Enantioselective synthesis of vicinal halohydrins via dynamic kinetic resolution

Article abstract of DOI:10.1021/ol052821k

(Chemical Equation Presented) Expanding the scope of enantioselective catalysis via DKR, transfer hydrogenation of a variety of cyclic α-halo ketones was accomplished using the Noyori/Ikariya (R,R)- or (S,S)-I catalysts and either HCO₂H/Et₃N or HCO₂Na/n-Bu ₄NBr in H₂O/CH₂Cl₂ as the hydrogen sources. Good yields of vicinal bromo-, chloro-, and fluorohydrins with excellent de and ee levels were achieved in most cases after a simple tuning of reaction conditions.

Full text of DOI:10.1021/ol052821k

ORGANIC
LETTERS
2006
Vol. 8, No. 1
127-130
Enantioselective Synthesis of Vicinal
Halohydrins via Dynamic Kinetic
Resolution
Abel Ros,† Antonio Magriz,† Hansjorg Dietrich,§ Rosario Ferna´ndez,*,‡
1
Eleuterio Alvarez,† and Jose´ M. Lassaletta*,†
Instituto de InVestigaciones Qu´ımicas, CSIC-USe, c/Ame´rico Vespucio 49,
Isla de la Cartuja, 41092 SeVille, Spain, Departamento de Qu´ımica Orga´nica,
Facultad de Qu´ımica, UniVersidad de SeVilla, Apdo. de Correos No. 553,
41071, SeVille, Spain, and Bayer CropScience GmbH, Industriepark Ho¨chst G836,
65926 Frankfurt, Germany
jmlassa@iiq.csic.es
Received November 22, 2005
ABSTRACT
Expanding the scope of enantioselective catalysis via DKR, transfer hydrogenation of a variety of cyclic
r
-halo ketones was accomplished
using the Noyori/Ikariya (R,R)- or (S,S)-I catalysts and either HCO2H/Et3N or HCO2Na/n-Bu4NBr in H2O/CH2Cl2 as the hydrogen sources. Good
yields of vicinal bromo-, chloro-, and fluorohydrins with excellent de and ee levels were achieved in most cases after a simple tuning of
reaction conditions.
Vicinal halohydrins are versatile building blocks and key
intermediates for the synthesis of many bioactive compounds,
and the development of methods for their asymmetric
synthesis has therefore attracted much attention.1 Though a
number of methods are known, there is still need of a general
approach to the enantioselective synthesis of cyclic cis vicinal
halohydrins.
with conventional separation techniques or classical kinetic
resolutions, is established as the most efficient technique for
the resolution of racemates. The seminal work by the Noyori3
and Geneˆt4 groups on the catalytic hydrogenation of â-ke-
toesters via DKR has found a number of applications2 and
stimulated the development of related reactions such as the
transfer hydrogenation of 1,2-diketones5 and of several types
of 2-substituted ketones.6 Recently, we have reported on the
transfer hydrogenation of R-alkyl(aryl) cyclic ketimines as
the first process involving reduction of CdN bond via DKR.7
Additionally, DKR techniques have also been applied to
On the other hand, dynamic kinetic resolution (DKR),2
not limited by the theoretical 50% maximum yield associated
† Instituto de Investigaciones Qu´ımicas.
‡ Universidad de Sevilla.
§ Bayer CropScience GmbH.
(1) Halohydrins and derivatives. In Fiesers’ Reagents for Organic
Synthesis; Smith, J. G., Fieser, M., Eds.; Wiley: New York, 1990. (b)
Bonini, C.; Righi, G. Synthesis 1994, 225. (c) Haufe, G. J. Fluor. Chem.
2004, 125, 875-894.
(2) Reviews: (a) Noyori, R.; Tokunaga, M.; Kitamura, M. Bull. Chem.
Soc. Jpn. 1995, 68, 36-56. (b) Huertas, F. F.; Minidis, A. B. E.; Ba¨ckwall,
J.-E. Chem. Soc. ReV. 2001 30, 321-331. (c) Pellisier, H. Tetrahedron 2003,
59, 8291-8327. (d) Vedejs, E.; Jure, M. Angew. Chem., Int. Ed. 2005, 44,
3974-4001.
(3) Noyori, R.; Ikeda, T.; Ohkuma, M.; Widhalm, M.; Kitamura, H.;
Akutagawa, S.; Sayo, N.; Saito, T.; Taketomi, T.; Kumobayashi, H. J. Am.
Chem. Soc. 1989, 111, 9134-9135.
(4) (a) Geneˆt, J. P.; Mallart, S.; Juge´, S. French patent 8,911,159, 1989.
(b) Geneˆt, J. P.; Pinel, C.; Mallart, S.; Juge´, S.; Thorimbert, S.; Laffite, J.
A. Tetrahedron: Asymmetry 1991, 2, 555.
(5) (a) Murata, K.; Okano, K.; Miyagi, M.; Iwane, H.; Noyori, R.; Ikariya,
T. Org. Lett. 1999, 7, 1119-1121. (b) Koike, T.; Murata, K.; Ikariya, T.
Org. Lett. 2000, 7, 3833-3836.
10.1021/ol052821k CCC: $33.50
© 2006 American Chemical Society
Published on Web 12/09/2005

diastereoselective nucleophilic substitutions of R-iodo- and
R-bromoesters and amides8 and to the hydrogenation of
R-chloro-â-ketoesters by Ru(II)-diphosphine catalysts.9
Even considering the sensibility of R-halo ketones toward
substitutions and/or eliminations, a global analysis of the
above information suggests that hydrogenation of haloketones
via DKR under appropriate conditions should provide a
valuable tool for the synthesis of the title compounds
(Scheme 1).
Scheme 2. Asymmetric Transfer Hydrogenation of R-Halo
Indanones and Tetralones
Scheme 1. Transfer Hydrogenation of R-Halo Ketones via
DKR; A Synthetic Route to Halohydrins
catalyst. Under these conditions (B), the desired reduction
takes place smoothly to afford cis-2-bromo-1-indanol 6 in
84% yield and with excellent ee >99% (Table 1, entry 1).
The chlorinated analogue 2 resisted even conditions A,12
leading to the desired product 7 in 88% yield, again with
excellent de and ee levels (entry 2). For comparison purposes,
conditions B were applied with similar results (entry 3).
A slow racemization of the halogen-containing stereocenter
was initially considered as a possible explanation for the long
reaction times required for completion. Though highly basic
conditions cannot be used, it was found that a slight
modification of the HCO2H/Et3N ratio has a strong influence
in the reaction rate. After a short screening, an optimum 2:1
HCO2H/Et3N ratio was found to accelerate strongly13 the
reduction of 2, affording cis chlorohydrin 7 in 83% yield
and 99% ee (entry 4).
The method was also extended to halogenated tetralones:
conditions B were applied to 2-bromotetralone 3, leading to
bromohydrine 8 with excellent diastero- and enantioselec-
tivity, but in a poor 22% yield (entry 5). Fortunately, a
satisfactory 64% yield with comparable de and ee was
achieved by increasing the amount of n-Bu4NBr to 30 mol
% (entry 6). For the chlorinated analogue 4, both the
“standard” conditions A and the modified phase transfer
conditions B afforded chlorohydrin 9 efficiently (entries 7
and 9), but best results were again observed by decreasing
the HCO2H/Et3N ratio to an optimum of 1.2:1, maintaining
excellent de and ee values in a much faster reaction13 (entry
10).
Experiments were initally performed with 2-bromo- and
2-chloro- indanones and tetralones (()-1-4 as substrates,
using the Noyori/Ikariya [RuCl(TsDPEN)(p-cymene)] cata-
lysts (R,R)- or (S,S)-I (Scheme 2) in 5:2 HCO2H/Et3N
azeotropic mixture as the solvent and hydrogen donor10
(conditions A). The alternative transfer hydrogenations from
2-propanol require a basic medium that would result in the
above-mentioned side reactions at the sensitive R-halogenated
center. On the other hand it was foreseen that the HCO2H/
Et3N system should enable the required enolization of the
substrates by bifunctional acid-basic catalysis under mild
conditions. When this strategy was applied to 2-bromoindan-
1-one 1, however, nucleophilic substitution by formate took
place to afford the undesired product 5 (Scheme 2). Based
in a recent report by Deng and co-workers,11 we performed
the reaction using aqueous HCO2Na as the hydrogen donor
in a biphasic system and n-Bu4NBr (2%) as a phase transfer
(6) (a) Ohkuma, T.; Ishii, D.; Takeno, H.; Noyori, R. J. Am. Chem. Soc.
2000, 122, 6510-6511. (b) Matsumoto, T.; Murayama, T.; Mitsuhashi, T.;
Miura, T. Tetrahedron Lett. 1999, 40, 5043-5046 (c) Mohar, B.; Valleix,
A.; Desmurs, J.-R.; Felemez, M.; Wagner, A.; Mioskowski, C. Chem.
Commun. 2001, 2572-2573. (d) Eustache, F.; Dalko, P. I.; Cossy, J. Org.
Lett. 2002, 4, 1263-1265. (e) Ohkuma, T.; Hattori, T.; Ooka, H.; Inoue,
T.; Noyori, R. Org. Lett. 2004, 6, 2681-2683. (f) Ohkuma, T.; Li, J.; Noyori,
R. Synlett 2004, 1383-1386.
The specific interest in fluorohydrins1c,14 prompted us to
study also R-fluoro ketones as substrates. Despite the singular
(7) Ros, A.; Magriz, A.; Dietrich, H.; Ford, M.; Ferna´ndez, R.; Lassaletta,
J. M. AdV. Synth. Catal. 2005, 374, 1917-1920.
(8) (a) Ben, R. N.; Durst, T. J. Org. Chem. 1999, 64, 7700-7706. (b)
Kubo, A.; Kubota, H.; Takahashi, M.; Nunami, K.-i. J. Org. Chem. 1997,
62, 5830-5837. (c) Camps, P.; Pe´rez, F.; Soldevilla, N. Tetrahedron:
Asymmetry 1998, 9, 2065-2079. (d) Caddick, S.; Afonso, C. A. M.;
Candeias, S. X.; Hitchcock, P. B.; Jenkins, K.; Murtagh, L.; Pardoe, D.;
Gil Santos, A.; Treweeke, N.; Weaving, R. Tetrahedron 2001, 57, 6589-
6605.
(9) (a) Geneˆt, J. P.; Cano de Andrade, M. C.; Ratovelomanana-Vidal,
V. Tetrahedron Lett. 1995, 36, 2063-2066. (b) Sayo, N.; Sano, N.;
Kumobayashi, H. EP 519763A2, 1992.
(10) Fujii, A.; Hashiguchi, S.; Uematsu, N.; Ikariya, T.; Noyori, R. J.
Am. Chem. Soc. 1996, 118, 2521-2522.
(11) Ma, Y.; Liu, H.; Chen, L.; Cui, X.; Zhu, J.; Deng, J. Org. Lett.
2003, 12, 2103-2106.
(12) The asymmetric Rh-catalized transfer hydrogenation of chloromethyl
ketones, unable to suffer â-eliminations, can also be performed in a similar
reaction medium: (a) Hamada, T.; Torii, T.; Izawa, K.; Noyori, R.; Ikariya,
T. Org. Lett. 2002, 4, 4373-4376. (b) Hamada, T.; Torii, T.; Izawa, K.;
Ikariya, T. Tetrahedron 2004, 60, 7411-7417.
(13) Comparison with the results reported in ref 10 reveals that the
reactions are even faster than for nonhalogenated analogues. Therefore, the
results cannot be solely explained in terms of a faster enolization of the
substrates. For a very recent study of the effect of pH in asymmetric transfer
hydrogenation of ketones in aqueous media, see: Wu, X.; Li, X.; King, F.;
Xiao, J. Angew. Chem., Int. Ed. 2005, 44, 3407-3411.
(14) (a) Maienfisch, P.; Hall, R. G. Chimia 2004, 58, 93-99. (b) Fluorine
in the Life Sciences (Special issue). ChemBioChem 2004, 5, 557-726.
128
Org. Lett., Vol. 8, No. 1, 2006

Table 1. Enantioselective Synthesis of Halohydrins via DKR
1
a Initial concentration of R-halo ketone. b 0.5 mol % unless otherwise stated. c Isolated yield. d Determined by H NMR. e Determined by HPLC unless
1
otherwise stated. f 2:1 HCO2H/Et3N used. g 30% of n-Bu4NBr used. h 1.2:1 HCO2H/Et3N used. i 0.1 mol %. j Determined by H and 19F NMR analysis of
the Mosher ester. k Determined by HPLC of the benzoate.
Org. Lett., Vol. 8, No. 1, 2006
129

reativity often exhibited by fluorinated compounds, a similar
behavior was observed in this case: transfer hydrogenation
of fluoroindanone 10 and fluorotetralone 11 proceeded via
DKR under conditions A to afford fluorohydrins 12 and 13
in excellent yields. Some trans isomers were observed in
3% and 25%, respectively (entries 11 and 14), most probably
due to the smaller steric repulsion by the fluorine atoms in
the transition states leading to trans products. The ee was
excellent for 13 (98% ee) but only moderate for 12 (74%
ee), suggesting a screening for better results. Higher dilution
resulted in better de and ee values, but much lower yields
(entries 12 and 15). Once again, the 1.2:1 HCO2H/Et3N
mixture afforded faster reactions13 and better results for 12
(92% yield, >99:1 cis/trans, 92% ee) and 13 (98% yield,
87:13 cis/trans, 96% ee); this last result was further improved
at higher dilution (0.5 M, 98% yield; 97:3 cis/trans, 97%
ee) (entries 13, 16, and 17).
lit.15 [R]25D -61.0 (c 0.62, CHCl3. (1R,2S)-7 had [R]20D -51.5
(c 0.8, CHCl3), lit.15 [R]25D -52.0 (c 0.6, CHCl3)], and those
of (1S,2R)-8 and (1R,2S)-20 were assigned by anomalous
dispersion effects in their corresponding X-ray diffraction
analysis (Figure 1).
Figure 1. X-Ray structures of (1S,2R)-8 and (1S,2R)-20.
Finally, the reactions of monocyclic substrates such as
cyclohexanone and cyclopentanone derivatives (()-14-17
were also investigated. Applying optimized conditions (B
for bromo ketones 14 and 16; A for chloro ketones 15 and
17), halohydrins 18-21 were isolated in good yields and
moderate to good ee’s, though minor amounts (7-15%) of
In conclusion, the catalytic transfer hydrogenation of
R-halo ketones via DKR appears as an efficient tool for the
synthesis of halohydrins, including bromo-, chloro-, and even
fluorohydrins. A simple tuning of the reaction conditions
allows the isolation of the desired products in good-to-
excellent yields and stereoselectivities in reasonable reaction
times.
Scheme 3. Transfer Hydrogenation of Monocyclic R-Halo
Acknowledgment. We thank the Spanish ‘Ministerio de
Ciencia y Tecnolog´ıa’ (grants CTQ2004-00290 and CTQ2004-
00241) and the ‘Junta de Andaluc´ıa’ for financial support.
A.R. and A.M. thank Bayer CropScience for predoctoral
fellowships and the donation of chemicals.
Ketones
Supporting Information Available: Experimental pro-
cedures, characterization data for new compounds, and
crystal structures for (1S,2R)-8 and (1R,2S)-20 in CIF format.
This material is available free of charge via the Internet at
http://pubs.acs.org.
trans isomers (Scheme 3) were observed in some cases
(entries 18-21).
OL052821K
The absolute configurations of (1R,2S)-6 and (1R,2S)-7
were assigned by comparison of their optical rotations with
literature data [(1R,2S)-6 had [R]20D +59.4 (c 0.75, CHCl3),
(15) Bowers, N. I.; Boyd, D. R.; Sharma, N. D.; Goodrich, P. A.;
Groocock, M. R.; Blacker, A. J.; Goode, P.; Dalton, H. J. Chem. Soc., Perkin
Trans. 1 1999, 1453-1461.
130
Org. Lett., Vol. 8, No. 1, 2006