Organic Letters
Letter
a
catalyst loadings while maintaining high yields. With adjust-
ments to concentration and reaction time, lower catalyst
loadings could be used with minimal loss in yield (entry 5).
TBBol and most of the methyl aniline are easily recoverable
upon purification, allowing for recycling.
Scheme 6. Nucleophile Variation with Relay Catalysis
Products like alkynyl enones 3g can be difficult to reliably
access and control, which is likely why there have only been
three reports of their use for enantioselective conjugate
additions.20 We found that these compounds could be
enantioselectively transformed into β-branched ketones by
subsequently using a chiral diol catalyst (Scheme 7). Although
Scheme 7. Enantioenriched Double Addition Products
a
b
c
Isolated yields. Reaction time 48 h. 1 equiv of LiBr for 6 h.
3g was formed in only 6 h from the alkynyl ketone (Scheme 6) or
48 h from the vinylogous amide (Scheme 3), the addition of the
second nucleophile to give 8 required 3 days for high conversion
with 96:4 er. This comparison clearly demonstrated the greater
reaction completion time for enones relative to vinylogous
amides. To our knowledge, there are no enantioselective reports
for the formation of β-alkynyl/β-alkenyl ketones.
In conclusion, a previously inaccessible conjugate addition
reaction has been formulated, and we present the first report of
organocatalyzed vinylogous substitution of vinylogous amides
and esters to provide conjugated β-substituted enones. We have
exploited this reactivity for relay catalysis to use propargyl
ketones directly. These transformations are catalyzed by an
easily accessed brominated biphenol organocatalyst, TBBol.
The organodiol and trifluoroborate nucleophiles perform the
equivalent transformation as transition metal cross-couplings,
but with increased functional group tolerance as proven by a
Glorius-inspired study. This method allows inclusion of a variety
of unsaturated substituents, including heteroaromatics and
alkynes. We are now applying this methodology to the synthesis
of more complex structures and of cross-conjugated organic
polymers.
Scheme 4), but almost all vinyl and some alkynyl trifluor-
oborates gave good yields. This was supported by the
observation that naphthyl nucleophiles, which have less
aromatic stabilization, produced higher yields.7 Aryl substitution
for styrenyl nucleophiles did not significantly affect yields (3b−
3d). Yields could be increased by individual optimization; for
example, increasing the reaction time to 48 h increased the yield
for 3g. Lithium bromide, previously used in conjugate additions
with aromatic nucleophiles, allowed formation of the β-
phenylenone 3e. The only example that performed worse in
the relay catalysis was diene 3f. Generally, the strength of this
method lies in accommodating heterocycles, alkynes, and other
sensitive functional groups that are problematic for other
strategies. Functional group tolerance was assessed as described
by Glorius,19 showing high tolerance in nearly all cases.17
Though a few functional groups were less tolerant of elevated
temperatures, this reaction experiences only minor reductions in
yield when the temperature is decreased as low as 50 °C, so
thermally sensitive groups could be preserved with an increase in
reaction time.17
This transformation excelled on a larger scale, with a nearly
quantitative yield on a 2 mmol scale (Table 3, entry 1). We note
that the conditions reported in Scheme 6 were broadly
applicable for a successful reaction. Table 3 demonstrates that,
for an individual substrate reaction, optimization allows for low
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
Table 3. Scale up and Optimization of a Specific Substrate
Experimental details and spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Jeremy A. May − Department of Chemistry, University of
Houston, Houston, Texas 77204-5003, United States;
TBBol
loading
PhNHMe
loading
a
entry
scale
concn
time yield
1
2
3
4
5
2 mmol
2 mmol
2 mmol
5 mmol
5 mmol
20 mol %
10 mol %
5 mol %
10 mol %
10 mol %
40 mol %
10 mol %
5 mol %
20 mol %
20 mol %
0.1 M
0.5 M
0.5 M
0.5 M
0.5 M
6 h
14 h
14 h
6 h
95%
Authors
60%
49%
55%
88%
Sasha Sundstrom − Department of Chemistry, University of
Houston, Houston, Texas 77204-5003, United States
Thien S. Nguyen − Department of Chemistry, University of
Houston, Houston, Texas 77204-5003, United States;
42 h
a
Isolated yields.
D
Org. Lett. XXXX, XXX, XXX−XXX