Org Prep Daily

August 27, 2008


Filed under: procedures — milkshake @ 7:15 pm

 A mixture of anh. acetonitrile 12mL and isopropyl alcohol 1.4mL (18mmol) in a 25mL flask was cooled to 0C and N,N,N’,N’-tetramethylguanidine 1.9 mL (15mmol) was added under Ar, followed by azidotrimethyl silane 2.0 mL (15mmol), dropwise over 5 min – an exothermic reaction. The resulting solution of TMG-azide was warmed up to RT and then transferred by syringe to 2-chloro-4-iodo-5-trifluoromethylpyridine 3.075g (10 mmol) solid. The mixture was stirred under Ar on a 40C bath for 6 hours, then cooled to ambient temperature and portioned between half-saturated NaHCO3 solution 70mL and ether 80mL. The aqueous phase was re-extracted with ether 80mL. The organic extracts were washed with additional half-saturated bicarbonate 70mL, combined, dried with magnesium sulfate and filtered. The obtained solution of crude azidopyridine was placed on ambient water bath, water 1mL was added followed by 1M trimethylphosphine solution in toluene 11mL (11 mmol; exothermic reaction). The mixture was stirred at RT for 30 min, then washed twice with water (2x250mL) to remove Me3PO, the aqueous phases were re-extracted with ether (250mL). The combined extracts were dried (MgSO4) and evaporated. The residue (2.0g) was re-crystallized from cyclohexane 120mL to provide 1.517g of a 95%-pure product as white feathers (77% overal).

1H(d6-DMSO, 400MHz): 8.170(s, 1H), 6.932(br s, 2H), 6.758(s, 1H); 19F(d6-DMSO, 376.5Mhz): -61.93 (s, 3F);

Note: The neat crude monoazido intermediate can be isolated as a colorless oil (and separated from a crystalline side-product, posibly derived from bis-azido pyridine) but 4-pyridylazides are rather unstable and reducing them in diluted state without further purification is a safer alternative. TMS-N3 is skin and gloves-permeable and causes unpleasant acute azide poisoning (= nasty headaches). PMe3 has a pungent, obnoxious odor.   

This procedure uses organic-soluble azide salt. TMG.HN3 can be isolated and stored; it is an extremely-hygroscopic crystalline solid (Org Prep Daily September 25, 2006). The preparation of the starting iodo pyridine was also discussed here, in Strange bits from Schlosser, on June 7, 2008.

August 26, 2008


Filed under: procedures — milkshake @ 12:35 am

meta-Hydrazinobenzoic acid 1.552g (10 mmol) was suspended in concentrated HCl 50mL. Arnold hexafluorophosphate salt 7.10g (15 mmol) was added, followed by acetic acid 100mL. The mixture was stirred for 10 min, then placed on a 100C oil bath and stirred under reflux for 3h 30 min. The reaction mixture was cooled to room temperature, filtered (the insoluble fraction was washed with water) and the combined filtrates were evaporated to dryness. The residue was suspended in water 100mL and stirred on ice bath for 1 hour, the precipitate was collected by filtration, washed with ice-cold water and dried by suction. The crude product was dissolved in a mixture of ethanol 45mL and water 140mL at reflux, charcoal 0.5g was added and refluxed for 5 min, then filtered while warm, the charcoal was washed with 3:1 (v/v) water-ethanol mixture (2x15mL) and the combined filtrates were allowed to cool to ambient temperature, filtered again from a small amount of oil, and the filtrates were stirred vigorously on ice bath for 1 hour. The precipitated product was collected by filtration, and re-crystallized for the second time (from a mixture of ethanol 100mL and water 200mL, 0C, fridge overnight) to provide 1.176g of a 95% pure product as a yellow-white solid (54.5% th)

LC/MS(+ESI): 217(M+1); 1H(d6-DMSO, 400MHz): 13.340(br s, 1H), 9.927(s, 1H), 9.370(s, 1H), 8.437(br t, 1.8Hz, 1H), 8.308(s, 1H), 8.176(ddd, 8.1Hz, 2.3Hz, 1.0Hz, 1H), 7.959(dt, d:7.8Hz, t:1.3Hz, 1H), 7.690(t, 7.9Hz, 1H)

Note: In the absence of conc HCl, the main product is the m-carboxyphenyl hydrazone of the pyrrole aldehyde (= 2:1 condenzation product of arylhydrazine with triformyl methane). HCl slows down the hydrolysis of the iminium groups. Arnold salt preparation was posted here on Feb 24, 2008.

August 19, 2008

Our lab you must not enter

Filed under: lab destruction — milkshake @ 10:04 pm

When I was fired from my first lab in college for the phosphine stinkup, no-one volunteered to have me so for awhile I had a bench and hood in the teaching labs. I was there alone, enthusiastic and without supervision. The glycidol story was mentioned already; I will describe two more memorable experiences:

Burning acrolein: We couldn’t buy things from Aldrich under communism and acrolein was unavailable from domestic supliers. Eventually I decided to make my own; there was an ancient lab procedure from glycerol by pyrolytic dehydration over KHSO4. (The yield is dreadful but we had a drum of glycerol in the stockroom).  I did it on a grand scale and I ended up with about 0.5L of crude acrolein containing lots of water. To remove the water I got the idea of using magnesium perchlorate as a drying agent - we had a big bottle of that stuff on the shelf and I was reading somewhere that Mg(ClO4)2 was a potent desiccant comparable to P2O5 in its dehydrating proves. No wimpy sodium sulfate for me.

So I was spooning perchlorate into my acrolein and it kept dissolving – I ended up adding a whole lot of it and it was still dissolving and the mix was getting alarmingly hot and yellow. “Oh no, the perchlorate is all soluble and my acrolein is now polymerizing because of it, I will lose it all – quick, I must distill it all at once to rescue it!”. So I put the mix onto a heating mantle, added a distillation adapter and condenser and turned the heat on.

The hood sash was down and I was few meters away when a brilliant orange light from within the flask illuminated the lab and the entire hood turned black in an eyeblink. With a tremendous “wroooommrrr” that rattled the windows, the mix instantly burned away like a rocket engine and then the flame died out – before I realized what I have just done. The flask was still in one piece (only the condenser flew out) and a foot-high layer of soot was now filling the hood. The black tongues got painted on the wall behind the hood, emanating from the few places where the hood leaked. I turned around and saw a black cloud hanging by the ceiling and slowly settling down like a pillow. The entire  lab got dusted with the greasy soot - a notebook lifted from the bench left a light rectangle behind…

It is inconcievable how much fluffy black dust can be produced from a half-liter of this mixture – I remember scooping out several buckets of soot that I had to smuggle out of the building. About six hours later (and a bottle of detergent) I was looking like a chimney sweep but the lab was all scrubbed clean and nobody found out about my perchlorate+acrolein jet propulsion experiment.

Milling KOH: I was about to reproduce some old-fashioned procedure that used a slurry of powdered KOH in toluene as a base. Now KOH is very hygroscopic – I tried to powder it with a mortar and pestle at first and the pellets were flying all over as I pounded on it while the stuff was melting into a puddle of lye. I realized the grinding had to be done very fast. Asking around, I found out that one faculty man owned a fancy electric grinder: The machine looked like a giant coffee-grinder on a blender; the container was made of heavy glass and the oversized motor had a beautiful aluminum casing.

“It’s the only power-grinder we have – You are not going to use it on anything corrosive, right?” – the owner asked. I assured him I wouldn’t.

The grinder worked amazingly well and in no time I had lots of free-flowing KOH dust (which I immediately bottled to keep it from getting soggy) – but I noticed as I was taking the grinder apart that I spilled some KOH dust onto the motor casing and the aluminum was getting pitted by the hydroxide. More worryingly still it looked like the caustic dust has gotten into the electric motor itself through the vent holes in the casing. It gotta be cleaned promptly.

I was not familiar with the Mr. Bean skit character back then, but with the same kind of single-mindedness I proceeded to wash up the motor casing in the sink. I was not careful and some water splashed through the vent holes  – and since the KOH dust got in there and the electric motor was  already wet, I decided that the motor deserved a proper rinse as well – I would dry it afterwards. So I had the water flowing in and through the motor.

The owner of the grinder dropped by later that afternoon to find out how it worked (and if I was ready to return it). I said I needed to clean it up a bit more – the motor was still very soggy and I prefered not having to explain how it got that way.

Wet glassware dries pretty fast when rinsed with acetone. Being in hurry I reached for a squeeze-bottle and washed the motor with acetone too – and surprise – the acetone coming out from the motor was dark brown and smelling just like shellac resin that is used to insulate the fine copper winding in  electric motors…

I was horrified, I realized I just ruined it completely and I better try to cover it up. I dried the motor with a heat gun and assembled the grinder. I gave it a good final polish and then I waited patiently until I saw its owner walking away from his lab – and then I sneaked in and put the grinder back in the cabinet as if nothing bad was done to it (I turned the pitted aluminum part away from the sight). Just as I was closing the door the owner returned. “Thank you – it worked great. I put your grinder back and it’s all clean now…”

But the luck was not with me. “OK - let me see if it still works” the guy says – and he takes this thing out and plugs it in the wall. A loud bang and a green-and-white lightning, the sparks flying all across the room and rolling on the floor before gradually dying out like embers. (I saw a street transformer once, blowing up like that but from a safer distance). We were standing there in silence for few long seconds – the only sound was the “klip-klop-klop” from the hallway as the circuit breakers gave up one by one and plunged the chemistry building into darkness.
The faculty guy then turns to me and says: “Thank you. Don’t hesitate if you need my help again.”

August 18, 2008

Chromenes: Baylis-Hillman-derived cyclization

Filed under: procedures — milkshake @ 11:01 pm


DABCO, 1,4-diazabicyclo[2.2.2]octane 4.5g was added to a mixture of 2-hydroxy-5-methoxybenzaldehyde 26.60g (174.8 mmol) and neat acrylonitrile 20mL. The mixture was diluted with additional acrylonitrile 40mL (5.2 eq. total) and refluxed on a 110C oil bath for 5 hours. (Note 1,2). The reaction mix was cooled to RT, diluted with ether 0.5L, shaken with 10% NaOH aq solution 250mL for 5 min then separated. The org phase was washed sequentially with water (250mL), 0.5M sulfuric acid (250mL) and then more water (2x250mL). The aqueous phases were re-extracted with ether (250mL). The combined org. extracts were dried (MgSO4) and evaporated. The solidified residue was dried on highvac. The crude product (a yellow solid, 30.2g) was re-crystallized from methanol (140mL, at 0C overnight, rinse with chilled MeOH) to provide 19.223g of a pure material (98%+) as light-yellow crystals. Evaporating the supernatants and re-crystallising the residue from methanol (50mL, -20C overnight) provided a second crop, 2.827g (96% pure by HPLC). A third crop 1.998g (97% pure) was obtained from the second supernatants (evaporation residue recryst from MeOH 20mL, -20C). The combined yield was 24.048g (73.5% th)

1H(d6-DMSO, 400MHz): 7.537(br s, 1H), 6.896(m, 3H), 4.803(d, 1.3Hz, 2H), 3.714(s, 3H)

24.00g of the nitrile from previous step (128.2 mmol) was combined with aq. solution of NaOH 40g in water 400mL(total volume).  The slurry was stirred vigorously under reflux on a 120C bath for 5 hours. Charcoal 1g was added, the mix was re-heated to reflux briefly, then cooled to ambient temperature and filtered (the charcoal was washed with additional water until the filtrates were no longer yellow). The combined filtrates were made strongly acidic with  conc. HCl (150mL, exothermic), the resulting slurry was cooled on ice bath, the precipitate was collected by filtration, washed thoroughly with water, dried by suction and then on highvac. The crude acid was dissolved in refluxing acetonitrile (0.6L), allowed to sit for 5 min, then rapidly filtered through a large Buchner funnel while hot and the Buchner funnel was rinsed with additional hot MeCN  (approx 10mL), the combined filtrates were re-heated to full dissolution and the mix was allowed to crystallize overnight. Filtration and a rinse with cold MeCN provided the first crop 18.546g as golden-yellow needles. The second crop 4.392g was obtained by evaporating the supernatants and re-crystallising the residue from MeCN 120mL. The third crop 0.888g was obtained analogously (from second supernatants, re-cryst from MeCN 20mL, yellow plates). The combined yield was 23.826g (90%Y) of a pure acid.

1H(d6-DMSO, 400MHz): 12.821(br s, 1H), 7.422(s, 1H), 6.957(d, 2.9Hz, 1H), 6.849(ddABX, 8.7Hz, 2.9Hz, 1H), 6.785(dAB, 8.8Hz, 1H), 4.827(d, 1.4Hz, 2H), 3.704(s, 3H)

Note 1: Acrylonitrile is a potent irritant - and a good carcinogen too. Use gloves, avoid the vapors. Asthmatics keep their inhaler at hand.

Note 2: The original procedure calls for 20 h reflux. In my hands there was no further change after 3 hours reflux on a 110C bath - so I eventually stopped it at 5 hours because DABCO also catalyzes acrylonitrile dimer formation. Fluka acrylonitrile (BHT stabilised material) was used straight from the bottle.

August 11, 2008

The Road to Boredom (and back)

Filed under: industry life — milkshake @ 6:41 am

Derek Lowe of the Pipeline wrote a very insightful column in the last Chemistry World issue, about the narrow repertoire of synthetic methods used in medchem projects. His take is that the need for cranking out compounds for testing (=as many as possible) drives the chemists towards fool-proof reactions with a good functional group compatibility and building block commercial availability. The narrow choice often leads to insoluble series with poor oral availability and PK problems and insufficient structural diversity. More serious still is the turn-off effect on the chemists:

…For one thing, skills do need to be kept sharp, and running a variety of different chemistries is the best way to do that. And safety seminars aside, medicinal chemists do not actually have limitless capacities for boredom. Running yet another long line of palladium coupling reactions or amine displacements begins, after a while, to feel like working at a sawmill. The blade takes longer to cut through some of the logs than others, but the boards all come out looking about the same.

I think the problem of poor solubility and ugly design became more serious with the advent of kinase projects; the kinase slit-like binding sites typically extend far enough to accommodate ligands consisting of multiple aryl rings put together like beads on a string. Gleevec, Lapatinib, Dasatinib have this sort of structure - but then again, various ugly molecules are used in cancer treatment; I am unsure if this design will work for other therapeutic areas also.  (I have been making kinase compounds for a good part of this decade and I still like the smaller + more compact molecules better).

I met a number of chemists in the industry that already gave up on reading journals - their argument was that there were too many journals and too many articles and most of it was not very useful to them and whenever they needed to find a reaction the Scifinder and Beilstein-Crossfire search engines did adequate job. (Which is true). But I noticed that one typically loses his chemistry interest about the same time when he stops reading the literature; I don’t know what is the cause and the effect here.

More than 90% of synthetic chemistry is routine stuff – and frequently frustrating one, too. There are easier and healthier professions to chose from. I believe that most people got into synthetic chemistry because they experienced a sense of wonder, and they just kept coming back for more. Mixing up obscure, dangerous chemicals to obtain shiny crystals at the end is a pretty awesome and esoteric way to make living. Designing your own experiments and figuring out their problems, inventing tricks to make the chemistry work, trying your nutty ideas (to see if they translate into good compounds) is enormously gratifying experience. If the curiosity is quenched and the excitement is taken away all what’s left is shaking the sep funnels, putting flasks on the rotovap and analyzing fractions as they come off the column…


There are various non-chemistry reasons why someone stops enjoying his particular project (personal-life problems, the lack of support, evil boss, problems with biology, the bureaucracy and politics, etc.) and the way to go about those difficulties is obvious. Instead I have few chemistry-related suggestions what to try, when the boredom and frustration takes over and the project becomes unsufferable:

1. Scaling-up. When chemistry does not work try some easy reliable procedure. Pushing through bulk material such as a commonly-used building block or an essential reagent that you made before helps to boost your self-confidence in times when your other chemistry failed you. Making a flask full of bright-yellow crystals is deeply satisfying and when you filter them, dry them and put them in a  bottle with a pretty label, when the NMR is clean, at least you don’t feel like a hack anymore. Besides if the material is useful to your group passing it selflessly around will make you popular.

2. Fluorine chemistry: Too many chemists opt to buy the fluorine-containing pieces without worrying how these molecules are made. There is a growing number of organofluorine building blocks available, companies like Apollo have a fat catalog full of them – but many important pieces are not available and easy chemistry to prepare them exists. Medicinal chemists shouldn’t be exhorted to work with F2 or anhydrous HF – but reagents like Deoxyfluor, Selectfluor, (PhSO2)2NF, NEt3.3HF are commercial, affordable, and are not too difficult to use (if the necessary precautions are taken). Many people are simply unaware that metabolically-stable difluoromethoxy group is readily introduced on a phenol OH by alkylating it with difluorocarbene (which is produced from chlorodifloroacetic acid) or that ArCF2CO2Et is easily made from Aryl iodides, BrCF2CO2Et and activated copper metal in DMSO under mild conditions, that CF3 group can be introduced  on aryl iodides with equal ease with catalytic CuI and sodium trifuloroacetate, that difluorocarbene in presence of PPh3 produces a Wittig reagent (that converts aldehydes to useful 1,1-difluoroalkenes), that trifluoromethyl anion generated from TMSCF3 adds to imines and aldehydes with ease etc.  There is a whole continent of a strange organofluorine chemistry and a medicinal chemist would do well to make himself familiar with these methods because apart from the nastiness of some HF-generating reagents these reactions tend to be well-behaved and predictable.

3. Metallation: Thanks to Schlosser and others there is a body of literature on position-selective lithiations of heterocycles, like pyridines and pyridimines, and there is also older literature on use of ortho-directing groups in benzene metellations. Very often these reactions are done with common reagents like BuLi, LDA, LiTMP, at simple conditions like THF -78C.  The functional group tolerability is not as great but this aryl CH-lithiation can be a powerful way of accessing simple building blocks with a special substitution pattern - a great help when changing the centerpiece ring in the series and run into the availability problem. 

Mg and Zn chemistry: Knochel is developing beautiful systems, for halogen-metal exchange, and many of his transmetallation reactions using secBu-Grignard and zinc reagents has been promptly adopted by process groups but medicinal chemists are lagging behind.  One can easily generate Grignards with ester ot even nitro group in the molecule, by transmetallation, and zinc reagents can provide much cleaner Negishi coupling than their Suzuki boronic acid counterparts.

Schwarz reagent, BBN-H borane: hydrometallation and hydroboration is a great way to access commercially-unavailable building blocks for Pd(0) catalysed cross-coupling reactions. BBN boranes do Suzuki-like sp3-carbon coupling with aryl, vinyl halides.

4. Cyclopropanation: Cyclopropyl substituents are of a great interest to a medicinal chemist on their own but they are great also for ring-opening reactions (they behave as a 3-carbon analog of C=C bond). In my opinion the enormously easy-to-use zinc promoted reactions (CH2I2 with ZnEt2)  and titanium-promoted cyclopropanation reactions (Cp2TiCl2 with Grignard) are neglected in medchem projects.

5. Asymmetric methods: There are so many of good ones and yet any medicinal chemist will always look first into buying the chirality – perhaps this has to do with the inconvenience of setting up a chiral column for analysis of the product ee. (One does not have this sort of excuse with chiral auxiliaries).  And some of the reactions are exceptionally easy to run, with commercial catalysts and and great functional group tolerance: Noyori Ru-TsDPHEN transfer hydrogenation of ketones, CBS reductions, Sharpless allyllic epoxidation, dihydroxylation and aminohydroxylation, Jacobsen asym epoxidation and epoxide hydrolysis kinetic resolution. There are Rh and Ru-phosphine C=C hydrogenation that go at modest pressures (50psi) and thus can be set on a Parr shaker. There is a whole field of organocatalysis, with simple catalysts like proline, doing great feats on simple aldehyde substrates - several stereocenters at once.  I think its mostly the laziness that medicinal chemists do not adopt these reactions more frequently even as most of them get trained to use them in grad school; as soon as they join pharma they learn to weed out the chiral centers from their molecules. Nature is chiral and even as it takes more time and effort to employ the asymmetric methods the methodology investment can be well worth the trouble – with a functional-group tolerant method like Noyori transfer hydrogenation, the development work needs to be done only once - and from then on the chemistry is just as easy to perform as a borohydride reduction. 

6. Making your own heterocycles. When you buy a boronic acid piece and slap it onto your molecule you make your final compounds faster – but often it is worth looking into how a particular ring system is made. The chemistry used may be ancient or completely new (Padwa is my hero), one can make everything from TOSMIC, etc. You would be amazed how many 5-membered rings are easily available from aldehyde or carboxylic acid.

7. Screening the ligand/solvent/base etc. Even the robust Pd(0)-catalysed reaction can become finicky for a particular class of substrates. There is the base, Pd-source, ligand, and solvent to choose  (apart from the temperature, concentration and time) and if you get one parameter wrong the reaction usually fails or stops at low conversion. Sometimes little time spent on methodology optimization pays off handsomely.

You should care about the chemistry methodology and do things not just to crank out the final compounds to fill up the testing queue. Your boss perhaps lost all his chemistry interest already and maybe he is unnerved about the project progress and pushes people hard –  but while you try not to get fired you don’t necessarily want to think like your boss (and end up wretched). If you continue to look at your research project with curiosity and do things also for the sake of your chemistry interest you are likely to be more original because thinking about the methodology will suggest new directions in your medchem project.  You may get acused of playing with chemistry and going off-tangent but you will likely remain more content and productive and you will continue to live your life in the lab - which could be a good or bad thing depending on the marriage situation.

August 6, 2008

Raising the stink

Filed under: industry life — milkshake @ 2:46 pm

A colleague stank up the lab at my previous company with a disposable pipette tip from ethanedithiol. He dropped the tip into a trash bin outside his hood; people soon complained so he dumped the bin content into a big garbage container located in our parking lot. It was a searing-hot Arizona summer day with no wind - and the stink got taken in by the A/C system of our neighbour, a robotic engineering company.

The robotic company owned the whole building and needed more space to expand their business. They wanted us out but we had a long-term lease signed with them. For years the robotic guys have been coming up with arguments about how we violated the lease terms. They reported us to EPA repeatedly, for problems like “burying chemical waste in the desert” (they could not provide information where the stuff was burried or the witness that actually saw the incident). We had EPA on us all the time - and whenever the inspectors gave us a surprise visit it was always the robotic company that ended-up fined instead (machine oil spilled on the ground, etc) while we managed a passing grade with each inspection…

This time the robotic guys reported us to the Poison Control Center. Without telling anyone at our company, they complained that we sickened their employees (they instructed their employees to take the day off - and recommended them to report to a hospital for a check-up: they told them otherwise they wouldn’t be eligible for a work-disability compensation in case they would become later ill). The poison control in turn called the military and advised them about a “poison gas release” contaminating the place - and soon the experts from the nearby Air Force base arrived in full gear. Men in bunny suits appeared on the scene, walking slowly about our parking lot and taking samples of everything with the utmost care. 

There was a fire station located right next door too and these firemen were not that busy in the spread-out Oro Valley suburbs - they were usually putting out the brush fires on the Catalina foothills and when the desert was not burning they were there at their station hanging about. Their chief was organising drills and sports-like competitions to keep up the morale - occasionaly they were rolling fire hoses or running in their gear up and down our parking lot. So when the space-suit men showed up we were not concerned; and we were rather curious, watching them - we thought the firestation dudes were finally doing something interesting! Then a $50,000 bill came - and with it a lively debate commenced, about who is paying the astronauts.

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