Organic Syntheses, Vol. 77, 1
Checked by Gavin F. Painter and Andrew B. Holmes.
1. Procedure
A. Bis(1,5-dichloro-2,4-pentanedione)copper(II) complex.
3 A dry,
1-L, three-necked, round-bottomed flask is equipped with a
250-mL addition funnel,
reflux condenser,
rubber septum with
nitrogen inlet, and a
magnetic stirrer bar. The reflux condenser is equipped with a line to an HCl trap (Note
1) and the apparatus is maintained under a positive flow of
nitrogen. The flask is charged with
aluminum chloride (65.0 g, 0.487 mol) followed by the addition of
nitrobenzene (82 mL) (
Caution! Evolution of HCl gas) via the addition funnel.
1,2-Dichloroethane (96 mL) (Note
2) is added via the addition funnel and the mixture is stirred until all solids dissolve (ca. 15 min). The resulting olive green solution is placed in an
ice bath, and the funnel is charged with
2,4-pentanedione (50.0 mL, 0.487 mol) (Note
3). The
2,4-pentanedione is added to the solution dropwise over 15 min (
Caution! Evolution of HCl gas), and the funnel is charged with
chloroacetyl chloride (85.0 mL, 1.07 mol) (Note
4). The
chloroacetyl chloride is added to the solution dropwise over 15 min, followed by removal of the ice bath. The dark green solution is allowed to warm for 30 min. The reflux condenser is replaced with a
thermometer and the addition funnel is replaced with a
jacketed short path distillation head connected to a vacuum adapter. The vacuum adapter on the distillation head is connected to the HCl trap and the flask is immersed in an
electrically heated oil bath equipped with a
magnetic stirrer and external thermometer (Note
5). The reaction is slowly heated over 2 hr to 60°C (Note
6) when
acetyl chloride begins to distill (collected at 39°C). The solution temperature is maintained between 60°C and 70°C for the course of the distillation (Note
7). When the distillate temperature falls below 35°C the oil bath is removed, and the solution is cooled to room temperature with an ice bath. The solution is poured into a
2-L Erlenmeyer flask containing 1 L of ice, concentrated
hydrochloric acid (80 mL), and a magnetic stirrer bar. The reaction flask is rinsed with
1 N HCl (3 × 50 mL), and the washings are added to the Erlenmeyer flask. The rust colored reaction mixture is stirred vigorously for 17 hr and the phases are separated. The aqueous phase is extracted with
diethyl ether (2 × 150 mL) and the organic layers are combined. The organic layers are added to
1 L of a saturated copper(II) acetate solution in a 2-L Erlenmeyer flask, and the resulting green-brown suspension is stirred vigorously with a magnetic stirrer for 3 hr. The solution is filtered through a
Buchner funnel, and the green solid is washed with
diethyl ether (3 × 100 mL). The solid is triturated with
125 mL of diethyl ether, refiltered, and washed with
diethyl ether (5 × 75 mL) to give
55.6-56.4 g of product as a green-gray powder (
57-58% based on
2,4-pentanedione) (Note
8).
B. (2R,4R)-1,5-Dichloro-2,4-pentanediol. Catalyst preparation: A
100-mL Schlenk flask is equipped with a magnetic stirrer bar, rubber septum, and an
argon vacuum line. The flask is flame-dried under vacuum and cooled under oxygen-free dry
argon (twice), and it is then charged with
1,5-cyclooctadieneruthenium(II) chloride (RuCl2, COD) (79.2 mg, 0.283 mmol) (Note
9) and
[(S)-BINAP, 212 mg, 0.340 mmol] (Note
10). The flask and its contents are purged by evacuation and flushed with
argon (twice).
Triethylamine (Et3N, 470 μL, 3.37 mmol) (Note
11) is added via syringe followed by
toluene (20 mL) via cannula. The solution is heated at reflux for 16 hr under
argon, then allowed to cool to room temperature. The resulting orange solution is concentrated by stirring while the flask is held at a vacuum of ca. 1 mm and the
toluene and excess
triethylamine are condensed in a liquid
nitrogen trap to give crude
[RuCl2-(S)-BINAP)]2-Et3N catalyst as an orange solid.
1,5-Dichloro-2,4-pentanedione. A 1-L, round-bottomed flask is charged with
bis(1,5-dichloro-2,4-pentanedione)copper(II) complex (22.0 g, 55.1 mmol) followed by
diethyl ether (200 mL) and
10% sulfuric acid (200 mL). The reaction is stirred vigorously until all the solid dissolves (ca. 45 min). The organic layer is separated and the aqueous phase is extracted with
ether (2 × 200 mL). The combined
ether layers are washed with
brine (2 × 300 mL) and dried
(Na2SO4). The drying agent is removed by filtration, and the ether phase is concentrated under reduced pressure. The resulting crude material (ca.
20 g) is hydrogenated without further purification (Note
12).
The crude dione (ca.
20 g) is dissolved in dry
methanol (MeOH, 40 mL) (Note
13), and the solution is degassed with a stream of dry oxygen-free
argon. This solution is transferred via cannula into the flask containing the freshly prepared
[RuCl2-(S)-BINAP)]-Et3N catalyst under
argon. The resulting suspension is stirred and heated with a hair dryer to dissolve the catalyst. The resulting solution is transferred via cannula under
argon pressure into a flame-dried,
250-mL Schlenk flask sealed with a septum and vented with a syringe needle. The septum is replaced with a
high-vacuum stopcock (Note
14) and the Schlenk flask is transferred to a nitrogen glove box where the contents are transferred to a 250-mL pressure reaction vessel equipped with a
magnetic stirring bar. The vessel is sealed (Note
15). The pressure vessel is then transferred from the glove box to an electrical heating jacket preheated to 70°C and the vessel is pressurized to 1250 psi with
hydrogen gas in an explosion proof fume hood. The vessel is heated until the internal temperature is 65°C, and the contents are stirred with a magnetic stirrer at that temperature for 12-14 hr (Note
16). The vessel is cooled to room temperature and cautiously vented to discharge excess
hydrogen gas. The reaction mixture is concentrated under reduced pressure and filtered through a plug of silica gel that is washed with 1:1
ethyl acetate/hexanes (ca. 300 mL). Solvent is removed on a rotary evaporator and the crude product is crystallized from a mixture of
hexane:dichloromethane (2:3, v/v), and the solid is collected by suction filtration and rinsed with a mixture of
hexane:
CH2Cl2 (2:3, v/v). The off-white solid is recrystallized from
hexane:
CH2Cl2 (2:3, v/v), to give three crops of crystals (Note
17). The combined yield of the white crystalline product is
7.66 g (
40%) (Note
18).
2. Notes
1. The reflux condenser is fitted with an outlet that is connected with
Tygon tubing to a Drechsel bottle and then an inverted funnel in a crystallizing dish filled with water which serves as the HCl trap (the submitters used Lab Glass #LG-8605).
2.
1,2-Dichloroethane, 99%, was purchased from Aldrich Chemical Company, Inc., and used without further purification.
3.
2,4-Pentanedione, 99+%, was purchased from Aldrich Chemical Company, Inc., and used without further purification.
4.
Chloroacetyl chloride, 98%, was purchased from Aldrich Chemical Company, Inc., and used without further purification.
5. The submitters heated the flask with a
heating mantle and wrapped the exposed part of the flask in glass wool. This serves as an insulator to allow the subsequent distillation to proceed at lower temperatures.
6. Care must be taken not to heat the reaction mixture above 70°C.
7. The distillation typically requires 8-10 hr. Note that there is a slow
nitrogen stream running
through the apparatus when set up as described. The checkers found that the
acetyl chloride only condensed when the
nitrogen flow was decreased or stopped.
8. The submitters obtained
58.6 g (
60%) of a gray powder.
12. The crude dione could be purified at this stage by Kugelrohr distillation (oven temp. 80°C at 1 mm) to give the
1,5-dichloro-2,4-pentanedione as a clear, colorless oil. The enol:keto ratio is ca. 5.7:1. The physical properties are as follows:
1H NMR (250 MHz, CDCl
3) (enol) δ: 4.07 (s, 4 H), 6.14 (bs, 1 H), the acidic OH was not recorded;
13C NMR (62.5 MHz, CDCl
3) (enol) δ: 44.1, 96.8, 187.3;
1H NMR (250 MHz, CDCl
3) (keto) δ: 3.95 (bs, 2 H), 4.16 (s, 4 H);
13C NMR (62.5 MHz, CDCl
3) (keto) δ: 48.3, 50.5, 196.2.
13. The checkers used
MeOH that had been freshly distilled from
sodium methoxide (NaOMe) that was stored over 3 Å molecular sieves under
argon. The submitters used
Fisher ACS certified methanol without purification.
14.
A J. Young high vacuum stopcock was purchased from Aldrich Chemical Compay, Inc.
15. A Bergof
250-mL autoclave with PTFE seal was used. The submitters did not use a glove box. They used a Parr #4751,
125-mL pressure vessel that was assembled with a glass liner and a magnetic stirring bar, but without the top fitting. They then purged the vessel with a stream of Ar, and then the reaction mixture was added from the Schlenk flask via cannula through the top opening of the pressure vessel. The valve block assembly was attached, and hydrogenation was begun. The reaction vessel was wrapped in heating tape or placed in a heating mantle and pressurized to 1250 psi with H
2 gas in an explosion proof
fume hood.
16. Temperature control is important for the success of the reaction. The internal temperature should be monitored, and the temperature should be held around 65°C. The submitters found that when the autoclave (Parr #4751) is heated with heating tape and the internal temperature cannot be monitored, an externally measured temperature of ca. 100°C is appropriate. Too high a temperature leads to cyclization of the diol to give
2-chloromethyl-4-hydroxytetrahydrofuran.
17. The second crop of crystals was obtained by concentrating the supernatant from the first crystallization under reduced pressure, then redissolving in a minimum
hexane:
CH2Cl2 (2:3, v/v). The third crop was obtained in a similar manner.
18. The submitters obtained
7.40 g (
39%). The physical properties are as follows: mp
85-86°C; [α]D24 +21.1 (CHCl
3,
c 1.125); IR (KBr) cm
−1: 3364, 2959, 2890, 1435, 1402, 1340, 1294, 1103, 1072, 1052, 910, 710;
1H NMR (250 MHz, acetone-d
6) δ: 1.70 (dd, 2 H, J = 6.9, 5.4), 3.50-3.65 (m, 4 H), 4.02-4.12 (m, 2 H), 4.22 (d, 2 H, J = 5.6);
13C NMR (62.5 MHz, acetone-d
6, APT) δ: 38.7, 50.8, 68.0. Anal. Calcd. for C
5H
10Cl
2O
2: C, 34.71; H, 5.83. Found C, 34.7; H, 5.8. The optical purity of the
1,5-dichloro-2,4-pentanediol can be assayed by its Mosher ester analysis. The checkers prepared the bis-Mosher ester from the (R,R)-diol with
(R)-(−)-α-methoxy-α-(trifluoromethyl)phenylacetyl chloride acid chloride as follows: A flame-dried flask, under
argon, is charged with
(2R,4R)-1,5-dichloro-2,4-pentanediol (10 mg, 0.058 mmol) and
4-dimethylaminopyridine (DMAP) (ca. 1 mg). The flask is evacuated, then repressurized with
argon. Following the addition of dry
Et3N (55 μL, 0.39 mmol)s (Note
11) and dry
CH2Cl2 (3 mL) (dried over
calcium hydride and stored over 4Å molecular sieves),
(R)-(−)-α-methoxy-α-(trifluoromethyl)phenylacetyl chloride (Aldrich Chemical Company, Inc.) (50 mg, 0.20 mmol) is added, and the reaction mixture is stirred at 25°C under
argon for 24 hr, at which time silica TLC (silica gel,
50% EtOAc/hexane) indicated that no diol remained. The reaction mixture is concentrated under reduced pressure and filtered through a plug of silica (CH
2Cl
2) to give the bis Mosher ester (
25 mg, 0.041 mmol,
71%);
[α]D22 +50.0 (
CHCl3,
c 0.30);
1H NMR (500 MHz, CDCl
3) δ: 2.20 (dd, 2 H, J = 7.3, 5.7 (central CH
2)), 3.53 (bs, 6 H, OMe), 3.57 (dd, 2 H, J = 12.1, 4.0), 3.69 (dd, 2 H, J = 12.0, 4.9), 5.13-5.21 (m, 2 H), 7.41-7.45 (m, 6 H), 7.50-7.55 (m, 4 H);
19F NMR (235 MHz, CDCl
3) δ: −69.6; FAB-MS m/z 627.0785 ([M+Na]
+, calcd. for C
25H
24Cl
2F
6O
6Na 627.0752), 605 (5), [M]
+, 535 (5), 472 (3), 371 (5), 189 (100). The diastereomeric bis Mosher ester derived from the (S,S)-diol and (R)-acid chloride displays the central CH
2 as a doublet of doublets (J = 7.5, 5.5) at δ 2.07.
19. The
KOH is ground with a
mortar and pestle in a fume hood, and the ether is used as supplied. The submitters noted that when very dry
KOH and
ether were used, the reaction did not proceed to completion. They then effected the reaction with
50% aqueous KOH solution instead of powdered
KOH, followed by a standard aqueous workup.
20. The submitters obtained
4.50 g (
45.0 mmol,
90%) from
8.65 g (50 mmol) of diol. A sample purified by Kugelrohr distillation (bp
65°C at 28 Torr) gave the following spectral data:
[α]D24 +57.6 (CHCl
3,
c 2.24); IR (neat) cm
−1: 3055, 2997, 2924, 1421, 1256, 980, 938, 912, 844, 792, 747;
1H NMR (300 MHz, CDCl
3) δ: 1.72 (t, 2 H, J = 5.7), 2.51 (dd, 2 H, J = 4.9, 2.6), 2.73 (dd, 2 H, J = 4.9, 4.1), 3.03-3.09 (m, 2 H);
13C NMR (75 MHz, CDCl
3, DEPT) δ: 36.2, 46.9, 49.5. Anal. Calcd. for C
5H
8O
2; C, 59.98; H, 8.05. Found C, 60.0; H, 8.2.
21. The enantiomeric purity of the
(R,R)-1,2:4,5-diepoxypentane was measured as 96% by comparing the sample with
(S,S)-1,2:4,5-diepoxypentane using GC analysis on a B-PH (beta-cyclodextrin, permethylated hydroxypropyl) GC column. The submitters prepared both (S,S)- and (R,R)-enantiomers with enantiomeric excess >97% using the enantiomeric
BINAP-Ru(II)Cl2 catalysts. The enantiomeric purity of their
1,2:4,5-diepoxypentane was assayed by GC analysis using a B-PH (β-cyclodextrin, permethylated hydroxypropyl) column (20 m × 0.25 mm × 0.25μ); split ratio = 100:1; column flow 1.0 mL/min.; 50°C - 5 min; 3°C/min until 150°C. Retention times: (R,R)-12.55 min; (S,S)-12.75 min.
All toxic materials were disposed of in accordance with "Prudent Practices in the Laboratory"; National Academy Press; Washington, DC, 1995.
3. Discussion
Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)
(R,R)-1,2:4,5-Diepoxypentane: D-threo-Pentitol, 1,2:4,5-dianhydro-3-deoxy- (12)- (109905-51-3)
Bis(1,5-dichloro-2,4-pentanedione) copper(II) complex: Copper, bis(1,5-dichloro-2,4-pentanedionato-O,O')- (12); (135943-96-3)
Aluminum chloride (8,9); (7446-70-0)
Nitrobenzene: HIGHLY TOXIC: Benzene, nitro- (8,9); (98-95-3)
2,4-Pentanedione (8,9); (123-54-6)
Chloroacetyl chloride: Acetyl chloride, chloro- (8,9); (79-04-9)
(2R,4R)-1,5-Dichloro-2,4-pentanediol: 2,4-Pentanediol, 1,5-dichloro-, [R-(R,R)]- (12);
(136030-28-9)
1,5-Cyclooctadieneruthenium(II) chloride: Ruthenium, dichloro[(1,2,5,6-η)-1,5-cyclooctadiene]- (9); (50982-12-2)
Triethylamine (8); Ethanamine, N,N-diethyl- (9); (121-44-8)
(S)-(−)-BINAP: (S)-(−)-2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl: Phosphine, [1,1'-binaphthalene]-2,2'-diylbis(diphenyl-, (S)- (10); (76189-56-5)
Ruthenium chloride-(S)-BINAP-triethylamine: Ruthenium, bis[[1,1'-binaphthalene]-2,2'-diylbis[diphenylphosphine]-P,P']di-μ-chlorodichloro(N,N-diethylethanamine)di- (12); (114717-51-0)
1,5-Dichloro-2,4-pentanedione: 2,4-Pentanedione, 1,5-dichloro- (9); (40630-12-4)
Hydrogen (8,9); (1333-74-0)
Potassium hydroxide (8,9); (1310-58-3)
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