· N-Benzylquininium Chloride
· (MW 451.01)
(chiral, nonracemic quaternary ammonium salt; catalyst for a variety of phase transfer reactions under basic conditions1)
Alternate Names: Quibec; BQC.
Physical Data: mp 180-181 °C, [a]19D -235.5° (c = 1.5, H2O);2 monohydrate: mp 169-172 °C (dec), [a]D -212.5° (c = 0.5, EtOH).3
Solubility: freely sol H2O, alcohols, acetone; slightly sol EtOAc; sparingly sol CHCl3.4
Form Supplied in: solid.
Purification: recrystallized from absolute EtOH.3
The combined use of catalytic amounts of N-benzylquininium chloride (1) with hydroxide bases (NaOH or KOH) has been explored for a variety of phase transfer reactions, including epoxidations, alkylations, and Michael reactions. The degree of stereoselectivity in product formation induced by the reagent can vary widely.5
BQC is derived from quinine, which is a member of the cinchona family of alkaloids. Ammonium salts derived from quinidine, a diastereomer of (1) at the hydroxyl substituent, have been used less frequently in catalysis than BQC. Quinidinium salts often give rise to products with enantioselectivity opposite to that from (1). Other related compounds, such as those derived from cinchonine and cinchonidine (which lack the methoxy substituent on the quinoline nucleus), have found application in organic synthesis. The cinchona alkaloids, as well as salt derivatives in which the benzyl group bears various substituents, have also been studied.6 Results from polymer-bound catalysts have not been promising.7
Benzylquininium chloride has shown good to excellent selectivity in the epoxidation of a,b-unsaturated ketones.8 Oxidation of quinone (2) in the presence of (1) with aqueous t-Butyl Hydroperoxide and Sodium Hydroxide in toluene gave rise to a 95% chemical yield of epoxide (3) in 78% ee (eq 1).2 Recrystallization improved the ee to 100% with 63% mass recovery. Aqueous Hydrogen Peroxide decreased both the yield (89%) and enantioselectivity (50% ee).
Enantiomerically enriched epoxides have also been generated using (1) in the Darzens reaction of a-chloro ketones with aldehydes, as well as through ring closure of racemic halohydrins.9 The extent of enantioselectivity for both reactions is similar (optical purity 6-8% ±1), suggesting a moderate degree of kinetic resolution occurring in each case.
Benzylquininium chloride has been studied as a catalyst for the asymmetric Michael reaction. Reaction of amidomalonate (5) and chalcone (4) with catalytic base and a variety of chiral, nonracemic ammonium salts in the absence of solvent produced (6) in yields of 41-68% and 20-68% ee (eq 2).10 The quinine-derived salt (1) was of intermediate effectiveness (38% ee, 47% yield) when compared to ephedrine-based catalysts. Although (1) was not specifically tested with regard to solvation effects, it is suggested that increased aggregation of reactive species under solid-liquid PTC conditions leads to enhanced organization and selectivity. Low levels of induction have been observed in other systems.11 A study comparing various
chiral alkaloid salts, bases, and reaction conditions on enantioselectivities in the conjugate addition of thiols and nitroalkanes to enones has been reported.12 Remarkable results have also been obtained in the cinchonium/cinchonidinium-catalyzed reaction of an indanone with methyl vinyl ketone.13 A direct comparison with a more efficient lanthanum-binaphthol complex has been reported.14
Phase-transfer alkylations have been studied using cinchona alkaloid derivatives; however, results have been more promising with the cinchonium/cinchonidinium series than with the quininium/quinidinium group.15 For example, catalytic asymmetric alkylation in high yield and selectivity has been achieved with N-(p-trifluoromethylphenyl)cinchonium bromide (p-CF3BCNB) (eq 3).16 A systematic investigation of reaction variables (catalyst type, solvent, concentration, temperature, stirring rate, leaving group, etc.) has produced a general method to prepare a-amino acids in 44-62% ee.17
- 1. For reviews of phase transfer reactions, see for example (a) Keller, W. E. Phase Transfer Reactions. Fluka Compendium; Thieme: Stuttgart, 1986; Vols. 1, 2. (b) Dehmlow, E. V. Phase Transfer Catalysis; Verlag Chemie: Deerfield Beach, 1980. (c) Starks, C. M.; Liotta, C. Phase Transfer Catalysis, Principles and Techniques; Academic Press: New York, 1978. (d) Dockx, J. S 1973, 441. (e) Dehmlow, E. V. AG(E) 1974, 13, 170. For a mechanistic review of hydroxide mediated reactions under PTC conditions, see: (f) Rabinovitz, M.; Cohen, Y.; Halpern, M.; AG(E) 1986, 25, 960.
- 2. Harigaya, Y.; Yamaguchi, H.; Onda, M. CPB 1981, 29, 1321.
- 3. Colonna, S.; Fornasier, R. JCS(P1) 1978, 371.
- 4. Jacobs, W. A.; Heidelberger, M. JACS 1919, 41, 2090.
- 5. Some doubts have been expressed with regard to the accuracy of reported results: Dehmlow, E. V.; Singh, P.; Heider, J. JCR(S) 1981, 292.
- 6. For example (a) Sera, A.; Takagi, K.; Katayama, H.; Yamada, H.; Matsumoto, K. JOC 1988, 53, 1157. (b) Wynberg, H.; Helder, R. TL 1975, 4057. (c) Helder, R.; Arends, R.; Bolt, W.; Hiemstra, H.; Wynberg, H. TL 1977, 2181.
- 7. Kelly, J.; Sherrington, D. C. Polymer 1984, 25, 1499.
- 8. (a) Helder, R.; Hummelen, J. C.; Laane, R. W. P. M.; Wiering, J. S.; Wynberg, H. TL 1976, 1831. (b) Wynberg, H.; Marsman, B. JOC 1980, 45, 158.
- 9. Hummelen, J. C.; Wynberg, H. TL 1978, 1089.
- 10. Loupy, A.; Sansoulet, J.; Zaparucha, A.; Merienne, C. TL 1989, 30, 333.
- 11. For example: (a) Jianguo, C.; Lingchong, Y. SC 1990, 20, 2895. (b) Brunner, H.; Zintl, H. M 1991, 122, 841. (c) Annunziata, R.; Cinquini, M.; Colonna, S. JCS(P1) 1980, 2422.
- 12. Colonna, S; Re, A.; Wynberg, H. JCS(P1) 1981, 547.
- 13. Conn, R. S. E.; Lovell, A. V.; Karady, S.; Weinstock, L. M. JOC 1986, 51, 4710.
- 14. Sasai, H.; Itoh, N.; Suzuki, T.; Shibasaki, M. TL 1993, 34, 855.
- 15. (a) Julia, S.; Ginebreda, A.; Guixer, J.; Tomas, A. TL 1980, 21, 3709. (b) Julia, S.; Ginebreda, A.; Guixer, J.; Masana, J.; Tomas, A.; Colonna, S. JCS(P1) 1981, 574.
- 16. (a) Hughes, D. L.; Dolling, U. H.; Ryan, K. M.; Schoenewaldt, E. F.; Grabowski, E. J. J. JOC 1987, 52, 4745. (b) Bhattacharya, A.; Dolling, U. H.; Grabowski, E. J. J.; Karady, S.; Ryan, K. M.; Weinstock, L. M. AG(E) 1986, 25, 476. (c) Dolling, U. H.; Davis, P.; Grabowski, E. J. J. JACS 1984, 106, 446.
- 17. The ee's can often be improved by recrystallization. O'Donnell, M. J.; Bennett, W. D.; Wu, S. JACS 1989, 111, 2353.
Mary Ellen Bos
R. W. Johnson Pharmaceutical Research Institute, Raritan, NJ, USA
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