Journal of the American Chemical Society
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This last example proves the utility of the method herein
Supporting Information
1
2
3
4
5
6
7
8
described. If the reaction had been optimized using 1 or 10
mol%, acid would have been incorrectly employed as addi-
tive also for the reaction with 0.1 mol% of catalyst. Even if the
reaction with 0.1 mol% had been optimized independently, a
single addition of base would have been insufficient to com-
plete the reaction. In both scenarios, the conclusion would
have been that the reaction cannot be completed with such a
small amount of catalyst.
The Supporting Information is available free of charge on the
ACS Publications website. Characterization of the catalytic
species and kinetic profiles by NMR; experimental procedure
for the construction of the ternary contour maps and for the
map-assisted reaction optimization.
AUTHOR INFORMATION
Corresponding Author
Finally, in order to prove the potential of the method beyond
NMR scale, we applied it in a gram-scale reaction with non-
deuterated solvent (Figure 4). We run a reaction with 5
mmol of dimethyl malonate 2a, 10 mmol of undistilled cin-
namaldehyde 1, and 1 mol% of catalyst I in ACS grade meth-
anol. The distribution of catalytic species was measured by
no-D NMR12 of an aliquot of the reaction. The correct addi-
tive and its amount were decided as described previously
(Figure 4, green triangles). Then, the proportional amount of
triethylamine was added to the main batch of the reaction
and it was confirmed that the distribution of catalytic species
was the expected one (Figure 4, blue square). Without fur-
ther modification, the reaction reached full conversion in 4
h, affording 1.16 g of the Michael adduct 3a (80% isolated
yield) with 92% ee.6
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Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
The research leading to these results has received funding
from the European Union FP7/2007-2013 under grant agree-
ment n⁰ PCIG 13-GA-2013-618589 (J.B.) and PIEF-GA-2013-
627895 (X.C.), from the IC JRF scheme (J.B.), and from The
University of Manchester (J.B.).
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