N-[4-(Trifluoromethyl)benzyl]cinchoninium Bromide1

[95088-20-3]  · C27H28BrF3N2O  · N-[4-(Trifluoromethyl)benzyl]cinchoninium Bromide  · (MW 533.47)

(chiral phase-transfer catalyst for asymmetric alkylations,2a amino acid synthesis,7 hydroxylations,6 Michael additions,3 and Robinson annulations2b)

Physical Data: mp 245 °C (dec).

Solubility: <10-5 M in toluene; 20 mM in toluene as dimer.2a

Form Supplied in: crystalline salt; commercially available. Can contain anywhere from 0 to 25 mol % of the dihydro analog, usually 15 mol %.

Handling, Storage, and Precautions: do not breath dust; avoid contact with skin and eyes.

Asymmetric Alkylation.1,2

N-[4-(Trifluoromethyl)benzyl]cinchoninium bromide (1) has been used as chiral phase-transfer catalyst1,2 in the alkylation of indanones (eq 1).2a For the alkylation of a-aryl-substituted carbonyl compounds the diastereomeric N-[4-(trifluoromethyl)benzyl]cinchonidinium bromide (2) was used to obtain the opposite stereochemistry (eqs 2 and 3).5 The asymmetric alkylation of oxindoles was used as the key step in an asymmetric synthesis of (-)-physostigmine (eq 4).4

In all cases it was reported that the trifluoromethyl group enhances the interaction in the prochiral ion pair, resulting in higher ee. The exception appears to be the asymmetric synthesis of a-amino acids via alkylation of the benzophenone Schiff base of glycine alkyl esters with allyl bromide, which produced a 56% ee with the trifluoromethyl-substituted catalyst compared to 66% with the unsubstituted catalysts N-benzylcinchoninium chloride (3) or N-benzylcinchonidinium chloride (4) (eq 5).7

The unsubstituted catalyst (3) was also used in an asymmetric Gabriel synthesis of a-amino acids via solid-liquid chiral phase-transfer alkylation of potassium phthalimide with 2-bromocarboxylates.10

In general, nonpolar solvents and less reactive alkyl halides (Cl > Br > I) give higher ee values. Aqueous 50% NaOH is the preferred base, as it acts as a dehydrating agent and keeps the organic solvent dry, thus promoting a tight ion pair. During the reaction the catalyst is extracted into the organic layer as a dimer of ammonium bromide and its zwitterionic oxide,2a but it reacts as a monomer resulting in an order of 0.5 for the catalyst in the alkylation reaction. The catalyst degrades during the reaction via Hofmann elimination to tertiary amines, which are readily removed by acid extractions during the workup.2a Therefore the catalyst usually cannot be recovered. An economical alternative catalyst is N-(3,4-dichlorobenzyl)cinchoninium chloride, which may give equivalent results.2a,3,4a,9 Reduction in catalyst concentration and reaction times may be achieved by addition of a very small amount of a PEG cocatalyst (PEG 400 or PEG p-isooctylphenyl ether).2e,9 The ee will depend on the interaction of the catalyst with the substrate in the ion pair and in certain cases an electron-donating substituent on the benzyl group may provide optimal interaction, as was found for an asymmetric Michael reaction using N-methyl-N-benzyl ephedrinium bromide as the phase-transfer catalyst.8

Asymmetric Michael Addition.

A chiral catalytic addition of methyl vinyl ketone to 2-propylindanone in 93% yield and 80% ee (S enantiomer) has been reported (eq 6).3

The (R) enantiomer was prepared with 40% ee using the cinchonidine catalyst (2). When the vinyl group of the catalyst was hydrogenated to the ethyl group (N-[4-(trifluoromethyl)benzyl]dihydrocinchonidinium bromide, 5), the ee improved to 52%. Equally good results were obtained using the basic catalyst dimer2a in a homogeneous system which allowed the use of Michael acceptors not compatible with hydroxide bases.

Asymmetric Hydroxylation.

The catalyst has been used for asymmetric a-hydroxylations of indanones and a-tetralones using the standard conditions in combination with oxygen and Triethyl Phosphite (eq 7).6 Substituents on the aromatic ring of the substrates will influence the p-p interaction in the ion pair and affect the ee. Similarly, (E)-2-ethylidene-1-tetralone was oxidized to the a-hydroxy ketone (eq 8).

Asymmetric Robinson Annulation.

2-Propyl-1-indanone undergoes Robinson annulation with the catalyst and methyl vinyl ketone (eq 6).3 Higher ee values were achieved using 1,3-dichloro-2-butene (Wichterle Reagent) as an MVK surrogate for the Michael addition and overall Robinson annulation (eq 9).2b,d,e

Using (2) as catalyst provided the (R) enantiomer in 99% yield, 78% ee. The key introduction of asymmetry during the synthesis of (+)-podocarp-8(14)-en-13-one was the phase-transfer-catalyzed Robinson annulation of 6-methoxy-1-methyl-2-tetralone with ethyl vinyl ketone. The authors carried out a comparative study of the N-(4-trifluoromethyl)benzyl derivatives of cinchonine, cinchonidine, dihydrocinchonine, and dihydrocinchonidine and found that (5) produced the highest ee of the desired (S) enantiomer at -45 °C using toluene and 60% aq KOH (eq 10).5


1. Dehmlow, E. V.; Dehmlow, S. S. Phase Transfer Catalysis; VCH: Weinheim, 1993; pp 80-91.
2. (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. (d) Dolling, U.-H.; Hughes, D. L.; Bhattacharya, A.; Ryan, K. M.; Karady, S.; Weinstock, L. M.; Grabowski, E. J. J. In Phase-Transfer Catalysis; Starks, C. M., Ed.; American Chemical Society: Washington, 1987; pp 67-81. (e) Dolling, U.-H.; Hughes, D. L.; Bhattacharya, A.; Ryan, K. M.; Karady, S.; Weinstock, L. M.; Grenda, V. J.; Grabowski, E. J. J. In Catalysis of Organic Reactions; Rylander, P. N.; Greenfield, H.; Augustine, R. L.; Eds.; Dekker: New York, 1988; pp 65-86.
3. Conn, R. S. E.; Lovell, A. V.; Karady, S.; Weinstock, L. M. JOC 1986, 51, 4710.
4. (a) Lee, T. B. K.; Wong, G. S. K. JOC 1991, 56, 872. (b) Chen, B. H.; Ji, Q. E. Acta Chim. Sinica 1989, 47, 350 (CA 1989, 111, 194 508).
5. Nerinckx, W.; Vandewalle, M. TA 1990, 1, 265.
6. Masui, M.; Ando, A.; Shioiri, T. TL 1988, 29, 2835.
7. (a) O'Donnell, M. J.; Bennett, W. D.; Wu, S. JACS 1989, 111, 2353. (b) O'Donnell, M. J.; Wu, S. TA 1992, 3, 591. (c) Imperiali, B.; Prins, T. J.; Fisher, S. L. JOC 1993, 58, 1613.
8. Loupy, A.; Zaparucha, A. TL 1993, 34, 473.
9. Dolling, U.-H. U. S. Patent 4 605 761, 1986 (CA 1987, 106, 4697).
10. Guifa, S.; Lingchong, Y. SC 1993, 23, 1229.

Ulf-H. Dolling

Merck Research Laboratories, Rahway, NJ, USA



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