There is a very informative discussion thread In the Pipeline today. It is about reactions that never work or are underwhelming in terms of yield and ease of workup/purification. So, to steal the subject, I would like to add few random notes:
PPA: A less viscous reagent alternative is called Eaton reagent, it is a P2O5 solution in methanesulfonic acid and you can buy it ready-made from Lancaster.
Azide reduction with phosphine: the iminophosphorane adduct is slow to hydrolyze in case of triphenyl phosphine, always use trimethylphosphine solution instead (stinky and expensive, but much faster, the phosphine is volatile and the phosphine oxide extracts into water).
Skraup: We called this kind of drastic conditions “Chemical Inquisition” in Prague. I guess it depends on the substrate. There are some high-yielding Sraups published in Org Process R&D journal, the process people typically use 3-nitrobenzenesulfonic acid as co-oxidant because the crap produced from the spent oxidant is soluble.
MnO2 oxidations: Like with silica or alumina, MnO2 is desactivated by moisture. You can re-activate it in glassware-drying oven, at 110-130C. (Works much faster after oven activation – but can be less selective. You can also add 4A powdered sieves). Non-polar solvents improve the reaction rate, sometimes doing the oxidation in cyclohexane instead of DCM is what is needed. Always use >20 equivalents to get to completion. BaMnO4 is a pretty good alternative to MnO2, and it is very easy to make (permanganate, Ba salt and KI as a reducing agent)
Grignard: Initiating the reaction is the tricky part, people have used 1,2-dibromomethane, iodine, TMSCl – but for me the best working initiation technique is to place few equivalents of Mg turnings into an oven-dried flask with a large egg-shaped stirbar, flush it thoroughly with dry argon, add few drops of Br2 and dry-stir the Mg turnings in the Br2 vapors overnight. Then add freshly distilled ether solvent via canula (the bromine color disappears) and then carefully your substrate. I got some Grignards like BrMg(CH2)3MgBr by this technique that are hard to make by other methods (unless you want to mess with Rieke Mg). The Mg turnings are fairly fragile and crushing them in oxygen-free and nitrogen-free environment uncovers a highly-reactive newly-formed surface which is further protected by MgBr2 formation. MgBr2 is soluble in ether. Please note that one has to use Ar because N2 reacts with fresh Mg surfaces, to produce dark Mg nitride.
Also, the Knochel transmetallation with iPrMgCl or iPrMgBr always worked great in my hands, with aryl iodides, at -20C.
Swern-like oxidation with SO3.pyridine in DMSO: the commercial SO3. pyridine often contains pyridine hydrogen sulfate impurity that can upset the reaction, always add few extra drops of pyridine and let the complex with DMSO form, before adding the alcohol.
Mitsunobu: The complex formation is pretty exothermic and overheated complex of DEAD with PPh3 decomposes quickly. Always start the reaction on ice bath. You can add phenol to phosphine before DEAD addition but secondary alcohols should not be premixed with the DEAD/PPh3 complex – a significant amount of eliminated product could form in absence of nucleophile. Use DIAD as a cheap and lazy DEAD alternative (the reactions take >2 times longer). You can use a slight excess of PPhe3 and kill the unreacted phosphine during workup, by adding few drops of 30% H2O2 (the oxidation is instantaneous). PPhe3O crystallizes quite nicely from a benzene-cyclohexane mixture so if your product is reasonably soluble you can dissolve the mix in benzene, dilute with cyclohexane and let it precipitate. The filtrates can be often applied onto a column directly, without evaporation.
DCC couplings: Acetonitrile or carbon tetrachloride are great solvents for DCC coupling, as dicyclohexyl urea is much less soluble there than in DCM or chloroform. You can dissolve the crude product in a small volume of ethyl acetate and put it in the fridge, to precipitate the last bits of the urea.
Lazy silyl protections: TfOSiR3 + lutidine usually works marvels, but ClSiR3 with DBU as a base plus catalytic DMAP in acetonitrile is in my opinion much more general than imidazole in DMF.
Hydrogenations: Pt on charcoal (5%) is much faster than Pd-C for ArNO2 reduction and unlike Pd-C, with some care one can reduce chloro-nitro compounds without the ring dechlorination (0.05-0.1 wt ratio of 5%Pt-C to substrate, in ethyl acetate or ethanol, H2 baloon, RT, 1 hour). Also, don’t use MeOH as a solvent in hydrogenations – unless you like to play with fire.
Vilsmeyer formylation: Oxalyl chloride in DMF usualy works faster and cleaner than the more traditional POCl3 in DMF. Oxalyl chloride is added first, with cooling on ice (gas evolution!), followed by substrate.
Thioamide preparation: Lawesson reagent is not fun to work up, for many substrates P2S5 is a nicer alternative.
Strecker aminonitrile hydrolysis to aminoacids: Aminonitriles tend to crap up during acidic hydrolysis to aminoacid, partial retro-Strecker happens. But if you formylate first with excess of formic-acetic mixed anhydride at RT without any base (96% formic acid is first mixed with an equal volume of acetic anhydride and allowed to sit under Ar for 4 hours, then the substrate is added) the acid hydrolysis of the formyl aminonitrile is very clean and N-formyl later falls off during HCl hydrolysis. This trick is was used by Vachal and Jacobsen in their tert-leucine paper. (I told them to try it.)
Initiating periodnane oxidations: Dess-Martin periodnane sometimes needs initiation, typicialy when a nice, freshly-made reagent is used. People have been adding a drop of tert-butanol or even a trace of water, to get the reaction started. But the addition of a small amount of pyridine works even better and the added advantage is that pyridine protects highly acid-labile groups in the molecule, like TES-O or 1-ethoxyethyl, from being cleaved by the reagent.
SeO2 allylic oxidations: Working up stoechiometric SeO2 reaction is awful, there is a nice Sharpless procedure for using catalytic SeO2 oxidation (5mol%) with salicylic acid as a co-catalyst and anhydrous tBuOOH (2-3 eqivs) as co-oxidant. It works well at 40C in DCM (in 1 day), the only complication is that salicylic acid gets slowly eaten and has to be replenished, I found that tetrazole is a better co-catalyst that does not have this stability problem. (Anhydrous tBuOOH solutions are somewhat expensive on large scale, diluting the 70% aqueous solution of tBuOOH with dichloromethane, saturating the aqueous layer with MgSO4 and extracting with dichloromethane and drying the extract with MgSO4 is easy way to make your own anhydrous solution).