Eventually you’ll move forward, with one or more reagents forming the compound of interest. With several results the next step is clear: take the highest yielding or most accessible reagent and optimize the conditions, varying the temperature, time, solvent, proton source, catalyst equivalents, etc.. Again, yield by NMR or GC/LC/HPLC traces will save time over a full purification.
If the best reaction remains low yielding after optimization, in my limited experience it’s time to get a better understanding of what’s going on in the flask. Either set up the reaction in an NMR tube, or if that’s not possible quench the reaction at various timepoints and do a set of crude NMRs or GC/LC/HPLC runs. Either approach gives qualitative information on the kinetics of the reaction(s), which can be used to determine if the low yield is due to transformation of the starting material into various side products or simply the result of decomposition of the final product.
Side product formation is probably the more challenging of the two situations, and can occasionally be (further) reduced by adding pathway-specific inhibitors. Modifications to the reagent itself may also be fruitful, but presumabely if this is the first hit in 100 reactions you’ll be relatively limited on that front .
With an unstable product the road forward is somewhat simpler. Overoxidation and the like can be partly controlled via slow addition of reagents (syringe pump), or if the expertise/equipment is available flow chemistry. In the worst case the crude NMR can be used to determine yield over time, and a mid-reaction quench can give good yield based on recovered starting material.
None of these are like the others
I’ll close with a quick disclaimer. No two projects are the same, and the problems you face will likely be unique as well. Above all pick what works and discard the rest.
 And far more expensive, outside of the range of most academic labs. One can dream.
 Few obscure conditions are fully tested for substrate scope. I once took an alkylation procedure used on a single non-aromatic primary alcohol and adapted it to a system with four protected hydroxyls, four protected amines and one very hindered secondary alcohol. It worked quite well.
 Standard solutions are useful here. Dissolve your compound of interest in a low molarity carrier solvent (DCM/ether/pentane/etc.), add via syringe, then remove the solvent under an inert gas stream if necessary.
 It may be possible to elaborate on the reagent, for example moving from proline to a more complex proline-based scaffold (ex). However, unless the other reagents are commercially available or you are in pilot plant setting this route will probably take far longer than is practical.