Org Prep Daily

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.

July 3, 2007

8-iodo-4,7-octadiynoic acid methyl ester

Filed under: Chris Douglas, procedures — milkshake @ 12:58 am

iodoacetylene1.gif

Silver nitrate (0.74 g, 4.40 mmol) was added to a solution of methyl 4,7-octadiynoate (6.77 g, 44.0 mmol) in THF (45 mL).  The suspension was shielded from light and stirred at rt for 5 min.  N-iodosuccinimide (10.1 g, 44.0 mmol) was added to the reaction mixture in one portion and stirring was maintained for 2h.   The reaction mixture was poured into 100 mL water and extracted with Et2O (3´100 mL).  The combined extracts were dried with Na2SO4 and concentrated onto Celite (20 g).  Purification of the resulting powder by flash chromatography (1:10 Et2O:Pentane) gave the title compound as a light and air sensitive colorless powder, 8.52 g (30.4 mmol, 69%).

1H NMR (500 MHz, CDCl3) d 3.70 (s, 3H), 3.30 (t, J = 2.2, 2H), 2.52–2.48 (m, 4H); 13C NMR (125 MHz, CDCl3) d 172.4, 87.9, 79.5, 73.8, 51.8, 33.2, 14.6, 11.8, –4.6; IR (film) 2997, 2950, 1730 cm-1 LRMS (CI, NH4) m/z, 294 (M + NH4)+, 277 (M + H)+, 168.  Calcd for C9H9IO2: C, 39.16; H, 3.29. Found C, 39.37; H, 3.34.

Note: 1-Iodo-phenylacetylene can be easily prepared using the same procedure. The yields can be slightly variable depending on the scale.

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March 16, 2007

(4S)-(4,5-dihydro-4-tert-butyl-2-oxazolyl) ferrocene and (2S)-N-(1-hydroxy-3,3-dimethylbutyl) ferrocenamide

Filed under: Chris Douglas, procedures — milkshake @ 2:10 pm

ferrocenyl-oxazoline.gif

(2S)-N-(1-hydroxy-3,3-dimethylbutyl) ferrocenamide

Ferrocene monocarboxylic acid (16.1 g, 70 mmol, Strem) was suspended in dichloromethane (340 mL) in a 3-neck flask fitted with a nitrogen inlet, septum, and an outgas tube bubbling into a 1L flask Erlenmeyer flask filled with 500 mL of 1 M NaOH. A small amount of DMF (~0.05 mL) was added to the suspension and oxalyl chloride (8.1 mL, 92 mmol) was added to the suspension dropwise over 5 min. The reaction became homogeneous as it was stirred for 1 h. The resulting solution was concentrated and the residue dissolved in dichloromethane (150 mL). The red-orange solution was transferred by cannula to a solution of L-tert-leucinol (8.50 g, 72.5 mmol) and triethylamine (31.7 mL, 220 mmol) in dichloromethane (370 mL) maintained at 0 °C. The reaction mixture was allowed to warm to rt over 3 h and ether (300 mL) was added. The reaction mixture was washed with a solution of NaOH (500 mL, 1M aqueous), dried over MgSO4, filtered through a pad of Celite and concentrated. The orange-brown residue was dissolved in boiling dichloromethane (300 mL) and the solution cooled to –20 °C and maintained for 12 h. The formed orange crystals were collected by vacuum filtration (17.85 g, 54 mmol, 77%). The filtrate was concentrated. The residue was dissolved in boiling dichloromethane (30 mL) and the solution was cooled to –20 °C and maintained for 12 h. A second crop of orange crystals was collected by vacuum filtration (4.94 g, 15 mmol, 21%). The combined crops of crystals (22.55 g, 68.6 mmol, 98%) were identical in all respects to the material prepared by alternative methods. (Ref 1)

Note: Clean your rotovap from any residual HCl after the first concentration. Recommend aspirator vs. diaphragm pump for the first concentration

(4S)-(4,5-dihydro-4-tert-butyl-2-oxazolyl) ferrocene

Methanesulfonyl chloride (MsCl, 8.3 mL, 100 mmol) was added to a solution of (2S)-N-(1-hydroxy-3,3-dimethylbutyl) ferrocenamide (22.55 g, 68.5 mmol) and triethylamine 30 mL (200 mmol) in dichloromethane 0.8L maintained at 0C. The reaction was allowed to warm to RT over 12 h and a solution of saturated aqueous NaHCO3 (0.5L) was added to the reaction mixture. The phases were separated and the aqueous portion was extracted with dichloromethane (2×300 mL) and the combined organic portions were dried over MgSO4 and filtered through a pad of Celite. The filtrate was concentrated and the resulting residue was taken up in boiling hexanes (200 mL) and the solution was decanted, leaving behind a small amount of insoluble brown residue. The resulting homogeneous solution was cooled to –20C and maintained at that temperature for 12 h. The orange needles that formed were collected by vacuum filtration and washed with hexanes (10 mL) to provide the title compound (18.49 g, 59.5 mmol, 87%). The filtrated was concentrated and the resulting residue dissolved in boiling hexanes (20 mL). The solution was cooled to –20 C for 12 h and a second crop of orange needles was collected as above (1.90 g, 6.1 mmol, 9%). The combined crops of needles (20.39 g, 65.6 mmol, 96%) were identical in all respects to the material prepared by alternative methods. (Ref 1)

Ref 1: Sammakia, T.; Latham, H. A.; Schaad, D. R. J. Org. Chem. 1995, 60, 10–11.

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Org Prep Daily has a new contributor

Filed under: Chris Douglas — milkshake @ 1:52 pm

I am delighted to announce that Chris Douglas submitted his improved procedure for making a ferrocene oxazolidine ligand to Org Prep Daily.

Thank you Chris – and best luck with your new group in Minnesota!

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