Org Prep Daily

November 21, 2009

1NMPP1

Filed under: procedures — milkshake @ 10:27 pm

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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 (2x100mL), 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)

November 19, 2009

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

Filed under: procedures — milkshake @ 6:32 am

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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.

November 10, 2009

Intramolecular Carboacylation with rhodium C-C insertion

Filed under: Chris Douglas, procedures — milkshake @ 2:57 pm

C-C insertion

To a cooled solution (–78 °C) of 8-bromoquinoline (2.25 g, 10.8 mmol) in THF (70 mL) in a flame-dried flask under N2 was added n-BuLi (2.5 M in hex, 6 mL, 15 mmol) drop-wise. The dark orange mixture was allowed to stir for 10 min. Aldehyde (2.84 g, 16.2 mmol, readily available from salicylaldehyde and 1-chloro-2-methyl-2-propene) was slowly delivered as a solution in THF (3 mL) over a span of 10 min to give a dark cloudy red solution. The reaction was stirred at –78 °C for 20 min, and allowed to warm to room temperature over 2 h. The clear orange solution was quenched with saturated NH4Cl (60 mL), and the layers were separated. The organic layer was washed with water (10 mL), and the combined aqueous washes were extracted with Et2O (2 x 50 mL). The combined organic portions were washed with brine (30 mL), dried over Na2SO4, and concentrated. The resulting orange-yellow residue was taken up in Et2O and a colorless precipitate formed. Collection of this precipitate by vacuum filtration gave the alcohol (1.80 g, 5.9 mmol, 55%), which was carried on directly. The intermediate alcohol (1.53 g, 5 mmol) was dissolved in DMSO (33 mL) and allowed to react with IBX (2.92 g, 10 mmol). The solution was maintained at room temperature for 2 h. Ethyl acetate (20 mL) and water (20 mL) were added, and the resulting colorless precipitate was removed by filtration through Celite. The layers were separated, and the aqueous portion was extracted with EtOAc (3 x 10 mL). The combined organics were washed with brine (20 mL), dried over Na2SO4, and concentrated. The yellow-orange oil was purified by column chromatography over silica gel (1:9 EtOAc:Hex) gave 1 as viscous yellow oil (1.20 g, 3.97 mmol, 79%, 43% over the two steps). Rf .23 (1:4 EtOAc:Hex)

1H NMR (300 MHz, CDCl3) δ 8.77 (dd, J = 1.8, 4.2 Hz, 1H), 8.13 (dd, J = 1.8, 8.4 Hz, 1H), 7.91 (dd, J = 1.8, 7.5 Hz, 1H), 7.81 (dd, J = 1.5,8.4 Hz, 1H), 7.78 (dd, J = 0.9, 6.6 Hz, 1H), 7.54 (app t, J = 7.8 Hz, 1H) 7.47-7.41 (m, 1H), 7.34 (dd, J = 4.2, 8.1 Hz, 1H), 7.05 (app t, J = 7.5, Hz, 1H), 6.81 (d, J = 8.1 Hz, 1H), 4.49-4.36 (m, 2H), 3.97 (s, 2H). 1.16 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 196.8, 158.1, 150.3, 145.9, 141.6, 139.7, 135.7, 133.6, 131.2, 129.8, 129.5, 128.2, 128.0, 125.8, 121.2, 120.5, 112.6, 112.2, 72.0, 18.7; IR (thin film) 3078, 2915, 1645, 1595, 1573, 1485, 1451, 1322, 1294, 1246, 1158, 1109, 1040, 1006, 926, 907, 798, 754, 626; HRMS (ESI) calcd for [C20H17NO2 + H]+ 304.1332, found 304.1329.

A 0.2 M solution of 1 in PhMe was prepared in a N2 atmosphere glove box. RhCl(PPh3)3 (10 mg, 0.01 mmol) catalyst was carefully weighed into a 1 dram vial, and the solution of 1 (0.5 mL, 0.1 mmol) was added followed by toluene (0.5 mL). The vial was capped with a PTFE lined screw-cap and resulting yellow-orange solution was maintained at 130 °C for 48 h. The cloudy brown mixture was removed from the glove box and concentrated onto Celite. Column chromatography (EtOAc:Hex) gave 2 as colorless viscous oil (28.7 mg, 0.095 mmol, 96%).  Rf 0.31 (1:4 EtOAc:Hex)

1H NMR (300 MHz, CDCl3) δ 8.94 (dd, J = 2.1, 4.5 Hz, 1H), 8.18 (dd, J = 1.8, 8.4 Hz, 1H), 7.91 (dd, J = 1.5, 8.4 Hz, 1H). 7.81 (dd, J = 1.8, 7.2 Hz, 1H), 7.56 (dd, J = 7.2, 8.1 Hz, 1H), 7.44 (dd, J = 4.2, 8.4 Hz, 1H), 7.13-7.07 (m, 2H), 6.83-6.78 (m, 2H), 4.72-4.55 (m, 2H), 3.97-3.75 (m, 2H), 1.55 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 204.7, 159.1, 150.5, 145.5, 140.1, 136.3, 135.5, 131.2, 129.0, 128.23, 128.2, 126.1, 122.9, 121.5, 120.4, 109.7, 83.0, 54.2, 44.4, 25.9; IR (thin film), 3045, 2961 1681, 1595, 1568, 1479, 1346, 1247, 1216, 970, 831, 792, 750; HRMS (ESI) calcd for [C20H17NO2 + H]+ 304.1332, found 304.1337. The structure was confirmed by HMQC, COSY, and HMBC.

8-bromoquinoline – a painless Skraup synthesis

Filed under: Chris Douglas, procedures — milkshake @ 2:44 pm

Skraup

A 1-L 3-neck round bottom flask was equipped with an overhead mechanical stirrer, an internal temperature thermometer, and a dropping funnel. The flask was charged with methanesulfonic acid (250 mL) and warmed with stirring to an internal temperature of 125 °C. 2-Bromoaniline (80.55 g, 0.468 mol) was added portion-wise, followed by meta-nitrobenzenesulfonic acid sodium salt (66.30 g, 0.293 mol) and FeSO4.7H2O (3.90 g, 14 mmol). The addition funnel was charged with glycerol (28.3 mL, 0.39 mol) and the glycerol was added dropwise over 15 min. Two additional portions of glycerol (2 x 28.3 mL, 0.78 mol) were added at three-hour intervals. After the last portion of glycerol was added the brown solution was maintained at 125 °C for 12 hours. The reaction mixture was allowed to cool to RT and water (250 mL) was added. The resulting brown-black solution was transferred to a 4-L beaker with the aid of 100 mL water. The beaker was placed in an ice bath and an aqueous NaOH solution (50% m/v) was added with stirring until the solution was basified to ~ pH 14. The heterogeneous mixture was extracted with Et2O (3 x 500 mL), allowing the emulsion to settle for ~10 min each time. The combined organic extracts were washed with brine (1 x 400 mL), dried over Na2SO4 and filtered through Celite. Concentration of the resulting solution to a viscous brown oil provided the title compound (86.55 g, 0.426 mol, 89%) in ~95% purity as judged by 1H NMR. The crude product was then purified by kugelrohr distillation (0.14 mm Hg; pot temp, 180–205 °C) to give a yellow oil that solidified on standing (83.69 g, 0.402 mol, 86%)

1H NMR (300 MHz, CDCl3): 8.98 (dd, J = 4.2, 1.8, 1H), 8.08 (dd, J = 8.3, 1.7, 1H), 7.98 (dd, J = 7.4, 1.4, 1H), 7.72 (dd, J = 8.1, 1.2, 1H), 7.39 (dd, J = 8.1, 4.2, 1H), 7.32 (t, J = 8.0, 1H); 13C NMR (75 MHz, CDCl3): 151.1, 145.0, 136.5, 133.0, 129.4, 127.7, 126.8, 124.5, 121.8.
This material identical to 8-bromoquinoline prepared by other methods.

November 2, 2009

Easy Iodination of Alkynes

Filed under: krest17, procedures — milkshake @ 8:23 pm

iodination1

The question was: how to perform this reaction in a clean way (no column purifications, no distillations), cheap (if possible, no Ag salts or any other expensive metals), easy (if possible, no Ar and no Schlenk flasks, open air, solvents from bottles), scalable (well, this combines first three I guess), general (yes, I needed a library of these compounds with different functional groups and had no desire to develop different procedures for each of them separately).
Quick look in SciFinder showed two procedures as mostly used and welcomed by scientists; (a) using silver nitrate and NIS (posted on this website some time ago by Chris Douglas  (b) deprotonation with nBuLi in THF or Ether under Ar followed by quench with I2. Obviously, they could not meet my criteria. First approach required using of Ag salts and not so cheap and stable NIS, second one needed anhydrous conditions, cooling, flammable nBuLi and yes – Schlenk flasks and Schlenk line. It is not like I could not do it and I do have Schlenk line under my hood, but… sometimes 10-15 min more in SciFinder can save a lot of pain in the neck.
So, I found procedure from Scott E. Denmark (Tetrahedron 2004, 60, 9695) for the desired iodination in MeOH/H2O using KOH as a base and I2 to deliver I+. Although, this procedure was used only for omega-OH acetylenes, which could be the trick, I decided to give a shot. Reaction worked as a magic – easy, open flask, no cooling or heating, all reactants are cheap and could be found in any lab, water from tap and methanol from bottle. Yields are generally over 80% and no column needed. Below are some selected substrates I did.

iodination2

Here is the magic procedure:

To a solution of alkyne (50 mmol) in MeOH (50 mL) was slowly added an aqueous solution of KOH (2.5 equiv) in water (10-12 mL) at rt. (I tried recommended 0°C and did not find any difference). After 10 min I2 (1.5 equiv.) was slowly added within 3-5 min at rt (I tried recommended 1.1 equiv. but could not reach full conversion). The mixture was diluted with H2O and extracted with pentane. The combined organic layers were concentrated and filtered through 3-5 cm plug of silica gel. Silica gel was washed with pentane till disappearance of spot of product on TLC. Pentane was evaporated and … that’s it. For all substrates I did so far purity of product was >95% by NMR and GC.

Thank you for reading.

New contributor and admin [1]

Filed under: Uncategorized — milkshake @ 8:03 pm

Welcome aboard, krest17
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Note 1: Thread hijackers and comment-section bandits, watch out:  Now there is two of us [2]
Note 2: Formally, Note 2 serves to remind you about the importance of Note 1 – but in reality it ribs CBC

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