Org Prep Daily

October 11, 2006

(S)-4-(benzyloxycarbonylamino)-3-hydroxybutyric acid

Filed under: procedures — milkshake @ 7:20 pm


(S)-4-hydroxypyrrolidin-2-one 4.99g (49.35mmol, Aldrich) and lithium hydroxide monohydrate 8.40g (200mmol, Aldrich) was dissolved in water 100mL. The mixture was stirred in a closed 0.5L flask at 40C for 24 hours. [The progress of hydrolysis was conveniently monitored by NMR, by diluting a small react. mix sample directly with D2O and taking  the proton spectra] . The reaction mixture was diluted with THF 160mL and water 100mL, cooled on ice bath and saturated with a stream of CO2 gas [generated in a separate flask from dry ice] at 5-10C for 20 min. Solid Cbz-OSu 11.714g (47mmol, Aldrich) was added in single portion followed by additional THF 40mL (to wash the funnel). The mixture was stirred at 5-10C for 30 min and then at 10-20C for 2h30min. The reaction mixture was acidified with conc. HCl 18mL (CO2 evolution!) and concentrated on rotavap down to about 80mL of total volume. The resulting slurry was placed into fridge (+5C) overnight. The precipitated crude product (9.30g) was collected by filtration, rinsed with a small volume of ice-cold water and dried on highvac. The supernatants were concentrated down to aprox 40mL volume, extracted twice with ethyl acetate (2x150mL), the extracts were washed with brine (100mL) , combined, dried (MgSO4) and evaporated. The residue (3.5g) was re-crystallized from a ethyl acetate -benzene 1:4 mixture to produce additional 1.40g of crude product. The combined two fractions of crude product (9.30g +1.40g) were re-dissolved in refluxing ethyl acetate 40mL. With heating, the mixture was carefully diluted with benzene 160mL, inoculated and allowed to crystallize at RT for 8 hours. The supernatants were decanted from the crystallized pure product, the crystalls (6.92g) were suspended in a mixture EtOAc-benzene 1:4 (40mL), collected by filtration, washed with EtOAc-benzene 1:1 (2x20mL) and dried on highvac. A second pure crop (1.741g) crystallized from the supernatants in a fridge over weekend (+5C, 2 days). The combined Y=8.661g(72.5%) of a white crystalline solid

1H(6-6, DMSO, 400MHz): 12.073(br s, 1H), 7.357(m, 5H), 7.243(t, 5.8Hz, 1H), 5.020(s, 2H), 4.923(br s, 1H), 3.883(br s, 1H), 3.006(m, 2H), 2.383(dd,15.2Hz, 4.0Hz, 1H), 2.149(dd, 15.2Hz, 8.7Hz, 1H); LC/MS (+ESI): 254 

Acid-promoted hydrolysis of the starting lactam (6M HCl, reflux) proceeded with a partial decomposition and extensive racemisation. The racemisation possibly takes place by OH beta-elimination/water addition; 4-aminocrotonic acid was identified as a major side-product. By contrast, LiOH-hydrolysis at 40C does not produce any measurable racemisation, as confirmed by 1H-NMR spectra of diasteremeric ureas, from (S)-N,N-dimethy-4-amino-3-hydroxybutyramide hydrochloride  (synthesized from the Cbz-protectd aminoacid) with opticaly-pure PhCHMeNCO 

October 10, 2006

3,4-diamino-5-(4′-hydroxybenzyl)-triazole and the Abominable Tetracyclic Monster

Filed under: procedures — milkshake @ 8:23 pm


2-amino-5-(p-hydroxybenzyl)-oxadiazole 11.525g (60.28mmol) was suspended in a mixture of water 80mL and anhydrous hydrazine 20mL and the mixture was refluxed under nitrogen on oil bath (190-200C) for 16 hours. The mixture was allowed to cool to RT and crystallize for 3 hours, then placed into a refrigerator (+5C) overnight. The crystallized product was quickly collected by filtration, rinsed with ice-cold water and dried by suction. The crude product was re-crystallized from water (250mL, refrigerator +5C overnight). Y=4.431g (35.5%) of the diaminotriazole as a white crystalline solid, about 95% pure by NMR. [The impurity is 4-amino-3,5-bis-(p-hydroxybenzyl)-triazole.]

1H(d6-DMSO, 400MHz): 9.234(br s, 1H), 7.034(app d, 8.6Hz, 2H), 6.664(app d, 8.6Hz, 2H), 5.453(br s, 2H), 5.338(s, 2H), 3.772(s, 2H); LC/MS(+cAPCI): 206(-cAPCI): 204

3,4-diamino-5-(p-hydroxybenzyl)-triazole 133.5mg (0.65mmol) and 4,7-dichloroisatin 130mg (0.60mmol) suspension in trifluoroethanol 8mL and water 4mL was stirred in a pressure glass tube at 125C for 2 hours. The stirring was continued at RT for additional 2 hours, the precipitated product was collected by filtration, washed with a mixture of methanol-water 1:1 (20mL) and then with a small volume of freezer-cooled methanol (-15C, 2mL). The product was dried on highvac. Y=209mg (90.5%) of a bright canary-yellow crystalline solid.

1H(d6-DMSO, 400MHz): 12.864(br s, 1H), 9.259(s, 1H), 7.797(d, 8.6Hz, 1H), 7.406(d, 8.6Hz, 1H), 7.250(app d, 8.6Hz, 2H), 6.674(app d, 8.6Hz, 2H), 4.408(s, 2H); LC/MS: (+cAPCI): 387, 385, (-cAPCI):385, 383

The hydrazinolysis of oxadiazole (followed by triazole ring closure) is messy but the desired product fortunately crystallizes out.

The yield of the corresponding 3,4-diamino-5-(p-fluorobenzyl)-triazole was better, probably because of its lower solubility: 2-amino-5-(p-fluorobenzyl)-oxadiazole 10.182g (52.7 mmol) with water 80mL and anh. hydrazine 20mL was refluxed under N2 for 24 hours (oil bath 190-200C). The mixture was let to crystallize at RT, overnight. The crude product was collected by filtration, washed with ice-cold water (10mL) and re-crystallized from water 60mL (+5C, overnight). Y=6.210g of diaminotriazole (56.5%) as a white crystalline solid, 95% pure. 1H(d6-DMSO, 400MHz): 7.267(app dd, 8.6Hz, 5.5Hz, 2H), 7.097(app t, 9.0Hz, 2H), 5.509(br s, 2H), 5.399(s, 2H), 3.884(s, 2H); 19F(d6-DMSO, 376.5MHz): -117.14(m, 1F)

4-Hydroxyphenacetyl hydrazide and 2-amino-5-(p-hydroxybenzyl)-oxadiazole

Filed under: procedures — milkshake @ 12:45 am


4-hydroxyphenylacetic acid methyl ester 99.98g (601.6mmol) solid was gradualy added with cooling on ambient water bath to a solution of anhydrous hydrazine 80mL (79.25g, 2.47mol) in methanol 400mL over 10 minutes. The mixture was stirred at RT for 1 day. The precipitated product (88.926g) was collected by filtration, compressed on Buchner funnel, washed with methanol (4x25mL) and dried on highvac. A second crop (8.120g) precipitated from supernatants at -20C (freezer) overnight. The combined yield was 94.046g (94%) of pure hydrazide as a white crystalline solid.

1H(d6-DMSO, 400MHz): 9.182(br s, 1H), 9.108(br s, 1H), 7.035(app d, 8.6Hz, 2H), 6.666 (app d, 8.6Hz, 2H), 4.176(br d, 3.1Hz, 2H), 3.207(s, 2H) [minor rotamer signals 8.25, 7.2, 6.8, 6.5, 4.4, 3.6 are present in the 1H spectra]. 13C(d6-DMSO, 100MHz): 170.66, 156.45, 130.47(2C), 127.00, 115.63(2C), 40.48

A suspension of 4-hydroxyphenacetyl hydrazide 23.78g (143.1mmol) and KHCO3 15.76g (157.4mmol) in methanol 200mL was cooled to 0C. With vigorous stirring, solid cyanogen bromide 16.07g (151.7 mmol) was added in a single portion, followed by additional methanol 20mL (to wash the funnel and flask walls). The reaction mixture was stirred at 0 to 5C for 2 hours, the cooling bath was allowed to warm up to ambient temperature over a 2 hour period, and the reaction was continued for extra 1 hour at RT. The reaction mixture was diluted with water 230mL and the reaction mixture was stirred in an open flask for 1 hour. The precipitated product (17.215g) was collected by filtration, washed with water and dried on highvac. A second crop (9.400g) of pure product was obtained by concentrating the supernatants (to remove all methanol) from a 40C bath and letting the concentrated supernatants crystallize at RT overnight. The combined yield was 26.615g (97%) of a white crystalline solid.

1H(d6-DMSO, 400MHz) 9.334(s, 1H), 7.040(app d, 9.0Hz, 2H), 6.839(br s, 2H), 6.706(app d, 8.6Hz, 2H), 3.879(s, 2H)

Cyanogen bromide is a nasty irritant – it could “bleach” the sense of smell. BrCN-burned nose (or hands) could take days to recover. Weighing the solid BrCN is best done in fume hood, with gloves, into a closed container (pre-weighted test-tube with a septa, for example) . Few rounds of walk – with a closed tube – between hood and balances are preferable to gassing the lab with BrCN vapors.  

Using the same reaction sequence, p-fluorophenylacetic acid methyl ester 25.66g (152.5 mmol) and anhydrous hydrazine 20mL in MeOH 120mL was heated to 60C (under reflux condenser) for 2 hours. The reaction mixture was evaporated to dryness and the residue was re-crystallized from 1-propanol 100mL (overnight to RT). Evaporating the supernatants and re-crystallizing the residue  from benzene provided a second crop. The combined Y=24.855g (97%) of pure hydrazide as a white flakes. 1H(d6-DMSO, 400MHz): 9.194(br s, 1H), 7.272(m, 2H), 7.107(m, 2H), 4.202(br d, 4.3Hz, 2H), 3.329(s, 2H); 19F(d6-DMSO, 376.5Mhz): -116.96(m, 1F). A suspension of the p-F-phenacetyl hydrazide 19.85g(118mmol) and KHCO3 14.77g(147.5gmmol) in methanol 150mL at 0C was treated with BrCN 13.77g (130mmol) with stirring the mixture on ice for 1 hour and then at RT for 17h. The reaction mixture was diluted with water 200mL and allowed to crystallize at 0C for 1 hour. The precipitated product was collected by filtration, a second fraction was obtained by concentrating supernatants. Combined Y=20.836g (91.5%) of pure 2-amino 5-(p-F-benzyl)-oxadiazole as a white crystalline solid. 1H(d6-DMSO, 400MHz): 7.289(m, 2H), 7.148(m, 2H), 6.873(br s, 2H), 4.014(s, 2H); 19F(d6-DMSO, 376.5MHz): -116.01(m, 1F)

October 9, 2006


Filed under: procedures — milkshake @ 2:57 am


1,5,7-Triazabicyclo[4,4,0]dec-5-ene 4.939g (35.48 mmol, Fluka) mixture with water 2mL and lithium hydroxide monohydrate 918mg (Aldrich) was heated in a closed pressure tube to 145C for 1 hour. The reaction mixture was purified on a short (3 inch-long) column of silica in mixture chloroform-methanol-conc. aq. ammonia 80:40:4 and the purified product was dried on highvac overnight. Y=5.265g (94%) of a white extremely hygroscopic solid.

Using the same reaction conditions and purification procedure, DBU 5.0mL (33.4mmol) and LiOH.H2O 420mg and water 2mL provided 1-(3′-aminopropyl)-caprolactam 4.973g (87%) as a colorless liquid.  

October 8, 2006

2-(2′,6′-dichlorophenyl)-2,2-difluoroacetyl chloride

Filed under: procedures — milkshake @ 9:41 pm


In an oven-dried flask filled with Ar gas, 6.822g of 2,6-dichloro-iodobenzene  (25.0mmol, Transworld) together with copper “activated nanopowder” 4.626g (72.8mmol, Aldrich) was suspended in anhydrous DMSO 150mL and the mixture was sparged with Ar gas for 10 min. Ethylester of bromodifluoroacetic acid 6.090g (30mmol, TCI-US) was added and the mixture was stirred under Ar at 60C for 11 hours (overnight). The reaction mixture was diluted with toluene 350mL, stirred for 15 min, filtered through a large medium-porosity glass Buchner funnel and the solids were washed with toluene. The filtrates were quickly washed with saturated ammonium chloride solution 400mL and then with sat. NaCl 200mL, the aqueous phases were re-extracted with toluene 150mL. The combined  extracts were dried (MgSO4) and evaporated on rotavap with help of oil pump. The residue was dried on higvac. [The ethyl ester intermediate is moisture-sensitive – it should not be allowed to sit in a sep funnel because the resulting acid is quite water-soluble].

The obtained crude Et-ester 6.67g (containing some iodo starting material) was dissolved in THF 100mL, water 60mL and LiOH-monohydrate 2.10g (50 mmol, Aldrich) was added and the mixture was stirred for 1 hour. The mixture was diluted with water 20mL and concentrated on rotavap to remove all THF. The residue was diluted with water 60mL, the precipitated unreacted iodo- starting material was removed by filtration. The filtrates were acidified with 4M HCl 50mL. The resulting emulsion was extracted three times with dichloromethane (3x150mL), the combined extracts were dried by adding activated 4A mol sieves powder, stirred for 10 min, filtered through Celite and evaporated. The residue was dried on higvac. Y=3.731g (62%) of a hygroscopic white crystalline solid

1H(CDCl3, 400MHz): 10.123(br s, 1H), 7.381(dAA’B, 7.8Hz, 2H), 7.305(dd, 9.0Hz, 7.0Hz, 1H); 13C(CDCl3, 100MHz): 166.94(t, 33Hz), 134.77, 131.87(2C), 130.55(2C), 127.73(t, 23Hz), 113.10(br t, 258Hz); 19F(CDCl3, 376.5MHz): -97.794(s, 2F)

The difluoroacid 3.696g (15.33 mmol) with added 2 drops of DMF was dissolved in dichloromethane 15mL with a gentle reflux. The mixture was placed on ambient bath and oxalyl chloride 2.7mL (30.9 mmol) was added (gas evolution). The flask was equipped with a Drierite-filled outlet tube and the mixture was stirred for 18 hours (overnight). The reaction mixture was concentrated on rotavap and then briefly dried at RT at 0.5 Torr. The residue was distilled on Kugelrohr apparatus on higvac (0.5 Torr) with air bath temperature set to 100C. Y=3.724g (93.5%) of a colorless, nasty-smelling liquid

1H(CDCl3, 400MHz): 7.418(m, 2H), 7.391(m, 1H); 19F(CDCl3, 376.5MHz): -93.668(s, 2F)

The Ulman coupling of BrCF2CO2Et with aryl iodides is a good, quite general method for making these alpha-difluorinated phenylacetic acids. The reaction proceeds through CuCF2CO2Et. The organocopper reagent is best made in situ from the bromoester. [The reagent could be pre-made as a stock solution if ICF2CO2Et is used at RT but this is inconvenient because the iododifluoroester has to be made – from the commercial bromodifluoroester by Zn matallation/I2 quench (and the yield of the prep is underwhelming). Finkelstein direct halogen exchange does not work in this case.]

Call For Authors

Filed under: Uncategorized — milkshake @ 3:36 am


sliva12.jpg Credit: Jirí Slíva

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