1-allyl-4-nitropyrazole

Pyrazole 40.0g (587.5mmol) was added spoon-by-spoon ino stirred conc. sulfuric acid (96%) 270mL in a 1L wide-mouth flask with cooling on ambient oil bath. 70% nitric acid 40mL was then added dropwise over 10 minutes (exothermic). The bath temperature was raised to 55C. The reaction mixture was stirred at 55C for 7 hours, then cooled to R.T. and poured onto ice (1kg) in a large beaker. The mixture was made basic (pH=8) by addition of concentrated ammonia (exothermic) and the pH of the obtained hot mixture was adjusted with 6M HCl to about pH=3. The mixture was allowed to crystallize at RT for 8 hours, the precipitated crude product was collected by filtration and washed with ice-cold water. Cooling the supernatants to +5C overnight (fridge) produced additional crude product. The combined two fractions of crude nitropyrazole (containing some inorganics) were re-crystallized from water (250mL, to RT overnight), the pure product (46.401g) was collected by filtration, washed with ice-cold water and dried on highvac. Evaporating the supernatants and re-crystallizing the residue from water 50mL provided additional 4.110g of pure product. Combined Y=50.511g (76%) of white large crystals. 1H(d6-DMSO, 400MHz): 13.938(br s, 1H), 8.558(s, 2H)

Cs2CO3 16.3g (50mmol) was quickly powdered (with a large spatula and a beaker – to break up the lumps, hygroscopic!) and placed in a 0.5L flask under Ar. 4-nitropyrazole 4.110g (36.35mmol) was added followed by anhydrous acetonitrile 300mL and allyl bromide 4.2mL (49.6mmol). The mixture was stirred under Ar for 75 min (HPLC indicated complete conversion in 1 hour), the salts were removed by filtration (washed with additional acetonitrile 100mL) and the filtrates were evaporated. The residue was purified on a column of silica (40g) in a gradient of ethyl acetate in hexane, 0 to 25% ethyl acetate. The purified product was dried on highvac. Y=5.360g (96%) of a colorless liquid.

1H(d6-DMSO, 400MHz): 8.879(s, 1H), 8.277(s, 1H), 6.301(m, 1H), 5.265(m, 1H), 5.191(m, 1H), 4.834(m, 2H)

In later experiments, the simplified nitropyrazole work-up and re-crystallization was used without a detriment to the yield: The nitration mixture (a 40 g-scale experiment) was poured onto crushed ice 1.0kg in a large beaker or polyethylene bucket (3L). With stirring, concentrated ammonia (28-30% NH3) was gradually added until the mixture was basic (about pH=8 by universal indicator paper), this took about 550-600mL of concentrated ammonia, depending on the ammonia concentration. The obtained hot solution was acidified by gradual addition of 6M HCl until pH about 3 was obtained. The mixture was allowed to crystallize at RT in an open beaker overnight (18 hours). The precipitated crude product was collected by filtration, compressed on the Buchner funnel, washed quickly with a small amount of ice-cold water (2x40mL) and dried by suction. The crude product was recrystallized from hot water (200mL, to RT, overnight). The precipitated product (45.5g) was collected by filtration, washed with ice-cold water (2x40mL), dried by suction and on highvac. Cooling the supernatants from re-crystallization in a refrigerator (+2 C) overnight, a second fraction (5.2g)  crystallized.

Note 1: It is important to use approximately 1 kg of ice: Too little ice (0.6kg) leads to overheating and splashing during neutralization with ammonia whereas too much ice dilutes the reaction mixture and reduces the yield of the nitropyrazole.

Note 2: The workup/purification of 4-nitropyrazole can be further simplified by not recovering the second fractions from supernatants (with only a small penalty on the yield): 50.0g of pyrazole was gradually added to conc. sulfuric acid (95-96%) 340mL with cooling on water bath, followed by conc. HNO3 (70%) 40mL. The mixture was heated to 55C for 7 h, cooled, poured on ice 1.25kg, alkalized by gradual addition of conc. NH4OH (approx 850mL, to pH>9, exothermic!), acidified to pH=3 with 6M HCl and allowed to cool and crystallise overnight at RT. The product was collected by filtration, quickly rinsed with ice-cold water and dried by suction. The crude product was re-dissolved in refluxing water 250mL and allowed to crystallize at RT for 6 hours. Filtered, rinsed with ice-cold water, dried by suction and on highvac. Y=60.15g (72.5%) of white plates.

2-(2′,6′-dichlorophenyl)-dithiane

2,6-dichlorobenzaldehyde 10.50g (60 mmol) was dissolved in chloroform 30mL with heating. The solution was cooled to R.T. and 1,3-propanedithiol 6.30mL (63mmol) was added. With cooling on ambient water bath, TMSCl 23mL (180mmol) was added dropwise over 10 min period (exothermic, gas evolution) and the resulting heterogennous mixture was stirred under Drierite-filled tube (as a gas outlet) for 20 hours. Two small spoons of 4A activated mol sieves powder were added (to absorb the dropplets of aq. HCl) and stirred for additional 30 minutes. The reaction mixture was filtered through a Celite pad (washed with chloroform) and the filtrates were evaporated. The obtained solid residue (16g) was dissolved in refluxing cyclohexane 100mL, filtered while hot (the filter funnel was rinsed with hot cyclohexane) and the filtrates were set aside to crystallize overnight (14 hours). The crystallized product (1st crop: 13.445g) was filtered, washed with hexane and dried on highvac. Evaporating the supernatants and re-crystallizing the residue from cyclohexane 20mL provided second pure crop (1.841g). Combined Y=15.286g (96%) of a white crystalline solid.

1H(CDCl3, 400MHz): 7.307(m, 2H), 7.128(t, 8.2Hz, 1H), 6.069(s, 1H), 3.144(td, t:14,4Hz, d:2.3Hz, 2H), 2.947(dt, d:14.2Hz, t:3.5Hz, 2H), 2.170(m, 1H), 2.019(m, 1H)

(R)-3-aminomethyl-4-methylmorpholine

The 5-hydroxymethyl-4-methyl-3-morpholinone 11.53g (79.43mmol), DMAP 61mg (0.5mmol) and triethylamine 11.6mL (83.4mmol) was dissolved in anhydrous chloroform (200mL) and cooled to 0C. Mesyl chloride 6.45 mL (83.4mmol) was added dropwise over 5 min period. The mixture was stirred at 0C for 90 min, then quenched by addition of water 20mL. The quenched mixture was stirred at RT for 10 min, acidified with 1M sulfuric acid (40mL) and separated. The aqueous phase was re-extracted with chloroform (3x100mL). The combined extracts were dried (MgSO4) and filtered. The filtrates were applied directly onto a column of silica (200g) packed in chloroform. The column was eluted with 20:1 chloroform-methanol mixture. The purified product was carefully dried on highvac to remove traces of chloroform. Y=16.86g (95%) of pure mesylate as a colorless honey. (Using identical procedure, the opposite enantiomer was obtained in 94%Y, 16.63g)

1H(CDCl3, 400MHz): 4.378(m, 2H), 4.229(dAB, 16.4Hz, 1H), 4.133(dAB, 16.8Hz, 1H), 3.828(dd, 12.5Hz, 2.7Hz, 1H), 3.561(m, 1H), 3.086(s, 3H), 3.066(s, 3H); 13C(CDCl3, 100MHz): 166.92, 68.14, 65.87, 64.12, 56.87, 37.76(br s), 33.79(br s)

N,N,N’,N’,-Tetramethylguanidinium azide 7.91g (50mmol) solid (hygroscopic!) was added in one portion to a solution of the mesylate 6.85g (30.68mmol) in anhydrous acetonitrile 20mL and the mixture was stirred under nitrogen at 70C for 1 day. The cooled mixture was quenched by addition of saturated aqueous ammonium chloride 80mL and extracted with ethyl acetate (3x200mL). The combined organic extracts were dried (MgSO4) and evaporated, then re-evaporated with anh THF.  The obtained crude azide (4.79g) was dissolved in anh THF 250mL, the solution was cooled to 0C and LAH 5.0g was gradualy added  (in 1g portions) with vigorous stirring and cooling on ice bath. The  mixture was then refluxed under nitrogen for 6 hours. The reaction mixture was cooled to 0C, quenched by carefull dropwise addition of water 5mL, then 15%NaOH 15mL and then water again 5mL. The quenched mixture was stirred at RT overnight (12 hours), the salts were removed by filtration (and washed with THF), the filtrates were concentrated. The obtained residue was distilled on Kugelrohr apparatus at 0.5Torr, air bath temperature 80-85C. Y=3.554g (89%) of a colorless liquid

1H(CD3CN, 400MHz): 3.750(m, 1H), 3.694(m, 1H), 3.502(td, t:11.3Hz,d:2.7Hz, 1H), 3.369(dd, 11.3Hz, 10.1Hz, 1H), 2.695(d, 2.7Hz, 1H), 2.684(d, 0.8Hz, 1H), 2.635(dt, d:9.4Hz, t:2.3Hz, 1H), 2.338(s, 3H), 2.229(m, 1H), 1.946(m, 1H), 1.531(br s, 2H); 13C(CDCl3, 100MHz): 70.70, 68.01, 65.75, 56.83, 43.56, 41.68 

(A procedure for preparation of tetramethylguanidinium azide was posted on Sept 25).

(R)-4-methyl-3-morpholinone-5-methanol

 

Chloroacetic anhydride is a nasty irritant: use gloves, do not spill, do not inhale vapors. The anhydride should look like a nice white crystalline solid. If soggy or dark, purify it before use by vacuum distillation (on Kugelrohr).

LAH 12.5g was added in 1 gram-sized portions into a vigorously-stirred solution of Cbz-D-Serine(OtBu)-OH 25.05g (84.8mmol) in anh. THF 0.5L in a 2L flask with cooling on ice bath. After complete LAH addition, the mix was refluxed for 6 hours. The reaction mixture was cooled to 0C, quenched very slowly by carefull addition of water 12.5mL (dropwise!), then 15% aq. NaOH (37.5mL) and then additional water (12.5mL). The mixture was stirred for 12 hours (overnight), filtered, the salts were thoroughly washed with THF and discarded. The filtrates were evaporated. The residue was dissolved in dichloromethane 100mL, cooled to 0C and a solution of chloroacetic anhydride 17.10g (100mmol) in dichloromethane (40mL) was added dropwise over 90min with cooling at 0C (addition funnel was used). The mixture was stirred at 0C for additional 30 min, the cooling bath was removed, the acylation was quenched by addition of sat NaHCO3 (300mL), stirred in an open flask at RT for 30 min. The org. phase was separated, washed with sat. NaHCO3 300ML, the aqueous phases were re-extracted with dichloromethane (2x150mL). The combined org. extracts were dried (MgSO4) and evaporated, the residue was dried on highvac. (0.5Torr, 60C, 1h). The residue was dissolved in anhydrous ethanol 150mL (non-denaturated), sodium methoxide 5.40g (100mmol) was added (in 3 portions) with cooling on ambient water bath. The mixture was stirred at RT for 10 min, then at 60C for 30 min. The obtained heterogennos mixture was evaporated, the residue was portioned between sat. ammonium chloride 150mL and chloroform 100mL. The aqueous phase was re-extracted with additional chloroform (3x100mL). The combined extracts were dried (MgSO4) and evaporated, the residue was distilled on Kugelrohr at 0.5 Torr, 90-130C air bath temp.

The obtained crude tBu-protected morpholinone (semi-solid distillate from Kugelrohr) was combined with TFA 100mL. The mixture was stirred for 2 hours, evaporated on highvac and re-evaporated with toluene. The obtained trifluoroacetate ester was dissolved in methanol 60mL, made basic by addition of concentrated aq. NH3 (12mL), stirred for 1 hour then evaporated and dried on highvac. The residue was stirred twice with cyclohexane (2x100mL), the upper phase decanted off, the bottom phase was heated with  toluene 100mL to reflux, cyclohexane 100mL was added, stirred for 1 hour at RT, the upper phase was decanted off. (This washing excersize was done to remove benzyl alcohol that carried over from the LAH reduction). The residue was dissolved in a 10:1 mixture of chloroform-methanol (10:1, 60mL), stirred for 30 min, the precipitated salts were removed by filtration (and washed with the 10:1 mixture), the filtrates were evaporated. The residue was purified on a column of silica (200g) in 10:1 chloroform-methanol mixture. The purified product was dried on highvac. Y=11.61g (94% overall) of a colorless honey.

1H(CDCl3, 400MHz): 4.143(m, 3H), 3.834(m, 3H), 3.294(m, 1H), 3.046(s, 3H), 2.719(br s, 1H); 13C(CDCl3, 100MHz): 167.73, 67.77, 64.73, 60.27, 58.93, 33,36(br s)

Using identical procedure, Cbz-L-Ser(OtBu)OH provided the S-enantiomer in 94%Y overall (11.63g)

CbzNH-lactone

 

The aminoacetonide 2.87g (Acros, 10.5 mmol) and triethylamie 2.5mL (18 mmol) was dissolved in dichloromethane 20mL and Cbz-OSu 2.617g (10.5 mmol) was added in one portion with cooling on ambient bath (exothermic). The mixture was stirred for 1 hour, then portioned between ethyl acetate 150mL and sat. bicarbonate 100mL. The organic phase was washed with additional sodium bicarbonate (100mL) and aqueous phases re-extracted with ethyl acetate (150mL). Combined organic extracts dried (MgSO4) and evaporated. The residue was dried on highvac. The obtained crude Cbz-protected acetonide ester (4.38g) was dissolved in dichloromethane 15mL, TFA 10mL was added, the mixture was stirred for 40 min then evaporated and dried on higvac. The residue was purified on a column of silica (150g) in a mix dichloromethane-ethyl acetate 1:2 (2 parts of EtOAc:1 part DCM, 4L total). Y=1.875g (61%) of a white crystalline solid.

1H(d6-DMSO, 400MHz): 7.343(m, 5H), 5.204(br s, 1H), 5.003(s, 2H), 4.615(m, 1H), 4.097(br s, 1H), 3.117(m, 2H), 2.623(ddAB, 17.3Hz, 12.6Hz, 1H), 2.368(m, 1H), 1.766-1.663(m, 4H)

2-(2′,6′-dichlorophenyl)-propionic acid

 

To a solution of o,o-dichlorophenylacetonitrile 18.60g (100mmol) in dichloromethane 100mL, 3.40g of Bu4NHSO4 (10mmol) and 25mL of iodomethane (400mmol) was added, followed by 50% aq. NaOH 100mL. The mixture was refluxed on oil bath (70-80C) for 18 hours (overnight). The reaction mixture was diluted with water 100mL with cooling (exothermic), ether 200mL and dichloromethane 100mL was added, shaken and separated. The aqueous layer was re-extracted with ether-dichloromethane 1:1 mixture (300mL). The org. extracts were washed with brine, combined, dried (MgSO4) and evaporated. The residue was suspended in ether 220mL, stirred for 1 hour, the insoluble Bu4NI (3.22g) was removed by filtration and washed with additional ether, the filtrates were evaporated and the residue dried on highvac. Y=20.105g (100%) of the pure propionitrile product as a white crystalline solid.

1H(CDCl3, 400MHz): 7.355(dAB, 7.8Hz, 2H), 7.214(ddAB, 8.6Hz, 7.4Hz, 1H), 4.833(q, 7.5Hz, 1H), 1.694(d, 7.5Hz, 3H); 13C(CDCl3, 100MHz): 134.83, 132.00, 129.91(2C), 129 (2C), 119.44, 27.47, 17.12

60% sulfuric acid 550g (obtained from 96% H2SO4 343g and 206mL of water) was combined with o,o-dichlorophenyl-2-propionitrile 10.076g (50.36mmol) and the mixture was refluxed with vigorous stirring on oil bath (160C) for 10 hours. The cooled mixture was diluted with water (0.5L) and stirred at R.T. for 1 hour to complete the crystallization of the crude product. The crude product was collected by filtration, washed with water. The material was suspended in water 0.5L, made strongly alkaline with 15% NaOH and stirred until complete dissolution (1 hour). A small spoon of charcoal was added, the mixture was filtered through a medium-porosity frit and the filtrate was acidified with excess of 4M HCl. The mixture was stirred for 10 min, the product was collected by filtration, washed with water, dried by suction and on highvac. Y=10.194g (92.5%) od a white crystalline solid.

1H(CDCl3, 400MHz): 7.299(d, 7.8Hz, 1H), 7.126(ddAB, 8.6Hz, 7.6Hz, 2H), 4.578(q, 7.0Hz, 1H), 1.532(d, 7.0Hz, 3H); 13C(CDCl3, 100MHz): 179.18, 136.78, 135.23, 128.79(2C), 128,76(2C), 42.17, 14.47

I believe the reason why no double-methylation occured is that Bu4NOH is probably not basic enough to deprotonate the 2-aryl-propionitrile. (The clash of o-Cl with the Me group of the nitrile anion causes the C=C=N(-)  to be out of plane of the aryl group, which means that unlike in the staring arylacetonitrile, the propionitrile anion is not stabilised by the conjugation with Ar.)