4
Tetrahedron
experiment in CH2Cl2 produced any trace of the cinnamate.
Table 4. Reaction of Esters and Amides with Benzaldehyde
Nonetheless, deprotection of the observed silyl ether with ethanol
and trifluoroacetic acid yielded -hydroxyester 4 in 81% yield
from ethyl acetate (eq 9). The failure of this very electron-poor
substrate11 to undergo elimination suggests that elimination may
proceed via an E1 mechanism; the required carbocation derived
from the trifluoromethylated product would be especially
unstable and difficult to form. In addition, coordination of the
silyl ether oxygen to TMSOTf (or another Lewis acid) may also
be slowed by the nearby electron-poor aromatic ring, which
would slow the elimination step regardless of the mechanism.
The result illustrated in eq 10 does stand in some contrast with
entry
product
yield (%)b
X
MeO
i-PrO
PhO
TMSO
Me(MeO)N
1
2
3
4
5
79
85
27
94c
93
3g
3h
3i
3j
5
the
reaction
of
acetophenone
with
4-
a. Reaction conditions: ester or amide (1.0 mmol),
benzaldehyde (1.2 mmol), i-Pr2NEt (1.2 mmol), TMSOTf (2.2
mmol), CH2Cl2 (2.5 mL), rt, 16 h. See Supporting Information
for details.
(trifluoromethyl)benzaldehyde (Table 1, entry 5), for which the
chalcone product is observed. The difference between the 4-
(trifluoromethyl)benzaldehyde results for ethyl acetate and
acetophenone suggest that both stabilization of carbocationic
character at the position and the acidity of the position
influence the progress of the reaction. While these characteristics
are consistent with an E1 reaction mechanism, they do not rule
out an E2 pathway or an E1cb pathway that proceeds via an enol
silane.
b. isolated yield after chromatography
c. Isolated as the carboxylic acid, contaminated with <5% of
an unidentified impurity.
In conclusion, the one-pot enol silane formation-Mukaiyama
aldol reaction has been shown to provide different types of aldol
products depending upon the stoichiometry of the TMSOTf. Past
experiments have shown that when the amine base is in excess of
the TMSOTf, the -silyloxycarbonyl forms in high yield. The
current work shows that an excess of TMSOTf with respect to
amine base efficiently yields the ,-unsaturated carbonyl. The
reaction appears to be general to aryl alkyl ketones, acetate
esters, and most unsaturated aldehydes.
Given the success with ethyl acetate, the reaction of
benzaldehyde in other convenient ester solvents was attempted.
Both methyl acetate and isopropyl acetate were suitably reactive
(eq 10), but neither approached the success of ethyl acetate.
Indeed, simple replacement of ethyl acetate with either methyl
acetate or isopropyl acetate under otherwise identical reaction
conditions as those described in Table 3 resulted in low
Acknowledgments
We thank the National Science Foundation RUI program
(CHE-1057591) and The Camille and Henry Dreyfus Foundation
for funding. A.T. gratefully acknowledges University of
Richmond Department of Chemistry for a summer fellowship.
conversions.
After some further experimentation, it was
discovered that incubation of the ester with TMSOTf and i-
Pr2NEt for fifteen minutes prior to addition of the aldehyde
provided significantly higher yields. Nonetheless, it appears that
ethyl acetate is an optimal substrate: First, it lacks the steric
encumbrance of isopropyl acetate. More subtly, the ammonium
salt byproducts generated under the reaction conditions appear to
be more soluble in methyl acetate than in ethyl acetate, which
may help drive the ethyl acetate reaction to higher conversion.
References and notes
1.
2.
For recent reviews, see: (a) Bukhari SNA, Jasamai M, Jantan I,
Ahmad W Mini-Rev. Org. Chem. 2013; 10; 73-83; (b) Liu S, You
H Eur. Chem. Bull. 2013; 2; 76-77.
(a) Mukaiyama T, Banno K, Narasaka K J. Am Chem. Soc. 1974;
96; 7503-7509; For conversion of enol silanes to chalcones, see:
(b) Boyer J, Corriu RJP, Perz R, Reye C J. Organomet. Chem.
1980; 184; 157-166; (c) Ishihara K, Kurihara H, Yamamoto H
Synlett 1997; 597-599; (d) Mashraqui SH, Kellogg RM J. Org.
Chem.1984; 49; 2513-2516; (e) Sutar RL, Joshi NN Ind. J. Chem.,
Sect. B 2014; 53B; 1553-1560; (f) Slough GA, Bergman RG,
Heathcock CH J. Am. Chem. Soc. 1989; 111, 938-949. For a
relevant review, see: (g) Palomo C, Oiarbide M, Garcia JM Chem.
Eur. J. 2002; 8; 36-44.
When CH2Cl2 was employed as the reaction solvent, these
were again suitably reactive as shown in Table 4 (entries 1 and
2).13 When phenyl acetate was employed, poor conversion and
multiple unidentified byproducts were observed. Morever,
product 3i proved unstable to chromatography, and only a small
amount could be isolated (entry 3). On the other hand,
employment of trimethylsilyl acetate as the enolate precursor3c
was very successful, providing cinnamic acid as the product in
excellent yield (entry 4). Finally, extension of this method to the
convenient Weinreb amide proceeded very well, yielding the
cinnamide with great efficiency (entry 5).
3.
(a) Downey CW, Johnson MW Tetrahedron Lett. 2007; 48; 3559-
3562; (b) Downey CW, Johnson MW, Tracy KJ J. Org. Chem.
2008; 73; 3299-3302; (c) Downey CW, Johnson MW, Lawrence
DH, Flesher AS, Tracy KJ J. Org. Chem. 2010; 75; 5351-5354;
(d) Downey CW, Dombrowski CM, Maxwell EN, Safran CL,
Akomah OA Eur. J. Org. Chem. 2013; 5716-5720; (e) Downey
CW, Ingersoll JA, Glist HM, Dombrowski CM, Barnett AT Eur.
J. Org. Chem. 2015; 7287-7291; (f) Downey CW, Johnson MW
Tetrahedron Lett. 2018; 59; 1268.
For examples of intramolecular versions of this reaction that
predate our own work, see: (a) Hoye TR, Dvornikovs V, Sizova E
Org. Lett. 2006; 8; 5191-5194; (b) Rassu G, Auzzas L, Pinna L,
Zombrano V, Battistini L, Zanardi F, Marzocchi L, Acquotti D,
Casiraghi G J. Org. Chem. 2001; 66; 8070-8075.
4.
5.
The dehydration of -hydroxycarbonyl compounds to yield
chalcones in the presence of acids is well precedented, as
highlighted in reference 2c.