| 89% |
With hydrogenchloride; In water; for 1.0h; |
Synthesis of 2,5-dichloro-2,5-dimethylhexane The synthesis was accomplished as previously described [Mayr, H., et al., Chem. Ber. 124: 203, 1999]. 2,5-Dimethyl-2,5-hexanediol (73.1 grams, 0.500 mol) was stirred with 37% aqueous HCl (250 ml) for 1 hour. The initially homogeneous mixture precipitated to yield a crystalline product. The product was extracted with 600 ml of petroleum ether and dried with CaCl2. Evaporation of the solvent yielded 81.9 grams (89%) of an NMR-spectroscopically pure solid, which was recrystallized from petroleum ether (mp: 68-68.5 C.) as 2,5-dichloro-2,5-dimethylhexane. |
| 87% |
With hydrogenchloride; In water; at 20℃; for 1.0h; |
To 2,5-dimethyl-2,5-hexanediol (10 g, 68.5 mmol) in a 500 mL flask was added reagent grade concentrated HCl (150 mL) and the solution was stirred at ambient temperature for 1 h. Water (100 mL) and CH2Cl2 (100 mL) were then added slowly and the layers were separated. The aqueous layer was washed with additional CH2Cl2 (100 mL). The combined organic layers were dried over MgSO4 and filtered thru silica gel pad. The solvent was removed to yield 10.9g (87%) of 2,5-dichloro-2,5-dimethylhexane. The dichloride was dissolved in 150 mL Of CH2Cl2 and 9.6 mL of toluene (90 mmol) was added. AlCl3 (390 mg, 2.9 mol) was added in portions over 5 min at ambient temperature. HCl is evolved and the solution turns dark red. The reaction was placed in an ice-bath and quenched with deionized water (120 mL). Hexane (150 mL) was added and the organic layer was removed. The aqueous layer was washed with additional hexane (150 mL). The combined organic layers were washed with water (200 mL) and brine (100 mL) and dried over MgSO4. The solvent was removed in vacuo to give l,l,4,4,6-pentamethyl-l,2,3,4- tetrahydronaphthalene as a colorless oil that crystallized after storage at -2O0C.[0155] Yield: 12 g (91%); low melting white solid; Rf = 0.7 in 100% hexane.[0156] 1H-NMR (CDCl3, 300 MHz) delta 1.32 (s, 12H), 1.7 (s, 4H), 2.34 (s, 3H), 6.85 (dd, IH), 7.14 (d, IH), 7.22 (d, IH)[0157] 13C-NMR (CDCl3, 75 MHz) delta 21.54, 32.26, 32.32, 34.29, 34.51, 35.57, 35.63, 126.64, 126.75, 127.21, 134.93, 142.00, 144.83. |
| 86.7% |
With hydrogenchloride; In water; at 20℃; for 0.5h; |
2, 5-Dimethyl 2, 5-hexanediol (21) (7.31 g) was added to concentrated hydrochloric acid (100 mL) and stirred vigorously at room temperature for 30 minutes. The obtained precipitate was collected by filtration, washed with water, and dissolved in dichloromethane. After washing with water and saturated brine, the organic layer was dried with anhydrous sodium sulfate. Filtration and concentration under reduced pressure gave the title compound (22) (7.93 g, yield 86.7%) as a white solid. |
| 85% |
With hydrogenchloride; In water; at 20℃; for 1.5h; |
Concentrated HCl (1.2 L, 14.4 mol) was added to commercial 2,5-dimethyl-hexane-2,5-diol (202 g, 1.4 mol) and the slurry was stirred at ambient temperature for 1.5 h.. The mixture was filtered.. The filter cake was washed with water (*3), dissolved in Et2O, washed successively with H2O, NaHCO3, and brine, dried over Na2SO4, and concentrated in vacuo.. Recrystallization of the resulting solid from Et2O gave the title compound as white crystals (216 g, 85%). 1H NMR (300 MHz, CDCl3): delta1.60 (s, 12H), 1.95 (s, 4H). |
| 85% |
With hydrogenchloride; In water; at 20℃; for 1.5h; |
Concentrated HCl (1.2 L, 14.4 mol) was added to commercial 2,5-dimethyl-hexane-2,5-diol (202 g, 1.4 mol) and the slurry was stirred at ambient temperature for 1.5 h. The mixture was filtered. The collected solid was washed with water (×3), dissolved in Et2O, washed successively with H2O, NaHCO3, and brine, dried over Na2SO4, and concentrated in vacuo. Recrystallization of the resulting solid residue from Et2O gave the title compound as white crystals (216 g, 85%). 1H NMR (300 MHz, CDCl3): delta 1.60 (s, 12H), 1.95 (s, 4H). |
| 85% |
With hydrogenchloride; In water; at 20℃;Inert atmosphere; |
A solution of 2,5-dimethyl-2,5-hexanediol 19(2.0 mmol) in 37% hydrochloric acid (42 mmol) was stirredat room temperature for 65 h. The mixture was extractedwith ethyl acetate and the organic phase was washed with5% NaHCO3 and dried over anhydrous MgSO4. The solventwas removed under reduced pressure. The product waspurified by flash chromatography and recrystallizationusing hexane as solvent, which furnished 2,5-dichloro-2,5-dimethyl hexane 20 as white crystals in 85% yield.mp 68 C; 1H NMR (300 MHz, CDCl3) delta 1.58 (s, 12H,3CH3), 1.93 (s, 4H, 2CH2); 13C NMR (75 MHz, CDCl3) delta 32.52, 41.14, 70.35. |
| 81% |
With hydrogenchloride; In water; for 0.25h; |
2,5-dimethyl-hexane-2,5-diol (10 g, 68.4 mmol) was placed in a reaction vessel with gentle stirring. Cone. HCI (aq, 80 mL) was added and the resulting mixture was stirred slowly for 15 mins. The resulting suspension was left standing for 2 h. It was then filtered and washed with 2x30 mL of water. A resulting solid was dried under high vacuum to afford the title compound T-1 (10.1 g, 81% yield). The analytical data matches those reported in the literature. |
| 79.91% |
With hydrogenchloride; In water; at 0 - 20℃; for 12.0h; |
2, 5-Dichloro-2, 5-dimethylhexane To a two-neck 250 mL RB flask charged with 2, 5-dimethyl-2, 5-hexanediol (15 g, 102.6 mmol), conc. HCl (60 mL) was added slowly at 0 C., and stirred at RT overnight. The reaction mixture was quenched with ice, obtained heterogeneous mixture was filtered and washed with water and dried under vacuum to yield a title compound as a white solid (15.0 g, yield: 79.91%): 1H NMR (300 MHz, CDCl3): 1.88 (s, 4H), 1.53 (s, 12H). |
| 73% |
With thionyl chloride; In dichloromethane; at 20℃; for 4.0h; |
Thionyl chloride (25 ml, 341.8 mmol) is added at ambient temperature to a solution of 2, 5-DIMETHYL-2, 5-HEXANEDIOL (20.0 g, 136.8 mmol) in 250 ml OF DICHLOROMETHANE. The reaction mixture is stirred for 4 hours. Then 250 ml of distilled water is added. The organic phase is separated and washed with 10% NAHCO3 solution (2X250 ml), then dried over MGS04 and evaporated to dryness to give the title compound (18.37 g, 73%). 'H NMR (CDCI3) : 1.57 (s, 12H, CH3) ; 1.92 (s, 4H, CH2). |
| 73% |
With thionyl chloride; sodium hydrogencarbonate; In dichloromethane; water; |
a) Preparation of 2,5-dichloro-2,5-dimethylhexane Thionyl chloride (25 ml, 341.8 mmol) is added at ambient temperature to a solution of 2,5-dimethyl-2,5-hexanediol (20.0 g, 136.8 mmol) in 250 ml of dichloromethane. The reaction mixture yellows and the agitation is continued for 4 hours. The progress of the reaction is controlled by thin film chromatography (eluent ether: petroleum ether=50:50). At the end of reaction, 250 ml of distilled water is added, it is decanted and the organic phase is neutralised using 2*250 ml of a 10% NaHCO3 solution. The product is dried with MgSO4 filtered and evaporated to dryness. 18.37 g of a solid 2,5-dichloro-2,5-dimethylhexane is obtained (gross yield=73%). NMR1H 200 MHz (CDCl3): 1.57 (s, 12H, Me); 1.92 (s, 4H, -CH2-). |
| 73% |
With hydrogenchloride; In water; |
For comparison in the biological evaluation (Fig. 1 and 2) of compounds 1 - 3, [8 and 9] and 30-32, [8b and 9b] an authentic sample of bexarotene and its ketone analog (33a) were synthesized, following the reported route (Boehm, et al. "Synthesis and Structure-Activity Relationships of Novel Retinoid X Receptor-Selective Retinoids." J. Med. Chem. 1994, 37, 2930-2941 ): a seven step, convergent synthesis that gave a 29% overall yield of bexarotene. The first sequence of steps to bexarotene concerned the SN1 conversion of 2,5-dimethyl-2,5-hexanediol (33b) to 2,5-dichloro-2,5- dimthylhexane (34) by HCI, and the subsequent aluminum trichloride catalyzed Friedel-Crafts alkylation of toluene to give 1 ,2,3,4-tetrahydro-l .l A4,6-pentamethylnapthalene (35) in 68% yield over two steps (Scheme 1 ). |
| 70% |
With hydrogenchloride; In water; at 20℃; for 16.0h; |
2,5-dimethylhexane-2,5-diol (10.0 g, 68.4 mmol) was stirred in 50 mL of conc. aq. HCl for 16 hr. The reaction was diluted with 50 mL of H2O and extracted with Et2O (3×50 mL). The combined organics were evaporated to 30 mL. A white crystalline solid precipitated and was collected via filtration (8.8 g, 70%) and was not purified further. 1H NMR (400 MHz, CDCl3): delta = 1.96 (s, 4H), 1.61 (s, 12H). 1H NMR matches literature.5 2,5-dichloro-2,5-dimethylhexane (5.50 g, 30.0 mmol) and o-bromotoluene (10.3 g, 60.0 mmol) were dissolved in 60 mL of DCM. AlCl3 (400 mg, 3.00 mmol) was added slowly over 5 minutes. The reaction was stirred for 1 hr under an Ar atmosphere. 50 mL of H2O was added to the reaction and the layers were separated. The aqueous was extract with hexane (3×50 mL). The combined organics were dried with MgSO4, filtered, and removed under vacuum to yield an oil. The oil was dissolved in 75 mL of boiling MeOH and then cooled in an ice bath. The mixture was filtered to yield white crystals (6.6 g, 78%). 1H NMR (400 MHz, CDCl3): delta = 7.43 (s, 1H), 7.15 (s, 1H), 2.35 (s, 3H), 1.66 (s, 4H), 1.26 (s, 12H). 1H NMR matches literature[5]. |
| 68% |
With hydrogenchloride; at 20℃; for 2.0h; |
Concentrated HCl (400 mL) was added to 2,5-dimethyl-2,5-hexanediol (50.0 g, 432 mmol) dropwise with gentle swirling. The diol flakes gradually dissolved and a white precipitate formed simultaneously. The reaction mixture was stirred at room temperature (RT) for 2h; the white precipitate was filtered off and was washed with water until pH ?7 followed by cold EtOH. The solid was dried under vacuum to afford 1 as a white solid (42.5g, 68%), mp 63-65 C (lit.2 63-65.8 C, lit.19 63-65C). 1H NMR (CDCl3): delta 1.95 (s, 4H), 1.60 (s, 12H). |
| 68% |
With hydrogenchloride; In water; at 20℃; |
(b) 2,5-Dichloro-2,5-dimethylhexane (1): Concentrated HCl (400 mL) was addedto 2,5-dimethyl-2,5-hexanediol (50.0 g, 432 mmol) dropwise with gentleswirling. The diol flakes gradually dissolved and a white precipitate formedsimultaneously. The reaction mixture was stirred at room temperature (RT) for2 h; the white precipitate was filtered off and was washed with water until pH7 followed by cold EtOH. The solid was dried under vacuum to afford 1 as awhite solid (42.5 g, 68%), mp 63-65 C (lit.2 63-65.8 C, lit.19 63-65 C). 1H NMR(CDCl3): d 1.95 (s, 4H), 1.60 (s, 12H). |
| 65.2 g (65%) |
With hydrogenchloride; In ethanol; |
Example 11: Preparation of (E)-methyl-4-[2-(3-bromomethyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)vinyl]benzoate HCl gas was added by bubbling through a gas dispersion tube to a solution of 100 g (684 mmol) of 2,5-dimethyl-2,5-hexanediol in 300 mL of ethanol. The reaction mixture slowly warmed from room temperature to 60 C. over 3 hours. The reaction mixture was cooled in a wet ice bath and a white solid was filtered off. The solid was washed with water and cold ethanol, then dried to give 65.2 g (65%) of 2,5-dichloro-2,5-dimethylhexane (M+=181). |
|
With hydrogenchloride; In conc. hydrogen chloride; |
2,5-Dichloro-2,5-dimethylhexane Hydrogen chloride gas was bubbled through a suspension of 48 g (0.33 mol) of 2,5-dimethyl-2,5-hexanediol in 600 ml conc. hydrogen chloride until the solution was saturated. The resulting crystalline produce was collected by filtration, washed repeatedly with water and dried on a vacuum line to give the title compound as a crystalline white solid. PMR (CDCl3): delta1.60 (12H, s), 1.94 (4H, s). |
|
With hydrogenchloride; In conc. hydrogen chloride; |
2,5-Dichloro-2,5-dimethylhexane Hydrogen chloride gas was bubbled through a suspension of 48 g (0.33 mol) of 2,5-dimethyl-2,5-hexanediol in 600 ml conc. hydrogen chloride until the solution was saturated. The resulting crystalline produce was collected by filtration, washed repeatedly with water and dried on a vacuum line to give the title compound as a crystalline white solid. PMR (CDCl3): delta1.60 (12H, s), 1.94 (4H, s). |
|
In hydrogenchloride; |
(a) 2,5-dichloro-2,5-dimethyl hexane A suspension of 14.6 g of 2,5-dimethyl-2,5-hexanediol in 150 cm3 of concentrated HCl is stirred, for 1 hour, at a temperature of about 5 C. The solid is then filtered, thoroughly washed with water and then dried at ambient temperature on potash and under reduced pressure. 16.5 g of 2,5-dichloro-2,5-dimethyl hexane in the form of white crystals melting at 65 C. are obtained. |
|
With hydrogenchloride; In conc. hydrogen chloride; |
EXAMPLE 1 2,5-Dichloro-2,5-dimethylhexane Hydrogen chloride gas was bubbled through a suspension of 48 g (0.33 mol) of 2,5-dimethyl-2,5-hexanediol in 600 ml conc. hydrogen chloride until the solution was saturated. The resulting crystalline product was collected by filtration, washed repeatedly with water and dried on a vacuum line to give the title compound as a crystalline white solid. PMR (CDCl3): delta1.60 (12H, s), 1.94 (4H, s). |
|
In hydrogenchloride; |
EXAMPLE 1 2,5-Dichloro-2,5-dimethylhexane Hydrogen chloride gas was bubbled through a suspension of 48 g (0.33 mol) of 2,5-dimethyl-2,5-hexanediol (Aldrich) in 600 ml of concentrated HCl until the solution was saturated. The resultant crystalline product was collected by filtration, washed repeatedly with water and dried on a vacuum line to give the title compound as a white crystalline material. PMR (CDCl3): delta 1.60 (12H, s), 1.94 (4H, s). |
|
In hydrogenchloride; dichloromethane; |
Example 1.1 2,5-dichloro-2,5-dimethylhexane First, 48 g (0.328 mole) of 2,5-dimethyl-2,5-hexanediol was suspended in 480 ml of concentrated hydrochloric acid, and the suspension was vigorously stirred at room temperature for 1 hour. After removal of the precipitated crystals by filtration, these crystals were dissolved in 120 ml of CH2 Cl2. This solution was washed with water, dried over MgSO4, and then evaporated to dryness, resulting in 49.3 g (82%) of the aforementioned compound. m.p. 65-66 C. NMR delta (CDCl3): 1.63 (12H, s, CH3 *4), and 1.97 (4H, s, CH2 *2). |
|
With hydrogenchloride; |
The synthesis of compound 8 is outlined below : To a solution of 2,5 dichloro-2, 5 [DIMETHYLHEXANE,] 2, (10 g, 54.7 [MMOL)] in toluene (270 mL 0.2 M) was slowly added aluminum trichloride (5.47 g, 41 [MMOL)] as a solid over 15 minutes time. The reaction was complete after 10 minutes as assayed by TLC in hexanes. The unreacted aluminum trichloride was quenched slowly with water over 10 minutes. Additional toluene (250 mL) was added to extract the product from the aqueous layer. The organic layer was passed through a pad of silica gel (40 [G)] and eluted with toluene. The organic layer was [EVAPORATED IN VACUO] to dryness to yield 1,1, 4,4, [6-PENTAMETHYL-1,] 2,3, 4-tetrahydronaphtalene, 4 (11g, 97% yield). To a solution containing 1,1, 4,4, [6-PENTAMETHYL-1,] 2,3, 4-tetrahydronaphtalene, 4, (20 g, 99 [MMOL)] and methyl 5- (chloromethyl)-2-furoate, 5, (17.28 g, 99 [MMOL)] in methylene chloride (500 mL 0.2 M aluminum trichloride (16.46 g, 124 [MMOL)] was added slowly as a solid at the reflux temperature. The solution was refluxed for an additional two hours. The reaction was monitored by TLC in 10% ethyl acetate/hexanes solution. The reaction was cooled to room temperature and the unreacted aluminum trichloride was quenched with water over 15 minutes. The crude product was extracted with methylene chloride and passed through silica gel (80 [G)] and eluted with methylene chloride. The solvent was [EVAPORATED IN VACUO] to syrup. The crude product was purified with silica gel (300g) via a plug [FILTERATION] column. Methyl [5- [ (3,] 5,5, 8, [8-PENTAMETHYL-5,] 6,7, 8-tetrahydro-2- naphthalenyl) methyl]-2-furoate, 6, was eluted with 2 % ethyl acetate/hexanes to afford 15.4 [G] (46 % yield). To a solution containing Methyl [5- [ (3,] 5,5, 8, 8-pentamethyl-5, 6,7, 8-tetrahydro-2-naphthalenyl) methyl]-2-furoate, 6, (15.1 g, 44 [MMOL)] in MeOH (175 mL) and water (175 mL), a solution of [NAOH] (3.53 g, 88.3 [MMOL)] in water (29 mL) was added. The reaction was stirred overnight at room temperature. After completion as judged by TLC, the solution was acidified with 1 M HCI to pH 2. The crude product was extracted in to organic layer using ethyl acetate and concentrated to afford 5- [[ (3, 5, 5, 8, 8-PENTAMETHYL-5, 6, 7, 8-TETRAHYDRO-2-NAPHTHALENYL) METHYL]-2-FUROIC] acid, 7 (15.0 g, 99 % yield). To a solution containing [5- [ (3,] 5,5, 8, [8-PENTAMETHYL-5,] 6,7, [8-TETRAHYDRO-2-NAPHTHALENYL)] methyl]- 2-furoic acid, 7, (20.15 g, 61.77 [MMOL)] in methylene chloride (310 mL), thionyl chloride (45 mL, 617. mmol) was added. The reaction was heated under reflux for 5 hours and another batch of thionyl chloride (45 mL, 617 [MMOL)] was added. The reaction was stirred overnight at room temperature. The solution was concentrated to a syrup and filtered through a pad of silica gel [(50G),] eluted with 3% ethyl acetate in hexanes, and [CONCENTRATED IN VACUO] to afford [5- [ (3,] 5,5, 8, [8-PENTAMETHYL-5,] 6,7, 8- tetrahydro-2-naphthalenyl) methyl]-2-furoyl chloride, 8 (17g, 80% yield). |
|
With hydrogenchloride; In diethyl ether; |
Intermediate: 2,5-dichloro-2,5-dimethylhexane Conc. HCl (37% v/v, d=1.18, 250 ml) was added carefully to 2,5-dimethyl-2,5-hexanediol (20 g, 137 mmol) in a 500 ml conical flask. The mixture was stirred for 24 h and then filtered and the precipitate was washed 3*200 ml with water. The white crystals were redissolved in diethylether and washed with 100 ml water, and then dried over MgSO4. The solvent was removed in vacuo to give 2,5-dichloro-2,5-dimethylhexane 12.9 g (50%) as a white solid; M.p.=62-64 C. |
|
With hydrogenchloride; In hexane; water; for 12.0h;Inert atmosphere; |
A mixture of 2,5-dimethylhexane-2,5-diol 13a (102.20 g, 0.70 mol) was added to 700 mL of concentrated hydrochloric acid, 50 mL of n-hexane was added, and the reaction was stirred for 12 hours.The filtrate was extracted with ethyl acetate (200 mL x 3) and the organic phases were combined, dried over anhydrous sodium sulphate, filtered, the filtrate was concentrated under reduced pressure and the filter cake was combined to give the title product crude 2 , 5-dichloro-2,5-dimethylhexane 13b (124.20 g, white powder) and the product was directly subjected to the next reaction without purification. |
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