(R)-2-[1-(Dimethylamino)ethyl]benzenethiol

[135190-26-0]  · C10H15NS  · (MW 181.30)

(catalyst precursor for enantioselective C-C bond forming reactions)

Physical Data: mp 133 °C.

Solubility: soluble in common organic solvents.

Form Supplied in: white solid; not commercially available.

Analysis of Reagent Purity: 1H NMR, elemental analysis.

Preparative Methods: the title compound can be prepared by reaction of (R)-2-[1-(dimethylamino)ethyl]phenyllithium with elemental sulfur (1).1 A solution of pure (R)-2-[1-(dimethylamino)ethyl]phenyllithium1 in THF is slowly added at -50 °C to a suspension of a stoichiometric amount of freshly sublimed sulfur. The solution is warmed to room temperature and quenched with an equimolar amount of a 10 M aqueous HCl solution. All volatiles are evaporated at reduced pressure and the residue is sublimed at 120 °C in vacuo (0.1 mmHg). The nitrogen-functionalized derivatives (R)-2-[1-(1-pyrrolidinyl) ethyl]benzenethiol2 and (R)-2-[1-(1-piperidinyl)ethyl]benzenethiol2 may be prepared in a similar way. It should be noted that reaction with Me3SiCl instead of HCl after the sulfur insertion reaction affords the corresponding trimethylsilyl thio ether, which also is a valuable catalyst precursor.1,2

Purification: sublimation in vacuo (0.1 mmHg).

Application as Catalyst Precursor in the Enantioselective 1,2-addition of Diorganozinc Compounds to Aldehydes

The enantioselective synthesis of secondary alcohols via a zinc-mediated 1,2 addition to aldehydes in the presence of a chiral catalyst, discovered by Mukaiyama3 and by Oguni,4 initiated a search for the ultimate catalyst system that has made this reaction one of the most studied.5 The best catalytic systems possess a b-amino alkoxide skeleton, containing two chiral carbon atoms, since these have the capability of forming a five-membered chelate ring when bonded to a metal center.6 A major disadvantage of this approach is the requirement of expensive enantiopure starting materials. The application of (R)-2-[1-(dimethylamino)ethyl]benzenethiol (1) as the catalyst precursor7 overcomes this disadvantage because the enantiopure starting material is relatively cheap and, moreover, available in both enantiomeric forms. It was shown that these thiolate catalysts are at least as selective and active as the b-amino alkoxide catalyst. In particular, the pyrrolidinyl- 2 and piperidinyl- 3 analogs exhibit enhanced selectivity and reactivity in the 1,2-addition reaction.2

Mechanistic studies have shown that the EtZn-thiolates derived from 1-3 are the actual catalysts. An X-ray crystal structure determination of the MeZn derivative of precursor 1 revealed a dimeric structure with bridging thiolate ligands, as shown below. In separate experiments, it was shown that reaction of either the thiol 1 or the corresponding trimethylsilyl thioether with Me2Zn affords this dimeric methylzinc thiolate.2

A mechanism has been put forward in which the rate-determining step in the 1,2-addition reaction is cleavage of the dimeric zinc thiolate into a transient species in which both the aldehyde substrate and the reagent, i.e. dialkylzinc, are present.2

Some representative results of the application of the catalyst precursors 1-3 in the enantioselective zinc-mediated 1,2-addition to aldehydes are compiled in 1 (2).

These data show that application of one of the catalyst precursors 1-3 in the enantioselective 1,2-addition combines excellent chemical yield with high enantioselectivity.

To overcome a main problem associated with homogeneous catalysis, i.e. the recovery of the catalyst, the latest development in this field comprises the functionalization of catalyst precursor 1-3 with perfluoroalkyl chains to enable catalysis to be carried out in an organic/perfluorinated two-phase solvent system. It has been demonstrated that this approach allows reuse of the catalyst several times.8 Recently, an elegant synthetic route towards the enantioselective synthesis of chiral allylic alcohols in which catalyst precursor 1 is used has been reported (3).9 This reaction sequence involves the hydrozirconation of an acetylenic compound followed by a transmetallation reaction with Me2Zn. The alkenyl group of the resulting heteroleptic alkenylzinc compound is selectively transferred to the aldehyde in the presence of catalyst precursor 1, giving the chiral allylic alcohol with reported enantiomeric excesses of up to 90%.

Application as Catalyst Precursor in Copper-Mediated Enantioselective C-C Bond Formation Reactions

At the present time, organocopper reagents are frequently used in synthetic organic chemistry. The discovery of the Gilman cuprate Me2CuLi,10 and the demonstration of its synthetic potential by House11,12 and Corey13 caused a major breakthrough in the applicability of organocopper compounds. A disadvantage, especially from a standpoint of ‘atom economy,’ in the application of stoichiometric cuprate reagents is the fact that one equiv of the potentially available organic groups is not used in the reaction and ends up as chemical waste. The idea of using a well-chosen non-transferable group has been applied in the enantioselective 1,4-addition of Grignard reagents to a,b-unsaturated enones, in the presence of catalytic amounts of a copper-arenethiolate derived from catalyst precursor 1. The arenethiolate acts as a non-transferable group and induces enantioselectivity (4).14,15

Copper arenethiolate 1-Cu can be prepared starting from (R)-2-[1-(dimethylamino)ethyl]benzenethiol and Cu2O,1 or from the corresponding trimethylsilyl thio ether and CuCl (5).16

The trimeric nature of catalyst 1-Cu in the solid state was unambiguously proven by an X-ray crystal structure determination (see below).1,17 This aggregate is retained in solution as shown by cryoscopic molecular weight determinations.1

An interesting feature of the crystals of 1-Cu is that they show triboluminescent behaviour.18 Compound 1-Cu has been applied successfully as a catalyst in the enantioselective Michael addition reaction involving a variety of substrates and Grignard reagents (6).19 The addition reaction proceeds with excellent chemical yields, and enantiomeric excesses of up to 70% have been reported. It was shown that the (R)-catalyst gives rise to the formation of (S)-products.19

Furthermore, 1-Cu has been applied as a catalyst in the asymmetric substitution reaction of Grignard reagents with allylic substrates (7).20,21 Under optimized experimental conditions, the g-product is obtained selectively in quantitative yield. However, the enantioselective induction is low to moderate (up to 40%).


1. Knotter, D. M.; van Maanen, H. L.; Grove, D. M.; Spek, A. L.; van Koten, G., Inorg. Chem. 1991, 30, 3309.
2. Rijnberg, E.; Hovestad, N. J.; Kleij, A. W.; Jastrzebski, J. T. B. H.; Boersma, J.; Janssen, M. D.; Spek, A. L.; van Koten, G., Organometallics 1997, 16, 2847.
3. Mukaiyama, T.; Soai, K.; Kobayashi, S., Chem. Lett. 1978, 219.
4. Oguni, N.; Omi, T., Tetrahedron Lett. 1984, 25, 2823.
5. Noyori, R.; Kitamura, M., Angew. Chem., Int. Ed. Engl. 1991, 30, 49.
6. Soai, K.; Niwa, S., Chem. Rev. 1992, 92, 833.
7. Rijnberg, E.; Jastrzebski, J. T. B. H.; Janssen, M. D.; Boersma, J.; van Koten, G., Tetrahedron Lett. 1994, 35, 6521.
8. Kleijn, H.; Rijnberg, E.; Jastrzebski, J. T. B. H.; van Koten, G., Org. Lett. 1999, 1, 853.
9. Wipf, P.; Ribe, S., J. Org. Chem. 1998, 63, 6454.
10. Gilman, H.; Jones, R. G.; Woods, L. A., J. Org. Chem. 1952, 17, 1630.
11. House, H. O.; Respess, W. L.; Whitesides, G. M., J. Org. Chem. 1966, 31, 3128.
12. Whitesides, G. M.; Fisher, W. F., Jr; San Fulippo, J., Jr; Bashe, R. W.; House, H. O., J. Am. Chem. Soc. 1969, 91, 4871.
13. Corey, E. J.; Posner, G. H., J. Am. Chem. Soc. 1967, 89, 3911.
14. Lambert, F.; Knotter, D. M.; Janssen, M. D.; van Klaveren, M.; Boersma, J.; van Koten, G., Tetrahedron Asymm. 1991, 2, 1097.
15. van Koten, G., Pure Appl. Chem. 1994, 66, 1455.
16. Knotter, D. M.; Janssen, M. D.; Grove, D. M.; Smeets, W. J. J.; Horn, E.; Spek, A. L.; van Koten, G., Inorg. Chem. 1991, 30, 4361.
17. Knotter, D. M.; van Koten, G.; van Maanen, H. L.; Grove, D. M.; Spek, A. L., Angew. Chem., Int. Ed. Engl. 1989, 28, 341.
18. Knotter, D. M.; Blasse, G.; van Vliet, J. P. M.; van Koten, G., Inorg. Chem. 1992, 31, 2196.
19. van Klaveren, M.; Lambert, F.; Eijkelkamp, D. J. F. M.; Grove, D. M.; van Koten, G., Tetrahedron Lett. 1994, 35, 6135.
20. van Klaveren, M.; Persson, E. S. M.; del Villar, A.; Grove, D. M.; Bäckvall, J.-E.; van Koten, G., Tetrahedron Lett. 1995, 36, 3059.
21. Meuzelaar, G. J.; Karlström, A. S. E.; van Klaveren, M.; Persson, E. S. M.; del Villar, A.; van Koten, G.; Bäckvall, J.-E., Tetrahedron 2000, 56, 2895.

Johann T. B. H. Jastrzebski & Gerard van Koten

Debye Institute, Utrecht University, The Netherlands



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