Highly regioselective Lewis acid-mediated aldol additions at the more encumbered α-side of unsymmetrical ketones

Full text of DOI:10.1021/ja973453l

J. Am. Chem. Soc. 1998, 120, 413-414
413
Communications to the Editor
Scheme 1
Highly Regioselective Lewis Acid-Mediated Aldol
Additions at the More Encumbered r-Side of
Unsymmetrical Ketones
Rainer Mahrwald* and Bilgi Gu¨ndogan
Institut fu¨r Organische und Bioorganische
Chemie der Humboldt-UniVersita¨t
Hessische Strasse 1-2, D-10 115 Berlin, Germany
ReceiVed October 3, 1997
Scheme 2
Regioselective reactions of enolates of unsymmetrical ketones
are of fundamental importance in organic synthesis, the most
familiar reactions being R-alkylations,1 aldol additions,2 and the
Michael addition.3 An unsymmetrical ketone can form the two
regioisomeric enolates 1 and 2 upon deprotonation (Scheme 1).2a,4
The deprotonation of unsymmetrical ketones results in the less
substituted enolate 1 by irreversible kinetic control, whereas those
reactions under thermodynamical control usually yield the more
substituted product 2. The latter product is produced during an
equilibrium with moderate regioselectivity.5 In the more favorable
cases, one regioisomer can greatly predominate in the equilibrium
mixture, but often the equilibrium constant is not sufficiently high
enough to achieve an acceptable regioselectivity. Furthermore,
even if one prepares a regiodefined enolate, problems may occur
with proton-transfer.6 There do exist a few methods for generating
the more-substituted enolates with high selectivity,7 but examples
of high regioselectivity obtained with these reactions are rare.
Table 1. Regioselective Aldol Addition of Unsymmetrical Ketones
Recently, Yamamoto et al. have described a case of high
regioselectivity obtained with R-alkylation. The reaction occurs
at the more hindered R-side of unsymmetrical ketones, through
the use of bulky aluminum alkoxides in the presence of lithium
diisopropylamide.8
We describe here a very simple and efficient method for the
direct aldol addition of aldehydes at the encumbered R-side of
unsymmetrical ketones. In the presence of substoichiometric
quantities of TiCl4, reactions of ketones with aldehydes at room
(1) Caine, D. In ComprehensiVe Organic Synthesis; Trost, B. M., Ed.;
Pergamon Press: Oxford, 1991; Vol. 3, pp 1-64.
(2) (a) Heathcock, C. H. In Modern Synthetic Methods 1992; Scheffold,
R., Ed.; VCH: Weinheim, 1992; pp 1-102. (b) Braun, M. In Houben-Weyl,
StereoselectiVe Synthesis; Helmchen, G., Hoffmann, R. W., Mulzer, J.,
Schaumann, E., Eds.; G. Thieme: Stuttgart, 1995; Vol. 21b, pp 1603-1735.
(c) Heathcock, C. H. In ComprehensiVe Organic Synthesis; Trost, B. M., Ed.;
Pergamon Press: Oxford, 1991; Vol. 2; pp 181-258.
(3) (a) Jung, M. E. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Ed.; Pergamon Press: Oxford, 1991; Vol. 4; pp 1-68. (b) Yamamoto, Y. In
Houben-Weyl, StereoselectiVe Synthesis; Helmchen, G., Hoffmann, R. W.,
Mulzer, J., Schaumann, E., Eds.; G. Thieme: Stuttgart, 1995; Vol. 21b, pp
2041-2155.
a The carbon atoms indicated with an asterisk are the encumbered
1
R-side. b Ratios were determined by H and 13C NMR (CDCl3, 300
MHz) on the crude material. c For a representative aldol addition see
ref 9c.
(4) Meckelburger, H. B.; Wilcox, C. S. In ComprehensiVe Organic
Synthesis; Trost, B. M., Ed.; Pergamon Press: Oxford, 1991; Vol. 2, pp 99-
132.
temperature resulted in high syn selectivity and good yields of
3-hydroxy ketones (Scheme 2).9
(5) (a) Negishi, E.; Matsushita, H.; Chatterjee, S.; John, R. A. J. Org. Chem.
1982, 47, 3188-3190. (b) Krafft, M. E.; Holton, R. A. J. Org. Chem. 1984,
49, 3669-3670.
These reactions were carried out in the absence of base, in
contrast to the previously reported method by Evans (TiCl4 and
base).10 Ketones are used directly in this reaction: no formation
of the activated corresponding silyl enol ether is required. As
an example, the TiCl4-mediated reaction of methyl ethyl ketone
with aldehydes gave a highly syn selective and high regioselective
(6) Patterson, J. W.; Fried, J. H. J. Org. Chem. 1974, 47, 2506-2509.
(7) (a) Yamago, S.; Machii, D.; Nakamura, E. J. Org. Chem. 1991, 56,
2098-2106 and references cited therein. (b) Ando, A.; Miura, T.; Tatematsu,
T.; Shiori, T. Tetrahedron Lett. 1993, 34, 1507-1510. (c) Noyori, R.; Nishida,
I.; Sakata, J. J. Am. Chem. Soc. 1983, 105, 1598-1608 and references cited
therein. (d) Duhamel, P.; Cahard, D.; Quesnel, Y.; Poirier, J.-M. J. Org. Chem.
1996, 61, 2232-2235. (e) Toru, T.; Wakayama, T.; Watanabe, Y.; Ueno, Y.
Phosphorus Sulfur Silicon 1992, 67, 253-256. (f) Szymoniak, J.; Lefranc,
H.; Besancon, J.; Moise, C. Synthesis 1995, 815-819.
(8) Saito, S.; Ito, M.; Yamamoto, H. J. Am. Chem. Soc. 1997, 119, 611-
612.
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414 J. Am. Chem. Soc., Vol. 120, No. 2, 1998
Communications to the Editor
aldol addition at the more encumbered R-side of the ketone
(Scheme 2). To widen the applicability of our results, reactions
utilizing various unsymmetrical ketones were conducted with the
obtained results summarized in Table 1. Excellent discrimination
between the more hindered R-side and the less-substituted R-side
of the ketone was also observed.
unsually high regioselectivity can be interpreted from observations
made by aldol additions of aldehydes to functionalized unsym-
metrical ketones in the presence of substoichiometric amounts
of TiCl4. For example, no aldol addition occurs at all by reacting
2.4-pentanedione or fluoracetone with benzaldehyde. These
ketones are too acidic for this reaction, due to their electron-
withdrawing substituents. Furthermore, aldol addition at the
unsubstituted R-side, through the reaction of 1-chloro-3-pentanone
with benzaldehyde, resulted in only poor yields under our
conditions. These results indicate the predominance of electronic
effects in the regioselective outcome of this reaction. The aldol
addition of aldehydes appears to occur at the less electronegative
R-side of unsymmetrical ketones or, from the stereochemical point
of view, at the more hindered and substituted R-side.
The mechanism involved in this reaction still remains unknown,
but investigations are currently in progress. Nonetheless, the
(9) (a) Mahrwald, R. Chem. Ber. 1995, 128, 919-921. (b) Mahrwald, R.
GIT 1996, 40, 43-44. (c) Benzaldehyde (1.0 mL, 10 mmol) and 3-heptanone
(1.4 mL, 10 mmol) were dissolved in 20 mL of anhydrous toluene. Under
inert conditions 110 µL (1 mmol) of titanium(IV) chloride was added dropwise
to this solution at room temperature. The solution was stirred for 16 h at
room temperature. After that time, 50 mL of diethyl ether was added and the
organic phase was rapidly extracted with water until the water phase was
neutral. The organic layer was separated and dried (Na2SO4) and the filtrate
concentrated in vacuo. The syn/anti ratio and the ratio of regioselectivity of
In conclusion, high regioselective addition of aldehydes at the
more encumbered R-side of unsymmetrical ketones was achieved
in a TiCl4-mediated aldol addition.
1
the crude aldol product was determined by H and 13C NMR spectroscopy.
(10) Evans, D. A.; Rieger, D. L.; Bilodeau, M. T.; Urpi, F. J. Am. Chem.
Soc. 1991, 113, 1047-1049.
(11) Chow, H.-F.; Seebach, D. HelV. Chim. Acta 1986, 69, 604-614.
(12) Masamune, S.; Mori, S.; van Horn, D.; Brooks, D. W. Tetrahedron
Lett. 1979, 20, 1665-1668.
Acknowledgment. This work was supported by the Deutsche
Forschungsgemeinschaft and the Fonds der Chemischen Industrie.
(13) Hoffmann, R. W.; Ditrich, K.; Fro¨bel, S. Liebigs Ann. Chem. 1987,
977-985.
JA973453L
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