1. Procedure (Note 1)
2. Notes
1. Prior to performing each reaction, a thorough hazard analysis and risk assessment should be carried out with regard to each chemical substance and experimental operation on the scale planned and in the context of the laboratory where the procedures will be carried out. Guidelines for carrying out risk assessments and for analyzing the hazards associated with chemicals can be found in references such as Chapter 4 of "Prudent Practices in the Laboratory" (The National Academies Press, Washington, D.C., 2011; the full text can be accessed free of charge at
https://www.nap.edu/catalog/12654/prudent-practices-in-the-laboratory-handling-and-management-of-chemical. See also "Identifying and Evaluating Hazards in Research Laboratories" (American Chemical Society, 2015) which is available via the associated website "Hazard Assessment in Research Laboratories" at
https://www.acs.org/content/acs/en/about/governance/committees/chemicalsafety/hazard-assessment.html. In the case of this procedure, the risk assessment should include (but not necessarily be limited to) an evaluation of the potential hazards associated with
(±)-2,2,2-trichloro-1-phenylethan-1-ol,
sodium bicarbonate,
dichloromethane,
sodium thiosulfate,
TEMPO,
pyridinium tribromide,
ethyl acetate,
magnesium sulfate, hexanes, silica gel,
toluene,
(S)-CBS-Bu,
catecholborane,
tetrahydrofuran,
sodium hydroxide,
hydrochloric acid,
sodium chloride,
diethyl ether,
acetonitrile,
1,1'-carbonyldiimidazole,
hydroxylamine hydrochloride,
imidazole,
sodium sulfate,
chloroform,
triethylamine, and
methanesulfonyl chloride.
2.
(±)-2,2,2-Trichloro-1-phenylethan-1-ol is prepared using the procedure described in
Org. Synth. 1968,
48, 27-29. The submitters prepared and provided the sample of
(±)-2,2,2-Trichloro-1-phenylethan-1-ol (~98% purity) used for checking.
(±)-2,2,2-Trichloro-1-phenylethan-1-ol is also commercially available.
3.
Dichloromethane (certified ACS) is purchased from Caledon Company and used as received.
4.
Sodium bicarbonate is purchased from Caledon Company and used as received. The saturated solution is prepared by adding 90 g of
sodium bicarbonate to 1000 mL of distilled
water.
5.
TEMPO is purchased from Sigma-Aldrich Fine Chemicals Company Inc.
6. An ice/water bath is used.
7.
Pyridinium tribromide (90% grade) is purchased from Sigma-Aldrich Fine Chemicals Company Inc and is used as received.
8. Portions of 5-10 g are added every 2 minutes, for a total addition of 15-20 minutes (a foam can form if the addition is too fast). The solution must be vigorously stirred (900 rpm or more).
9. The reaction is monitored by TLC analysis on silica gel using a mixture of Et
2O:hexanes (1:9) and visualization with UV light and KMnO
4 (R
f of starting material = 0.16, R
f of product = 0.68).
10.
Sodium thiosulfate is purchased from Merck KGaA. The 5% w/w solution is prepared by dissolving 78 g of
sodium thiosulfate pentahydrate (
Na2S2O3·5H2O) in 1000 mL of distilled water.
11. The red solution becomes yellow upon the addition of
sodium thiosulfate.
12. A TLC analysis is performed on the last drop of filtration to be sure that all the product has been collected.
13. The checkers recommend the concentration of the crude on a rotary evaporator in a fume hood due to the presence of pyridine.
14. Submitters suggested purification by distillation using the following conditions: The crude material is suspended in hexanes (200 mL) (
Note 15) and silica gel (30 g) (
Note 16) is added to trap the colored impurities. The mixture is filtered through a pad of silica gel (15 g), washed with hexanes (600 mL) and the filtrate is evaporated
in vacuo (38 °C, 375 to 35 mmHg). The resulting pale yellow liquid is distilled under reduced pressure (oil-bath: 80 °C to 120 °C, 0.2 mmHg, main fraction: bp 55-64 °C at 0.2 mmHg). The distillation short path is equipped with a 15 cm Vigreux column and grease is used for all joints. Checkers found that purification by distillation as described did not reliably provide the highest purity product (
Note 17).
15. Hexanes (certified ACS) is purchased from Fisher Scientific Company and used as received.
16. Silica gel F60 type, 40-63 µm (230-400 mesh) is purchased from Zeochem AG Inc.
17. The checkers found that an additional purification by flash chromatography was necessary after distillation to obtain analytically pure product.
18. A second reaction performed on half-scale provided 15.0 g (79%) of the same product, after purification by distillation and chromatography. Analytical data for
2,2,2-trichloro-1-phenylethan-1-one (
1). R
f = 0.66-0.69
(Et
2O:hexanes (1:9));
1H NMR
pdf(400 MHz, CDCl
3) δ: 7.48-7.53 (m, 2H), 7.62-7.66 (m, 1H), 8.25-8.28 (m, 2H);
13C NMR
pdf(100 MHz, CDCl
3) δ: 95.6, 128.5, 129.2, 131.6, 134.4, 181.4; IR (film, ATR-FTIR) 1709, 1596, 1448, 1221, 1005, 820, 650 cm
-1; HRMS (ESI+) calc. for C
8H
6Cl
3O [M+H]
+: 222.9479; found: no exact mass found by ESI+; Anal. calc. for C
8H
5Cl
3O: C, 43.00, H, 2.26; found: C, 43.21, H, 2.19.
19. Dry
toluene from a column purification solvent system (using activated alumina and CuO (treated with H
2) columns) under argon atmosphere is employed.
20.
(S)-CBS-Bu catalyst (1.00 M in
toluene) is purchased from Sigma-Aldrich Fine Chemicals Company Inc.
21. The checkers used commercially available solution of catalyst (
Note 20). The submitters prepared a solution of
(S)-CBS-Bu according to the following procedure: A 100 mL round-bottomed flask, equipped with a magnetic stirrer, is charged with
n-butylboronic acid (780 mg, 7.70 mmol, 1.10 equiv),
(S)-diphenyl-prolinol (1.77 g, 7.00 mmol, 1.00 equiv) and
toluene (35 mL). The flask is then equipped with a Dean-Stark apparatus filled with
toluene, put under argon, stirred and heated to reflux overnight. The solution is then used directly in the reaction without any purification.
22. Checkers found that the reaction with commercially available
(S)-CBS-Bu catalyst (1.00 M in
toluene) proceeded with the same efficiency, with respect to yield and level of enantioselection, as described by the submitters.
23. A dry ice/acetone bath is used. A period of 20-30 min is typically needed to reach -78 °C inside the reaction mixture.
24. A 1 M solution of
catecholborane in
THF (1.05 M according to the specification sheet) is purchased from Sigma-Aldrich Fine Chemicals Company Inc.
25. An internal thermostat probe is used to monitor the temperature of the solution. Addition rate (one drop every 5 seconds approximately) is carefully controlled to maintain the temperature below -65 °C.
26. The dry ice/acetone bath should not be removed during the warming to allow a slow increase of the temperature of the solution mixture. The checkers note that the warming of the solution to room temperature as described in this note by the submitters took 24-36 h.
27.
Water is added dropwise (two drops per second) as rapid evolution of H
2 is observed.
28. The aqueous layer becomes green/black during the washing. The aqueous washings are performed until the aqueous layer becomes light brown. The checkers observed that the basic wash slightly warmed and slow phase separation was noted in the 4th and 5th wash.
29. Approx. 2000 mL of eluent is required.
30. The checkers noted a slightly higher level of enantioselection on half-scale experiment (14.5 g, 65.0 mmol of
1), which afforded 14.6 g of alcohol
2 as colorless liquid (>99% yield, 96% ee).
31. Analytical data for
(R)-2,2,2-trichloro-1-phenylethan-1-ol (
2). R
f = 0.24-0.27 (Et
2O:hexanes (2:8));
1H NMR
pdf(400 MHz, CDCl
3) δ: 3.41 (d,
J = 4.0 Hz, 1H), 5.21 (d,
J = 3.9 Hz, 1H), 7.38-7.45 (m, 3H), 7.62-7.65 (m, 2H);
13C NMR
pdf(100 MHz, CDCl
3) δ: 84.6, 103.2, 127.9, 129.3, 129.6, 134.9; IR (film, ATR-FTIR) 3450, 1454, 1059, 817, 743 cm
-1; [#945;]
D24 -39.2 (c 1.00, CHCl
3); Enantiomeric ratio is determined to be 97.1:2.9 by analytical HPLC, using the following conditions: Chiracel-OD chiralpak column (4.6 mm x 250 mm, particle size 10 μm, part #14025); 10% isopropanol in hexanes for 30 min, flow 1.0 mL/min, 210 nm detection; retention time: t
major = 8.5 min and t
minor = 11.4 min; HRMS (ESI+) calc. for C
8H
7Cl
3NaO [M+Na]
+: 246.9455; found: no exact mass found by ESI+; Anal. Calcd for C
8H
7Cl
3O: C, 42.61, H, 3.13, found: C, 42.99, H, 3.05.
32. Dry
acetonitrile from a solvent purification system (using two neutral activated alumina columns) under argon atmosphere is employed.
33.
1,1'-Carbonyldiimidazole is purchased from Alfa Aesar
and stored in glovebox prior to use.
34. Portions of 5 g are added every minute.
35. The solution becomes heterogeneous over time. A white precipitate appears a few minutes after the addition of
CDI.
36. The reaction is monitored by TLC analysis on silica gel using EtOAc:hexanes (2:8) and visualization with UV light and KMnO
4 (R
f of starting material
= 0.5, R
f of intermediate = 0.2).
37. The
hydroxylamine hydrochloride salt is purchased from Sigma-Aldrich Fine Chemicals Company Inc.
38.
Hydroxylamine hydrochloride is hygroscopic and is dried in an oven (110 °C) overnight before use.
39.
Imidazole (99% grade) is purchased from Alfa Aesar and used as received.
40. The precipitate disappears for a while before another beige precipitate appears after the addition.
41. The reaction is monitored by TLC analysis on silica gel using
EtOAc in hexanes (3:7) and visualization with UV light and KMnO
4 (R
f of product = 0.34).
42. Checkers observed some solid formation in the crude material.
43.
Chloroform is purchased from Fisher Chemicals and used as received.
44. Checkers found that upon concentration of the mother liquor to approx. 100 mL, additional product precipitates. This second crop of product is an equal mixture of product
3 and starting material
2 and can give another ~1 g of the product
3 upon purification by flash chromatography (
Note 46).
45. Checkers noted formation of product
3 with similar efficiency and with the similar purity for first and second crops on half-scale experiment (13.5 g, 60.0 mmol of
2), affording 14.8 g of product
3 as colorless solid (87%) in first crop.
46. Analytical data for
(R)-2,2,2-trichloro-1-phenylethyl hydroxycarbamate (
3). R
f = 0.34-0.37 (EtOAc:hexanes (3:7));
1H NMR
pdf(400 MHz, CDCl
3) δ: 6.30 (s, 1H), 6.88 (br, 1H), 7.36-7.45 (m, 3H), 7.56-7.59 (m, 3H) (OH under this band);
13C NMR
pdf(100 MHz, CDCl
3) δ: 84.2, 99.1, 128.1, 129.7, 130.1, 132.6, 156.8; IR (solid, ATR-FTIR) 3326, 1743, 1453, 1245, 1118, 751 cm
-1; mp 93-96 °C (checkers note the mp for purified product is 97-100 °C); [α]
D25 -35.8 (c 1.00, CHCl
3); HRMS (ESI+) calc. for C
9H
8Cl
3NNaO
3 [M+Na]
+: 305.9462; found: 305.9464; Anal. calc. for C
9H
8Cl
3NO
3: N, 4.92, C, 37.99, H, 2.83; found: N, 4.81, C, 37.99, H, 2.71. (A sample is purified by flash chromatography eluting with MeOH in DCM (3:97) before performing the elemental analysis. NMR spectra of both, the product before and after purification are provided. The crude product (93.5% w/w) is directly used for subsequent reaction.).
47. Consistent with the submitters observations, the checkers observed no difference in use of product
3 directly from first crop or after chromatographic purification (Note 46). Checkers found that the purity of the isolated product in the first crop is 92.0% n/n, 93.5% w/w, exactly the same as provided by submitters. The product
3 is isolated along with remaining starting alcohol
2.
48. Dry DCM from a column purification solvent system (using two neutral activated alumina columns) under argon atmosphere is employed.
49. Anhydrous
triethylamine from a solvent purification system (using two neutral activated alumina columns) under argon atmosphere is employed.
50.
Methanesulfonyl chloride is purchased from Sigma-Aldrich Fine Chemicals Company Inc. and is freshly distilled under vacuum over P
2O
5 prior to use.
51. The reaction is monitored by TLC analysis on silica gel using EtOAc:hexanes (1:2) and visualization with UV light and KMnO
4 (R
f of product = 0.47).
52. Shaking too violently will produce an emulsion.
53. The checkers isolated analytically pure product
4 reliably by flash column chromatography, and careful analysis of the fractions prior to collection. Due to close elution of a byproduct (
1H NMR resonance at 6.28 ppm) with product
4, fractions containing product were subject to
1H NMR analysis in addition to TLC analysis. Only fractions with >99% purity of product are combined, concentrated, and dried
in vacuo. Any mixed fractions are combined, concentrated, and re-purified by a second flash column chromatography using the same eluent with the 100-fold mass of silica gel compared to the mass of the mixed fraction. Checkers recommend a height-to-diameter ratio of the column between 6-8 for the second flash chromatography.
54. While the submitters described purification of
4 by crystallization, after significant experimentation the checkers were not able to confirm this method as a reliable means for purification of
4. Thus, the checkers used flash chromatography conditions based on those described in Lebel, H.; Piras, H; Bartholoméüs, J
Angew. Chem. Int. Ed. 2014,
53, 7300-7304.
55. Checkers found that concentration of the pure product from
dichloromethane is necessary to remove trace amounts of
Et2O. The sample is dried
in vacuo in a 500-mL round-bottomed flask for 48 h to afford solvent-free product
4.
56. Checkers noted that the purification of compound
3 had no impact on success of reaction step D, consistent with the submitters' observations. Checkers performed reaction step D on ~1 g scale with both crude (first crop, 92% purity) and purified compound
3 (
Note 46) and observed similar yields, and overall outcome consistent with results described here for the multi-gram scale.
57. Analytical data for
(R)-2,2,2-trichloro-1-phenylethyl (methylsulfonyl)oxycarbamate (
4): R
f = 0.47-0.50 (EtOAc:hexanes (3:7));
1H NMR
pdf(400 MHz, CDCl
3) δ: 3.20 (s, 3H), 6.35 (s, 1H), 7.40-7.49 (m, 3H), 7.60-7.63 (m, 2H), 8.46 (s (br), 1H);
13C NMR
pdf(100 MHz, CDCl
3) δ: 36.7, 85.2, 98.6, 128.4, 129.7, 130.5, 131.7, 153.8; IR (solid, ATR-FTIR) 3276, 2940, 1753, 1455, 1374, 1234, 1182, 1092, 969, 787, 699 (cm
-1); mp = 75-81 °C;[α]
D24 -15.9 (c 1.47, CHCl
3); HMRS (ESI+) calc. for C
10H
10Cl
3NNaO
5S [M+Na]+: 383.9259; found: 383.9240; Anal. calc. for C
10H
10Cl
3NO
5S: N, 3.86, C, 33.12, H, 2.78, S, 8.84; found: N, 3.91, C, 33.38, H, 2.74, S, 8.87.
3. Discussion
Appendix
Chemical Abstracts Nomenclature (Registry Number)
2,2,2-Trichloro-1-phenylethan-1-one; 2,2,2-Trichloroacetophenone: Ethanone, 2,2,2-trichloro-1-phenyl-; (2902-69-4)
(±)-2,2,2-Trichloro-1-phenylethan-1-ol: Benzenemethanol, α-(trichloromethyl)-; (2000-43-3)
(R)-2,2,2-Trichloro-1-phenylethan-1-ol: Benzenemethanol, α-(trichloromethyl)-, (αR)-; (2) (53432-39-6)
TEMPO: 1-Piperidinyloxy, 2,2,6,6-tetramethyl-; (2564-83-2)
Pyridinium tribromide: Hydrogen tribromide, compd. with pyridine (1:1); (39416-48-3)
n-Butylboronic acid: Boronic acid, B-butyl-; (4426-47-5)
(S)-Diphenylprolinol: 2-Pyrrolidinemethanol, α,α-diphenyl-, (2S)-; (112068-01-6)
Catecholborane: 1,3,2-Benzodioxaborole; (274-07-7)
(R)-2,2,2-Trichloro-1-phenylethyl hydroxycarbamate: Carbamic acid, N-hydroxy-, (1R)-2,2,2-trichloro-1-phenylethyl ester; (3) (1391854-32-2)
1,1'-Carbonyldiimidazole (CDI): Methanone, di-1H-imidazol-1-yl-; (530-62-1)
Hydroxylamine hydrochloride: Hydroxylamine, hydrochloride (1:1); (5470-11-1)
(R)-2,2,2-Trichloro-1-phenylethyl (methylsulfonyl)oxycarbamate: Methanesulfonic acid, [[(1R )-2,2,2-trichloro-1-phenylethoxy]carbonyl]azanyl ester; (4) (1391853-96-5)
Triethylamine: Ethanamine, N,N-diethyl-; (121-44-8)
Mesyl chloride: Methanesulfonyl chloride; (124-63-0)
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