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4 For an example see: M. R. Garnsey, D. Lim, J. M. Yost and
D. M. Coltart, Org. Lett., 2010, 12, 5234–5237.
5 (a) M. Murakata, M. Nakajima and K. Koga, J. Chem. Soc., Chem.
Commun., 1990, 1657–1658; (b) M. Imai, A. Hagihara, H. Kawasaki,
K. Manabe and K. Koga, J. Am. Chem. Soc., 1994, 116, 8829–8830;
(c) M. Imai, A. Hagihara, H. Kawasaki, K. Manabe and K. Koga,
Tetrahedron, 2000, 56, 179–185; (d) C. E. Stivala and A. Zakarian,
J. Am. Chem. Soc., 2011, 133, 11936–11939.
6 Trost and Stoltz have both described Pd-catalyzed allylic alkylation
of ketones through allyl enol carbonates and silyl enol ethers for the
introduction of an allyl group in some substrates. For example see:
(a) B. M. Trost and J. Xu, J. Am. Chem. Soc., 2005, 127, 2846–2847;
(b) B. M. Trost and J. Xu, J. Am. Chem. Soc., 2005, 127, 17180–17181;
(c) B. M. Stoltz, et al., Chem. – Eur. J., 2011, 17, 14199–14223.
7 A general method for the organocatalytic alkylation of ketones is
unknown. However MacMillan have achieved the alkylation of
aldehydes via transient chiral enamine derivatives. For example
see: (a) D. A. Nicewicz and D. W. C. MacMillan, Science, 2008, 322,
77–80; (b) T. D. Beeson, A. Mastracchio, J.-B. Hong, K. Ashton and
D. W. C. MacMillan, Science, 2007, 316, 582–585. Aldehyde alkyla-
tions have also been reported by List and Enders. For examples see:
(c) N. Vignola and B. List, J. Am. Chem. Soc., 2004, 126, 450–451;
(d) D. Enders, C. Wang and J. W. Bats, Angew. Chem., Int. Ed., 2008,
47, 7539–7542.
8 A large variation in yields is observed in the literature. The direct
alkylation of ketones occurred in consistently low yields in our
hands. For a literature example of the allylation of 3-pentanone
(o30% yield) see: G. A. Molander and C. D. Losada, J. Org. Chem.,
1997, 62, 2935–2943.
9 For an example of the use of dimethylhydrazones see: K. Surendra
and E. J. Corey, J. Am. Chem. Soc., 2008, 130, 8865–8869.
10 For a review of chiral diamines see: J. C. Kizirian, Chem. Rev., 2008,
108, 140–205.
Scheme 4 Use of an easily-prepared chiral diamine.
asymmetric alkylation rather than (or at least in addition to)
asymmetric deprotonation is operative.18 Interestingly, the low
nucleophilicity of LDA indicates that this methodology could be
extended to the a-substitution of hydrazones derived from
aldehydes, and esters.
Preliminary investigations show that easily-prepared chiral
diamines such as 1319 can mediate these transformations also
(Scheme 4). In contrast to sparteine, these ligands can be easily
modified. Optimisation of ligands such as 13 and application to
asymmetric alkylation reactions are currently underway.
In summary, to the best of our knowledge this report details
the first example of asymmetric alkylation to a non-chiral
acyclic aza(enolate). Optimisation studies involving the use of
other chiral diamines are ongoing and will be reported in due
course.
11 For a review see: D. Hoppe and T. Hense, Angew. Chem., Int. Ed.
Engl., 1997, 36, 2282–2316.
12 (a) A. Deiters and D. Hoppe, J. Org. Chem., 2001, 66, 2842–2849;
(b) P. Beak and H. Du, J. Am. Chem. Soc., 1993, 115, 2516–2518;
(c) K. M. B. Gross, Y. M. Jun and P. Beak, J. Org. Chem., 1997, 62,
7679–7689; (d) S. Wu, S. Lee and P. Beak, J. Am. Chem. Soc., 1996,
118, 715–721; (e) P. Tebben, F. Hintze and D. Hoppe, Angew. Chem.,
Int. Ed. Engl., 1990, 29, 1422–1433; ( f ) D. Stead, P. O’Brien and
A. Sanderson, Org. Lett., 2008, 10, 1409–1412; (g) D. Stead,
G. Carbone, P. O’Brien, K. R. Campos and A. Sanderson, J. Am.
Chem. Soc., 2010, 132, 7260–7261.
We thank Science Foundation Ireland (09/RFP/CHS2353)
and the Irish Research Council for funding.
Notes and references
1 (a) M. C. Kohler, S. E. Wengryniuk and D. M. Coltart, Asymmetric
a-alkylation of aldehydes, ketones, and carboxylic acids, in Stereo-
13 (a) M. J. McGrath and P. O’Brien, J. Am. Chem. Soc., 2005, 127,
16378–16379; (b) J. L. Bilke, S. P. Moore, P. O’Brien and J. Gilday,
Org. Lett., 2009, 11, 1935–1938.
selective Synthesis of Drugs and Natural Products, John Wiley & Sons. 14 A range of different cleavage methods (Amberlysts 15 hydrogen
Inc., Hoboken, NJ, 1st edn, 2013, pp. 183–213; (b) D. Enders,
L. Wortmann and R. Peters, Acc. Chem. Res., 2000, 33, 157–169;
form beads in acetone–water, copper chloride in THF and ozone in
DCM) were investigated. All gave similar enantioselectivity.
(c) A. Job, C. E. Janeck, W. Bettray, R. Peters and D. Enders, 15 G. Carbone, P. O’Brien and G. Hilmersson, J. Am. Chem. Soc., 2010,
Tetrahedron, 2002, 58, 2253–2329. 132, 15445–15450.
2 (a) K. C. Nicolaou, K. Ajito, A. P. Patron, H. Khatuya, P. K. Richter 16 Removal of this high boiling point solvent in the presence of volatile
and P. Bertinato, J. Am. Chem. Soc., 1996, 118, 3059–3060; (b) K. C. ketones proved difficult. Ketone product was lost as a result.
Nicolaou, A. P. Patron, K. Ajito, P. K. Richter, H. Khatuya, 17 A notable decrease in mass was observed upon lengthy rotary
P. Bertinato, R. A. Miller and M. J. Tomaszewski, Chem. – Eur. J.,
1996, 2, 847–868.
3 (a) D. Lim and D. M. Coltart, Angew. Chem., Int. Ed., 2008, 47,
5207–5210; (b) S. E. Wengryniuk, D. Lim and D. M. Coltart, J. Am.
evaporation.
18 For a thorough discussion of the origins of enantioselectivity in
related systems see: P. Beak, A. Basu, D. J. Gallagher, Y. S. Park and
S. Thayumanavan, Acc. Chem. Res., 1996, 29, 552–560.
Chem. Soc., 2011, 133, 8714–8720. Coltart’s methodology also 19 See ref. 12f for an example of the use of diamine 13 in asymmetric
elegantly allows for a,a0-bisalkylation.
deprotonation reactions.
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