TRANSFORMATION OF PSEUDOEPHEDRINE AMIDES INTO HIGHLY ENANTIOMERICALLY ENRICHED ALDEHYDES, ALCOHOLS, AND KETONES
Checked by William J. Smith, III and William R. Roush.
1. Procedure
2. Notes
1.
Lithium aluminum hydride (95%) was obtained from Aldrich Chemical Company, Inc.
, and was stored under an atmosphere of
nitrogen.
2.
Hexanes used in the preparation of LiAlH(OEt)
3 was distilled from
calcium hydride
under an atmosphere of
nitrogen.
3.
Ethyl acetate used in the preparation of LiAlH(OEt)
3 was distilled from
calcium hydride under an atmosphere of
argon.
4.
Slow addition of
ethyl acetate is crucial in order to achieve complete reaction in the reduction step. Rapid addition of
ethyl acetate (≤5 min) results in incomplete reduction of the amide.
5.
(1S,2S)-Pseudoephedrine-(R)-2-methylhydrocinnamamide was prepared as described in the preceding procedure.
6.
Tetrahydrofuran was distilled from
sodium benzophenone ketyl
under an atmosphere of
nitrogen.
7.
Trifluoroacetic acid was obtained from Mallinckrodt, Inc.
, and was used without further purification.
8.
This operation is necessary to hydrolyze the pseudoephedrine aminal which forms as a direct product of the reduction, in addition to the desired aldehyde. The use of the additional
700 mL of 1 N aqueous hydrochloric acid
solution was found to be crucial for this hydrolysis reaction.
9.
The pH of the aqueous phase following the addition of
sodium bicarbonate is approximately 4. If the pH is less than 4, additional
sodium bicarbonate should be added until the pH is 4 or slightly above. Small amounts of the
pseudoephedrine aminal remain at this point, but are hydrolyzed during the rotary evaporation step.
10.
Rotary evaporation was conducted at or below 30°C to prevent trifluoroacetic acid-induced decomposition of the aldehyde as well as its evaporative loss.
11.
The product exhibits the following properties:
[α]
D
25 +13.3° (MeOH,
c 0.46);
1H NMR (300 MHz, C
6D
6) δ: 0.69 (d, 3 H, J = 6.9), 2.0-2.2 (m, 2 H), 2.72 (dd, 1 H, J = 13.2, 5.4), 6.8-7.1 (m, 5 H), 9.29 (d, 1 H, J = 1.2)
;
13C NMR (75 MHz, CDCl
3) δ: 13.1, 36.5, 48.0, 126.3, 128.4, 128.9, 138.7, 204.3
; IR (neat) cm
−1: 3028, 2971, 2932, 2814, 2716, 1723 (C=O), 1496, 1454, 742, 701
; HRMS (EI) m/z 148.0890 [(M
+) calcd for C
10H
12O: 148.0888]. Anal. Calcd. for C
10H
12O: C, 81.04, H, 8.16. Found: C, 80.98, H, 8.25.
12.
The ee of this product was determined by oxidation
4 to the corresponding carboxylic acid (see following paragraph) followed by preparation and analysis of the corresponding
(R)-α-methylbenzylamide.
A 25-mL, round-bottomed flask equipped with a Teflon-coated magnetic stirring bar is charged with
26 mg (0.18 mmol) of (R)-α-methylbenzenepropanal
,
4.0 mL of 2-methyl-2-propanol
,
1.0 mL (2.0 mmol) of a 2.0 M solution of 2-methyl-2-butene in tetrahydrofuran (purchased from Aldrich Chemical Company, Inc., and used as received), and a solution of
0.17 g (1.9 mmol) of sodium chlorite (Aldrich Chemical Company, Inc.; 80% technical grade) and
0.20 g (1.4 mmol) of sodium dihydrogen phosphate monohydrate (Aldrich Chemical Company, Inc.) in 2.0 mL of water. The reaction flask is sealed with a rubber septum and the yellow, biphasic mixture is stirred vigorously at 23°C for 50 min, then partially concentrated by the removal of tetrahydrofuran, 2-methyl-2-butene, and 2-methyl-2-propanol on the rotary evaporator. The residue is transferred to a 125-mL separatory funnel with 50 mL of water and
0.5 mL of saturated aqueous sodium bicarbonate
solution and the aqueous mixture is extracted with two
7-mL portions of 10%
ethyl acetate-hexanes
. The aqueous phase is acidified to pH 2 by the addition of
1.5 mL of 1 N aqueous hydrochloric acid
solution, and the acidified solution is extracted with three
15-mL portions of ethyl acetate
. The latter ethyl acetate extracts are combined, dried over anhydrous sodium sulfate
, filtered, and concentrated under reduced pressure to afford 27 mg of crude
(R)-α-methylbenzenepropanoic acid
. The corresponding (R)-α-methylbenzylamide was prepared and analyzed by capillary gas chromatography as described in the following paragraph.
The following procedure describes the preparation and analysis of the (R)-α-methylbenzylamide of (R)-α-methylbenzenepropanoic acid. A flame-dried, 10-mL, round-bottomed flask equipped with a Teflon-coated magnetic stirring bar and a rubber septum is charged with
25 mg (0.15 mmol) of (R)-α-methylbenzenepropanoic acid
,
31 mg (0.23 mmol) of 1-hydroxybenzotriazole hydrate
,
44 mg (0.23 mmol) of 1-(3-dimethylamino)propyl-3-ethylcarbodiimide hydrochloride
, and
0.50 mL of anhydrous N,N-dimethylformamide
. This mixture is stirred at 23°C for 10 min, then cooled to 0°C in an ice-water bath. To the cooled solution,
24 μL (0.19 mmol) of R-(+)-α-methylbenzylamine
and
86 μL (0.62 mmol) of triethylamine
are added. Within 1 min, a fine white precipitate appears. The mixture is stirred for 1 hr at 0°C, then warmed to 23°C. After stirring for 20 hr at 23°C, the mixture is transferred to a 30-mL separatory funnel with
10 mL of dichloromethane
. The product solution is extracted, sequentially, with four
10-mL portions of 1 N aqueous hydrochloric acid
solution,
10 mL of saturated aqueous sodium bicarbonate
solution, and 10 mL of water. The organic layer is dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a white crystalline solid. The solid residue is dissolved in ethyl acetate for capillary gas chromatographic analysis. The analysis is carried out using a Chirasil-Val capillary column (25 m × 0.25 mm × 0.16 μm, Alltech, Inc.) under the following conditions: oven temp. 180°C, injector temp. 250°C, detector temp. 275°C. The following retention times are observed: 10.55 min (major diastereomer), 11.61 min (minor diastereomer). It should be noted that the retention times can vary greatly depending on the age and condition of the column.
1-Hydroxybenzotriazole hydrate, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N-dimethylformamide and R-(+)-α-methylbenzylamine were purchased from Aldrich Chemical Company, Inc.
and used without further purification.
Triethylamine was purchased from Aldrich Chemical Company, Inc.
and was distilled from calcium hydride under an atmosphere of nitrogen.
13.
Diisopropylamine was obtained from Aldrich Chemical Company, Inc.
, and distilled from
calcium hydride under an atmosphere of
nitrogen.
14.
Butyllithium (2.5 M solution in hexanes) was purchased from Aldrich Chemical Company, Inc.
, and titrated against
diphenylacetic acid.
5
15.
Borane-ammonia complex (90%) was obtained from Aldrich Chemical Company, Inc.
, and stored and transferred under
nitrogen.
16.
The foam is found to impede, but not prevent, magnetic stirring.
17.
As the addition proceeds, the foam dissipates and stirring becomes increasingly more facile.
18.
In addition to quenching excess hydride, the acidification and subsequent extraction steps remove pseudoephedrine and any tertiary amine reaction by-product; the latter is otherwise difficult to remove by column chromatography.
19.
The residue contains
(R)-β-methylbenzenepropanol and an alkoxy borane species that undergoes quantitative hydrolysis to
(R)-β-methylbenzenepropanol during the subsequent chromatography step. As an alternative to flash column chromatography, the alkoxy borane species can be cleaved by treatment of the residue with
1 N aqueous sodium hydroxide
solution.
20.
The product exhibits the following properties:
[α]
D
25 +11.2° (
benzene,
c 4.2);
1H NMR (300 MHz, C
6D
6) δ: 0.62 (t, 1 H, J = 5.2), 0.77 (d, 3 H, J = 6.7), 1.70 (m, 1 H), 2.22 (dd, 1 H, J = 13.3, 8.0), 2.62 (dd, 1 H, J = 13.3, 6.2), 3.15 (m, 2 H), 7.0-7.2 (m, 5 H)
;
13C NMR (75 MHz, CDCl
3) δ: 16.4, 37.7, 39.6, 67.4, 125.7, 128.2, 129.0, 140.6
; IR (neat) cm
−1: 3332 (OH), 3001, 2956, 2922, 2872, 1603, 1495, 1454, 1378, 1032, 986, 739, 700
; HRMS (CI) m/z 148.0890 [(M + NH
4+
)
. Anal. Calcd for C
10H
14O: C, 79.96; H, 9.39. Found: C, 79.67; H, 9.05.
21.
The ee of the alcohol was determined by analysis of the corresponding Mosher ester derivative
6 by high resolution
1H NMR spectroscopy (400 MHz, C
6D
6). The preparation of the Mosher ester is described below.
A 10-mL, round-bottomed flask equipped with a Teflon-coated magnetic stirring bar is charged with
40 mg (0.17 mmol) of (trifluoromethyl)phenylacetic acid
. Dry
benzene (2 mL) is added and the resulting solution is concentrated. The flask is sealed with a rubber septum containing a needle adapter to an argon-filled balloon and is charged with
1.0 mL of dichloromethane
. To the resulting clear solution is added
19 μL (0.22 mmol) of oxalyl chloride
and
2.0 μL (0.026 mmol) of anhydrous N,N-dimethylformamide
. The latter addition causes bubbling, which persists for ~10 min. The mixture is stirred an additional 20 min at 23°C, then cooled to 0°C in an ice-water bath. The adapter to the argon-filled balloon is replaced with a needle leading to a source of vacuum and the flask is cautiously evacuated. After 30 min stirring under reduced pressure (0.5 mm) to remove dichloromethane and excess oxalyl chloride, the flask is flushed with argon. The resulting crude preparation of (S)-(+)-α-methoxy-α-(trifluoromethyl)phenylacetyl chloride is dissolved in
1.0 mL of dichloromethane
, and the resulting clear solution is transferred via cannula to an ice-cooled, 10-mL, round-bottomed flask equipped with a Teflon-coated magnetic stirring bar and a rubber septum and containing a solution of
9.0 mg (0.060 mmol) of (R)-β-methylbenzenepropanol
,
2.0 mg (0.016 mmol) of 4-dimethylaminopyridine
, and
42 μL (0.30 mmol) of triethylamine
in
0.5 mL of dichloromethane
. The ice-water bath is removed, and the clear yellow reaction solution is stirred at 23°C for 24 hr. The reaction mixture is transferred to a 30-mL separatory funnel with
10 mL of dichloromethane
, and the solution is extracted, sequentially, with two
10-mL portions of saturated aqueous ammonium chloride
solution, two
10-mL portions of saturated aqueous sodium bicarbonate
solution, and 10 mL of water. The organic layer is dried over anhydrous sodium sulfate
, filtered, and concentrated under reduced pressure to give a yellow oil. The residue is purified by passage through a Pasteur pipette half-filled with 230-400 mesh silica gel using 30% ethyl acetate-hexanes
as the eluent. Care is taken to collect all fractions containing the Mosher ester. Concentration of these fractions under reduced pressure affords a clear, colorless oil that is analyzed by 1H NMR spectroscopy (400 MHz, C6D6). Integration of a pair of doublets of doublets corresponding to the major diastereomer (3.97-4.04 ppm and 3.76-3.82 ppm) against those corresponding to the minor diastereomer (3.86-3.95 ppm) allows accurate determination of the ee of the original alcohol.
(R)-(+)-α-Methoxy-α-(trifluoromethyl)phenylacetic acid, oxalyl chloride, 4-dimethylaminopyridine, and anhydrous N,N-dimethylformamide were obtained from Aldrich Chemical Company, Inc.
, and were used without further purification. Benzene and dichloromethane used in the preparation of the Mosher ester were obtained from EM Science and were distilled from calcium hydride under a nitrogen atmosphere.
22.
Toluene was purchased from EM Science and was distilled from
calcium hydride under a
nitrogen atmosphere.
23.
This step is conducted to dry the amide, as well as to render it a fine powder.
24.
Ether was purchased from EM Science
and was distilled from
sodium benzophenone ketyl under a
nitrogen atmosphere.
25.
This product exhibits the following properties:
[α]
D
25 −79.0° (
benzene,
c 2.1);
1H NMR (300 MHz, C
6D
6) δ: 0.85 (t , 3 H, J = 7.3 ), 1.07 (d, 3 H, J = 6.9), 1.23 (sx, 2 H, J = 7.4), 1.45 (m, 2 H), 2.25 (dt, 1 H, J = 7.3, 16.9), 2.39 (dt, 1 H, J = 7.3, 16.9), 2.55 (dd, 1 H, J = 7.3, 13.2), 2.83 (sx, 1 H, J = 7.0), 2.97 (dd, 1 H, J = 7.1, 13.2), 7.20 (m, 5 H)
;
13C NMR (75 MHz, CDCl
3) δ: 13.9, 16.5, 22.3, 25.6, 39.1, 41.7, 48.1, 126.2, 128.3, 128.9, 139.8, 214.4
; IR (neat) cm
−1: 3028, 2959, 2932, 2873, 1947, 1878, 1805, 1712 (C=O), 1604, 1496, 1454, 1406, 1375, 1130, 1032, 992, 746, 700
; HRMS (EI) m/z 204.1517 [(M)
+ calcd for C
14H
20O: 204.1514]. Anal. Calcd. for C
14H
20O: C, 82.30; H, 9.87. Found: C, 82.14; H, 9.59.
26.
The checkers also obtained
2-3% of
(R)-3-butyl-2-methyl-1-phenylheptan-3-ol
, resulting from addition of 2 equiv of
butyllithium to the amide carbonyl. This by-product stains brightly on analytical TLC plates (
phosphomolybdic acid or
cerium molybdate stain) and has an R
f of 0.2 in 5%
EtOAc-
hexanes.
27.
The ee of this product was determined by reduction to the corresponding alcohol with
lithium aluminum hydride followed by preparation and analysis of the Mosher ester derivatives
6 by
1H NMR spectroscopy (400 MHz, C
6D
6), as described in the following procedure.
A flame-dried, 10-mL, round-bottomed flask equipped with a Teflon-coated magnetic stirring bar is charged with
102 mg (0.50 mmol) of (R)-2-methyl-1-phenyl-3-heptanone
and sealed with a rubber septum containing a needle adapter to an argon-filled balloon. The flask is charged with
1.0 mL of ether
and cooled to 0°C whereupon
0.75 mL (0.75 mmol) of a solution of lithium aluminum hydride in ether
(1.0 M) is added slowly via syringe. After stirring the reaction mixture for 15 min at 0°C, the septum is removed and 1 mL of water is added cautiously dropwise until gas evolution subsides. To the resulting cloudy mixture is added
2 mL of 15% w/v aqueous sodium hydroxide
solution. This mixture is transferred to a 30-mL separatory funnel with 10 mL of water, and the resulting solution is extracted with three
10-mL portions of dichloromethane
. The combined organic extracts are dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. This crude preparation of diastereomeric alcohols (ca. 1:1 ratio) is used directly in the subsequent esterification step with the Mosher acid chloride, as described below.
A 0.3 M solution (
0.50 mL, 0.15 mmol) of R-(+)-α-methoxy-α-(trifluoromethyl)phenylacetyl chloride in dichloromethane
is transferred via cannula to an ice-cooled, 10-mL, round-bottomed flask equipped with a Teflon-coated magnetic stirring bar and containing a solution of 10 mg (0.05 mmol) of the crude alcohol,
6 mg (0.05 mmol) of 4-dimethylaminopyridine
, and
71 μL (0.51 mmol) of triethylamine
in
1.0 mL of dichloromethane
. The ice-water bath is removed, and the clear yellow reaction solution is stirred at 23°C for 24 hr. The reaction mixture is transferred to a 30-mL separatory funnel with
10 mL of dichloromethane
, and the solution is extracted, sequentially, with two
10-mL portions of saturated aqueous ammonium chloride
solution, two
10-mL portions of saturated aqueous sodium bicarbonate
solution, and 10 mL of water. The organic layer is dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a yellow oil. The residue is purified by passage through a Pasteur pipette half-filled with 230-400 mesh silica gel using 30% ethyl acetate-hexanes
as the eluent. Care is taken to collect all fractions containing the Mosher esters. Concentration of these fractions under reduced pressure affords a clear, colorless oil that is analyzed by 1H NMR spectroscopy (400 MHz, C6D6). Integration of a pair of doublets of doublets corresponding to the major diastereomer pairs (2.67 ppm) against those corresponding to the minor diastereomer pairs (2.74 ppm) allows accurate determination of the ee of the original ketone. 1.0 M
Lithium aluminum hydride solution in ether and 4-dimethylaminopyridine were obtained from Aldrich Chemical Company, Inc.
, and were used without further purification.
Dichloromethane used in the preparation of the Mosher ester was obtained from EM Science
and was distilled from calcium hydride under a nitrogen atmosphere. (R)-(−)-α-Methoxy-α-(trifluoromethyl)phenylacetyl chloride was prepared from (S)-(−)-α-methoxy-α-(trifluoromethyl)phenylacetic acid, as described in (Note 21).
28.
The ee determined by the checkers was 97% ee.
The procedures in this article are intended for use only by persons with prior training in experimental organic chemistry. All hazardous materials should be handled using the standard procedures for work with chemicals described in references such as "Prudent Practices in the Laboratory" (The National Academies Press, Washington, D.C., 2011 www.nap.edu). All chemical waste should be disposed of in accordance with local regulations. For general guidelines for the management of chemical waste, see Chapter 8 of Prudent Practices.
These procedures must be conducted at one's own risk. Organic Syntheses, Inc., its Editors, and its Board of Directors do not warrant or guarantee the safety of individuals using these procedures and hereby disclaim any liability for any injuries or damages claimed to have resulted from or related in any way to the procedures herein.
3. Discussion
Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)
(R)-α-Methylbenzenepropanal:
Benzenepropanal, α-methyl-, (R)- (9); (42307-59-5)
Lithium aluminum hydride:
Aluminate (1−), tetrahydro-, lithium (8);
Aluminate (1−), tetrahydro-, lithium, (I-4)- (9); (16853-85-3)
Ethyl acetate:
Acetic acid, ethyl ester (8,9); (141-78-6)
[1S(R),2S]-N-(2-Hydroxy-1-methyl-2-phenylethyl)-N, 2-dimethylbenzene
propionamide:
(1S,2S)-Pseudoephedrine-(R)-2-methylhydrocinnamide:
Benzenepropanamide, N-(2-hydroxy-1-methyl-2-phenylethyl)-N, α-dimethyl-,[1S-[1R(R),2R]]- (13); (159345-08-1); [1S-[1R(S),2R]]- (13); (159345-06-9)
Lithium triethoxyaluminum hydride:
Aluminate (1−), triethoxyhydro-, lithium (8);
Aluminate (1−), triethoxyhydro-, lithium, (I-4), (9); (17250-30-5)
Trifluoroacetic acid:
Acetic acid, trifluoro- (8,9); (76-05-1)
(R)-β-Methylbenzenepropanol:
Benzenepropanol, β-methyl-, (R)- (10); (77943-96-5)
Diisopropylamine (8);
2-Propanamine, N-(1-methylethyl)- (9); (108-18-9)
Butyllithium:
Lithium, butyl- (8,9); (109-72-8)
Borane-ammonia complex: EXPLODES WHEN HEATED:
Borane, monoammoniate (8,9); (13774-81-7)
Lithium amidotrihydroborate:
Borate (1−), amidotrihydro-, lithium, (I-4)- (11); (99144-67-9)
(R)-2-Methyl-1-phenyl-3-heptanone:
3-Heptanone, 2-methyl-1-phenyl-, (R)- (13); (159213-12-4)
2-Methyl-2-propanol:
tert-Butyl alcohol (8);
2-Propanol, 2-methyl- (9); (75-65-0)
2-Methyl-2-butene:
2-Butene, 2-methyl- (8,9); (513-35-9)
Sodium dihydrogen phosphate:
Phosphoric acid, monosodium salt (8,9); (7558-80-7)
(R)-α-Methylbenzenepropanoic acid:
Benzenepropanoic acid, α-methyl-, (R)- (8); (14367-67-0)
1-Hydroxybenzotriazole hydrate:
1H-Benzotriazole, 1-hydroxy-, hydrate (12); (12333-53-9)
1-(3-Dimethylamino)propyl-3-ethylcarbodiimide hydrochloride:
Carbodiimide,
[3-(dimethylamino)propyl]ethyl-, monohydrochloride (8);
1,3-Propanediamine,
N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochloride (9); (25952-53-8)
N,N-Dimethylformamide: CANCER SUSPECT AGENT:
Formamide, N,N-dimethyl- (8,9); (68-12-2)
(R)-(+)-α-Methylbenzylamine:
Benzylamine, α-methyl-, (R)-(+)- (8);
Benzenemethanamine, α-methyl-, (R)- (9); (3886-69-9)
Triethylamine (8);
Ethanamine, N,N-diethyl- (9); (121-44-8)
(R)-(+)-α-Methoxy-α-(trifluoromethyl)phenylacetic acid:
Hydratropic acid,
β,β,β-trifluoro-α-methoxy-, (+)- (9); (20445-31-2)
Benzene: CANCER SUSPECT AGENT: (8,9); (71-43-2)
Oxalyl chloride (8);
Ethanedioyldichloride (9); (79-37-8)
(S)-(+)-α-Methoxy-α-(trifluoromethyl)phenylacetyl chloride:
Hydratropoyl chloride,
β,β,β-trifluoro-α-methoxy-, (+)- (8,9); (20445-33-4)
4-Dimethylaminopyridine: HIGHLY TOXIC:
Pyridine, 4-(dimethylamino)- (8);
4-Pyridinamine, N,N-dimethyl- (9); (1122-58-3)
Phosphomolybdic acid:
Molybdophosphoric acid (9); (51429-74-4)
Cerium (III) molybdate:
Molybdic acid, cerium salt (9); (53986-44-0)
(S)-(−)-α-Methoxy-α-(trifluoromethyl)phenylacetic acid:
Hydratropic acid,
β,β,β-trifluoro-α-methoxy-, (S)-(−)- (8);
Benzeneacetic acid,
α-methoxy-α-(trifluoromethyl)-, (S)- (9); (17257-71-5)
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