2-formyl-5-methylpyrrole-4-carboxylic acid

D-glucosamine hydrochloride 6.470g (Acros; 30mmol) was suspended in methanol 100mL and tert-butyl acetoacetate 9.50g (60mmol) was added, followed by triethylamine 8.5 mL (61 mmol). The mixture was refluxed on a 80C bath for 1 hour with vigorous stirring. The reaction mixture was evaporated and the residue was dissolved in water (about 150mL) with potassium carbonate 2.8g (solid, 20 mmol) added. The mixture was extracted twice with ether (2×150mL) and the organic phases were back-extracted twice with additional water (2×150mL). [The organic phases were discarded]. The combined aqueous extracts containing the pyrrole product were transferred into a 1L beaker, fresh ether 100mL was added and the mixture was placed on ambient water cooling bath. With vigorous stirring, a solution of KI04 29.0g (135 mmol) in water (about 150mL) was gradually added over 15 min period with vigorous stirring (delayed gas evolution and foaming!).  When the potassium periodate addition was complete the mix was stirred for extra 30 min. More ether (400mL) was added and the mixture was shaken and separated. The aqueous phase was re-extracted with additional ether 200mL. The organic phases were washed saturated aq. sodium bicarbonate three times (3×250mL), combined, dried (MgSO4) and evaporated. The syrupy residue gradually solidified on highvac.

This crude tert-butyl ester-aldehyde (5.05g) was dissolved in neat TFA 60mL. After 30 min the dark mixture was evaporated to dryness. The obtained solid residue was suspended in water, the solids were collected by filtration, washed thoroughly with water on the Buchner funnel, dried by suction and then on highvac. Y=2.940g of a tan solid (64% overall)

1H(d6-DMSO; 400MHz): 12.384 (br s, 1H), 12.105(very br s, 1H), 9.405(s, 1H), 7.263(d, 2.5Hz, 1H), 2.454(s, 3H)

Once Upon A Time

(Credit: Sergio Leone)

Happy New Year!

Predetermined Conclusions 2

I suddenly found myself in HR office this Wednesday in front of assembled top four bosses, faced with immediate dismissal. The story was that I argued with a security guard few weeks before – which I have not done - but they already had it all prepared nicely (they investigated it for over two weeks but they did not bother to ask my boss or me about it - and they kept the meeting secret to the last minute) and there they would not allow any facts get in a way of their neat story. They yelled and bullied - that I better shut up and sign the papers they are giving me to sign or they will fire me right there. Needles to say, the HR meeting did not go down too well - but it became noticebly nicer towards the end, especially after the boss of the translational research institute screamed on top of his voice that he is in control of the entire budget and that I am messing with the wrong guy – and then stormed out. (He threatened to leave the meeting unless I apologize for saying that their story makes no sense - and I observed that it would be perhaps helpful if he could leave the meeting).

What they insisted on was that I must undergo anger management treatment with therapist of their own choosing and they handed me a consent form – to sign away all my confidentiality over to HR, and to confirm that this is actually an employer-mandated psychiatric treatment that I am taking voluntarily so that HR could receive regular status reports from my therapist.

I guess they just tried to find out if I have any interesting personal problems and see how I am struggling through with the help of their therapist – who would then send a nice summary to HR about my treatment plan and attendance and they would just add it in the file…

I knew that they were considering layoffs next January because of the funding problems and from their nastiness I figured out that this was a cute method to have me certified as a nut so as to not to have worry about wrongful dismissal case from me in the future. Bending over and taking it from both ends would only save me couple weeks at best. So I boxed up my stuff, loaded it in my car and wrote back that  I can see someone if they insist but I am not signing away my shrink’s confidentiality over to HR. I also wrote  that it was a fine inquisition meeting – and that they should check the facts because there are people who can easily confirm that the guard story is a fabrication and that I hope they will at least have the decency to clear my name with the same eagerness with witch they have now besmirched it.

The next day my e-mail client stopped working and the PC logged itself off. That gave a hint that I should probably head down to HR so I said the goodbyes to my colleagues, handed back my keys + keycard and it was over in a civil way within few minutes.

As to why this has been staged the way it happened, there are several reasons but I think the main one was that the people I worked for got from me all what they needed, my salary just got past six figure and they were faced the financial pressure to have someone let go - in our group the potdocs cannot find staff jobs anywhere (and are willing to survive on indefinite postdoc-ship often due to the visa situation). I have had complained too much about the people here being left intentionally off the publications and cheated from their co-authorship on patents. I have been with the institute from the beginnig, and I am not an easy person to put up with, over the five years they had plenty about me on file - so they thought they can easily make it look like it I am creating some serious trouble and therefore they had no other choice but to let me go…

The reason why I wrote down all this unpleasant story is to firsthand inform my colleagues and friends who are reading this page because I did not have the time to speak with everybody before leaving.

Predetermined conclusions

In the last year of elementary school I got encouraged to take part in the science fair – The top winners of the national highschool science project competition could possibly earn the admission to a college of their choosing. I was a new chemistry club member and it was decided there that I ought to try an analytical chemistry project –  an assay to determine content of vitamin C in various foods by titration. There is a simple redox method and I could compare how the processing and contact with metals diminished the ascorbic acid content. (Cooked food has less ascorbic acid because it gets oxidized and metals catalyze the oxidation etc. etc.)

So I started on this stuff but it bothered me a bit when I was reading in the book that described this analytical method that there are actually other components  in the food that also have reducing properties and they would show up in this titration and I had no way of telling them apart from ascorbic acid or figuring out their relative ratio – so my result would always end up higher, as a sum of two unknown values. The club boss suggested that I should not dwell on this over too much –  after all, it was an established method and I was only doing a modest experimental work to practice for more serious research – and that I ought to get on with the work for which she had the plan laid out for me. So I listened and did the whole thing.

Next, before I even completed writing up the ascorbic acid stuff – and since we were working so well together – the chemistry club boss suggested that the second project I should try is to measure lead in fruit picked from trees growing along the roads because of the health issues posed by the wide-spread use of leaded gasoline at that time. There is dithizone, a ligand that makes a deep purple complex with lead and she had a spectrophotometer in the lab which she wanted to put to some use and it would be much more interesting project – one that had a chance of winning awards for our club…

A small problem arose when I finished the calibration curves for the dithizone-lead complex standards and proceeded to apples picked from trees along a busy road:  it turned out that there was not much lead in those apples (I could barely detect a hint of the colored complex but there was no way to quantify that on this instrument). I got promptly sent out on missive to try to find some more-contaminated fruit so that we can have material to support our serious study –  I was told to make sure to pick the fruit only when there was no rain for few days, and that I should prepare the samples from the surface layer only. (How exactly you separate the surface in a reproducible way was not obvious to me – but reproducibility was apparently not the biggest concern in our project). When I asked if this really was the way to go about the  sample collection, it was made clear to me that I better find some lead-laden fruit somewhere soon or she will not waste her time with me anymore. So I stopped attending that chemistry club and resumed my research on home-made fireworks and rockets and methods for  ethanethiol production – the projects in which I found some encouragement from my non-chemist buddies.

1NMPP1

.

1,1-dicyano-2-methoxy-2-(1′-naphtylmethyl)-ethylene 9.175g (36.95 mmol) and t-Bu-hydrazine hydrochloride 4.65g (37.3 mmol) was suspended in absolute ethanol 0.25L and triethylamine 5.3mL was added dropwise over 7 min period. After stirring at RT for extra 10 min, the mixture was placed on oil bath (90C) and refluxed overnight (18 hours).  The cooled reaction mix was evaporated and the residue was portioned between DCM 150mL and water 100mL. The aqueous phase was re-extracted twice with DCM (2×100mL), the combined extracts were dried (Na2SO4) and evaporated. The residue was purified on a column of silica (250g) in DCM, eluted with straight DCM 0.3L and then 20:1 DCM+EtOAc (v/v; 2L).

The obtained 5-amino-1-tert-butyl-4-cyano-3-(1′-naphtylmethy)-pyrazole (cream-colored crystalline solid, 7.15g, 63.5%Y) was flushed with Ar in a 1L flask, formamide 100mL was added, the flask was equipped with a straight glass tube as air-cooled condenser and the mixture was deoxygenated by a highvac/Ar purge. The mixture was stirred on a 180C oil bath under Ar for 7 hours. The mixture was allowed to cool to R.T., the formed slurry was gradually diluted with water (60mL) and the mix was stirred for additional 30 min. The precipitated product was collected by filtration, thoroughly washed with water, dried by suction and on highvac. The crude product (7.05g) was dissolved in ethanol 0.5L at reflux. One spoon of charcoal was added, the mix was stirred at reflux for additional 10 min then filtered while still warm (the charcoal was washed with additional ethanol) and the filtrate was evaporated to dryness. The obtained foamy residue was re-crystallized from a mix of benzene 30mL and cyclohexane 20mL (RT, overnight). The crystallized product was collected by filtration, washed with 1:1 benzene-cyclohexane mix and then with hexanes, dried by suction and on highvac.
Y=7.788g (57% overall Y) of a cream-colored crystalline solid as a 2:1 co-crystal with benzene.

1H(d6-DMSO, 400MHz): 8.905(very br s, 2H), 8.473(s, 1H), 8.249(m, 1H), 7.936(m, 1H), 7.816(d, 8.2Hz, 1H), 7.555(m, 2H), 7.395(dd, 8.1Hz, 7.2Hz, 1H), 7.153(d, 7.0Hz, 1H), 4.873(s, 2H), 1.654(s, 9H); LC/MS(+ESI): 332(M+1)

Note 1:  1NMPP1 is commercially available but very dear

Note 2:  To remove the benzene trace (the compound is intended for biology use) the purified material was re-dissolved in ethanol 150mL, the solution was carefully concentrated on rotovap from a 50C bath down to about 1/3 volume and the remaining solution was slowly diluted down with water – about 200mL – until cloudy, the crystallization was then induced mechanically (by scratching the solution against the flask joint). The resulting slurry was stirred on ice bath for 1 hour. The precipitate was collected by filtration, washed with ice water, dried by suction and on highvac. This provided 6.012g of pure product free of benzene (Y=49% overall). 1H(d6-DMSO, 400MHz): 8.319(m, 1H), 8.141 (s, 1H), 7.921(m, 1H), 7.793(d, 8.2Hz, 1H), 7.541(m, 2H), 7.391(dd, 8.1Hz, 7.3Hz, 1H), 7.145(d, 7.0Hz, 1H), 7.027(very br s, 2H), 4.875(s, 2H), 1.662(s, 9H)

1,1-dicyano-2-methoxy-2-(1′-naphtylmethyl)-ethylene

.

This procedure employs methyl triflate. The final product is a strong irritant. See the notes below.

A slurry of 1-naphtaleneacetic acid 26.00g (140 mmol) in dichloromethane 60mL in a 250mL round flask was placed on ambient water bath and neat oxalyl chloride 13.0mL (150 mmol) was added followed by 5 drops of DMF (not more, else the gas evolution commences too fast). The flask was equipped with a Drierite-filled gas outlet tube and stirred on ambient bath overnight (8h30 min, the gas evolution ceased and the mix became homogennous). The flask was equipped with a vacuum distillation shortpath adaptor, placed on oil bath and the solvent was distilled off at atmospheric pressure from a 80C bath. The residue was then vacuum-distilled at 0.4-0.5 Torr from 80C to 135C bath, the pure acyl chloride distilled at 110C/0.45 Torr. Y=26.11g of a light orange-yellow oily liquid (91%Y)

60% NaH in mineral oil, 5.0g (125 mmol) was loaded into Ar-flushed 1L round flask with a large stirbar. Anhydrous THF 0.5 L (approx) was added via canula and the slurry was cooled on ice bath. Neat CH2(CN)2 4.40g (66.5 mmol) was added in one portion (gas evolution!) [1] and the mix was stirred on ice for 30 min. An addition funnel was charged with benzene 20mL and 1-naphtylacetyl chloride 12.00g (58.63 mmol) and this solution was then dropwise added into vigorously stirred reaction mix on ice bath under Ar (gas evolution) over a 30 min period. The addition funnel was washed with benzene 10mL and the washings were also added to the reaction mix. 10 min after complete addition, the cooling bath was removed and the reaction mix was stirred at RT overnight (7h30min). The reaction mix was then briefly sonicated (1 min) to break few remaining unreacted chunks of NaH, then carefully evaporated to dryness. The obtained foamy residue containing the Na-enolate salt intermediate was suspended in anh MeCN 0.5L (added via canula) and then stirred under Ar and occasionally sonicated  over a 30 min period until all chunks disappeared and a cloudy solution formed. The mixture was placed on ice bath and after 20 min on ice, neat methyl triflate [2] 9.0mL (81.5 mmol) was added by a syringe dropwise over a 10 min period. After additional 10 min stirring on ice, the cooling bath was removed and the mixture was stirred at RT under Ar overnight (15h30 min).  At this point the TLC and HPLC indicated disappearance of the acylmalononitrile intermediate and a formation of two products in about 3:1 ratio.  The reaction was quenched by addition of triethylamine 7.0 mL, stirred for 15 min and then evaporated to dryness. The residue was suspended in toluene (100mL), the slurry was filtered through a medium-porosity glass Buchner funnel (150mL size), the insoluble material was thoroughly washed with additional toluene (150mL) and discarded. The filtrates were evaporated and the residue was dissolved in a mix of DCM and toluene (20+20mL), the mix was applied onto a column of silica (250g) in straight DCM and eluted with DCM. The pure methoxy product migrated first and separated nicely from the sideproduct on silica in DCM. Y=9.200g (63%) of a pale yellow sticky goo that gradually solidified on highvac into a hard white crystalline mass. The product is a potent irritant [3].

1H(CDCl3, 400MHz): 7.932 (m, 1H), 7.912 (m, 1H), 7.864 (d, 8.3Hz, 1H), 7.622 (m, 1H), 7.572 (m, 1H), 7.473 (dd, 8.2Hz, 7.2Hz, 1H), 7.263 (dd, 7.1Hz, 6.2Hz, 1H), 4.448 (s, 2H), 3.935 (s, 3H); 13C(CDCl3, 100MHz): 186.48. 134.05, 131.05, 129.31, 129.12, 127.75, 127.25, 126.53, 125.62, 125.17, 122.28, 113.29, 111.51, 67.83, 59.51, 34.44

Note 1: It is better to add solid malononitrile rather than a warm molten liquid – the liquid tends to solidify in the syringe

Note 2: Methyl triflate is a supremely toxic and dangerous alkylating agent as discussed previously. Use nitrile gloves throughout, keep the triflate in the hood at all times, treat the rotovap and the rotovap waste with a great care until decontaminated with ammonia.

Note 3: The product is completely odorless but a rather creepy irritant – the structure is closely related to CS tear gas commonly used by the police and military. Use gloves, do not spill it outside hood, do not breath vapors (= swollen itchy nose for hours afterwards; certizine pills are a pretty useful thing to have at hand). For the love of God wash your hands with a soap before going to bathroom.  The material is best used right away as a goo – before it solidifies – crushing a hard crystalline solid is no fun with a strong irritant.