Catalytic conjugate addition of acyl anion equivalents promoted by fluorodesilylation

Article abstract of DOI:10.1021/ol403041k

The conjugate addition of acyl anion equivalents derived from 2-silyl-1,3-dithianes to α,β-unsaturated ketones and esters has been achieved using a substoichiometric amount of TBAF. High yields and short reaction times are observed for the addition of aryl-1,3-dithianes to a variety of cyclic and acyclic α,β-unsaturated carbonyl acceptors. Observation of the reactive anion by ¹³C NMR spectroscopy and extension to an asymmetric variant is also presented.

Full text of DOI:10.1021/ol403041k

Letter
pubs.acs.org/OrgLett
Catalytic Conjugate Addition of Acyl Anion Equivalents Promoted by
Fluorodesilylation
Scott E. Denmark* and Lindsey R. Cullen
Roger Adams Laboratory, Department of Chemistry, University of Illinois, 600 South Mathews Avenue, Urbana, Illinois 61801,
United States
S
* Supporting Information
ABSTRACT: The conjugate addition of acyl anion equivalents derived from 2-silyl-1,3-dithianes to α,β-unsaturated ketones and
esters has been achieved using a substoichiometric amount of TBAF. High yields and short reaction times are observed for the
addition of aryl-1,3-dithianes to a variety of cyclic and acyclic α,β-unsaturated carbonyl acceptors. Observation of the reactive
anion by 13C NMR spectroscopy and extension to an asymmetric variant is also presented.
he natural reactivity pattern of carbonyl compounds leads
to the ready construction of consonant or odd functional
equivalents using fluorodesilylation.8a−c Generation of nucleo-
philes by catalytic fluorodesilylation has been successful in a
variety of contexts, including carbonyl allylation,8d alkynyla-
tion,8e trifluoromethylation,8f and Mukaiyama aldol reactions.8g
These methods are operationally simple and use readily
available quaternary ammonium fluoride salts (e.g., TBAF) as
catalysts. The method reported herein extends fluorodesilyla-
tion to the reaction of sulfur-stabilized high pKa anions as acyl
anion equivalents.9 Similar to the Stetter reaction, this method
is catalytic but retains the high reactivity of stoichiometric
lithio-acyl anion equivalents, allowing for the addition of acyl
anions to less reactive, cyclic Michael acceptors. Additionally,
the products derived from this method are partially protected,
allowing differentiation between the two carbonyl moieties.
Initial investigation focused on the conjugate addition of
(trimethylsilyl)phenyldithiane (1a) to 2-cyclohexenone (2a)
promoted by a substoichiometric amount of tetrabutylammo-
nium fluoride trihydrate (Table 1). Gratifyingly, exclusive 1,4-
addition was observed for this reaction. The amount of
silyldithiane was important because of partial quenching of the
active carbanion by the water introduced from TBAF. An
equimolar ratio of silyl dithiane to enone resulted in only
moderate yields of 3a (entry 1) due to competitive addition of
the intermediate enolate (ii, see Scheme 2) to 2a. A slight
excess of dithiane 1a (1.5 equiv) resulted in nearly quantitative
conversion to the desired product after 30 min at −78 °C
(entry 2). Increasing the quantity of 1a further was not
beneficial (entry 3). To our surprise, the loading of fluoride
could be reduced as low as 0.5 mol % (entires 4−7) with no
impact on the yield. This is especially advantageous for the
potential application of chiral, nonracemic, quaternary
ammonium fluoride catalysts.
T
group relationships. To access dissonant or even relationships
with carbonyl compounds requires charge-affinity inversion or
umpolung.1a A classic application of this concept concerns the
construction of 1,4-dicarbonyl compounds.1b In this case, a new
carbon−carbon bond can be formed by inducing an electro-
phile (aldehyde) to react as a nucleophile at the carbonyl
carbon (acyl anion) with α,β-unsaturated carbonyl acceptors.
The prevalence of the 1,4-dicarbonyl motif in natural
products,1c,d as well as their pivotal role in the construction
of aromatic heterocycles,1e−g has stimulated the development of
methods for their construction.
Current approaches to the synthesis of 1,4-dicarbonyl
compounds include transition-metal hydroacylation,2 acyl
radical additions,3 and umpolung based methods.1a Classical
umpolung methods focus on derivatization of an aldehyde to an
acyl anion equivalent (e.g, 1,3-dithiane,4 cyanohydrin5),
followed by stoichiometric deprotonation using a strong base.
Conjugate addition of these organolithium species to α,β-
unsaturated acceptors is often plagued by competitive 1,2-
addition. High selectivity for the 1,4-addition product requires
use of stoichiometric additives such as HMPA6a or copper
salts6b or more stabilized anionic equivalents.6c More recently,
the Stetter reaction has been developed as an alternative
method for the catalytic generation of acyl anion equivalents
under mild conditions using NHC catalysts.7 Despite significant
development, the Stetter reaction still suffers from limitations
because of the lower nucleophilicity of the Breslow
intermediate.7d Most methods require activated acyclic Michael
acceptors (i.e., alkylidene malonates, nitroalkenes, etc.) and are
particularly sensitive to steric effects. Additions to simple cyclic
acceptors are rarely reported.7e
To expand the scope of acyl anion chemistry, a research
program was initiated for the catalytic generation of acyl anion
Received: October 22, 2013
Published: December 11, 2013
© 2013 American Chemical Society
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a
2-substituted (1c) aryldithianes also participated. The corre-
sponding aldehydes of these substrates are nonoptimal
substrates in the analogous Stetter reaction.
Table 1. Optimization of Silyl Phenyl Dithiane Addition
A number of α,β-unsaturated carbonyl acceptors did not
participate successfully under the optimized reaction conditions
(Figure 1). Competitive 1,2-addition was observed for α,β-
unsaturated ester 5 and aldehyde 6, and the optimized reaction
conditions resulted in recovered starting material.10 Highly
electrophilic acceptors 7 and 8, which are effective substrates
for Stetter reactions, are unreactive because of the inability of
the stabilized metallo-ketenimine or enolate anions to desilylate
the starting silyl dithiane. This may allow for chemoselective
reactions of multi acceptor-containing substrates which are not
possible with current methods. The reactive acyl anion is also
significantly basic (pKa ∼ 30) and methyl enones such as 9
undergo enolization to the corresponding silyl enol ethers.
b
c
entry
equiv of 1a
equiv of TBAF (mol %)
yield (%)
1
2
3
4
5
6
7
1.0
1.5
2.0
1.5
1.5
1.5
1.5
10
10
10
5
58
94
91
92
96
91
96
2.5
1
0.5
a
All reactions were performed on a 0.25 mmol scale in THF [0.08 M]
at −78 °C for 30 min, followed by quenching with 2 M Cl3CCO2H in
b
c
THF. Equivalents based upon 2a. Isolated yield of chromato-
graphically homogeneous material.
With optimized conditions in hand, the conjugate addition of
arylsilyldithianes (1a−c) to a variety of α,β-unsaturated
carbonyl acceptors (2a−l) was explored (Table 2). Excellent
yields were obtained for additions to cyclic enones, including
five- and seven-membered rings (3b and 3c, respectively). In
view of the high reactivity of the intermediate anion, sterically
encumbered enones (3d and 3e) were also viable substrates,
although extended reaction times or elevated temperatures
were necessary. The addition to (R)-carvone proceeded with
excellent yield, although 3f was obtained as a mixture of
diastereomers. Additions to acyclic (3g) and benzo-fused (3h)
enones proceeded uneventually, and enoate substrates such as
coumarin (3i) and methyl cinnamate (3j) were also reactive,
albeit requiring longer reaction times. Electron-poor (1b) and
Figure 1. Unsuccessful Michael acceptors.
Attempts to extend this method to alkylsilyldithiane
substrates met with difficulty. The increase in pKa for
alkyldithianes resulted in enolization of 2a. Conjugate addition
may be favored by increasing the stabilization of the anion by
partial oxidation of the dithiane moiety. Thus, monosulfone
substrate 1d was prepared.11 The 4,4-diethyl variant of the
dithiane was employed to suppress deprotonation at C(3).
Gratifyingly, reaction of 1d with 2a under the optimized
reaction conditions led to exclusive 1,4-addition (Scheme 1) to
a,b
Table 2. Reaction Scope of Aryl 2-Silyl-1,3-dithiane Conjugate Addition
a
All reactions were performed on a 1.0 mmol scale of 2 with 1.5 equiv of 1 in THF [0.08 M] at −78 °C, followed by quenching with 2 M
b
c
d
Cl3CCO2H in THF. Yields refer to chromatographically homogeneous, isolated products. Reaction performed at 0 °C. Yield refers to a mixture of
three diastereomers. Yield of recrystallized material after column chromatography.
e
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Letter
give differentially protected 1,4-diketone 3m in near-quantita-
tive yield.
Scheme 3. Conjugate Addition Utilizing Chiral Fluoride
Catalyst
a
a
Scheme 1. Application to Alkyl Acyl Anion Surrogates
a
See the Supporting Information for experimental details.
a
See the Supporting Information for experimental details.
The proposed catalytic cycle is initiated by fluorodesilylation
of the 2-silyldithiane to generate a sulfur-stabilized dithianyl
anion (i) (Scheme 2). Conjugate addition of this anion to an
α,β-unsaturated carbonyl compound results in the generation of
an ammonium enolate (ii), which then regenerates the reactive
dithianyl anion by silylation to form the silyl enol ether (iii) of
the 1,4-adduct. Acidic workup of the reaction furnishes the
conjugate addition product as a masked 1,4-dicarbonyl
compound. Thus, this process is initiated by fluoride but the
enolate is responsible for catalytic turnover. Because the
quaternary ammonium counterion is conserved throughout the
cycle, the possibility for asymmetric induction using a chiral,
nonracemic ammonium fluoride salt becomes apparent.
(dimethylamino)sulfonium difluorotrimethylsilicate), previ-
ously used by Reich et al. was more successful.12 The dramatic
changes in the chemical shifts observed indicate significant
charge delocalization into the benzene ring (Scheme 4). The
upfield shifts in the ortho and para carbon signals (indicated by
green lines) match the similar carbon shifts for the HMPA-
solvent separated 2-lithio-2-phenyldithiane (117.5 ppm and
104.1 ppm, respectively)13 providing strong evidence that this
reaction proceeds through an ion-pair intermediate.
Scheme 4. 13C NMR Spectroscopic Observation of Dithianyl
a
Anion
Scheme 2. Proposed Mechanism of Catalytic Conjugate
Addition of Dithianyl Anions
Accordingly, chiral, nonracemic ammonium fluoride catalysts
based upon the cinchona alkaloid scaffold were examined.
Fluoride catalyst 10 was prepared from the corresponding
quaternary ammonium bromide salt by ion exchange
chromatography. The salt was obtained as a stable, free-
flowing, hydroscopic powder when isolated as a methanol
solvate (see the Supporting Information for details). Although
catalyst 10 effected the 1,4-addition for a variety of substrates,
only modest enantioenrichment was evident (Scheme 3).
Optimization of the chiral catalyst is ongoing.
Finally, the structure of the dithianyl nucleophile was probed
using 13C NMR spectroscopy to distinguish a free anion from a
hypervalent silicate species. Initial attempts to observe the ion
pair with the standard fluoride catalyst (TBAF·3H2O) proved
unsuccessful because of rapid protonation of the anion by
water. The anhydrous fluoride source, TAS-F (tris-
a
Reaction performed on a 0.13 mmol scale in a 5-mm NMR tube in
THF-d8 [0.19 M] at −78 °C.
In conclusion, the addition of acyl anion equivalents to
unactivated α,β-unsaturated ketones and esters using a
fluorodesilylation strategy has been developed. This method
is operationally simple and uses a readily available quaternary
ammonium fluoride salt as the catalyst. The masked 1,4-
diketone products were obtained in excellent yields and with
short reaction times. This method is complementary in scope
to existing methods for the synthesis of 1,4-dicarbonyl
compounds. Preliminary results are promising in the expansion
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(e) Capperucci, A.; Cere,
Pollicino, S. Synlett 2002, 1447.
̀
V.; Degl’Innocenti, A.; Nocentini, T.;
of scope to alkyl-acyl anion equivalents as well as for
development of an asymmetric variant.
(10) Under optimized conditions (3 mol % TBAF, THF, −78 °C, 7
h) very poor conversion to the 1,2-adduct was observed (9%) for
substrate 6. Increased fluoride loading (10 mol % TBAF) allowed for
full conversion of the starting material, yielded the 1,2-adduct in 80%
yield. See the Supporting Information for full details. Addition of
dithianyl nucleophiles to aromatic aldehyde acceptors is known to be
promoted by a substoichiometric amount of a Lewis based additive;
see ref 9c,d.
ASSOCIATED CONTENT
* Supporting Information
Full experimental procedures, analyses, characterization data,
and NMR data. This material is available free of charge via the
Internet at http://pubs.acs.org.
■
S
(11) Preparation adapted from the following precedent: (a) Carlson,
R. M.; Helquist, P. M. J. Org. Chem. 1968, 33, 2596. (b) Gokel, G. W.;
Gerdes, H. M.; Dishong, D. M. J. Org. Chem. 1980, 45, 3634. See the
Supporting Information for details.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: sdenmark@illinois.edu.
(12) Biddle, M. M.; Reich, H. J. J. Org. Chem. 2006, 71, 4031.
(13) For NMR studies of lithio-dithianes, see: (a) Abatjoglou, A. G.;
Eliel, E. L.; Kuyper, L. F. J. Am. Chem. Soc. 1977, 99, 8262. (b) Juaristi,
Notes
The authors declare no competing financial interest.
́
E.; Cruz-Sanchez, J. S.; Ramos-Morales, F. R. J. Org. Chem. 1984, 49,
ACKNOWLEDGMENTS
We are grateful to the W. M. Keck Foundation for generous
financial support.
4912. (c) Reich, H. J.; Borst, J. P.; Dykstra, R. R. Tetrahedron 1994, 50,
■
5869.
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