[157303-88-3]  · C20H36N4  · (MW 332.53)

chiral tetradentate ligand that has been shown to be an effective auxiliary for enantioselective alkylation,1-7 Michael additions,7-9 and aldolization10 in stoichiometric and in some cases catalytic amounts

Alternate Name: (R)-(-)-N-{2-[N-(2-dimethylaminoethyl)-N-methylamino]ethyl}-1-phenyl-2-piperidinoethylamine; (R)-N-[2-(dimethylamino)ethyl]-N-methyl-N-[1-phenyl-2-(1-piperidinyl)ethyl]-1,2-ethanediamine; N-[(2R)-6,9-dimethyl-2-phenyl-3,6,9-triazadecyl]piperidine.

Physical Data: [a]D25 -57.1 (c 2.0, benzene).

Solubility: most organic solvents.

Form Supplied in: clear, colorless oil; not commercially available.

Analysis of Reagent Purity: 1H NMR; Elemental Analysis.

Purification: column chromatography (silica, CHCl3/MeOH 9:1 then CHCl3/i-PrNH2 20:1) followed by bulb-to-bulb distillation (290 °C bath temperature, 0.8 mmHg).

Preparative Methods: the original literature11 reports that (R)-(-)-N-{2-[N-(2-dimethylaminoethyl)-N-methylamino]ethyl}-1-phenyl-2-piperidinoethylamine (1) can be prepared from (R)-phenylglycine in six steps. Thus, (R)-phenylglycine is first protected as the N-Cbz-amino acid, and is then condensed with piperidine in the presence of diethylphosphorocyanidate (DEPC) and triethylamine to provide the corresponding amide. Removal of the Cbz protecting group under acidic conditions gives amino amide, which is subsequently reduced with LiAlH4. The primary amine is amidated upon treatment with N-[2-(dimethylamino)ethyl]-N-methylglycine and DEPC, and the resulting product is reduced with BH3·THF to afford 1 (1).

Handling, Storage, and Precautions: presumably, as with all amines, air-oxidation will occur over time; store in a cool, dry place away from light; avoid oxidizing agents.


There have been numerous studies focused on asymmetric methods in synthetic organic chemistry.12 These investigations can be classified into two main categories: either diastereoselective or enantioselective. In the diastereoselective strategy, an appropriate substrate is covalently attached to a chiral auxiliary and the incipient stereogenic center is introduced via an intramolecular bias established by the chiral appendage. In the enantioselective approach, an achiral substrate is directly transformed into a chiral product via an intermolecular interaction it establishes with the chiral auxiliary. Koga et al. have shown that chiral tetradentate amines such as 1 can be used in enantioselective synthesis.1-10 Treatment of an achiral lithium enolate with 1 and lithium bromide generates a ternary complex, which reacts in an enantioselective manner with electrophiles.

The structure of 1 is similar to lithium diisopropyl amide (LDA) in that there are two bulky alkyl groups attached to the amide nitrogen.6,11 In 1, however, one of the alkyl groups has been modified to contain a chiral center at the a-position and a piperidinyl substituent at the b-position. Upon deprotonation, the tertiary amino group of the piperidine acts as an internal ligation site for lithium (2). The N-lithio derivative of 1 has a number of useful characteristics: (i) in solution it will form a stable, five-membered chelated structure; (ii) because the a-phenyl substituent will, for steric reasons, orient itself exclusively trans to the other alkyl appendage, the lone pair electrons residing on the amide nitrogen must reside cis to the phenyl ring in the chelate, thus making this nitrogen chiral; (iii) in solution, aggregates of the complex will form to satisfy lithium's valency; and (iv) the use of an external additive could be used to control the degree of aggregation in solution.6,11

Enantioselective Alkylations and Catalytic Asymmetric Alkylations

a-Substitution of a carbonyl-containing substrate via generation of an enolate ion followed by subsequent reaction with an electrophile remains one of the most fundamental transformations in synthetic organic chemistry. A more recent advance to this type of transformation is the ability to perform this conversion in an enantioselective manner. This type of alkylation is illustrated by the reaction of 1 with the lithium enolate derived from 1-tetralone (2).

The lithium enolate of cyclohexanone1,4,6 has been used as an efficient substrate for this same reaction; 53% (90% ee). Alternatively, the parent carbonyl compound can be employed if the lithium amide of 1, prepared by treating 1 with 1.0 equiv of n-BuLi, is used instead of the amine.6 Both the chemical yield and the degree of asymmetric induction are dependent on reaction conditions, e.g. solvent and reaction time. It has been observed4,6 that in strongly ligating solvents (e.g. DME, THF, or diethyl ether), the yield is higher, however, the degree of asymmetric induction tends to be lower. Opposite trends are observed in non-ligating solvents (e.g. toluene). Additionally, as the reaction time is lengthened the degree of asymmetric induction increases. This observation has been correlated to the concentration of lithium bromide present in the reaction mixture. Initially, there is no lithium bromide in solution, however, as the alkylation proceeds lithium bromide is generated in situ. Accordingly, if lithium bromide is added at the beginning of the reaction, the % ee is dramatically increased. It is, therefore, most convenient to perform this reaction using the silyl enol ether substrate and to treat it with methyllithium-lithium bromide to generate the lithium enolate-lithium bromide complex (3, 1).

This methodology has also been applied to the alkylation of five- and six-membered N-alkylated lactams and lactones3 (4 and 5). In both cases, 1 is first converted to the corresponding lithium amide and pre-complexed with lithium bromide. Furthermore, in the case of the lactams, it was observed that the use of 2,2,5,5-tetramethyltetrahydrofuran (TMTHF) as the solvent resulted in higher yields and greater enantiomeric excess.

The use of 1 for the preparation of a chiral quaternary center via asymmetric alkylation has also been investigated.2 Although 1 has proven to be an effective reagent for the enantioselective generation of tertiary centers, its use for generating quaternary centers has been of only marginal use (6). However, other chiral tetradentate amines can be used for this purpose.2

In an extension of this methodology, it has been demonstrated that in some cases the enantioselective alkylation of lithium enolates can be achieved by means of a catalytic amount of 1.1,5-7 As in the stoichiometric version (vide supra), the reaction conditions play a crucial role in determining the yield and % ee. One fundamental modification in the catalytic version is the addition of two equiv of an achiral bidentate amine [e.g. N,N,N,N-tetramethylethylenediamine (TMEDA) or N,N,N,N-tetramethylpropylene diamine (TMPDA)] to trap the large excess of lithium bromide present at the beginning of the reaction. This catalytic asymmetric variant is illustrated by the reaction of the lithium enolate of 1-tetralone with a variety of electrophiles (7). In this example, the optimal reaction conditions were determined to be 0.05 equiv of 1, 2.0 equiv of TMPDA, and 10.0 equiv of the alkyl halide.

Enantioselective Aldol Reactions

The use of 1 for generating two contiguous stereocenters via an asymmetric aldol condensation has also been investigated,10 but only with marginal success. For example, reaction of the lithium enolate derived from tert-butyl propionate with the N-lithio derivative of 1, followed by condensation with benzaldehyde, provided a mixture of anti and syn aldol products in poor-to-modest % ee (8).

Although 1 is of only limited utility, further studies have shown that other chiral tetradentate amines can perform this type of transformation with yields for the anti product greater than 80% and in greater than 95% ee.

Enantioselective Michael Additions

Amine 1 has also been used as an effective ligand for enantioselective Michael reactions of ketone lithium enolate donors with various benzylidene acceptors.9 As representative examples, the lithium enolates of aryl methyl ketones were reacted with dimethyl benzylidenemalonate in the presence of 1 (9). The lithium enolate was generated from the corresponding ketone by treatment with hexamethyldisilazide in the presence of lithium bromide in toluene. The resulting enolate was then exposed to 1 and allowed to stir for 30 min to form the desired ternary complex. After addition of the benzylidene acceptor, the desired products were isolated in acceptable yields and with high % ee.

In an analogous manner,8 a-substituted phenyl ketones have been used to afford Michael adducts containing two vicinal chiral tertiary centers in both high diastereo- and enantioselectivity (10, 2).

Related Reagents.

(R)-N-[2-(2-methoxyethyloxy)ethyl]-1-phenyl-2-piperidinoethylamine; (R)-N-[2-(2-dimethylaminoethyloxy)ethyl]-1-phenyl-2-piperidinoethylamine.

1. Imai, M.; Hagihara, A.; Kawasaki, H.; Manabe, K.; Koga, K., Tetrahedron 2000, 56, 179.
2. Yamashita, Y.; Odashima, K.; Koga, K., Tetrahedron Lett. 1999, 40, 2803.
3. Matsuo, J.; Kobayashi, S.; Koga, K., Tetrahedron Lett. 1998, 39, 9723.
4. Murakata, M.; Yasukata, T.; Aoki, T.; Nakajima, M.; Koga, K., Tetrahedron 1998, 54, 2449.
5. Imai, M.; Hagihara, A.; Kawasaki, H.; Manabe, K.; Koga, K., J. Am. Chem. Soc. 1994, 116, 8829.
6. Shindo, M.; Koga, K., J. Synth. Org. Chem., Jpn. 1995, 53, 1021.
7. Odashima, K.; Koga, K., Yakugaku Zasshi 1997, 117, 800.
8. Yasuda, K.; Shindo, M.; Koga, K., Tetrahedron Lett. 1997, 38, 3531.
9. Yasuda, K.; Shindo, M.; Koga, K., Tetrahedron Lett. 1996, 37, 6343.
10. Uragami, M.; Tomioka, K.; Koga, K., Tetrahedron Asym. 1995, 6, 701.
11. Shirai, R.; Aoki, K.; Sato, D.; Kim, H.; Murakata, M.; Yasukata, T.; Koga, K., Chem. Pharm. Bull. 1994, 42, 690.
12. (a) O'Brian, P., J. Chem. Soc., Perkin Trans. 1 2001, 95. (b) Seebach, D.; Beck, A. K.; Heckel, A., Angew. Chem., Int. Ed. Engl. 2001, 40, 92. (c) Arya, P.; Qin, H., Tetrahedron 2000, 56, 917. (d) Regan, A. C., J. Chem. Soc., Perkin Trans. 1 1999, 357. (e) Seebach, D.; Hintermann, T., Helv. Chim. Acta. 1998, 81, 2093. (f) Wills, M., J. Chem. Soc., Perkin Trans. 1 1998, 3101. (g) O'Brian, P., J. Chem. Soc., Perkin Trans. 1 1998, 1439. (h) Regan, A. C., Contemp. Org. Synth. 1997, 4, 1. (i) Ager, D. J.; Prakash, I.; Schaad, D. R., Aldrichimica Acta 1997, 30, 3. (j) Ager, D. J.; Prakash, I.; Schaad, D. R., Chem. Rev. 1996, 96, 835. (k) Evans, D. A., Aldrichimica Acta 1982, 15, 23. (l) Evans, D. A. In Asymmetric Synthesis; Morrison, J. D., Ed.; Academic Press: New York, 1984; Vol. 3, Part B, 2-101. (m) Cowden, C. J., In Organic Reactions; Paquette, L. A., Ed.; John Wiley & Sons: New York, 1997; Vol. 51, 1-200.
13. Ireland, R. E.; Mueller, R. H.; Williard, A. K., J. Am. Chem. Soc. 1976, 98, 2868.
14. Seebach, D.; Beck, A. K.; Heckel, A., Angew. Chem., Int. Ed. Engl. 1988, 27, 1624.

Douglas M. Krein & Todd L. Lowary

The Ohio State University, Columbus, Ohio, USA

Copyright 1995-2000 by John Wiley & Sons, Ltd. All rights reserved.