Lime (and Pt-C)

A slurry of calcium hydroxide 5.18g (70mmol) in a neat mixture of 2-chloro-3-nitrotoluene 6.580g (38.34mmol) and 4,4-(ethylenedioxo)-piperidine 13mL (100mmol) was stirred without solvent in a closed pressure glass flask at 180C for 10 hours (overnight).  The flask was cooled to ambient temperature, the sludge was diluted with ether 100mL and briefly sonicated to break the lumpy solids. The inorganics were removed by filtration, washed with additional ether (150mL) and discarded. The combined filtrates were washed with 1M aqueous citric acid (2x200mL), then with water (200mL) and saturated NaHCO3 (200mL). The aqueous phases were re-extracted with ether (200mL). The combined extracts were dried (MgSO4) and evaporated. The obtained oil was dissolved in cyclohexane 50mL and the solution was left to RIP at RT for 1 day. Decanting the supernatants and washing the deposited chunky orange crystals with pentane and in vacuo drying provided 7.762g of a pure product. The combined supernatants and pentane washings were passed through a 2x2inch pad of silica, the silica was then washed with dichloromethane 150mL and the combined filtrates were evaporated. The evaporation residue was re-crystallised from cyclohexane 10mL to provide the second crop, 1.312g of pure product as a bright-yellow gem quality rhombs.
The combined yield was 9.074g (85%Y).

This nitro-compound, 7.760g (27.88mmol) was then hydrogenated in the presence of 5% platinum on carbon, 0.51g [Aldrich 205931] in ethyl acetate (150mL) at RT under hydrogen balloon for 3h 30min. The mixture was filtered through a pad of Celite to remove the catalyst (the pad was washed with additional EtOAc) and the filtrates were evaporated. The crystalline residue was dried on highvac. Y=6.860g (99%) of a white crystalline solid.

1H(d6-DMSO, 400MHz): 6.704(t, 7.6Hz, 1H), 6.496(dd, 7.8Hz, 1.2Hz, 1H), 6.253(d, 7.2Hz, 1H), 4.857(br s, 2H), 3.905(m, 4H), 3.204(td, t:11.5Hz, d:2.3Hz, 2H), 2.786(br m, 2H), 2.195(s, 3H), 1.812(td, t:11.7Hz, d:4.6Hz, 2H), 1.655(br d, 11.1Hz, 2H); 13C(d-6DMSO, 100MHz): 145.63, 135.66, 134.76, 125.45, 118.91, 112.15, 106.61, 63.64, 63.52, 47.24(2C), 35.97(2C), 19.41

All experiments that are fit to print

During thesis defense in Prague, one professor asked me: “The experimental procedure on page 64 is describing an explosion – please would you care to elaborate more on this?”  I found myself explaining that the material, racemic glycidol, was made only once for the project and there was, uh, a mishap as described – and I got enough material to carry forward so I had no urgency to re-do the preparation under more controlled conditions… What I did not tell them then was that the volcano which erupted three years before was set up with blessings of a man working for the said professor.

I needed glycidol and I couldn’t afford to buy it from Aldrich – so I made a whole bunch of chloropropane diol by hydrolysis of epichlorohydrine and I was going to treat it with methoxide. As I couldn’t find a reliable lit procedure for my particular substrate and being lab-naive, I asked a faculty dude about a general chlorohydrine ring-closing conditions. He suggested that I should use chloroform as a solvent for the reaction, and run it at 0C. “But isn’t chloroform supposed to react with methoxide?” I asked him.  “Sure it will – that’s the beauty of the system, the solvent reaction will mop-up any unreacted methoxide so it won’t ruin your epoxide. We in sugar chemistry are using this trick all the time”.

Alrighty, then: I dissolved the chlorohydrine thing – all 136 grams of it –  in chloroform 0.5L and slowly added 1.5 mol of methoxide solution. The addition was not exothermic; in fact the reaction seemed calm like a lamb.  About 3 hours later I removed the cooling bath and as I was walking away suddenly a thermometer flew by. There was a whooshing sound while the geyser commenced – from the flask neck where the addition funnel was just moments before… I slammed the hood sash down and bolted for the door.  Later I found that there was enough left in the flask to proceed with the workup (alongside with the cleanup). The chloroform/methoxide trick did not work as advertised though: there was lot of  methoxypropane diol in my glycidol and I had to do a fractional vacuum distillation on Vigreaux to obtain the pure stuff, in 8.5% yield. 

Few years later I visited the lab and looked into that hood and sure enough, the dried up white cake of salts – round and pretty like a giant camembert – was still there, hanging from the ceiling…

2-Bromo-4-iodopyridine-5-carboxaldehyde

2-Bromo-4-iodo-5-cyanopyridine 25.320g (81.97mmol) solid in a 2L round flask with a large egg-shaped stirbar was flushed with Ar and anhydrous toluene 1L was added via canula. The mixture was stirred and gently heated until complete dissolution, then cooled to 0C. With vigorous stirring on ice bath, diisobutylaluminum hydride solution 1M in hexane, 83mL was added by syringe, dropwise over a 20 min period. The mixture was stirred at 0C for additional 90 min, then cooled down to -78C. Ice-cooled mixture of 2M aqueous sulfuric acid 170mL and THF 350mL was gradually added into the reaction mix with vigorous stirring, the cooling bath was then removed and the mixture was let stirring in open flask (gas evolution) at ambient temperature overnight (15 hours). The next day water 400mL was added and the mixture was stirred for additional 30 min and separated. The organic phase was washed with water 500mL and saturated bicarbonate 500mL. The aqueous phases were re-extracted with ethyl acetate 500mL. The combined organic extracts were dried with MgSO4 and concentrated on rotovap down to aprox 300mL total volume from a 30C bath and cooled to RT. The precipitated product (13.398g, 98% pure, a cream-colored fluffy fibrous crystals) was collected by filtration, washed with toluene (4x20mL) and hexane and dried on highvac. The filtrates were evaporated to dryness. The residue was re-crystallized from acetonitrile 80mL (dissolved at reflux, 2h at RT, then at 0C overnight) filtered, rinsed with chilled acetonitrile and dried, to provide the second crop of product 7.814g (95% pure) as a tan crystalline solid. The combined yield was 21.212g (83% th).

1H(d6-DMSO, 400MHz): 9.950(s, 1H), 8.573(s, 1H), 8.434(s, 1H); 13C(d6-DMSO, 100MHz): 193.46, 151.48, 146.35, 138.54, 130.74, 112.97

The nitrile preparation was described here on July 1, 2008

2-bromo-4-iodo-5-cyanopyridine

A 2L round flask equipped with a large egg-shaped stirbar was flushed with a stream of Ar. Solid LiBr 0.96g (11mmol) was added, followed by anhydrous THF 0.5L and diisopropyl amine 17mL (120 mmol). The obtained solution was cooled to 0C, BuLi 2.5M solution 44mL (110 mmol) was added by syringe over 10min, the mixture was stirred for additional 5 min and the ice bath was then replaced with a dry ice/acetone bath. Meanwhile, 2-bromo-5-cyanopyridine 19.838g (108.4 mmol) was dissolved under Ar in anh THF 0.25L and the solution was cooled to 0C. Using a wide canula, the ice-cooled solution of the cyanopyridine was transferred into the LDA solution at -78C, along the flask wall and with vigorous stirring, over a 10 min period (the flask and the cannula was rinsed with additional anh THF, 2x15mL). After complete addition the reaction mixture was gently swirled by hand – to wash down any crystals of the cyanopyridine on the flask wall above the reaction mixture. The mixture was then stirred for additional 15 min at -78C. Iodine 30.5g (120 mmol) solution in anh. THF 220mL pre-cooled on ice bath was added rapidly (4 min, along the flask wall), the reaction mixture was stirred at -78C for additional 30 min, the cooling bath was then removed and the flask was allowed to warm up close to the ambient temperature (over approx 1 hour interval). Without any quench, the reaction mixture was concentrated on rotovap from a 25C bath. A solution of sodium metabisulfite 35g in water 250mL was carefully combined with saturated bicarbonate solution 550mL (CO2 effervescence!) and this combined solution was then added to the oily evaporation residue. The resulting slurry was stirred vigorously for 30 min, the precipitated product was then collected by filtration, washed with copious quantity of water and dried by suction. The obtained crude product was suspended in methanol 1L and the mixture was refluxed for 30 min. Activated charcoal 4g was added (carefully) and the mix was refluxed for additional 10 min, then filtered while warm. The charcoal was washed with some additional refluxing methanol, 100mL. The combined filtrates were placed in a fridge at 0C overnight. The crystallised product (tan prisms, 19.434g, 99% pure by HPLC) was collected by filtration, washed with chilled methanol (100mL) and dried by suction and on highvac. The supernatants were evaporated and the residue was re-crystallised from methanol 0.3L (re-dissolved at reflux, then placed in a freezer at -20C overnight), to yield the second, dark brown-colored crop 5.920g (95% pure by HPLC). The combined yield was 25.354g (75.5% th).

1H(d6-DMSO, 400MHz): 8.752(d, 0.3Hz, 1H); 8.495(d, 0.3Hz, 1H)

Note: One should use 1:1 LDA/substrate ratio and keep the lithiation time short. Exceeding the LDA stoechiometry encourages formation of non-polar impurities that are rather difficult to remove. Also, the starting cyanopyridine has tendency to fall out of the THF solution at low temperature – so it is important to wash down any crystals stuck on the flask walls above the reaction mix.

Credit: I am grateful to my colleague Par who found that this substrate lithiates with LDA into the 4-position.