[42882-31-5]  · C12H13N  · 1-(1-Naphthyl)ethylamine  · (MW 171.26) (+)

[3886-70-2] (-)


(chiral reagent used for resolution of carboxylic acids,1 alcohols,2 and lactones;3 a chiral derivatization agent used for chromatographic resolution of carboxylic acids4 and alcohols;5 can serve as a chiral solvating agent6)

Alternate Name: NEA.

Physical Data: (±) form: bp 156 °C/15 mmHg; d 1.063 g cm-3. Oxalate: mp 221 °C (dec). (S)-(-) isomer: bp 153 °C/11 mmHg; d 1.060 g cm-3; [a]25 -80.8° (neat); [a]20 -59° (c = 5, MeOH). Oxalate: mp 232 °C (dec). (R)-(+) isomer: bp 153 °C/11 mmHg; d 1.060 g cm-3; [a]25 +82.8° (neat); [a]20 +60° (c = 5, MeOH). Oxalate: mp 240 °C.

Solubility: sol alcohol, ether; insol H2O.

Form Supplied in: clear liquid; both enantiomers and the racemate are all widely available.

Analysis of Reagent Purity: the enantiomeric purity of the reagent can be determined by either NMR or HPLC analysis of derivatives produced from a-methoxy-a-(trifluoromethyl)benzyl isocyanate,7 a-methoxy-a-(trifluoromethyl)benzyl acid chloride,8 or 2-methoxy-1,1-binaphthyl-2-carboxylic acid chloride.9

Preparative Methods: racemic 1-(1-naphthyl)ethylamine can be resolved with camphoric acid,10 tartaric acid,11 L-menthyl hydrogen phthalate,11 di-O-isopropylidene-2-ketogulonic acid,11,12 and (S)-(-)-(2-phenylcarbamoyloxy)propionic acid.13 These procedures can also be used to enhance the enantiomeric purity of the reagent.

Handling, Storage, and Precautions: use in a well-ventilated fume hood.

Resolution of Carboxylic Acids.

The enantiomers of 1-(1-naphthyl)ethylamine are used to resolve racemic carboxylic acids by selective crystallization of diastereomeric salts. For example, crystallization of racemic 3-bromobutyric acid with (R)-(+)-NEA followed by acidification of the diastereomeric salt afforded (S)-(+)-3-bromobutyric acid (eq 1).1 In the same manner, resolution with (S)-(-)-NEA yielded (R)-(-)-3-bromobutyric acid after liberation of the amine (eq 1).1

Resolution of alcohols can be achieved following derivatization with phthalic anhydride.2 Racemic 1-undecyn-3-ol was converted into a phthalic monoester derivative and resolved with (R)-(+)-NEA (eq 2). Liberation of the resolved phthalic ester and saponification yielded (R)-(+)-alcohol in 92% optical purity (eq 2). Similarly, the (S)-(-) alcohol is obtained upon resolution with (S)-(-)-NEA (eq 2).

Optically active lactones are also readily available through this classical resolution technique. The racemic lactone is hydrolyzed to the hydroxy acid and resolved with (S)-(-)-NEA (eq 3).3 After crystallization, the dextro (+)-lactone is regenerated upon acidification of the chiral salt. Resolution of the lactone with (R)-(+)-NEA leads to the levo (-)-lactone (eq 3).3

Chromatographic Resolutions.

1-(1-Naphthyl)ethylamine serves as a chiral derivatization agent useful in preparing diastereomeric amides from racemic acids for chromatographic resolution.4 For example, various terpenoid acids, after conversion to the diastereomeric amides using (R)-(+)-NEA, were analyzed by HPLC to define the enantiomeric composition (eq 4).4 Application of the procedure has been used to analyze the enantiomeric purity of several carboxylic acid derivatives.14

In some cases the resolution of the diastereomeric amides on silica gel is sufficiently large to achieve preparative separation. The preparative separation of diastereomeric hydroxy amides has proved useful in supplying quantities of enantiomerically pure lactones (eq 5).15

Nonracemic NEA is equally useful in preparing diastereomeric carbamates. Typically, the carbamates are derived from alcohols and (R)-(+)-naphthylethyl isocyanate,16 which is conveniently prepared from (R)-(+)-NEA (see (R)-1-(1-Naphthyl)ethyl Isocyanate). However, the diastereomeric carbamates may also be produced by treating the chloroformate derivative of a racemic alcohol with (R)-(+)-NEA.5 Preparative separation of racemic 1-heptyn-3-ol was achieved through chromatographic separation of the diastereomeric carbamates prepared via the chloroformate derivative (eq 6).17 The carbamates are conveniently cleaved by the action of trichlorosilane (see Trichlorosilane).18

Chiral Solvating Agent.

NEA is an effective chiral solvating agent for NMR determination of enantiomeric purity.6,19 The combination of enantiomerically pure NEA (3-5 mol excess) and racemic solute causes the NMR spectra of the diastereomerically solvated enantiomers to differ. Since NEA is an efficient hydrogen-bond acceptor, it solvates better if the solute is a hydrogen-bond donor. (R)-(+)-NEA has been used to determine the enantiomeric purity of a variety of substrates.20

Chiral Stationary Phases for GC and HPLC.

Enantiomerically pure NEA has been used to prepare a variety of chiral stationary phases for liquid,21 gas,22 and supercritical fluid23 chromatography. These stationary phases are used to separate enantiomers without derivatization of the substrate with a chiral agent.

Related Reagents.

(R)-1-(1-Naphthyl)ethyl Isocyanate.

1. (a) Sato, T.; Kawara, T.; Nishizawa, A.; Fujisawa, T. TL 1980, 21, 3377. (b) Sato, T.; Naruse, K.; Fujisawa, T. TL 1982, 23, 3587.
2. Mori, K.; Nukada, T.; Ebata, T. T 1981, 37, 1343.
3. Corey, E. J.; Snider, B. B. JOC 1974, 39, 256.
4. Bergot, B. J.; Anderson, R. J.; Schooley, D. A.; Henrick, C. A. J. Chromatogr. 1978, 155, 97.
5. Pirkle, W. H.; Adams, P. E. JOC 1979, 44, 2169.
6. Burlingame, T. G.; Pirkle, W. H. JACS 1966, 88, 4294.
7. Nabeya, A.; Endo, T. JOC 1988, 53, 3358.
8. Dale, J. A.; Dull, D. L.; Mosher, H. S. JOC 1969, 34, 2543.
9. Miyano, S.; Okada, S.; Hotta, H.; Takeda, M.; Suzuki, T.; Kabuto, C.; Yasuhara, F. BCJ 1989, 62, 3886.
10. Samuelson, E. CA 1924, 18, 1833.
11. Newman, P. Optical Resolution Procedures for Chemical Compounds; Manhattan College: New York, 1978; Vol. 1, p 230.
12. Mohacsi, E.; Leimgruber, W. OS 1976, 55, 80.
13. Brown, E.; Viot, F.; Le Floc'h, Y. TL 1985, 26, 4451.
14. (a) Eberhardt, R.; Glotzmann, C.; Lehner, H.; Schlogl, K. TL 1974, 4365. (b) Bergot, B. J.; Baker, F. C.; Lee, E.; Schooley, D. A. JACS 1979, 101, 7432. (c) Mori, K.; Masuda, S.; Suguro, T. T 1981, 37, 1329. (d) Vandewalle, M.; Van der Eycken, J.; Oppolzer, W.; Vullioud, C. T 1986, 42, 4035. (e) Hiratake, J.; Inagaki, M.; Yamamoto, Y.; Oda, J. JCS(P1) 1987, 1053.
15. Pirkle, W. H.; Adams, P. E. JOC 1980, 45, 4111.
16. Pirkle, W. H.; Hoekstra, M. S. JOC 1974, 39, 3904.
17. Overman, L. E.; Bell, K. L.; Ito, F. JACS 1984, 106, 4192.
18. Pirkle, W. H.; Hauske, J. R. JOC 1977, 42, 2781.
19. (a) Pirkle, W. H.; Beare, S. D. JACS 1967, 89, 5485. (b) Pirkle, W. H.; Burlingame, T. G. TL 1967, 4039. (c) Pirkle, W. H.; Beare, S. D. TL 1968, 2579.
20. (a) Weisman, G. R. In Asymetric Synthesis; Morrison, J. D., Ed.; Academic: New York, 1983; Vol. 1, Chapter 8. (b) Pirkle, W. H.; Hoover, D. J. In Topics in Stereochemistry; Wiley: New York, 1982; Vol. 13, p 263.
21. (a) Oi, N.; Nagase, M.; Doi, T. J. Chromatogr. 1983, 257, 111. (b) Pirkle, W. H.; Hyun, M. H. JOC 1984, 49, 3043. (c) Pirkle, W. H.; Hyun, M. H. J. Chromatogr. 1985, 322, 295. (d) Lloyd, M. J. B. J. Chromatogr. 1986, 351, 219. (e) Dappen, R.; Meyer, V. R.; Arm, H. J. Chromatogr. 1986, 361, 93.
22. (a) Weinstein, S.; Feibush, B.; Gil-Av, E. J. Chromatogr. 1976, 126, 97. (b) Oi, N.; Kitahara, H.; Inda, Y.; Doi, T. J. Chromatogr. 1981, 213, 137. (c) Oi, N.; Kitahara, H.; Inda, Y.; Doi, T. J. Chromatogr. 1982, 237, 297.
23. Bradshaw, J. S.; Aggarwal, S. K.; Rouse, C. A.; Tarbet, B. J.; Markides, K. E.; Lee, M. L. J. Chromatogr. 1987, 405, 169.

John M. McGill

Eli Lilly and Company, Lafayette, IN, USA

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