Organic Syntheses, Vol. 77, 50
Checked by James Unch and David J. Hart.
1. Procedure
C. (Ss,R)-(+)-Methyl N-(p-toluenesulfinyl)-3-amino-3-phenylpropanoate (4):
3 An oven-dried,
250-mL, round-bottomed flask equipped with a
magnetic stirrer and a rubber septum is charged with
8.4 mL of sodium bis(trimethylsilyl)amide (NaHMDS) (16.7 mmol) in tetrahydrofuran (Note
12). The reaction mixture is diluted with
80 mL of anhydrous ether (Note
13), the solution is cooled to −78°C using a dry ice/acetone bath, and
1.3 mL of methyl acetate (16.7 mmol) (Note
14) is added dropwise via syringe over 20 min. In a separate, oven-dried,
100-mL, round-bottomed flask, equipped with a magnetic stirrer, rubber septum and under an
argon purge, is placed
2.65 g (10.9 mmol) of (S)-(+)-N-(benzylidene)-p-toluenesulfinamide (3) in 50 mL of anhydrous ether. The solution of
3 is cooled to 0°C and added by cannula over 60 min into the reaction flask containing the enolate. The flask is rinsed with
10 mL of anhydrous ether and cooled to −78°C prior to adding it to the reaction mixture by cannula. After the mixture is stirred for 45 min, it is quenched at this temperature with
4 mL of aqueous saturated ammonium chloride (Note
15), warmed to room temperature, and diluted with
50 mL of ethyl acetate. The solution is transferred to a
250-mL separatory funnel, washed with water (2 × 50 mL), and the aqueous phases are combined and washed with
ethyl acetate (2 × 20 mL). The combined organic phases are washed with aqueous saturated
sodium chloride (2 × 40 mL), dried over anhydrous
magnesium sulfate and filtered. The solution is concentrated using a rotary evaporator (33°C and 13 mm), followed by drying under high vacuum (30°C and 0.05 mm) to give a yellow solid (
2.7 g) (mp
82-85°C). This material is dissolved in
5 mL of ethyl acetate and
5 mL of methylene chloride, diluted with
125 mL of pentane, and stored at −20°C overnight (Note
16). The slightly yellow suspended solid is filtered, washed with cold
pentanes (2 × 15 mL; ca. −20°C), and dried under high vacuum to remove residual solvent to afford
2.1-2.3 g (
61-66%) of analytically pure
4 (Note
17), (Note
18) and (Note
19).
2. Notes
1. All glassware was predried at 120°C for at least 4 hr and cooled to room temperature prior to use in a desiccator.
2.
(1R,2S,5R)-(−)-Menthyl (S)-p-toluenesulfinate was purchased from Aldrich Chemical Company, Inc., or can be prepared by the following procedures: (a) Hulce, M.; Mallamo, J. P.; Frye, L. L.; Kogan, T. P.; Posner, G. H.
Org. Synth., Coll. Vol. VII 1990, 495; (b) See also Reference
4
6. The submitters indicate that use of a
high vacuum pump results in removal of most of the
menthol at this point. The checkers used a standard rotary evaporator (33°C at 16 mm) and observed that the residual yellow paste retains the
menthol.
7. The physical properties of
(S)-(+)-p-toluenesulfinamide were as follows: mp
110-112°C;
[α]D20 +79.7° (CHCl
3,
c1.2), IR (KBr) cm
−1: 3200, 3094;
1H NMR (CDCl
3) δ: 2.42 (s, 3 H), 4.33 (s, 2H), 7.32 (d, 2 H, J = 8), 7.64 (d, 2 H, J = 8);
13C NMR (CDCl
3) δ: 21.3, 125.3, 129.5, 141.4, 143.4. Anal. Calcd for C
7H
9NOS: C, 54.18; H, 5.85. Found: C, 54.22; H, 5.86.
9.
Benzaldehyde was used from a freshly opened bottle purchased from Aldrich Chemical Company, Inc.
10. A magnetic stirring bar is used for initial stirring. A thick slurry develops and when magnetic stirring becomes impossible, the mixture is stirred with a metal spatula for about 1 min.
11. The physical properties of
(S)-(+)-N-(benzylidene)-p-toluenesulfinamide were as follows: mp
80-81°C ee >95%;
[α]D20 +122.8° (
CHCl3,
c 1.2); IR (KBr) cm
−1: 3050, 1607, 1574, 1449, 1104, 1072;
1H NMR (CDCl
3) δ: 2.4 (s, 3 H), 7.32 (d, 2 H, J = 8.0), 7.4-7.52 (m, 3 H), 7.64 (d, 2 H, J = 8.0), 7.81-7.86 (m, 2 H), 8.74 (s, 1 H);
13C NMR (CDCl
3) δ: 21.5, 124.7, 128.8, 129.5, 129.7, 132.5, 133.7, 141.6, 141.7, 160.0. Anal. Calcd for C
14H
13NOS: C, 69.11; H, 5.39. Found: C, 68.84; H, 5.50.
14. Anhydrous
methyl acetate was purchased from Aldrich Chemical Company, Inc., and used without further purification.
15. The submitters indicate that completion of the reaction is confirmed by TLC on
silica gel using
50% ethyl acetate in hexanes as the eluant.
16. The submitters indicate that
4 can also be purified by flash chromatography using
25% ethyl acetate/hexanes on silica gel (30 g/g of crude product), Merck grade 60 (230-400 mesh) was purchased from Aldrich Chemical Company, Inc.
17. The submitters indicate that the observed yield was
89% when the reaction was carried out on a 1.0-g scale.
18. The diastereomeric excess was determined by
1H NMR (300 MHz, CDCl
3) by evaluating the p-tolyl methyl group (major δ 2.41 ppm: minor δ 2.36 ppm) or carbomethoxy group (major δ 3.60 ppm: minor δ 3.64 ppm).
19. The spectral properties of
(Ss,R)-(+)-methyl N-(p-tolylsulfinyl)-3-amino-3-phenylpropanoate (4) are as follows: >98% de;
[α]D20 116.84° (
CHCl3,
c. 1.74) [checkers recorded
[α]D18 111.1° (CHCl
3,
c 1.74)]; mp
88-89°C; IR (KBr) cm
−1: 3155, 1737, 1436, 1295, 1170, 1044, 804, 700;
1H NMR (CDCl
3) δ: 2.41 (s, 3 H), 2.86 (d, 2 H, J = 6.3), 3.60 (s, 3 H), 4.90 (q, 1 H, J = 6.1), 5.01 (d, 1 H, J = 5.4), 7.28-7.45 (m, 7 H), 7.60 (d, 2 H, J = 8.2);
13C NMR (CDCl
3) δ: 21.2, 41.9, 51.7, 54.7, 125.3, 127.1, 127.9, 128.6, 129.4, 140.3, 141.3, 142.1, 171.1; MS m/z 317 (M
+), 269, 196, 178, 139, 121, 104, 91, 77. Anal. Calcd for C
17H
19NO
3S: C, 64.33; H, 6.03. Found: C, 64.38; H, 6.12.
20. A freshly opened bottle of
methanol (certified A.C.S., purchased from Aldrich Chemical Company, Inc.) was used without further purification or drying.
22. The submitters indicate that the reaction can be monitored for the formation of
5 by thin layer chromatography (
silica gel;
50% EtOAc/hexanes).
23.
Reagent grade anhydrous ethyl ether was purchased from Aldrich Chemical Company, Inc.
24. Aqueous
hydrochloric acid (37%) certified A.C.S. PLUS was purchased from Fisher Chemical Fisher Scientific and diluted to 15% with water.
26. Certified
A.C.S. grade methylene chloride was purchased from Aldrich Chemical Company, Inc. and used as received.
Sodium bicarbonate A.C.S. grade was purchased from Fisher Scientific Company.
27. The final pH should be at least 8.0 (by pH paper) to ensure that all the salt has been deprotonated.
28. The checkers recorded
[α]D18 +18.9° (CHCl
3,
c 1.85) for this material and noted some unidentified impurities in the
1H NMR spectrum. The submitters indicate that
3 mL of methanol can be added to the yellow liquid followed by filtration to remove precipitated solids.
29. The spectral properties of this material are as follows: bp
55-60°C (oven temperature) at 0.05 mm; >98 % ee,
[α]D20 +22.6° (CHCl
3,
c 1.85); IR (neat) cm
−1: 3378, 3026, 2950, 1734, 1603, 1436, 1171, 1020, 762, 700;
1H NMR (CDCl
3) δ: 1.87 (br s, 2 H, exchangeable with D
2O), 2.66 (d, 2 H, J = 6.9), 3.68 (s, 3 H), 4.42 (t, 1 H, J = 6.7), 7.25-7.35 (m, 5 H);
13C NMR (CDCl
3) δ: 43.9, 51.5, 52.5, 126.1, 127.3, 128.5, 144.6, 172.4. Anal. Calcd for C
10H
13NO
2: C, 67.00; H, 7.32. Found: C, 66.50; H, 7.41.
All toxic materials were disposed of in accordance with "Prudent Practices in the Laboratory", National Academy Press: Washington, DC, 1995
3. Discussion
Although the diastereoselective addition of nucleophiles to imines offers an attractive route to chiral amine derivatives, most chiral nonracemic imines suffer from low reactivity (electrophilicity), resulting in no reaction or competitive reduction with organometallic reagents. Other problems include enolization of aliphatic imines, poor diastereoselectivities caused by syn/anti isomerism, and moisture sensitivity resulting in moderate or low yields. When primary amines are the objective, removing the N-auxiliary often leads to epimerization or destruction of the product.
An earlier synthesis of sulfinimines, involving the addition of metal ketimines to the
menthyl p-toluenesulfinate (Andersen reagent), was limited because an aromatic group was required to be present and the more valuable aldehyde-derived sulfinimines were unavailable.
6 An asymmetric oxidation approach using chiral oxaziridines suffered from moderate ee's (<90%).
7 tert-Butylsulfinimines are available in a series of steps starting with
tert-butyl disulfide.
8 The method described here affords these valuable building blocks from commercially available starting materials and aromatic and aliphatic aldehydes.
2 Although β-amino acids are less common than α-amino acids, they are important constituents of natural products, precursors of the β-lactams and increasingly used to modify proteins.
9 The synthesis of
β-phenylalanine methyl ester is an example of the general synthesis of this important class of amino acids using sulfinimines.
3,6,10,11,12 Exclusive formation of the sulfinamide
4 is probably a consequence of the anion stabilizing N-sulfinyl group; analogous reactions of N-alkyl- and N-arylimines produce cyclized β-lactams. An added feature of the N-sulfinyl group in
4 is that it is easily removed under mild conditions.
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