4,4-dimethylpentanoic acid

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 604.45 g (2.3 mol, 1 eq.) portion of PPh3 was dissolved in 724 mL CCl4 in a 2 L three-necked round-bottom flask under N2 to give a hazy solution. A stirbar was added and the flask was fitted with a water-cooled condenser topped with a N2 inlet/outlet, mechanical stirrer and shaft, and an addition funnel. The addition funnel was charged with a solution of ExxonMobil Neoheptanoic Acid Prime (300 g, 2.30 mol uncorrected for purity) in 300 mL CCl4. This material was 94.1% purity with an isomer balance of 43.0% 2,2-dimethylpentanoic acid (DMPA), 37.6% 2-ethyl-2-methylbutanoic acid (EMBA), and 13.5% 2,2,3-trimethylbutanoic acid (TMBA) by GC analysis (using FID detection; uncorrected for response factor). The acid solution was added dropwise at room temperature while stirring over a 1 hour period. No immediate reaction was observed other than a decrease in haziness to give a clear solution. After stirring under N2 for an additional hour at room temperature, the addition funnel was removed and the contents of the flask were heated at reflux (˜80° C.) for 3 h. The formation of a white precipitate was observed upon heating. Subsequently, the mixture was cooled to room temperature and filtered. Solvent was removed from the filtrate using a rotary evaporator. The residue was cooled in a refrigerator for 24 h and subsequently crushed with a spatula and extracted with 800 mL hexane for 2 hours. Solids were removed by filtration and the hexane filtrate depleted of volatiles using a rotary evaporator and high vacuum (at 50° C.) to give 200 g of a crude material containing product, phosphine-containing residues, unreacted acid, and other species (most likely neoheptanoic anhydrides). Fractional distillation of the crude material gave neoheptanoic acid chloride as the first boiling fraction (50° C./2.4×10−2 torr; 57.4 g, 17%); higher boiling fractions contained species assigned as neoheptanoic anhydrides (13C NMR C═O 173.1-173.0 ppm; IR υC═O 1808 and 1741 cm−1) and free acids. Elemental analysis calc. for C17H13ClO: C, 56.57; H, 8.82; Cl, 23.85; O, 10.76. Found: C, 56.64; H, 8.96; Cl, 23.60. 1H NMR (CDCl3, 400 MHz): δ 2.17 (septet, J=6.9 Hz, CHMe2 of TMBA), 1.81 (app. sextet, J=7.3 Hz), 1.64-1.53 (m), and 1.35-1.29 (m) (probably CH2 groups of EMBA and DMPA), 1.28 (s, probably CMe2 of DMPA), 1.21 and 1.20 (2 singlets, probably CMeEt of EMBA and CMe2 of TMBA), 0.94-0.88 (m, CHMe2 of TMBA, CH2Me of EMBA, and CH2Me of DMPA). 13C NMR (CDCl3, 125 MHz): δ 180.53 (C═O of TMBA), 180.11 (C═O of DMPA), 179.75 (C═O of EMBA), 57.23 (CMeEt of EMBA), 56.17 (CMe2 of TMBA), 52.84 (CMe2 of DMPA), 42.55 (CH2 of DMPA), 34.34 (CHMe2 of TMBA), 31.41 (CH2 of EMBA), 25.11 (CMe2 of DMPA), 21.46 (CMe2 of TMBA), 20.38 (CMeEt of EMBA), 17.93 (CH2Me of DMPA), 17.22 (CHMe2 of TMBA), 14.32 (CH2Me of DMPA), 8.58 (CH2Me of EMBA). Isomer ratio (average of C═O and CR2 resonances): 12.6% TMBA, 42.1% EMBA, 45.4% DMPA. IR (NaCl disk): 2970 (s), 2940 (sh), 2877 (sh), 1789 (vs, υC═O), 1698 (m, may be acid υC═O from incidental hydrolysis), 1460 (m), 1387 (w), 1369 (sh), 1194 (w), 1066 (w), 1009 (w), 975 (w), 961 (w), 916 (vs), 888 (m), 864 (m), 804 (vs), 756 (w), 743 (w) cm1. to give a hazy solution A stirbar was added cooled condenser topped with a N2 inlet/outlet, mechanical stirrer The acid solution was added dropwise at room temperature No immediate reaction to give a clear solution After stirring under N2 for an additional hour at room temperature the addition funnel was removed the contents of the flask were heated upon heating Subsequently, the mixture was cooled to room temperature filtered Solvent was removed from the filtrate a rotary evaporator The residue was cooled in a refrigerator for 24 h subsequently crushed with a spatula extracted with 800 mL hexane for 2 hours Solids were removed by filtration a rotary evaporator and high vacuum (at 50° C.) to give 200 g of a crude material Fractional distillation of the crude material

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 1 liter glass flask is added one mole of neoheptanoic acid and 1 gm of potassium hydroxide (solid), to provide the base catalyst for the subsequent ethoxylation reaction. Gaseous nitrogen is introduced to purge oxygen from the flask. A conventional bubbler device provided with NUJOL® oil is provided in the nitrogen gas feed line to the reaction flask. Gases discharged from the reaction flask are passed through a second such bubbler device. With continuous nitrogen flow through the flask, the temperature of the neo-acid/base mixture is raised to 150° C. at a rate of about 10° C./min. by means of a heating mantle. Thereafter, gaseous nitrogen flow is stopped and is replaced with gaseous ethylene oxide which is permitted to bubble through the neo-acid mixture. Periodic withdrawal of samples of the reaction mixture are made which are titrated to determine the level of residual neo-acid. The addition of ethylene oxide is controlled such that substantially all of the ethylene oxide introduced is reacted, thereby avoiding gaseous throughput through the gas withdrawal line of the reaction vessel. The adsorption of the ethylene oxide is also controlled such that there is no substantial rise in temperature of the reaction vessel due to any reaction exotherm. When it is determined that the proper amount of ethylene oxide has been added (via titration, as described above), the flow of ethylene oxide is terminated, and the reaction vessel is again purged with gaseous nitrogen and allowed to cool to room temperature. (An excess of ethylene oxide should be avoided). The crude product is then washed with water until the washwater is determined to be neutral. The monoethyoxylate thereby obtained is distilled at a pressure of 100 mmHg. to provide the base catalyst for the subsequent ethoxylation reaction Gaseous nitrogen is introduced to purge oxygen from the flask A conventional bubbler device provided with NUJOL® oil is provided in the nitrogen gas feed line to the reaction flask to bubble through the neo-acid mixture The addition of ethylene oxide introduced is reacted due to any reaction exotherm has been added (via titration, as described above) the flow of ethylene oxide is terminated the reaction vessel is again purged with gaseous nitrogen The crude product is then washed with water until the washwater The monoethyoxylate thereby obtained is distilled at a pressure of 100 mmHg

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Using analogous methodology 4-t-butyl-1-(3,3-dimethylbutyl) -2,6,7-trioxabicyclo[2.2.2 ]octane and 1-(3,3 - dimethylbutyl) -4-n-propyl-2,6,7-trioxabicyclo[2.2.2]octane-3-carbonitrile were prepared from 4,4-dimethylpentanoic acid (G. M. Whitesides et al J. Amer. Chem. Soc. 1967, 89, 1135).

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4,4-Dimethyl-pentanoic acid methyl ester (7.0 g, 48.5 mmol, 1.0 eq.) was treated with a solution of NaOH (4.0 g, 100 mmol, 2.1 eq.) in water (5 mL). The homogeneous solution was allowed to stir for 4-5 hours. The reaction was diluted with CH2Cl2 and the aqueous layer was extracted with CH2Cl2 (50 mL×3). The aqueous layer was acidified with 6M HCl to pH˜1.5 and extracted with ethyl acetate (50 mL×3). The combined ethyl acetate fractions were dried over MgSO4, filtered and evaporated to provide 4,4-dimethyl-pentanoic acid (5.35 g, 41.1 mmol, 85%) as a colorless oil: 1H NMR (CDCl3, 400 MHz) δ 0.89 (s, 9H), 1.53-1.57 (m, 2H), 2.26-2.30 (m, 2H). the aqueous layer was extracted with CH2Cl2 (50 mL×3) extracted with ethyl acetate (50 mL×3) The combined ethyl acetate fractions were dried over MgSO4 filtered evaporated

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Using analogous methodology 4-t-butyl-1-(3,3-dimethylbutyl) -2,6,7-trioxabicyclo[2.2.2 ]octane and 1-(3,3 - dimethylbutyl) -4-n-propyl-2,6,7-trioxabicyclo[2.2.2]octane-3-carbonitrile were prepared from 4,4-dimethylpentanoic acid (G. M. Whitesides et al J. Amer. Chem. Soc. 1967, 89, 1135).

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4,4-Dimethyl-pentanoic acid methyl ester (7.0 g, 48.5 mmol, 1.0 eq.) was treated with a solution of NaOH (4.0 g, 100 mmol, 2.1 eq.) in water (5 mL). The homogeneous solution was allowed to stir for 4-5 hours. The reaction was diluted with CH2Cl2 and the aqueous layer was extracted with CH2Cl2 (50 mL×3). The aqueous layer was acidified with 6M HCl to pH˜1.5 and extracted with ethyl acetate (50 mL×3). The combined ethyl acetate fractions were dried over MgSO4, filtered and evaporated to provide 4,4-dimethyl-pentanoic acid (5.35 g, 41.1 mmol, 85%) as a colorless oil: 1H NMR (CDCl3, 400 MHz) δ 0.89 (s, 9H), 1.53-1.57 (m, 2H), 2.26-2.30 (m, 2H). the aqueous layer was extracted with CH2Cl2 (50 mL×3) extracted with ethyl acetate (50 mL×3) The combined ethyl acetate fractions were dried over MgSO4 filtered evaporated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: This material was prepared in analogy to example 8 step C) from piperidine-4-carboxylic acid (4-trifluoromethoxy-phenyl)-amide (0.144 g) and 4,4-dimethyl-pentanoic acid (0.065 g) to give the desired 1-(4,4-dimethyl-pentanoyl)-piperidine-4-carboxylic acid (4-trifluoromethoxy-phenyl)-amide (0.178 g) as an off-white solid. MS (ESI): 401.25 (MH+).