Base baths

The classic soak bath is a mix of isopropyl alcohol with a generous amount of concentrated aqueous KOH. The disadvantage is that is tends to evaporate over time, is flammable and it shouldn’t be poured in the sink because EPA can bust you for sending isopropanol down the drain. There is one good base bath alternative without isopropanol – that contains aqueous KOH with K3PO4 (or any other K-phosphate, with extra KOH to make stuff strongly basic) mixed with some diluted liquid anionic household or laundry detergent. A common grade based on greasy-chain sulfonic acids works best.  The foaming is not much of a problem if you don’t overdo it with the detergent, few spoons is enough for a bucket. Please note that Na-phosphates or NaOH cannot be used as a substitute because Na3PO4 hydrate is poorly soluble and crashes out of the mix. Also some weird detergents tend to form an oily layer if the mix is too concentrated and salty – on the first try one should test the compatibility of the detergent before mixing vats of the bath solution.

This phosphate-based alkaline bath without iPrOH works very nicely for an overnight soak and I would encourage all alkaline bath-lovers to give it a try.

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I wash my dirty glassware as soon as it is produced – it is much easier to wash before the stuff dries on.  I prefer doing fewer experiments in parallel but clean and wash inbetween so that at the end of the day the hood is nice and organized again and cleared of the clutter. Hot water and acetone mostly does it for me, for difficult cases the bottles with 2M NaOH, 6M HCl and DMF are at hand. (The particularly nasty pieces of glassware are saved until I feel brave enough to play with piranha mix.) I stopped using base baths because they take space and I don’t like to fish in a bucket full of slippery glassware soaking in a caustic mix. Aluminum parts and frited funnels are eaten in base baths and the forgotten pieces of the glassware are slowly etched. But if you want your flasks picture-pretty then base bath is the way to go.

Update: The actual ratio for a large base bath tank that holds approx 100 liters of of solution is: 1 kilo of common grade 85% KOH pellets dissolved in about 2 liters of water, add 250g of K3PO4 in about 2 liters of water, dilute up to 100 liters total volume, then add a whole bottle of liquid non-scented color-free laundry detergent containing 32 laundry loads (we use a Publix grocery store “Free and Clear” brand with a little dirty boy on the bottle, it is supposed to contain a mix of anionic and non-ionogenic detergents and costs about $3 a bottle)

Patentz

 Credit: Jiri Sliva

I have gone on a tirade here about how writing your own patents is insidious because one gets encouraged by the demons in his head, the management and the patent lawyers to fudge things a bit and that’s exactly how some medicinal chemists start cheating. I deleted that piece because it wasn’t written well. I may come back to the subject when I calm down – though I should explain now what set me off to ramble about these things: I submitted a bunch of experimental procedures for a patent application in which I was the sole person doing the synthetic work. After the provisional patent was issued I found out that two fictitious experimental procedures were included in the patent submission – our patent lawyers found it expedient to dream them up. When I protested, the lawyers explained to me that they really didn’t have to tell me and I shouldn’t worry about such additions because they are being done by experts. From the lively debate that ensued I learned that I was using incorrect English. What I call a fake experimental procedure is actually a prophetic example. What I call bullshit is a modus operandi. I think it is reasuring to find the lawyer jokes so accurate.

Faked Experiments

When I came to US to join a small startup biotech company, my first assignment was to re-synthesize an active literature compound – a repulsive-looking peptidomimetic macrocycle. The compound was to be used in validating a new bioassay; the father of our young CEO needed the compound for his academic research. Our company “initiated a collaboration” with his group and that meant somebody ought to synthesize the stuff. Nobody volunteered but I was new and couldn’t protest – and my boss gushed that I could deliver the compound in six weeks. It took me over six moths of a full-time work – I was repeatedly offered reassignment to another project but I refused since I did not like to admit a failure. 

The SynLet. paper describing the synthesis that I was supposed to reproduce had no experimental procedures and the used starting material was not commercial or described in the literature. The only procedure for the starting material was in the PhD thesis of a person who did also the work on this published macrocycle. The procedures in the thesis were rather vague,  they never worked in my hands or in the hands of another chemist. I soon noticed that a hydrolytically-unstable silylated amine intermediate in the first step of a multistep sequence was formed in less than 50% NMR yield under conditions described in the thesis and the entire material was then immediately decomposed if the workup specified in the thesis was used. So I obtained this sensitive intermediate by alternate procedure, purified it by Kugelrohr distillation and took it to the next step – which also failed. Eventually I realized that the irreproducible thesis procedures were meant to be a “simplified” version of a known synthetic sequence. This original unmodified sequence worked exactly just as described so I  changed the protecting groups on the material in the end and then I could proceed with making the actual macrocycle.

I had a number of unpleasant surprises following the scheme and finally the key condensation reaction did not work at all. The reagents they “used” in the published scheme were different from the lit reference that they gave as a precedent for this step – and neither of these methods gave any trace of the desired product, on many attempts. I was getting desperate. Eventually I found a synthetic chemist whom I could talk to, from the group that published this irreproducible stuff. As I was describing my troubles he was laughing. It turns out that what they published was apparently an unmodified synthetic scheme from some grant proposal – with made-up yields. (They never retracted anything even after I alerted the PI about the problem. And they kept re-publishing this mess, once in PNAS then Synlett and later I think in Chem. Rev.)

My inside friend told me what kind of method they would use in such a case – different from the one published – so I was able to complete the molecule, convince my superiors that the problem was with the published baloney rather than with my freshly – minted MS degree from Eastern Europe. Looking back I think the PI in question knew from the beginning that his published work was irreproducible. But he could not afford to retract because he had to keep hyping the “technology platform” of his troubled small company in order to make the investors to continue pouring money in. (He also tried to plagiarize our methodology – I carelessly talked about my unpublished work and he published our results as his own, Cordova-style.) His company folded in the end.

 Credit: Jiri Sliva

5-Bromofurane-2-sulfinic Acid Lithium Salt

2,5-dibromofurane 1.570g (TCI-US, 6.95 mmol) solution in anh THF 15mL was cooled under Ar to -78C and BuLi 2.5M solution in hexanes 2.6mL (6.50 mmol) was added dropwise over 8 min period. The mixture was stirred for additional 15 min, then quenched at -78C with a stream of sulfur dioxide gas (Aldrich lecture bottle; above the reaction mixture level) for about 10 min; the volume of reaction mix increased by about 8 mL. The cooling bath was removed and the excess of condensed SO2 was blown off with a stream of Ar gas (about 30 min at RT). The reaction mixture was portioned between water 100mL and hexanes 100mL, the organic phase was re-extracted with additional water (2x25mL). The aqueous extracts were washed with additional hexanes (40mL). The aqueous extracts were combined and evaporated. The obtained solid residue was dried on highvac. Y=1.274g (90% th) of a light tan semicrystalline solid, approx 95% pure by NMR, HPLC.

1H(d6-DMSO, 400MHz): 6.430(d, 3.2Hz, 1H), 6.276(d, 3.2Hz, 1H); 13C(d6-DMSO, 100MHz): 172.38, 119.89, 111.68, 107.79; LC/MS(-ESI): 209, 211

Direct preparation of 2-Aminopyridines from pyridine N-oxides

There is a lovely JOC note from Merck Process group:

The N-oxide is transformed to N-tert-butylamino intermediate and then deprotected in situ with TFA in a one-pot operation. The procedure works well with a wide variety of substrates: pyridines, quinolines, isoquinolines. The few examples of unsymmetrically-substituted pyridine-oxides that had both the 2 and 6 positions free provided a mix of the two ortho amino regioisomers. [This is an improved version of the amination procedure with TsCl, NH3 that was useful for 2-aminoquinoline scale-up: Couturier et al, Org Process R & D, 10 (2006), 534-8.]

Another related simple procedure for acylamidation of N-oxides from Pfizer process group uses RCONCO that is generated generated in situ from RCONH2 and oxalyl chloride:

 

This acylamination procedure is however limited to quinolines, isoquinolines and phenanthrolines; pyridine N-oxides fail in the acylamidation. 

New reactions from Carreira

A fundamentally useful addition reaction that gives good yields with variety of substrates in ethanol at room temperature on a gram scale.
Markovnikov product, no stereoselectivity with chiral substrates, no ee’s reported with Jacobsen Co-salene as a catalyst (so probably there aren’t any). 
The catalysts are either commercial or 1 step to make. The azides can be transformed to triazoles or amines in situ. Works great with safrole.