Noyori asymmetric transfer hydrogenation

RuCl2(cymene) 24mg (Aldrich, 0.04mmol Ru) and (S,S)-TsDPEN 40mg (0.096mmol, Aldrich) in a 250mL (14/20 joint) round flask equipped with a stopcock was flushed with Ar using a long needle.  Dichloromethane (4mL, from Aldrich SureSeal) was added and the mixture was stirred under Ar (without reflux condenser) on 40C oil bath for 1 hour. The Ru-salt and the ligand dissolved. After 1 h, the solvent was removed by blowing a stream of Ar into the flask on the 40C bath. De-ionised water 16mL was added into the dry flask (with a film of active catalyst on the wall) and was de-gassed by vac/Ar purge (3-times). A mixture of solid HCO2Na 2.72g (40mmol), CTAB 15mg (0.04mmol) and the starting F-spiroketone 1.110g (4.0 mmol) was added and the flask was flushed with a stream of Ar. Ethyl acetate 2 mL (a good grade, not deoxygenated)  was added and the mixture was stirred vigorously under Ar at 40C for 16 hours (the crystals of the starting material gradualy dissolved, the progres was monitored by TLC). The cooled reaction mixture was extracted twice with EtOAc (2x100mL). The combined extracts were dried (with 4A powdered molecular sieves), filtered and evaporated. The residue was purified on a column of silica (80g) in a gradient of methanol in chloroform, 0 to 2.7% of MeOH, then 2.7% isocratic. Y=1.123g (100%) of a light-yellow sticky glass.  

The optical purity was assayed using a reverse-phase chiral HPLC column, Chiralpak AD-RH, in water-acetonitrile (no TFA) at 50 or 55C, at 0.8mL/min. The e.r. was 0.5:99.5 by integration. The opposite ligand enantiomer provided 100%Y of the product with e.r. = 99.4:0.6 (with the minor enantiomer peak eluting on the tail of the main one).

The 1H-NMR spectra in DMSO show a 1:1 mixture of rotamers about the amide bond. 1H(d6-DMSO, 400MHz): 7.168(dd, 9.4Hz, 3.1Hz, 1H), 6.977(td, t:8.6Hz, d:3.1Hz, 1H), 6.802(dd, 9.0HZ, 4.8Hz, 1H), 5.509(dd, 6.0Hz, 2.7Hz, 1H), 4.672(m, 1H), 4.039(m, 1H), 3.595(m, 1H), 3.411(m, 0.5H), 3.282(m, 0.5H), 3.049(m, 0.5H), 2.919(m, 0.5H), 2.086(m, 1H), 2.008(s, 1.5H), 1.993(s, 1.5H), 1.805-1.469(m, 5H)

Out on vacation

I am taking a week off. The next update will appear probably on Monday 23rd. Thank you for reading Org Prep Daily. Please, let me know if you want to have your synthetic procedures posted here. (‘Call For Authors’, Oct 8).

  Credit: Adolf Born

Spirochromanones

Pyrrolidine 0.25mL (3.0mmol) was added to a mixture of 2-hydroxy-5-chloroacetophenone 6.176g (36.2mmol) and 1-acetyl-4-piperidone 5.113g (36.2mmol)  in methanol 12mL. The mixture was heated under reflux (Ar, oil bath 80C) for 11 hours. The reaction mixture was diluted with ether 80mL and allowed to crystallize at RT for 1 hour. The precipitated product was collected by filtration, washed with ether (2x20mL) and dried on highvac. Y=8.286g (78%) of a white crystalline solid.

1H(d6-DMSO, 400MHz): 7.658(m, 2H), 7.151(d, 8.7Hz, 1H), 4.084(app br d, 10.0Hz, 1H), 3.632(app br d, 13.9Hz, 1H), 3.360(m, 1H), 2.966(td, t:12.5Hz, d:3.0Hz, 1H), 2.876(s, 2H), 2.003(s, 3H), 1.900(app br t, 16.0Hz, 2H), 1.721(m, 1H), 1.569(m, 1H)

 

The same procedure and scale, Y=8.487g (76%) of a white crystalline solid 1H(d6-DMSO, 400MHz): 7.641(s, 1H), 7.149 (s, 1H), 4.089(app br d, 13.3Hz, 1H), 3.630(app br d, 13.9Hz, 1H), 3.347(m, 1H), 2.948(td, t:12.5Hz, d:2.8Hz, 1H), 2.833(s, 2H), 2.341(s, 3H), 2.002(s, 3H), 1.894(app br t, 16.0Hz, 2H), 1.716(m, 1H), 1.564(m, 1H)  

  

Pyrrolidine 0.455mL with 2-hydroxy-5-fluoroacetophenone 10.110g (65.59mmol) and 1-acetyl-4-piperidone 5.113g (65.59mmol)  in methanol 22mL was heated under reflux (Ar, oil bath 80C) for 10 hours. The reaction mixture was diluted with ether 150mL and allowed to crystallize at RT for 8 hours. The precipitated pure product (11.176g) was collected by filtration, washed with ether (4x20mL) and dried on highvac. Cooling the supernatants to 5C (fridge, over weekend), additional product 3.930g precipitated. This second crop was re-crystallized from a mixture benzene-cyclohexane 1:2 to provide 3.761g of a pure product. Combined Y=14.937g (82%) of a light tan crystalline solid

1H(d6-DMSO, 400Mz): 7.494(td,t:8.4Hz,d:3.2Hz,1H), 7.436(dd,8.4Hz,3.2Hz, 1H), 7.160(dd,9.0Hz.4.3Hz,1H), 4.090(br m, 1H), 3.638(br m, 1H), 3.370(m, 1H), 2.976(m, 1H)2.870(s, 2H), 2.009(s, 3H), 1.906(app br t, 2H), 1.726(m, 1H), 1.575(m, 1H); 19F(d6-DMSO, 376.5MHz): -121.92 (m, 1F)

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

(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 

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

 

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

 

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)