Enantiodivergent Synthesis of Tertiary α-Aryl 1-Indanones: Evidence Toward Disparate Mechanisms in the Palladium-Catalyzed Decarboxylative Asymmetric Protonation

Article abstract of DOI:10.1021/acs.joc.7b00303

Herein, we describe a study into the scope and origin of an enantiodivergent effect in the palladium-catalyzed decarboxylative asymmetric protonation. By switching the achiral proton source, both enantiomers of a series of tertiary α-aryl-1-indanones are readily accessed from the corresponding α-aryl-β-keto allyl esters. In this example of dual stereocontrol, enantioselectivities up to 94% (S) and 92% (R) were achieved using Meldrum's acid and formic acid, respectively. In an attempt to rationalize this switch in absolute configuration an investigation of the ambiguous mechanism of the decarboxylative asymmetric protonation was conducted. A novel catalytic cycle for the reaction with formic acid is proposed and subjected to a variety of experimental studies.

Full text of DOI:10.1021/acs.joc.7b00303

Article
pubs.acs.org/joc
Enantiodivergent Synthesis of Tertiary α‑Aryl 1‑Indanones: Evidence
Toward Disparate Mechanisms in the Palladium-Catalyzed
Decarboxylative Asymmetric Protonation
Cian Kingston and Patrick J. Guiry*
Synthesis and Solid State Pharmaceutical Centre, Centre for Synthesis and Chemical Biology, School of Chemistry, University
College Dublin, Belfield, Dublin 4, Ireland
S
* Supporting Information
ABSTRACT: Herein, we describe a study into the scope and origin of an enantiodivergent effect in the palladium-catalyzed
decarboxylative asymmetric protonation. By switching the achiral proton source, both enantiomers of a series of tertiary α-aryl-1-
indanones are readily accessed from the corresponding α-aryl-β-keto allyl esters. In this example of dual stereocontrol,
enantioselectivities up to 94% (S) and 92% (R) were achieved using Meldrum’s acid and formic acid, respectively. In an attempt
to rationalize this switch in absolute configuration an investigation of the ambiguous mechanism of the decarboxylative
asymmetric protonation was conducted. A novel catalytic cycle for the reaction with formic acid is proposed and subjected to a
variety of experimental studies.
presence of molecular sieves in the reaction mixture and are not
a comment on the nature of the reaction. Similar monocyclic
and fused aromatic compounds bearing α-alkyl, silyl ether, allyl,
and benzyl substituents were accessed in comparable yields but
slightly lower ee’s to those obtained with formic acid.
INTRODUCTION
■
Palladium-catalyzed decarboxylative asymmetric protonation
(DAP) is a powerful tool for the enantioselective synthesis of
tertiary stereocenters adjacent to a carbonyl. Originally, the
racemic decarboxylative protonation was developed by Tsuji
and co-workers as a mild method of allyl β-keto ester
hydrogenolysis to avoid the alternative harsh hydrolysis and
decarboxylation conditions.1 Using a palladium catalyst in the
presence of triethylammonium formate, a variety of linear and
cyclic tertiary α-alkyl ketones were isolated in excellent yields
with ester, ether, and other ketone functionalities well tolerated
(Figure 1, A). Several years later an enantioselective variant was
Recently our laboratory utilized the DAP for the preparation
of tertiary α-aryl stereocenters in the first catalytic asymmetric
synthesis of isoflavanones.6 In contrast to other enantioselective
approaches to tertiary α-aryl ketones, the best results were
obtained with very sterically hindered di-ortho substituted
arenes with ee’s up to 92%.7 Interestingly, further investigation
of the model α-arylated isoflavanone revealed a novel
enantiodivergent effect based on the choice of proton source
(Figure 1, D).8 Enantiodivergent methodology, wherein
enantioselectivity is determined by a factor other than the
supposed chiral promoter, is an attractive route to both product
enantiomers, particularly when both enantiomers of the
required chiral ligand are not readily available.9 Interestingly,
Stoltz had observed no such effect in their studies with α-alkyl,
allyl, or benzyl substituents. Based on the mechanistic
ambiguity of the DAP, it was speculated the enantiodivergence
may result from a change in pathway depending on the proton
source used. Our research group conducted preliminary testing
of the enantiodivergent methodology in the synthesis of tertiary
́
reported by Muzart and Henin using (2-methyl-1-indenyl)-
benzyl or allyl carbonates in the presence of a palladium catalyst
and chiral proton source (Figure 1, B).2 With initial ee’s up to
40%, further investigation greatly expanded the scope of the
reaction to α-alkyl, benzyl, phenyl, and fluorine substituted allyl
or benzyl β-keto esters.3 Subsequently, Stoltz and co-workers
reported the DAP of allyl β-keto esters using a chiral palladium-
PHOX system and formic acid (Figure 1, C).4 A variety of
monocyclic and fused aromatic compounds with α-alkyl, fluoro,
allyl, and benzyl substituents were accessed in excellent ee’s up
to 94%. A homogeneous variant using Meldrum’s acid as the
proton source was developed shortly thereafter to avoid the
substrate-dependent optimization of the amount of sieves and
acid required in the heterogeneous formic acid reaction.5 In this
case, the terms homo- and heterogeneous only refer to the
Received: February 8, 2017
© XXXX American Chemical Society
A
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a
Table 1. Screening of Reaction Conditions
conversion
ee
b
c
d
entry
deviation from standard conditions
none
(%)
(%)
1
>99 (92)
>99
93 (S)
85 (S)
44 (S)
89 (S)
80 (S)
88 (S)
78 (S)
93 (S)
0 (S)
2
2-(Me)-THF
3
MTBE
>99
4
1,4-dioxane
>99
5
L2 instead of L1, 1,4-dioxane
7 °C
0.015 M
>99
6
>99
7
>99
8
0.06 M
>99
9
(η3-C3H5)2Pd2Cl2
half catalytic loading
formic acid (6 equiv)
formic acid, Pd(OAc)2, dioxane, 4 Å m·s
Pd(OAc)2, dioxane, 4 Å m·s
>99
10
11
12
13
47
92 (S)
50 (R)
89 (R)
8 (S)
>99
>99 (86)
39
a
See the Supporting Information for complete optimization results
b
c
(Table S1, Figure S1). Entries 2−13 tested after 18 h. Determined
by H NMR spectroscopy of the crude product, isolated yields in
parentheses. Determined by supercritical fluid chromatography using
1
d
Figure 1. Development of the enantiodivergent decarboxylative
asymmetric protonation.
a chiral stationary phase.
with (S)-tBu PHOX (L2) indicating that the electron deficient
nature of the ligand is crucial for optimal enantioinduction
(Table 1, entry 5). Reducing the temperature and concen-
tration had a negative effect (Table 1, entries 6−7) while
increasing the concentration produced no change in ee (Table
1, entry 8). While full conversion was seen using (η3-
C3H5)2Pd2Cl2, the product formed was racemic (Table 1,
entry 9). A drop in conversion was seen upon halving the
catalyst loading (Table 1, entry 10). Gratifyingly, upon
switching to formic acid as the proton source the enantiomeric
product was formed in an ee of 50% (Table 1, entry 11)
indicating that in the case of this indanone substrate the
absolute configuration of the product was acid dependent. The
ee increased significantly to 89% when the previously optimized
reaction conditions for formic acid were applied (Table 1, entry
12).8 The (S)-enantiomer was formed once again using
Meldrum’s acid under these optimized heterogeneous con-
ditions, albeit in a reduced conversion (39%) and an ee of only
8%.
Scope of the Enantiodivergent Protonation. A series of
α-aryl-β-keto allyl esters 1b−n were readily accessed in low to
good yields using aryllead triacetate reagents (Scheme 1).17
The aryllead triacetate reagents may be synthesized via direct
plumbation or transmetalation methods. Upon application of
the established homogeneous and heterogeneous reaction
conditions to substrates 1a−1n, the corresponding products
were obtained in good to excellent yields and low to excellent
enantioselectivities (Scheme 2). In all cases where the reactions
led to product enantioenrichment, either enantiomer could be
selectively obtained by judicious choice of the proton source. In
addition to the effect that the level of electron density of the
aryl substituent had on the reaction, the exact substituent
pattern had a marked effect on the level of enantioselectivity
achieved. To our delight, good to excellent enantioselectivities
were observed for both enantiomeric series with other di-ortho
substituted electron rich aryl substituents, such as 1a−d.
α-aryl aliphatic monocyclic ketones.10 Disappointingly, the
opposite enantiomers were obtained in just two of the seven α-
aryl substrates investigated. However, based on the low
enantioselectivities of the products with formic acid (0−63%
ee) and limited number of substrates examined, further testing
across a range of substrates was deemed necessary before the
synthetic utility of the methodology is accurately determined.
Furthermore, we aimed to elucidate a definitive mechanism for
the heterogeneous DAP in an attempt to explain the acid-
dependent enantiodivergence.
In choosing an appropriate molecular scaffold for our
investigation we became interested in the synthesis of tertiary
α-aryl 1-indanones due to their prevalence as, and as precursors
for, a range of pharmaceuticals11 and other useful materials
such as dyes.12 The enantioselective synthesis of α-substituted-
tertiary-1-indanones has been investigated previously but with a
limited substrate scope.2,3a,4a,5a,13 Only two examples of α-
arylated products were found with phenyl- and para-
methoxyphenyl-substituted products synthesized in moderate
ee’s.14
RESULTS AND DISCUSSION
■
Reaction Condition Optimization. Our study com-
menced with the synthesis of allyl β-keto ester model substrate
1a. α-Acylation of 1-indanone using sodium hydride and diallyl
carbonate was followed by α-arylation with the corresponding
aryllead triacetate reagent.15 The 2,4,6-trimethoxyphenyl-
substituted β-keto allyl ester 1a was chosen as the model
substrate for reaction optimization. After some experimenta-
tion, a combination of Pd2dba3·CHCl3, the chiral P,N-ligand L1
and Meldrum’s acid in THF at 40 °C produced the optimal
result, delivering (S)-2a in an ee of 93% and 92% isolated yield
within 1 h (Table 1, entry 1).16 Variation of the solvent had a
deleterious effect upon the enantioselectivity of the product
(Table 1, entries 2−4). Similarly, a drop in ee was observed
B
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Scheme 1. Synthesis of Substrates
a
Scheme 2. Substrate Scope
a
The absolute configurations of 2b−2n were tentatively assigned by analogy to the model substrate. The absolute configurations of 2o−2q were
tentatively assigned by comparing the sign of optical rotation to literature values. MA = reaction performed with Meldrum’s acid, FA = reaction
performed with formic acid.
Moderate to good ee’s were seen with a comparatively electron
poor aryl group in 2e. While the methoxy-substituted
naphthalene system 2f was formed in an excellent ee using
the homogeneous reaction conditions, an ee of only 21% was
obtained using formic acid. A drop in the enantioselectivity was
observed for mono-ortho substituted products 2g and 2h.
Furthermore, products 2i−k lacked ortho substitution com-
pletely and were synthesized in poor enantioselectivities. The
results demonstrate the importance of ortho methoxy-
substitution on the aryl ring to obtain high levels of
enantioinduction. We believe, the stereoelectronic effect of
the ortho substituent may prohibit a planar orientation of the
indanone enolate and aryl ring. This may lead to higher
enantioselectivities by introducing a steric effect in the
transition state of the protonation or by prohibiting
conjugation, leading to an unstabilized enolate. While, methyl-
and trifluoromethyl-substitution on the indanone backbone of
the model substrate were well tolerated (2l, 2n), a drop in ee
was seen for dichlorinated 2m in the homogeneous reaction.
Significantly higher ee’s were achieved using Meldrum’s acid in
the case of products 2d, 2e, 2f, 2i, 2j, and 2k while the opposite
trend was observed with 2g and 2m.
To investigate the scope of the enantiodivergence, α-methyl,
allyl, and benzyl substrates were also subjected to the optimized
conditions (Scheme 2).18 No switch in absolute configuration
was observed for alkyl and allyl products 2o and 2p. The
opposite enantiomers were obtained for α-benzyl 1-indanone
2q indicating the switch in absolute configuration of the
product is dependent upon a sterically hindered α-substituent.
Mechanistic Background of the DAP. With the
successful application of the enantiodivergent protonation to
a range of substrates, we began an investigation to explain the
switch in selectivity for the α-aryl substrates. The absolute
configuration of the protonated products was shown to be acid-
dependent. Therefore, we hypothesized the contrasting
selectivities may be due to a change in mechanism upon
switching the proton source. We began by examining the
various mechanisms proposed throughout the development of
the DAP. Although the racemic decarboxylative protonation
was reported over three decades ago, a definitive mechanism
C
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extensively investigated decarboxylative asymmetric allylic
alkylation.19 The mechanism features protonation of an
oxygen-bound palladium enolate by Meldrum’s acid directed
by a chiral palladium-PHOX system. The isolation of C-
allylated Meldrum’s acid is indicative of soft nucleophilic attack
by the conjugate base on the allyl fragment, releasing the
palladium catalyst back into the cycle.
Scheme 3. Proposed Catalytic Cycle for the Protonation by
Meldrum’s Acid
Plausible Catalytic Cycles for the Heterogeneous
DAP. With a catalytic cycle for the homogeneous protonation
already proposed, we began a mechanistic investigation of the
heterogeneous protonation. Stoltz and co-workers suggested a
very similar mechanism with formic acid to that with
Meldrum’s acid based on similar patterns of selectivity.22
Such a catalytic cycle was not disclosed at the time, but is now
illustrated below (Scheme 4, Catalytic Cycle A). Upon
oxidative addition of the palladium catalyst to the substrate
and decarboxylation (steps A, B), intermolecular protonation of
palladium enolate II by formic acid yields the desired product
and allyl palladium formate complex III (step C). The Pd0
catalyst, CO2 and propene are released by decarboxylation and
reductive elimination (step D, E).23 However, our enantiodi-
vergent results led us to re-evaluate this mechanistic proposal in
a bid to explain the curious switch in selectivity. Hence, a novel
alternative catalytic cycle was envisaged and must also be
considered (Scheme 4, Catalytic Cycle B). As a hard oxo-
nucleophile it is known formate may coordinate to palladium
directly.1b Catalytic cycle B begins in the same manner as
before with oxidative addition of the palladium catalyst to the
substrate. However, on this occasion formate coordinates to
palladium before decarboxylation may occur, thereby displacing
β-keto acid II (step B). Upon fragmentation of intermediate III
(steps C, D) the catalyst is regenerated. Expelled β-keto acid II
undergoes a second oxidative addition by the active palladium
species (step E) and decarboxylation (step F) to form
hydridopalladum species VI.24 In contrast to the homogeneous
protonation, the protonated product is formed via intra-
molecular reductive elimination (step G). Such a fundamentally
different enantiodetermining step to the proposed homoge-
neous protonation may explain the switch in selectivity we have
has not been elucidated. Tsuji proposed a metal-assisted
decarboxylative pathway to form a palladium enolate which is
subsequently protonated to yield the desired ketone.19 Shimizu
favored an anion exchange pathway to form a β-keto acid in situ
which undergoes decarboxylation and tautomerisation to yield
the product.20 Likewise, asymmetric protonations have also
been subject to investigation without conclusive elucidation of a
catalytic cycle. UV and IR spectroscopic analysis of Muzart’s
enantioselective reaction using benzyl β-keto esters also
indicated the formation of β-keto acid in situ.21 The subsequent
decarboxylation and tautomerisation appears to be catalyzed by
the chiral proton source. In 2006, Stoltz and co-workers
investigated the mechanism of the heterogeneous DAP via
deuterium-labeling studies.4a The results were inconclusive and
a catalytic cycle remained ambiguous. Further deuterium-
labeling studies by our research group were similarly
inconclusive.8 In 2008, Stoltz and co-workers did propose a
plausible catalytic cycle for the homogeneous protonation
(Scheme 3) based on the similarity of the kinetics to their
Scheme 4. Plausible Catalytic Cycles A and B for DAP with Formic Acid as a Proton Source
D
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observed. However, a definitive stereochemical rationale would
also require determination of the regioselectivity of the
hydridopalladium enolate (Scheme 4, far right).25
Scheme 6. Deuterium-Labeling Studies
Identification of Divergent Byproducts. Due to the
general uncertainty regarding the mechanism of the heteroge-
neous DAP, initial experiments were designed to test our
overall mechanistic hypothesis. In both heterogeneous catalytic
cycle A and B (Scheme 4), the allyl group of the starting
material is ultimately expelled as propene. To avoid the difficult
isolation and quantification of the proposed gaseous byproduct,
phenylated substrate 3 was applied in the reaction (Scheme 5,
Scheme 5. Identification of Divergent By-Products in the
DAP
conducted with HCO2H and deuterated molecular sieves. No
D-incorporation into the product was observed (Scheme 6, eq
3). Furthermore, only 8% D-incorporation was found with the
addition of D2O to the reaction mixture (5 equiv., Scheme 6, eq
4), corresponding with previous deuterium labeling studies.8
To test for traces of water from the formic acid as the proton
source, sodium formate was applied in the reaction. The
product (S)-2a was isolated in a 29% yield (Scheme 7, eq 1)
eq 1). Under the optimized heterogeneous conditions, the
propene surrogate trans-β-methylstyrene 4 was formed in a
64% yield. Testing the reaction without the metal−ligand
complex gave only recovered starting material. In contrast, in
the proposed homogeneous mechanism the allyl fragment is
sequestered by deprotonated Meldrum’s acid. Consequently,
upon switching to the organic proton source with the same
conditions, no trans-β-methylstyrene 4 was observed (Scheme
5, eq 2). Instead, the corresponding diallylated Meldrum’s acid
5 was isolated along with the enantioenriched (S)-2a.
Scheme 7. Investigation of an Unidentified Proton Source
Deuterium-Labeling Studies. Previous reports measured
the incorporation of the oxygen-bound deuterium (38−35% D-
incorporation) and formyl deuterium (<1% D-incorporation)
into the α-stereocenter of the ketone product using isotopically
labeled formic acids.4a,8 The somewhat low levels of the
oxygen-D incorporation indicated the presence of an additional
unidentified protonating agent while the fate of the formyl-D
was not resolved. Formic acid’s ability to provide a hydride
which may subsequently add to a chiral palladium enolate
complex was noted but not tested. Using phenylated substrate
3, deuterium incorporation into both the final product and
expelled propene surrogate, trans-β-methylstyrene 4, could now
be quantified for the first time (Scheme 6). In both catalytic
cycle A and B the oxygen-bound hydrogen is incorporated into
the final product and the formyl hydrogen is transferred to the
propene byproduct. Gratifyingly, using DCO2H, NMR analysis
revealed <1% D-incorporation in the product and 80−90% in
the isolated trans-β-methylstyrene 4 (Scheme 6, eq 1).
Switching to HCO2D, 49% D-incorporation was observed in
the product and 0% in the isolated trans-β-methylstyrene 4
(Scheme 6, eq 2). The specific patterns of deuteration observed
in the two experiments are in accordance with the proposed
mechanisms and explain the previously ambiguous fate of the
formyl proton. However, 49% deuterium incorporation into the
product using HCO2D was still surprisingly low due to the
rigorous drying procedures and anhydrous solvents utilized. To
test for the possibility of residual water in the molecular sieves
as the alternative source of the α-proton, the DAP was
providing further indication of an alternative proton source to
the acidic proton of formic acid. Residual water from the
molecular sieves was tested for once again by their removal
(Scheme 7, eq 2). Again, the product was isolated in a 29%
yield and the alternative source of the α-proton remains
unidentified.
Investigation of a β-Keto Acid Intermediate. In an
attempt to distinguish between the possible catalytic cycles for
the heterogeneous DAP we investigated the formation of a β-
keto acid intermediate (Scheme 8), as proposed in Catalytic
Cycle B. However, none of the corresponding β-keto methyl
ester 6 was isolated upon cooling the reaction mixture and
addition of ten equivalents of trimethylsilyldiazomethane.
The transient nature of the β-keto acid intermediate may
limit the possibility of formation of β-keto methyl ester 6. The
rapid degradation of intermediate II may also disfavor the
possibility of oxidative addition to afford intermediate V, as
proposed in Catalytic Cycle B. However, this appears to be the
E
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(Hz). High-resolution mass spectra [electrospray ionization (ESI-
TOF)] (HRMS) were measured on a micromass LCT orthogonal
time-of-flight mass spectrometer with leucine enkephalin (Tyr-Gly-
Phe-Leu) as an internal lock mass. Infrared spectra were recorded on a
Scheme 8. Investigation of a β-Keto Acid Intermediate
FT-IR spectrometer and are reported in terms of wavenumbers (νmax
)
with units of reciprocal centimeters (cm−1). Microwave experiments
were conducted in a CEM Discover S-class microwave reactor with
controlled irradiation at 2.45 GHz using standard sealed microwave
process Pyrex vials and an external surface sensor to monitor the
temperature. (Note: The microwave reactor was only used to further
dry molecular sieves during some deuterium labeling experiments.)
Optical rotation (α) values were measured at room temperature and
specific rotation ([α]D20) values are given in deg·dm−1·cm3·g−1.
Melting points were determined in open capillary tubes. Supercritical
fluid chromatography (SFC) was performed on a Waters UPC2 system
using a Chiralpak IA-3, IC-3, or ID-3 column.
only means to access the hydridopalladium enolate inter-
mediate VI, which as noted previously, may be key to the
observed enantiodivergence. Further studies are required before
the comprehensive mechanism of the DAP with formic acid is
elucidated.
CONCLUSIONS
Typical Procedure A: Preparation of β-Keto Esters S1a−S1d.
Acylation procedure was adapted from the literature.27 A flask was
charged with NaH (60% dispersion in mineral oil, 2.5 equiv). THF
(1.92 M) was added and the resultant solution cooled to 0 °C (ice/
H2O bath). A solution of 1-indanone (1.0 equiv) in THF (3.20 M)
was added dropwise. The solution was allowed to warm to room
temperature. After 15 min, diallyl carbonate (1.5 equiv) was added
dropwise. After 16 h, the solution was quenched with saturated
aqueous NH4Cl and extracted with EtOAc (3 × 20 mL). The
combined organics were dried over anhydrous Na2SO4, filtered, and
concentrated in vacuo. In the case of S1a the crude product was
purified via silica gel column chromatography (pentane/Et2O, 85:15).
For S1b, S1c, and S 1d the crude product was washed through a pad
of silica using Et2O.
Allyl 1-oxo-2,3-Dihydro-1H-indene-2-carboxylate (S1a). Prepared
according to typical procedure A using 1-indanone (7.4 g, 56 mmol).
The product was isolated as a brown oil (7.5 g, 62%). Spectroscopic
analysis is in good accordance to literature.27
Allyl 5-Methyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (S1b).
Prepared according to typical procedure A using 5-methyl-1-indanone
(1.0 g, 6.8 mmol). The isolated crude orange oil was used in the next
step without further purification.
■
In summary, we have developed an efficient enantiodivergent
synthesis of sterically hindered tertiary α-aryl-1-indanones from
the corresponding α-aryl-β-keto allyl esters. In contrast to our
previous results, both enantiomers of a variety of substrates
were readily obtained in high enantioselectivities. Particularly
excellent ee’s were achieved with sterically hindered aryl groups,
providing a complementary route to existing α-arylation
methodologies. Based on the experimental evidence outlined
above, we believe the decarboxylative asymmetric protonation
with formic acid may proceed via one of two distinct catalytic
cycles. Further studies are currently underway to elucidate the
correct mechanism and the reason for the enantiodivergence
with sterically hindered α-substituents.
EXPERIMENTAL SECTION
■
General Information: Materials and Methods. Unless other-
wise noted, reactions were performed with rigorous exclusion of air
and moisture, under an inert atmosphere of nitrogen in flame-dried
glassware with magnetic stirring using anhydrous solvents. Reactions
were heated using an oil bath. N2-flushed stainless steel cannulas or
plastic syringes were used to transfer air and moisture-sensitive
reagents. All reagents were obtained from commercial sources and
used without further purification unless otherwise stated. Aryllead
triacetate reagents and (S)-(CF3)3-tert-Bu-PHOX were prepared
according to the previously reported procedures.6a All anhydrous
solvents were obtained from commercial sources and used as received
with the following exceptions: diethyl ether (Et2O), dichloromethane
(CH2Cl2), and toluene (PhCH3) were dried by passing through
activated alumina columns. Tris(dibenzylideneacetone)dipalladium(0)
chloroform adduct was prepared via the method of Zalesskiy et al.26
Pd(OAc)2 was purchased from Strem. Powdered activated 4 Å
molecular sieves were purchased from Sigma-Aldrich and were stored
in an oven at 120 °C. In vacuo refers to the evaporation of solvent
under reduced pressure on a rotary evaporator. Thin-layer
chromatography (TLC) was performed on aluminum plates precoated
with silica gel F254. They were visualized with UV-light (254 nm)
fluorescence quenching, or by charring with an acidic vanillin solution
(vanillin, H2SO4 in ethanol). Flash column chromatography was
carried out using 40−63 μm, 230−400 mesh silica gel.
Allyl 5,7-Dichloro-1-oxo-2,3-dihydro-1H-indene-2-carboxylate
(S1c). Prepared according to typical procedure A using 5,7-dichloro-
1-indanone (1.0 g, 5.0 mmol). The isolated crude brown oil was used
in the next step without further purification.
Allyl 1-oxo-4-(Trifluoromethyl)-2,3-dihydro-1H-indene-2-carbox-
ylate (S1d). Prepared according to typical procedure A using 4-
trifluoromethyl-1-indanone (1.0 g, 5.0 mmol). The isolated crude
colorless oil was used in the next step without further purification.
Typical Procedure B: Preparation of α-Aryl-β-keto Allyl
Esters 1a−1n. Arylation procedure was adapted from the literature.10
To a stirred solution of β-keto allyl ester (1 equiv) and aryllead
triacetate (1.1 equiv) in CHCl3 (0.6 M) in a Schlenk flask (25 mL),
was added dropwise pyridine (3.3 equiv). The resulting mixture was
heated at 40 °C for 18 h, filtered through a plug of Celite, and washed
with CHCl3. The organic layer was washed with 6% H2SO4 (2 × 50
mL), extracted with CHCl3 (2 × 50 mL), and the combined organic
extracts were washed with water (2 × 50 mL) and brine (50 mL),
dried over anhydrous Na2SO4, and filtered. The solvent was reduced in
vacuo and resulting residue purified via silica gel column chromatog-
raphy (pentane/Et2O or pentane/EtOAc).
Instrumentation. 1H NMR spectra were recorded on a 300, 400, or
500 MHz spectrometer. 13C NMR spectra were recorded on a 400 or
500 MHz spectrometer at 101 or 126 MHz. 19F NMR spectra were
recorded on a 400 MHz spectrometer at 376 MHz. Chemical shifts (δ)
are reported in parts per million (ppm) downfield from
Allyl 1-oxo-2-(2,4,6-Trimethoxyphenyl)-2,3-dihydro-1H-inden-2-
carboxylate (1a). Prepared according to typical procedure B using
β-keto allyl ester S1a (1.63 g, 7.54 mmol) to afford the product as an
orange solid (1.77 g, 61%). Column chromatography conditions =
pentane/EtOAc, 80:20; Rf = 0.26 (30% EtOAc in pentane); mp
=111−113 °C; IR (NaCl): ν = 3054 (CC−H), 1721 (Ketone: C
1
tetramethylsilane and for H NMR are referenced to residual proton
1
O), 1590 (Aromatic CC) cm−1; H NMR (300 MHz, CDCl3) δ
in the NMR solvent (CDCl3 = δ 7.26 ppm). 13C NMR are referenced
to the residual solvent peak (CDCl3 = δ 77.16 ppm). All 13C spectra
are 1H decoupled. NMR data are represented as follows: chemical shift
(δ ppm), integration, multiplicity (s = singlet, d = doublet, t = triplet, q
= quartet, dd = double doublet, m = multiplet, app. d = apparent
doublet, app. t. = apparent triplet), coupling constant (J) in Hertz
7.84−7.74 (1H, app. d, J = 7.4 Hz), 7.55 (1H, app. t, J = 7.4 Hz), 7.42
(1H, app. d, J = 7.4 Hz), 7.35 (1H, app. t, J = 7.4 Hz), 6.12 (2H, s),
5.95−5.79 (1H, m), 5.24−5.14 (2H, m), 4.70−4.53 (2H, m), 4.35
(1H, d, J = 17.1 Hz), 3.76 (3H, s), 3.60 (6H, s), 3.00 (1H, d, J = 17.1
Hz) ppm; 13C{1H}NMR (101 MHz, CDCl3) δ 200.3, 170.1, 160.7,
F
DOI: 10.1021/acs.joc.7b00303
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
158.4, 152.2, 135.4, 134.6, 132.4, 127.3, 126.2, 124.3, 118.1, 111.8,
92.3, 66.6, 61.7, 55.8, 55.5, 39.9 ppm; HRMS (ESI-TOF): calcd. for
C22H21O6 [M−H+] 381.1338; found 381.1329.
CDCl3) δ 7.90 (1H, app. d, J = 7.5 Hz), 7.82−7.76 (2H, m), 7.63 (1H,
app. t, J = 7.5 Hz), 7.56−7.31 (5H, m), 7.21 (1H, d, J = 9.0 Hz), 5.78−
5.64 (1H, m), 5.14−5.00 (2H, m), 4.72−4.48 (3H, m), 3.67 (3H, s),
3.31 (1H, d, J = 17.0 Hz) ppm; 13C{1H}NMR (101 MHz, CDCl3) δ
200.0, 171.3, 154.2, 151.4, 135.7, 134.9, 132.8, 131.6, 130.5, 130.1,
129.1, 127.7, 126.6, 126.4, 124.4, 123.9, 123.7, 123.6, 118.5, 115.5,
66.9, 64.1, 56.6, 40.3 ppm; HRMS (ESI-TOF): calcd. for C24H20O4Na
[M+Na+] 395.1259; found 395.1268.
Allyl 2-(2,6-Dimethoxyphenyl)-1-oxo-2,3-dihydro-1H-indene-2-
carboxylate (1b). Prepared according to typical procedure B using
β-keto allyl ester S1a (0.500 g, 2.31 mmol) to afford the product as a
brown solid (0.709 g, 87%). Column chromatography conditions =
pentane/EtOAc, 75:25; Rf = 0.37 (30% EtOAc in pentane); mp
=131−132 °C; IR (NaCl): ν = 3054 (CC−H), 1720 (Ketone: C
O), 1606 (Aromatic CC) cm−1; 1H NMR (400 MHz, CDCl3) 7.79
(1H, app. d, J = 7.7 Hz), 7.52 (1H, app. t, J = 7.4, 1.3 Hz), 7.39 (1H,
app. d, J = 7.7 Hz), 7.33 (1H, app. t, J = 7.4 Hz), 7.15 (1H, t, J = 8.3
Hz), 6.52 (2H, d, J = 8.3 Hz), 5.97−5.72 (1H, m), 5.31−5.02 (2H, m),
4.73−4.48 (2H, m), 4.37 (1H, d, J = 17.1 Hz), 3.70−3.48 (6H, s), 3.02
(1H, d, J = 17.1 Hz) ppm; 13C{1H}NMR (101 MHz, CDCl3) δ 199.6,
169.7, 157.5, 151.7, 135.2, 134.4, 132.0, 128.5, 127.1, 125.9, 123.9,
118.9, 117.8, 105.5, 104.7, 66.2, 61.5, 55.6, 39.4 ppm; HRMS (ESI-
TOF): calcd. for C21H20O5Na [M+Na+] 375.1208; found 375.1209.
Allyl 1-oxo-2-(2,3,6-Trimethoxyphenyl)-2,3-dihydro-1H-indene-2-
carboxylate (1c). Prepared according to typical procedure B using β-
keto allyl ester S1a (0.290 g, 1.34 mmol) to afford the product as an
orange oil (0.079 g, 15%). Column chromatography conditions =
pentane/EtOAc, 80:20; Rf = 0.40 (30% Et2O in pentane); IR (NaCl):
ν = 3055 (Aromatic C−H), 2992 (sp3C−H), 1714 (Ketone: CO)
Allyl 2-(2,4-Dimethoxyphenyl)-1-oxo-2,3-dihydro-1H-indene-2-
carboxylate (1g). Prepared according to typical procedure B using
β-keto allyl ester S1a (0.400 g, 1.85 mmol) to afford the product as an
orange oil (0.461 g, 71%). Column chromatography conditions =
pentane/EtOAc, 80:20; Rf = 0.25 (30% Et2O in pentane); IR (NaCl):
ν = 3078 (Aromatic C−H), 2941 (sp3C−H), 1747 (Ester CO)
1
cm−1; H NMR (300 MHz, CDCl3) δ 7.77 (1H, app. d, J = 7.7 Hz),
7.54 (1H, app. t, J = 7.5 Hz), 7.46−7.36 (2H, m), 7.04 (1H, d, J = 8.5
Hz), 6.48 (1H, d, J = 2.5 Hz), 6.39 (1H, dd, J = 8.5, 2.5 Hz), 5.88−
5.76 (1H, m), 5.24−5.06 (2H, m), 4.76−4.55 (2H, m), 4.14 (1H, d, J
= 17.3 Hz), 3.77 (3H, s), 3.75 (3H, s), 3.59 (1H, d, J = 17.3 Hz) ppm;
13C{1H}NMR (101 MHz, CDCl3) δ 201.4, 170.2, 160.4, 158.3, 153.5,
135.7, 135.3, 132.1, 128.0, 127.7, 126.5, 124.8, 122.2, 118.2, 103.8,
99.6, 66.4, 64.0, 55.5, 41.1 ppm; HRMS (ESI-TOF): calcd. for
C21H21O5 [M+H+] 353.1389; found 353.1395.
Allyl 1-oxo-2-(2,3,4-Trimethoxyphenyl)-2,3-dihydro-1H-indene-2-
carboxylate (1h). Prepared according to typical procedure B using β-
keto allyl ester S1a (0.400 g, 1.85 mmol) to afford the product as an
orange oil (0.488 g, 69%). Column chromatography conditions =
pentane/EtOAc, 75:25; Rf = 0.45 (25% EtOAc in pentane); IR
(NaCl): ν = 3054 (CC−H), 1712 (Ketone: CO), 1603
1
cm−1; H NMR (300 MHz, CDCl3) δ 7.79 (1H, app. d, J = 7.6 Hz),
7.54 (1H, app. t, J = 7.6 Hz), 7.45−7.30 (2H, m), 6.77 (1H, d, J = 9.0
Hz), 6.56 (1H, d, J = 9.0 Hz), 5.96−5.80 (1H, m), 5.31−5.08 (2H, m),
4.81−4.47 (2H, m), 4.38 (1H, d, J = 17.1 Hz), 3.75 (3H, s), 3.60 (6H,
s), 3.05 (1H, d, J = 17.1 Hz) ppm; 13C{1H}NMR (101 MHz, CDCl3)
δ 199.4, 169.6, 151.4, 147.4, 135.4, 134.6, 132.2, 127.4, 126.1, 125.2,
124.1, 117.8, 112.0, 106.1, 66.5, 61.9, 60.3, 56.3, 56.0, 40.1 ppm;
HRMS (ESI-TOF): calcd. for C22H22O6Na [M+Na+] 405.1314; found
405.1316.
Allyl 2-(2-Methoxy-4,6-dimethylphenyl)-1-oxo-2,3-dihydro-1H-in-
dene-2-carboxylate (1d). Prepared according to typical procedure B
using β-keto allyl ester S1a (0.500 g, 2.31 mmol) to afford the product
as a yellow solid (0.698 g, 79%). Column chromatography conditions
= pentane/EtOAc, 80:20; Rf = 0.27 (30% Et2O in pentane); mp
=116−117 °C; IR (NaCl): ν = 3073 (Aromatic C−H), 3055 (CC−
H), 1722 (Ketone: CO) cm−1; 1H NMR (300 MHz, CDCl3) δ 7.82
(1H, app. d, J = 7.6 Hz), 7.56 (1H, app. t, J = 7.4 Hz), 7.43 (1H, app.
d, J = 7.6 Hz), 7.36 (1H, app. t, J = 7.4 Hz), 6.62 (1H, s), 6.57 (1H, s),
5.92−5.79 (1H, m), 5.30−5.09 (2H, m), 4.70−4.55 (2H, m), 4.42
(1H, d, J = 17.1 Hz), 3.56 (3H, s), 3.05 (1H, d, J = 17.1 Hz), 2.26 (3H,
s), 2.11 (3H, s) ppm; 13C{1H}NMR (101 MHz, CDCl3) δ 200.3,
170.5, 157.1, 152.4, 137.9, 137.4, 135.4, 134.9, 131.9, 127.6, 126.6,
126.3, 125.7, 124.6, 118.7, 111.1, 66.9, 64.6, 55.5, 39.9, 21.9, 21.3 ppm;
HRMS (ESI-TOF): calcd. for C22H23O4 [M+H+] 351.1596; found
351.1607.
1
(Aromatic CC) cm−1; H NMR (300 MHz, CDCl3) δ 7.84 (1H,
app. d, J = 7.6 Hz), 7.62 (1H, app. t, J = 7.6 Hz), 7.50−7.30 (2H, m),
6.80 (1H, d, J = 8.7 Hz), 6.53 (1H, d, J = 8.7 Hz), 5.92−5.80 (1H, m),
5.32−5.07 (2H, m), 4.78−4.55 (2H, m), 4.37 (1H, d, J = 17.5 Hz),
3.87−3.76 (9H, m), 3.20 (1H, d, J = 17.5 Hz) ppm; 13C{1H}NMR
(101 MHz, CDCl3) δ 201.0, 169.9, 153.7, 152.9, 151.6, 142.0, 135.6,
135.2, 131.8, 127.7, 127.0, 126.4, 124.7, 122.0, 118.4, 106.3, 66.6, 64.4,
60.6, 60.3, 56.1, 41.5 ppm; HRMS (ESI-TOF): calcd. for C22H22O6Na
[M+Na+] 405.1314; found 405.1319.
Allyl 2-(Benzo[d][1,3]dioxol-5-yl)-1-oxo-2,3-dihydro-1H-indene-2-
carboxylate (1i). Prepared according to typical procedure B using β-
keto allyl ester S1a (0.400 g, 1.85 mmol) to afford the product as an
orange oil (0.491 g, 79%). Column chromatography conditions =
pentane/Et2O, 70:30; Rf = 0.33 (30% Et2O in pentane); IR (NaCl): ν
= 3080 (Aromatic C−H), 3016 (CC−H), 1745 (Ester CO)
1
cm−1; H NMR (300 MHz, CDCl3) δ 7.81 (1H, app. d, J = 7.7 Hz),
7.62 (1H, app. t, J = 7.4 Hz), 7.47 (1H, app. d, J = 7.7 Hz), 7.39 (1H,
app. t, J = 7.4 Hz), 6.98 (1H, d, J = 2.0 Hz), 6.91−6.83 (1H, dd, J =
8.2, 2.0 Hz), 6.73 (1H, d, J = 8.2 Hz), 5.90 (2H, s), 5.86−5.77 (1H,
m), 5.30−5.10 (2H, m), 4.67−4.57 (2H, m), 4.16 (1H, d, J = 17.3
Hz), 3.56 (1H, d, J = 17.3 Hz) ppm; 13C{1H}NMR (101 MHz,
CDCl3) δ 200.0, 170.3, 151.9, 147.9, 147.0, 135.7, 135.0, 131.9, 131.4,
128.0, 126.2, 125.1, 120.7, 118.5, 108.4, 108.2, 101.2, 66.5, 64.9, 40.8
ppm; HRMS (ESI-TOF): calcd. for C20H17O5 [M+H+] 337.1076;
found 337.1091.
Allyl 2-(2,6-Dimethylphenyl)-1-oxo-2,3-dihydro-1H-indene-2-car-
boxylate (1e). Prepared according to typical procedure B using β-keto
allyl ester S1a (0.400 g, 1.85 mmol) to afford the product as a yellow
oil (0.407 g, 69%). Column chromatography conditions = pentane/
EtOAc, 80:20; Rf = 0.61 (30% Et2O in pentane); IR (NaCl): ν = 3064
1
(Aromatic C−H), 3016 (CC−H), 1747 (Ester CO) cm−1; H
Allyl 2-(4-Methoxyphenyl)-1-oxo-2,3-dihydro-1H-indene-2-car-
boxylate (1j). Prepared according to typical procedure B using β-
keto allyl ester S1a (0.400 g, 1.85 mmol) to afford the product as an
orange oil (0.403 g, 68%). Column chromatography conditions =
pentane/Et2O, 85:15; Rf = 0.32 (30% Et2O in pentane); IR (NaCl): ν
= 3073 (Aromatic C−H), 3039 (CC−H), 1745 (Ester CO)
NMR (400 MHz, CDCl3) δ 7.85 (1H, app. d, J = 7.7 Hz), 7.61 (1H,
app. t, J = 7.5 Hz), 7.50 (1H, app. d, J = 7.7 Hz), 7.39 (1H, app. t, J =
7.5 Hz), 7.11−6.97 (3H, m), 5.94−5.77 (1H, m), 5.27−5.10 (2H, m),
4.71−4.56 (2H, m), 4.50 (1H, d, J = 17.2 Hz), 3.18 (1H, d, J = 17.2
Hz), 2.18 (6H, s) ppm; 13C{1H}NMR (101 MHz, CDCl3) δ 200.4,
170.7, 153.2, 138.8, 137.0, 135.5, 135.2, 131.3, 130.0, 128.0, 127.0,
126.3, 125.3, 119.1, 68.3, 67.2, 40.0, 23.2 ppm; HRMS (ESI-TOF):
calcd. for C21H21O3 [M+H+] 321.1491; found 321.1501.
1
cm−1; H NMR (300 MHz, CDCl3) δ 7.78 (1H, app. d, J = 7.6 Hz),
7.51 (1H, app. t, J = 7.1 Hz), 7.49 (1H, app. d, J = 7.6 Hz), 7.45−7.33
(3H, m), 6.90−6.83 (2H, m), 5.92−5.74 (1H, m), 5.24−5.03 (2H, m),
4.68−4.59 (2H, m), 4.14 (1H, d, J = 17.4 Hz), 3.67 (3H, s), 3.59 (1H,
d, J = 17.4 Hz) ppm; 13C{1H}NMR (101 MHz, CDCl3) δ 200.4,
170.6, 159.0, 152.1, 135.6, 135.1, 131.6, 130.3, 128.7, 128.1, 126.3,
125.2, 118.5, 114.1, 66.4, 64.7, 55.4, 40.7 ppm; HRMS (ESI-TOF):
calcd. for C20H19O4 [M+H+] 323.1283; found 323.1294.
Allyl 2-(2-Methoxynaphthalen-1-yl)-1-oxo-2,3-dihydro-1H-in-
dene-2-carboxylate (1f). Prepared according to typical procedure B
using β-keto allyl ester S1a (0.200 g, 0.925 mmol) to afford the
product as a yellow solid (0.197 g, 57%). Column chromatography
conditions = pentane/EtOAc, 80:20; Rf = 0.39 (25% EtOAc in
pentane); mp =104−105 °C; IR (NaCl): ν = 3051 (Aromatic C−H),
2997 (CC−H), 1698 (Ketone: CO) cm−1; 1H NMR (300 MHz,
Allyl 1-oxo-2-Phenyl-2,3-dihydro-1H-indene-2-carboxylate (1k).
Procedure was adapted from the literature.28 To a mixture of
G
DOI: 10.1021/acs.joc.7b00303
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The Journal of Organic Chemistry
Article
phenylboronic acid (1.08 g, 8.89 mmol), lead tetraacetate (3.94 g, 8.89
mmol), and mercury(II) acetate (0.283 g, 0.889 mmol) was added
CHCl3 (13.3 mL) under nitrogen atmosphere. After stirring for 1 h at
40 °C a solution of β-keto allyl ester S1a (1.75 g, 8.08 mmol) in
pyridine (1.9 mL, 24.3 mmol) was added and stirred for 18 h at 40 °C.
The reaction mixture was allowed to cool to ambient temperature,
filtered through plug of Celite and washed with CHCl3 (2 × 15 mL).
The organic layer was washed with aq. sulfuric acid (3 M, 25 mL) and
the aq. layer was extracted with CHCl3 (2 × 15 mL). The combined
organic layers were washed with water (25 mL), dried over anhydrous
Na2SO4, filtered, and the solvent was removed in vacuo. The resulting
residue was purified via silica gel column chromatography (pentane/
Et2O) to yield the product as a yellow oil (0.580 g, 25%). Column
chromatography conditions = pentane/Et2O, 99:1; Rf = 0.25 (30%
Et2O in pentane); IR (NaCl): ν = 3059 (CC−H), 3026 (Aromatic
NMR (376 MHz, CDCl3) δ −62.2 ppm; HRMS (ESI-TOF): calcd. for
C23H21O6F3Na [M+Na+] 473.1188; found 473.1165.
Typical Procedure C: Preparation of α-Substituted-β-keto
Allyl Esters 1o−1q. Alkylation/benzylation/allylation of S1a was
adapted from the literature.18 β-Keto allyl ester S1a (1 equiv) was
added to a suspension of anhydrous K2CO3 (2.0 equiv) in acetone
(0.75 M) in a round-bottom flask (25 mL). To the reaction mixture
was added the electrophile (2.0 equiv) and the reaction mixture was
then heated to 50 °C for 14 h. The mixture was cooled, filtered, and
the solids washed with acetone. The filtrate was concentrated and the
resulting residue purified via silica gel column chromatography
(pentane/Et2O, 90:10).
Allyl 2-Methyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (1o).
Prepared according to typical procedure C using β-keto allyl ester S1a
(0.973 g, 4.50 mmol) and iodomethane as the electrophile to afford
the product as a yellow oil (0.681 g, 66%). Spectroscopic analysis is in
good accordance to literature.18
1
C−H), 1709 (Ester CO), 1604 (Aromatic CC) cm−1; H NMR
(400 MHz, CDCl3) δ 7.84 (1H, app. d, J = 7.7 Hz), 7.64 (1H, td, J =
7.5, 1.2 Hz), 7.49 (1H, app. d, J = 7.7 Hz), 7.45−7.38 (3H, m), 7.36−
7.30 (2H, m), 7.30−7.23 (1H, m), 5.88−5.73 (1H, m), 5.31−5.09
(2H, m), 4.72−4.55 (2H, m), 4.22 (1H, d, J = 17.3 Hz), 3.60 (1H, d, J
= 17.3 Hz) ppm; 13C{1H}NMR (101 MHz, CDCl3) δ 200.1, 170.4,
152.2, 138.7, 135.7, 135.2, 131.5, 128.8, 128.1, 127.7, 127.5, 126.3,
125.3, 118.6, 66.6, 65.5, 40.9 ppm; HRMS (ESI-TOF): calcd. for
C19H16O3Na [M+Na+] 315.0997; found 315.0986.
Allyl 2-Allyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (1p).
Prepared according to typical procedure C using β-keto allyl ester
S1a (0.973 g, 4.50 mmol) and allyl bromide as the electrophile to
afford the product as a brown oil (0.846 g, 73%). Rf = 0.42 (20% Et2O
in pentane); IR (NaCl): ν = 3078 (Aromatic C−H), 2981, 2928, 1417
(sp3C−H), 1740 (Ester CO), 1707 (Ketone CO), 1606, 1589
1
(Aromatic CC), 1152 (C−O) cm−1; H NMR (300 MHz, CDCl3)
δ 7.77 (1H, app. d, J = 7.7 Hz), 7.62 (1H, td, J = 7.7, 1.1 Hz), 7.47
(1H, app. d, J = 7.7 Hz), 7.39 (1H, app. t, J = 7.7 Hz), 5.92−5.74 (1H,
m), 5.72−5.53 (1H, m), 5.29−4.98 (4H, m), 4.60 (2H, dt, J = 5.5, 1.4
Hz), 3.66 (1H, d, J = 17.4 Hz), 3.16 (1H, d, J = 17.4 Hz), 2.96−2.82
(1H, m), 2.71−2.54 (1H, m) ppm; 13C{1H}NMR (101 MHz, CDCl3)
δ 202.1, 170.6, 153.2, 135.6, 135.3, 132.8, 131.7, 127.9, 126.5, 124.9,
119.5, 118.4, 66.2, 60.2, 39.2, 36.1 ppm; HRMS (ESI-TOF): calcd. for
C16H16O3Na [M+Na+] 279.0997; found 279.0999.
Allyl 5-Methyl-1-oxo-2-(2,4,6-trimethoxyphenyl)-2,3-dihydro-1H-
indene-2-carboxylate (1l). Prepared according to typical procedure B
using crude β-keto allyl ester S1b (0.689 g) to afford the product as a
colorless solid (0.936 g, 35% over two steps). Column chromatog-
raphy conditions = pentane/EtOAc, 85:15; Rf = 0.29 (15% EtOAc in
pentane); mp =123−124 °C; IR (NaCl): ν = 3004 (Aromatic C−H),
1714 (Ester CO), 1607, 1585 (Aromatic CC), 1120 (C−O)
1
cm−1; H NMR (300 MHz, CDCl3) δ 7.69 (1H, d, J = 7.8 Hz), 7.23
Allyl 2-Benzyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (1q).
Prepared according to typical procedure C using β-keto allyl ester S1a
(0.973 g, 4.50 mmol) and benzyl bromide as the electrophile to afford
the product as a yellow oil (0.906 g, 66%). Spectroscopic analysis is in
good accordance to literature.18
Substrate Preparation for the Identification of Divergent
Byproducts. Cinnamyl 1H-Imidazole-1-carboxylate (S2). Procedure
was adapted from the literature.29 To a 250 mL flask with a magnetic
stirring bar was added 1,1′-carbonyldiimidazole (2.43 g, 15.0 mmol)
and 100 mL THF. The flask was cooled in an ice−water bath. A
solution of cinnamyl alcohol (1.34 g, 10.0 mmol) in 30 mL
dichloromethane was added slowly and stirred for 2 h. The solvent
was reduced in vacuo and resulting residue purified via silica gel
column chromatography (pentane/EtOAc) to afford the product as a
colorless solid (1.47 g, 64%). Spectroscopic analysis is in good
accordance to literature.29
Cinnamyl 1-oxo-2,3-Dihydro-1H-indene-2-carboxylate (S3). n-
Butylithium (2 mL, 2.5 M in hexanes, 5 mmol) was added dropwise to
a well stirred solution of HMDS (1 mL, 5 mmol) in THF (24 mL) at 0
°C in a round-bottom flask (100 mL, 2-neck). The solution was stirred
for 30 min then cooled to −78 °C. 1-Indanone (0.489 g, 3.70 mmol)
in THF (17 mL) was then added dropwise. After 1 h cinnamyl 1H-
imidazole-1-carboxylate S2 in THF (3 mL) was added dropwise and
the reaction mixture stirred at −78 °C for 1 h. The reaction was
warmed to rt, stirred for 16 h and quenched with saturated aqueous
NH4Cl solution (70 mL). The mixture was then extracted with Et2O
(3 × 35 mL), the combined organic layers dried over anhydrous
Na2SO4, filtered, and the solvent was removed in vacuo. The resulting
residue was purified via silica gel column chromatography (pentane/
Et2O, 90:10 to 80:20) to afford the product as a clear oil (0.832 g,
77%). Rf = 0.37 (15% Et2O in pentane); IR (NaCl): ν = 3077 (C
C−H), 3000 (Aromatic C−H), 1711 (Ester CO), 1606 (Aromatic
CC) cm−1; 1H NMR (300 MHz, CDCl3) δ 7.79 (1H, d, J = 7.5 Hz),
7.68−7.61 (1H, m), 7.52−7.47 (1H, m), 7.45−7.29 (6H, m), 6.70
(1H, app. d, J = 15.8 Hz), 6.31 (1H, dt, J = 15.8, 6.4 Hz), 4.86 (2H, dd,
J = 6.4, 1.2 Hz), 3.78 (1H, dd, J = 8.3, 4.1 Hz), 3.59 (1H, dd, J = 17.2,
4.1 Hz), 3.40 (1H, dd, J = 17.2, 8.3 Hz) ppm; 13C{1H}NMR (101
MHz, CDCl3) δ 199.4, 169.1, 153.7, 136.3, 135.6, 135.4, 134.8, 129.6,
(1H, app. s, 1H), 7.17 (1H, dd, J = 7.8, 0.5 Hz), 6.12 (2H, s), 5.95−
5.75 (1H, m), 5.31−5.08 (2H, m), 4.68−4.50 (2H, m), 4.28 (1H, d, J
= 17.0 Hz), 3.78 (3H, s), 3.61 (6H, s), 2.95 (1H, d, J = 17.0 Hz), 2.42
(3H, s) ppm; 13C{1H}NMR (101 MHz, CDCl3) δ 199.7, 170.3, 160.6,
158.5, 152.6, 145.7, 133.1, 132.4, 128.6, 126.6, 124.2, 118.1, 111.8,
92.3, 66.5, 61.9, 55.8, 55.5, 39.6, 22.2 ppm; HRMS (ESI-TOF): calcd.
for C23H24O6Na [M+Na+] 419.1471; found 419.1452.
Allyl 5,7-Dichloro-1-oxo-2-(2,4,6-trimethoxyphenyl)-2,3-dihydro-
1H-indene-2-carboxylate (1m). Prepared according to typical
procedure B using crude β-keto allyl ester S1c (1.074 g) to afford
the product as a colorless solid (1.383 g, 61% over two steps). Column
chromatography conditions = pentane/EtOAc, 85:15; Rf = 0.32 (15%
EtOAc in pentane); mp =119−120 °C; IR (NaCl): ν = 3075 (CC−
H), 3029 (Aromatic C−H), 2980, 1440 (sp3C−H), 1721 (Ester C
O), 1607, 1581 (Aromatic CC), 1121 (C−O) cm−1; 1H NMR (300
MHz, CDCl3) δ 7.34−7.31 (1H, m), 7.30−7.27 (1H, m), 6.11 (2H, s),
5.93−5.81 (1H, m), 5.31−5.11 (2H, m), 4.68−4.57 (2H, m), 4.31
(1H, d, J = 17.5 Hz), 3.77 (3H, s), 3.65 (6H, s), 2.96 (1H, d, J = 17.5
Hz) ppm; 13C{1H}NMR (101 MHz, CDCl3) δ 195.8, 170.0, 160.8,
158.3, 155.0, 140.5, 132.8, 132.2, 130.5, 129.2, 125.0, 118.2, 111.8,
92.4, 66.7, 62.2, 56.1, 55.5, 39.3 ppm; HRMS (ESI-TOF): calcd. for
C22H20O6Cl2Na [M+Na+] 473.0535; found 473.0554.
Allyl 1-oxo-4-(Trifluoromethyl)-2-(2,4,6-trimethoxyphenyl)-2,3-di-
hydro-1H-indene-2-carboxylate (1n). Prepared according to typical
procedure B using crude β-keto allyl ester S 1d (1.021 g) to afford the
product as a colorless solid (1.319 g, 59% over two steps). Column
chromatography conditions = pentane/EtOAc, 85:15; Rf = 0.29 (15%
EtOAc in pentane); mp =96−97 °C; IR (NaCl): ν = 3081, 947 (C
C−H), 3016 (Aromatic C−H), 2982 (sp3C−H), 1735 (Ketone C
O), 1713 (Ester CO), 1601, 1592 (Aromatic CC), 1124 (C−O)
1
cm−1; H NMR (300 MHz, CDCl3) δ 7.98 (1H, app. d, J = 7.6 Hz),
7.84 (1H, app. d, J = 7.6 Hz), 7.51 (1H, t, J = 7.6 Hz), 6.13 (2H, s),
5.97−5.76 (1H, m), 5.32−5.09 (2H, m), 4.69−4.48 (3H, m), 3.79
(3H, s), 3.62 (6H, s), 3.13 (1H, d, J = 17.9 Hz) ppm; 13C{1H}NMR
(101 MHz, CDCl3) δ 199.0, 169.6, 161.0, 158.4, 149.6, 137.0, 132.2,
131.3 (q, J = 4.7 Hz), 128.1 (q, J = 32.4 Hz), 127.8, 127.8, 124.0 (q, J
= 273.4 Hz), 118.4, 111.1, 92.3, 66.8, 61.3, 55.8, 55.6, 38.7 ppm; 19F
H
DOI: 10.1021/acs.joc.7b00303
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
128.7, 128.3, 128.0, 126.8, 126.7, 124.9, 122.8, 120.9, 66.4, 53.5, 30.5
ppm; HRMS (ESI-TOF): calcd. for C19H16O3Na [M+Na+] 315.0997;
found 315.0998.
3.40 (4H, m), 3.19 (0.5H, dd, J = 16.8, 4.7 Hz), 3.09 (0.5H, dd, J =
16.8, 4.7 Hz). 13C{1H}NMR (101 MHz, CDCl3) δ 208.0, 207.2, 153.4,
153.3, 152.5, 151.9, 149.0, 147.6, 147.4, 147.1, 137.0, 134.3, 127.1,
126.4, 126.3, 123.8, 123.7, 112.0, 111.3, 106.6, 105.7, 61.8, 59.6, 56.4,
55.9, 44.8, 44.0, 4.5, 34.5 ppm; HRMS (ESI-TOF): calcd. for
C18H18O4 [M+] 298.1205; found 298.1197.
2-(2-Methoxy-4,6-dimethylphenyl)-1-indanone (2d). Prepared
according to typical procedure D using α-aryl-β-keto allyl ester 1d
(52.6 mg, 0.150 mmol) to afford the product as a colorless solid (17.0
mg, 43%). Column chromatography conditions = pentane/Et2O,
75:25; Rf = 0.33 (30% Et2O in pentane); mp =133−134 °C; IR
(NaCl): ν = 3055 (Aromatic C−H), 2987 (sp3C−H), 1712 (Ketone:
CO) cm−1; 1H NMR (400 MHz, CDCl3) δ 7.84 (1H, app. d, J = 7.6
Hz), 7.60 (1H, app. t, J = 7.4 Hz), 7.47 (1H, app. d, J = 7.6 Hz), 7.40
(1H, app. t, J = 7.4 Hz), 6.73−6.50 (2H, m), 3.91 (1H, dd, J = 8.3, 5.2
Hz), 3.55−3.42 (4H, m), 3.13 (1H, dd, J = 16.7, 5.2 Hz), 2.38 (3H, s),
2.31 (3H, s) ppm; 13C{1H}NMR (101 MHz, CDCl3) δ 207.5, 157.1,
152.9, 138.1, 137.7, 137.1, 134.2, 127.1, 126.3, 124.9, 123.9, 123.9,
110.4, 55.4, 47.5, 34.3, 21.6, 20.3 ppm; HRMS (ESI-TOF): calcd. for
C18H18O2 [M+] 266.1307; found 266.1315.
Cinnamyl 1-oxo-2-(2,4,6-Trimethoxyphenyl)-2,3-dihydro-1H-in-
dene-2-carboxylate (3). Prepared according to typical procedure B
using cinnamyl 1-oxo-2,3-dihydro-1H-indene-2-carboxylate S3 (0.792
g, 2.71 mmol) to afford the product as an colorless oil (1.113 g, 90%).
Column chromatography conditions = pentane/EtOAc, 90:10; Rf =
0.33 (30% EtOAc in pentane); IR (NaCl): ν = 3079 (CC−H),
3011 (Aromatic C−H), 1707 (Ester CO), 1605, 1588 (Aromatic
CC), 1118 (C−O) cm−1; 1H NMR (300 MHz, CDCl3) δ 7.81 (1H,
d, J = 7.6 Hz), 7.61−7.52 (1H, m), 7.43 (1H, d, J = 7.6 Hz), 7.40−7.16
(6H, m), 6.57 (1H, d, J = 15.9 Hz), 6.27 (1H, dt, J = 15.9, 6.3 Hz),
6.11 (2H, s), 4.88−4.67 (2H, m), 4.37 (1H, d, J = 17.1 Hz), 3.77 (3H,
s), 3.58 (6H, s), 3.01 (1H, d, J = 17.1 Hz) ppm; 13C{1H}NMR (101
MHz, CDCl3) δ 200.3, 170.3, 160.7, 158.4, 152.2, 136.5, 135.4, 134.7,
133.8, 128.6, 127.9, 127.3, 126.7, 126.2, 124.4, 123.6, 111.7, 92.3, 66.5,
61.8, 55.9, 55.5, 39.9 ppm; HRMS (ESI-TOF): calcd. for C28H26O6Na
[M+Na+] 481.1627; found 481.1633.
Typical Procedure D: Racemic Decarboxylative Asymmetric
Protonation. Racemic protonation of α-substituted-β-keto allyl esters
1a−1q was adapted from the literature.10 Pd(OAc)2 (0.10 equiv) and
dppe (0.125 equiv) were added to a Schlenk flask (25 mL), and 1,4-
dioxane (2.5 mL) was added. The suspension was stirred at 40 °C for
60 min, and formic acid (6.00 equiv) was added, followed immediately
by α-substituted-β-keto allyl ester (1.00 equiv) in 1,4-dioxane (2.5
mL) from a round-bottom flask (25 mL, 2-neck). The reaction mixture
was stirred at 40 °C for 10 h, cooled to room temperature, filtered
through a plug of Celite, and washed with Et2O. The solvent was
removed in vacuo, and the resulting residue was purified by silica gel
column chromatography (pentane/Et2O).
2-(2,4,6-Trimethoxyphenyl)-1-indanone (2a). Prepared according
to typical procedure D using α-aryl-β-keto allyl ester 1a (50.0 mg,
0.131 mmol) to afford the product as an orange solid (23.5 mg, 60%).
Column chromatography conditions = pentane/Et2O, 95:5 to 80:20;
Rf = 0.63 (50% EtOAc in pentane); mp =124−125 °C; IR (NaCl): ν =
3054 (Aromatic C−H), 2988 (sp3C−H), 1713 (Ketone: CO) cm−1;
1H NMR (400 MHz, CDCl3) δ 7.81 (1H, app. d, J = 7.6 Hz), 7.58
(1H, app. t, J = 7.3 Hz), 7.45 (1H, app. d, J = 7.6 Hz), 7.37 (1H, app. t,
J = 7.3 Hz), 6.19 (1H, s), 6.09 (1H, s), 4.34−4.26 (1H, m), 3.82 (3H,
s), 3.80 (3H, s), 3.49−3.38 (4H, m), 3.08 (1H, dd, J = 16.7, 5.1 Hz)
ppm; 13C{1H}NMR (101 MHz, CDCl3) δ 207.9, 160.4, 159.2, 158.6,
153.2, 137.0, 133.9, 126.8, 126.1, 123.6, 109.4, 91.3, 90.9, 55.9, 55.4,
55.4, 43.3, 34.3 ppm; HRMS (ESI-TOF): calcd. for C18H19O4 [M
+H+] 299.1283; found 299.1284.
2-(2,6-Dimethylphenyl)-1-indanone (2e). Prepared according to
typical procedure D using α-aryl-β-keto allyl ester 1e (48.1 mg, 0.150
mmol) to afford the product as a colorless solid (27.4 mg, 77%).
Column chromatography conditions = pentane/Et2O, 93:7; Rf = 0.58
(30% Et2O in pentane); mp =142−143 °C; IR (NaCl): ν = 3056
1
(Aromatic C−H), 2985 (sp3C−H), 1717 (Ketone: CO) cm−1; H
NMR (400 MHz, CDCl3) δ 7.90 (1H, app. d, J = 7.5 Hz), 7.67 (1H,
app. t, J = 7.5 Hz), 7.54 (1H, app. d, J = 7.5 Hz), 7.47 (1H, app. t, J =
7.5 Hz), 7.15−7.07 (2H, m), 7.03 (1H, dd, J = 8.3, 4.7 Hz), 4.27 (1H,
dd, J = 8.5, 5.5 Hz), 3.69 (1H, dd, J = 17.4, 8.5 Hz), 3.16 (1H, dd, J =
17.4, 5.5 Hz), 2.46 (3H, s), 1.91 (3H, s) ppm; 13C{1H}NMR (101
MHz, CDCl3) δ 206.5, 152.6, 137.8, 137.0, 136.5, 136.4, 134.9, 129.5,
128.3, 127.9, 127.2, 126.6, 124.3, 50.2, 34.1, 21.4, 20.9 ppm; HRMS
(ESI-TOF): calcd. for C17H16O [M+] 236.1201; found 236.1192.
2-(2-(Methoxy)naphthalen-1-yl)-1-indanone (2f). Prepared ac-
cording to typical procedure D using α-aryl-β-keto allyl ester 1f
(34.1 mg, 0.092 mmol) to afford the product as an orange solid (23.5
mg, 89%). Column chromatography conditions = pentane/Et2O, 95:5
to 90:10; Rf = 0.28 (30% Et2O in pentane); mp =136−138 °C; IR
(NaCl): ν = 3055 (Aromatic C−H), 2987 (sp3C−H), 1712 (Ketone:
1
CO) cm−1; H NMR (400 MHz, CDCl3) δ 8.02 (0.7H, d, J = 8.5
Hz), 7.95 (0.2H, d, J = 7.4 Hz), 7.90 (0.7H, d, J = 7.6 Hz), 7.87−7.76
(2H, m), 7.71 (0.3H, t, J = 7.4 Hz), 7.64 (0.7H, t, J = 7.2 Hz), 7.60−
7.30 (3.9H, m), 7.30−7.25 (0.7H, m), 7.22−7.15 (0.3H, m), 6.92
(0.3H, d, J = 8.5 Hz), 5.10 (0.3H, dd, J = 8.4, 5.3 Hz), 4.51 (0.7H, dd, J
= 8.4, 5.3 Hz), 3.97 (0.8H, s), 3.69 (1H, dd, J = 17.1, 8.4 Hz), 3.61
(2.2H, s), 3.41 (0.3H, dd, J = 17.1, 5.3 Hz), 3.21 (0.7H, dd, J = 17.1,
5.3 Hz) ppm; 13C{1H}NMR (101 MHz, CDCl3) δ 207.4, 154.4, 152.8,
137.1, 134.9, 134.4, 133.9, 129.8, 129.6, 129.2, 129.2, 128.9, 127.8,
127.3, 127.0, 126.9, 126.4, 124.5, 123.9, 123.7, 123.5, 122.9, 122.6,
114.2, 113.7, 57.3, 56.2, 46.2, 45.7, 35.3, 34.4 ppm; HRMS (ESI-
TOF): calcd. for C20H16O2 [M+] 288.1150; found 288.1156.
2-(2,6-Dimethoxyphenyl)-1-indanone (2b). Prepared according to
typical procedure D using α-aryl-β-keto allyl ester 1b (52.9 mg, 0.150
mmol) to afford the product as an orange solid (18.9 mg, 47%).
Column chromatography conditions = pentane/Et2O, 95:5 to 80:20;
Rf = 0.25 (30% Et2O in pentane); mp =159−160 °C; IR (NaCl): ν =
2937, 1473 (sp3C−H), 1706 (Ketone: CO), 856 (Aromatic C−H)
1
cm−1; H NMR (400 MHz, CDCl3) δ 7.82 (1H, app. d, J = 7.6 Hz),
7.59 (1H, app. t, J = 7.5), 7.46 (1H, app. d, J = 7.6 Hz), 7.39 (1H, app.
t, J = 7.5 Hz), 7.20 (1H, t, J = 8.3 Hz), 6.61 (1H, d, J = 8.3 Hz), 6.51
(1H, d, J = 8.3 Hz), 4.39 (1H, dd, J = 8.4, 5.2 Hz), 3.85 (3H, s), 3.54−
3.44 (4H, m), 3.11 (1H, dd, J = 16.7, 5.2 Hz) ppm; 13C{1H}NMR
(101 MHz, CDCl3) δ 207.5, 158.7, 158.0, 153.1, 137.0, 134.0, 128.2,
126.9, 126.1, 123.6, 117.0, 104.5, 104.1, 56.0, 55.5, 43.5, 34.2 ppm;
HRMS (ESI-TOF): calcd. for C17H16O3 [M+] 268.1099; found
268.1106.
2-(2,4-Dimethoxyphenyl)-1-indanone (2g). Prepared according to
typical procedure D using α-aryl-β-keto allyl ester 1g (46.2 mg, 0.131
mmol) to afford the product as a colorless solid (22.2 mg, 63%).
Column chromatography conditions = pentane/Et2O, 95:5 to 80:20;
Rf = 0.22 (30% Et2O in pentane); mp =119−120 °C; IR (NaCl): ν =
3054 (Aromatic C−H), 2982 (sp3C−H), 1712 (Ketone: CO)
1
cm−1; H NMR (300 MHz, CDCl3) δ 7.84 (1H, app. d, J = 7.5 Hz),
7.63 (1H, app. t, J = 7.5 Hz), 7.48 (1H, app. d, J = 7.5 Hz), 7.42 (1H,
app. t, J = 7.5 Hz), 7.08 (1H, d, J = 8.9 Hz), 6.52−6.43 (2H, m), 3.89
(1H, dd, J = 8.3, 4.9 Hz), 3.81 (3H, s), 3.68−3.49 (4H, m), 3.17 (1H,
dd, J = 17.0, 4.9 Hz) ppm; 13C{1H}NMR (101 MHz, CDCl3) δ 207.3,
160.3, 158.2, 153.4, 136.9, 134.6, 130.9, 127.3, 126.4, 124.1, 121.3,
104.5, 99.4, 55.5, 55.5, 50.1, 35.3 ppm; HRMS (ESI-TOF): calcd. for
C17H16O3 [M+] 268.1099; found 268.1088.
(2,3,4-Trimethoxyphenyl)-1-indanone (2h). Prepared according to
typical procedure D using α-aryl-β-keto allyl ester 1h (34.0 mg, 0.089
mmol) to afford the product as an orange oil (14.8 mg, 56%). Column
chromatography conditions = pentane/Et2O, 95:5 to 80:20; Rf = 0.16
2-(2,3,6-Trimethoxyphenyl)-1-indanone (2c). Prepared according
to typical procedure D using α-aryl-β-keto allyl ester 1c (34.0 mg,
0.089 mmol) to afford the product as a brown oil (19.1 mg, 72%).
Column chromatography conditions = pentane/Et2O, 95:5 to 80:20;
Rf = 0.17 (30% Et2O in pentane); IR (NaCl): ν = 3054 (Aromatic C−
1
H), 2988 (sp3C−H), 1711 (Ketone: CO) cm−1; H NMR (400
MHz, CDCl3) δ 7.83 (1H, app. t, J = 7.4 Hz), 7.59 (1H, app. t, J = 7.4
Hz), 7.46 (1H, app. d, J = 7.4 Hz), 7.39 (1H, app. t, J = 7.4 Hz), 6.79
(1H, d, J = 8.9 Hz), 6.60 (0.5H, d, J = 8.9 Hz), 6.54 (0.5H, d, J = 8.9
Hz), 4.37−4.27 (1H, m), 3.92−3.73 (6H, m, J = 31.3, 13.6 Hz), 3.59−
I
DOI: 10.1021/acs.joc.7b00303
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The Journal of Organic Chemistry
Article
(30% Et2O in pentane); IR (NaCl): ν = 3054 (Aromatic C−H), 2985
(sp3C−H), 1710 (Ketone: CO) cm−1; 1H NMR (400 MHz,
CDCl3) δ 7.83 (1H, app. d, J = 7.6 Hz), 7.62 (1H, app. t, J = 7.5 Hz),
7.48 (1H, app. d, J = 7.6 Hz), 7.41 (1H, app. t, J = 7.5 Hz), 6.83 (1H,
d, J = 8.5 Hz), 6.62 (1H, d, J = 8.5 Hz), 3.89−3.76 (7H, m), 3.68 (3H,
s), 3.59 (1H, dd, J = 17.1, 6.7 Hz), 3.14 (1H, dd, J = 17.1, 4.7 Hz)
ppm; 13C{1H}NMR (101 MHz, CDCl3) δ 207.4, 153.4, 153.4, 151.7,
142.4, 136.8, 134.7, 127.5, 127.0, 126.5, 124.5, 124.1, 107.2, 60.8, 60.5,
56.2, 50.3, 36.2 ppm; HRMS (ESI-TOF): calcd. for C18H18O4 [M+]
298.1205; found 298.1213.
2-(Benzo[d][1,3]dioxol-5-yl)-1-indanone (2i). Prepared according
to typical procedure D using α-aryl-β-keto allyl ester 1i (33.0 mg,
0.098 mmol) to afford the product as an orange oil (20.3 mg, 82%).
Column chromatography conditions = pentane/Et2O, 92:8; Rf = 0.35
(30% Et2O in pentane); IR (NaCl): ν = 3055 (Aromatic C−H), 2987
(sp3C−H), 1711 (Ketone: CO) cm−1; 1H NMR (400 MHz,
CDCl3) 7.79 (1H, d, J = 7.7 Hz), 7.63 (1H, td, J = 7.5, 1.2 Hz), 7.52−
7.48 (1H, m), 7.43−7.38 (1H, m), 6.74 (1H, d, J = 7.8 Hz), 6.66 (1H,
dd, J = 7.8, 1.8 Hz), 6.61 (1H, d, J = 1.8 Hz), 5.90 (2H, s), 3.79 (1H,
dd, J = 8.3, 4.0 Hz), 3.65 (1H, dd, J = 17.4, 8.3 Hz), 3.19 (1H, dd, J =
17.4, 4.0 Hz); 13C{1H}NMR (101 MHz, CDCl3) δ 206.09, 153.65,
148.14, 146.76, 136.29, 135.19, 133.50, 127.90, 126.56, 124.70, 121.34,
108.66, 108.21, 101.16, 53.23, 36.11 ppm; HRMS (ESI-TOF): calcd.
for C16H12O3 [M+] 252.0786; found 252.0774.
= 7.6 Hz), 7.51 (1H, app. t, J = 7.6 Hz), 6.19 (1H, s), 6.09 (1H, s),
4.34 (1H, dd, J = 8.5, 5.1 Hz), 3.83 (3H, s), 3.80 (3H, s), 3.69 (1H, dd,
J = 17.1, 8.5 Hz), 3.46 (3H, s), 3.19 (1H, dd, J = 17.1, 5.1 Hz) ppm;
13C{1H}NMR (101 MHz, CDCl3) δ 206.6, 160.8, 159.3, 158.5, 150.6
(q, J = 2.1 Hz), 138.6, 130.7 (q, J = 4.7 Hz), 128.0 (q, J = 32.1 Hz),
127.4, 127.2, 124.1 (q, J = 273.3 Hz), 108.8, 91.4, 91.1, 56.0, 55.5, 43.0,
33.3 ppm; 19F NMR (376 MHz, CDCl3) δ −62.3 ppm; HRMS (ESI-
TOF): calcd. for C19H17O4F3Na [M+Na+] 389.0977; found 389.0979.
2-Methyl-1-indanone (2o). Prepared according to typical proce-
dure D using α-methyl-β-keto allyl ester 1o (34.5 mg, 0.150 mmol) to
afford the product as a yellow oil (20.3 mg, 91%). Column
chromatography conditions = pentane/EtOAc, 95:5; spectroscopic
analysis is in good accordance to literature.4a
2-Allyl-1-indanone (2p). Prepared according to typical procedure
D using α-allyl-β-keto allyl ester 1p (38.4 mg, 0.150 mmol) to afford
the product as a brown oil (10.1 mg, 39%). Column chromatography
conditions = pentane/EtOAc, 95:5; spectroscopic analysis is in good
accordance to literature.32
2-Benzyl-1-indanone (2q). Prepared according to typical procedure
D using α-benzyl-β-keto allyl ester 1q (46.0 mg, 0.150 mmol) to afford
the product as a yellow oil (25.5 mg, 77%). Column chromatography
conditions = pentane/EtOAc, 95:5; spectroscopic analysis is in good
accordance to literature.33
Typical Procedure E: Homogeneous Decarboxylative Asym-
metric Protonation. Homogeneous protonation of α-substitued-β-
keto allyl esters 1a−1q was adapted from the literature.10 Pd2dba3·
CHCl3 (0.05 equiv) and (S)-(CF3)3-t-Bu PHOX (0.125 equiv) were
dissolved in THF in a Schlenk flask (25 mL) and stirred at 40 °C for
30 min. α-Substituted-β-keto allyl ester (1 equiv) and Meldrum’s acid
(2.5 equiv) were dissolved in THF (0.03 M) in a round-bottom flask
(25 mL, 2-neck) and added to the Pd-complex solution, maintained at
40 °C, in one portion. The reaction mixture was stirred at 40 °C for 1
h, cooled to room temperature, filtered through a plug of Celite and
washed with Et2O. The solvent was removed in vacuo, and the
resulting residue was purified by silica gel column chromatography
(pentane/Et2O).
2-(4-Methoxyphenyl)-1-indanone (2j). Prepared according to
typical procedure D using α-aryl-β-keto allyl ester 1j (42.0 mg,
0.130 mmol) to afford the product as an orange solid (27.0 mg, 87%).
Column chromatography conditions = pentane/Et2O, 95:5; spectro-
scopic analysis is in good accordance to literature.30
2-(Phenyl)-1-indanone (2k). Prepared according to typical
procedure D using α-aryl-β-keto allyl ester 1k (43.9 mg, 0.150
mmol) to afford the product as a brown solid (23.3 mg, 75%). Column
chromatography conditions = pentane/Et2O, 95:5; spectroscopic
analysis is in good accordance to literature.31
5-Methyl-2-(2,4,6-trimethoxyphenyl)-1-indanone (2l). Prepared
according to typical procedure D using α-aryl-β-keto allyl ester 1l
(59.5 mg, 0.150 mmol) to afford the product as a colorless solid (40.3
mg, 86%). Column chromatography conditions = pentane/EtOAc,
85:15; Rf = 0.43 (30% EtOAc in pentane); mp =151−152 °C; IR
(NaCl): ν = 2995, 801 (Aromatic C−H), 2961, 1454 (sp3C−H), 1704
(Ketone: CO), 1111 (C−O) cm−1; 1H NMR (300 MHz, CDCl3) δ
7.70 (1H, d, J = 7.8 Hz), 7.24 (1H, app. s), 7.18 (1H, app. d, J = 7.8
Hz), 6.18 (1H, s), 6.09 (1H, s), 4.27 (1H, dd, J = 8.4, 5.2 Hz), 3.82
(3H, s), 3.80 (3H, s), 3.53−3.32 (4H, m), 3.03 (1H, dd, J = 16.7, 5.2
Hz), 2.45 (3H, s) ppm; 13C{1H}NMR (101 MHz, CDCl3) δ 207.6,
160.5, 159.3, 158.8, 153.8, 145.0, 134.9, 128.2, 126.6, 123.6, 109.7,
91.5, 91.0, 56.0, 55.6, 55.5, 43.6, 34.3, 22.2 ppm; HRMS (ESI-TOF):
calcd. for C19H20O4Na [M+Na+] 335.1259; found 335.1271.
5,7-Dichloro-2-(2,4,6-trimethoxyphenyl)-1-indanone (2m). Pre-
pared according to typical procedure D using α-aryl-β-keto allyl
ester 1m (67.7 mg, 0.150 mmol) to afford the product as a colorless
solid (33.2 mg, 60%). Column chromatography conditions = pentane/
EtOAc, 85:15; Rf = 0.58 (30% EtOAc in pentane); mp =159−160 °C;
IR (NaCl): ν = 3061 (Aromatic C−H), 2961, 1442 (sp3C−H), 1721
(Ketone: CO), 1585, 1569 (Aromatic CC), 1113 (C−O), 807
(C−Cl) cm−1; 1H NMR (300 MHz, CDCl3) δ 7.33 (2H, s), 6.15 (1H,
s), 6.09 (1H, s), 4.31 (1H, dd, J = 8.6, 5.4 Hz), 3.79 (6H, s), 3.51 (3H,
s), 3.37 (1H, dd, J = 17.1, 8.6 Hz), 3.03 (1H, dd, J = 17.1, 5.4 Hz)
ppm; 13C{1H}NMR (101 MHz, CDCl3) δ 203.2, 160.7, 159.3, 158.6,
156.6, 140.1, 132.4, 131.6, 128.9, 125.1, 108.9, 91.4, 91.1, 56.0, 55.8,
55.5, 44.0, 33.5 ppm; HRMS (ESI-TOF): calcd. for C18H16O4Cl2Na
[M+Na+] 389.0323; found 389.0312.
(S)-2-(2,4,6-Trimethoxyphenyl)-1-indanone ((S)-2a). Prepared
according to typical procedure E using α-aryl-β-keto allyl ester 1a
(50.0 mg, 0.131 mmol) to afford the product (34.0 mg, 87%), identical
in all respects to the previously prepared racemic sample, with the
20
exception of [α]D = −50.1 (c 0.30, CHCl3); SFC (see Table S1).
(S)-2-(2,6-Dimethoxyphenyl)-1-indanone ((S)-2b). Prepared ac-
cording to typical procedure E using α-aryl-β-keto allyl ester 1b (50.0
mg, 0.142 mmol) to afford the product (35.7 mg, 94%), identical in all
respects to the previously prepared racemic sample, with the exception
20
of [α]D = −48.1 (c 1.00, CHCl3); SFC (see Table S1).
(S)-2-(2,3,6-Trimethoxyphenyl)-1-indanone ((S)-2c). Prepared
according to typical procedure E using α-aryl-β-keto allyl ester 1c
(24.5 mg, 0.064 mmol) to afford the product (13.8 mg, 72%), identical
in all respects to the previously prepared racemic sample, with the
20
exception of [α]D = −11.8 (c 0.40, CHCl3); SFC (see Table S1).
(S)-2-(2-Methoxy-4,6-dimethylphenyl)-1-indanone ((S)-2d). Pre-
pared according to typical procedure E using α-aryl-β-keto allyl ester
1d (50.0 mg, 0.143 mmol) to afford the product (35.3 mg, 93%),
identical in all respects to the previously prepared racemic sample, with
the exception of [α]D20 = −47.3 (c 0.40, CHCl3); SFC (see Table S1).
(S)-2-(2,6-Dimethylphenyl)-1-indanone ((S)-2e). Prepared accord-
ing to typical procedure E using α-aryl-β-keto allyl ester 1e (48.1 mg,
0.150 mmol) to afford the product (26.1 mg, 74%), identical in all
respects to the previously prepared racemic sample, with the exception
20
of [α]D = −47.1 (c 2.20, CHCl3); SFC (see Table S1).
(S)-2-(2-(Methoxy)naphthalen-1-yl)-1-indanone ((S)-2f). Pre-
pared according to typical procedure E using α-aryl-β-keto allyl ester
1f (55.9 mg, 0.150 mmol) to afford the product (41.2 mg, 95%),
identical in all respects to the previously prepared racemic sample, with
the exception of [α]D20 = −63.9 (c 1.60, CHCl3); SFC (see Table S1).
(S)-2-(2,4-Dimethoxyphenyl)-1-indanone ((S)-2g). Prepared ac-
cording to typical procedure E using α-aryl-β-keto allyl ester 1g (52.9
mg, 0.150 mmol) to afford the product (37.7 mg, 94%), identical in all
4-(Trifluoromethyl)-2-(2,4,6-trimethoxyphenyl)-1-indanone (2n).
Prepared according to typical procedure D using α-aryl-β-keto allyl
ester 1n (67.6 mg, 0.150 mmol) to afford the product as an orange oil
(42.3 mg, 77%). Column chromatography conditions = pentane/
EtOAc, 85:15; Rf = 0.48 (30% EtOAc in pentane); IR (NaCl): ν =
3061 (Aromatic C−H), 2921, 2852, 1442 (sp3C−H), 1728 (Ketone:
1
CO), 1612, 1594 (Aromatic CC), 1113 (C−O) cm−1; H NMR
(300 MHz, CDCl3) δ 7.98 (1H, app. d, J = 7.6 Hz), 7.85 (1H, app. d, J
J
DOI: 10.1021/acs.joc.7b00303
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
respects to the previously prepared racemic sample, with the exception
of [α]D = −1.61 (c 1.30, CHCl3); SFC (see Table S1).
Bu-PHOX (11.1 mg, 0.01875 mmol), and 1,4-dioxane (2.5 mL) were
added. The mixture was stirred at 40 °C for 30 min prior to the
addition of formic acid (34 μL, 0.90 mmol) followed immediately by a
solution of α-substituted-β-keto allyl ester (0.15 mmol) in 1,4-dioxane
(2.5 mL) from a round-bottom flask (25 mL, 2-neck). The reaction
mixture was stirred at 40 °C for 18 h, filtered through a plug of Celite,
and washed with Et2O. The filtrate was concentrated in vacuo and
purified by silica gel column chromatography (pentane/Et2O).
(R)-2-(2,4,6-Trimethoxyphenyl)-1-indanone ((R)-2a). Prepared
according to typical procedure F using α-aryl-β-keto allyl ester 1a
(57.4 mg, 0.150 mmol) to afford the product (36.2 mg, 81%), identical
in all respects to the previously prepared racemic sample, with the
20
(S)-(2,3,4-Trimethoxyphenyl)-1-indanone ((S)-2h). Prepared ac-
cording to typical procedure E using α-aryl-β-keto allyl ester 1h (50.0
mg, 0.131 mmol) to afford the product (29.6 mg, 76%), identical in all
respects to the previously prepared racemic sample, with the exception
20
of [α]D = −16.0 (c 0.40, CHCl3); SFC (see Table S1).
(S)-2-(Benzo[d][1,3]dioxol-5-yl)-1-indanone ((S)-2i). Prepared ac-
cording to typical procedure E using α-aryl-β-keto allyl ester 1i (50.5
mg, 0.150 mmol) to afford the product (23.6 mg, 62%), identical in all
respects to the previously prepared racemic sample, with the exception
20
of [α]D = +34.7 (c 0.60, CHCl3); SFC (see Table S1).
20
exception of [α]D = +24.6 (c 2.11, CHCl3); SFC (see Table S1).
(S)-2-(4-Methoxyphenyl)-1-indanone ((S)-2j). Prepared according
to typical procedure E using α-aryl-β-keto allyl ester 1j (48.4 mg, 0.150
mmol) to afford the product (25.1 mg, 70%), identical in all respects
to the previously prepared racemic sample, with the exception of
(R)-2-(2,6-Dimethoxyphenyl)-1-indanone ((R)-2b). Prepared ac-
cording to typical procedure F using α-aryl-β-keto allyl ester 1b (52.9
mg, 0.150 mmol) to afford the product (33.8 mg, 84%), identical in all
respects to the previously prepared racemic sample, with the exception
20
[α]D = +24.2 (c 1.70, CHCl3); SFC (see Table S1).
20
of [α]D = +36.0 (c 1.79, CHCl3); SFC (see Table S1).
(S)-2-(Phenyl)-1-indanone ((S)-2k). Prepared according to typical
(R)-2-(2,3,6-Trimethoxyphenyl)-1-indanone ((R)-2c). Prepared
according to typical procedure F using α-aryl-β-keto allyl ester 1c
(57.4 mg, 0.150 mmol) to afford the product (35.4 mg, 79%), identical
in all respects to the previously prepared racemic sample, with the
procedure E using α-aryl-β-keto allyl ester 1k (43.9 mg, 0.150 mmol)
to afford the product (26.3 mg, 84%), identical in all respects to the
20
previously prepared racemic sample, with the exception of [α]D
=
+6.4 (c 0.12, CHCl3); SFC (see Table S1).
20
exception of [α]D = +26.8 (c 1.56, CHCl3); SFC (see Table S1).
(S)-5-Methyl-2-(2,4,6-trimethoxyphenyl)-1-indanone ((S)-2l). Pre-
pared according to typical procedure E using α-aryl-β-keto allyl ester
1l (59.5 mg, 0.150 mmol) to afford the product (34.7 mg, 74%),
identical in all respects to the previously prepared racemic sample, with
the exception of [α]D20 = −37.8 (c 0.21, CHCl3); SFC (see Table S1).
(S)-5,7-Dichloro-2-(2,4,6-trimethoxyphenyl)-1-indanone ((S)-
2m). Prepared according to typical procedure E using α-aryl-β-keto
allyl ester 1m (67.7 mg, 0.150 mmol) to afford the product (48.0 mg,
87%), identical in all respects to the previously prepared racemic
(R)-2-(2-Methoxy-4,6-dimethylphenyl)-1-indanone ((R)-2d). Pre-
pared according to typical procedure F using α-aryl-β-keto allyl ester
1d (52.6 mg, 0.150 mmol) to afford the product (38.9 mg, 97%),
identical in all respects to the previously prepared racemic sample, with
the exception of [α]D20 = +27.6 (c 1.67, CHCl3); SFC (see Table S1).
(R)-2-(2,6-Dimethylphenyl)-1-indanone ((R)-2e). Prepared accord-
ing to typical procedure F using α-aryl-β-keto allyl ester 1e (48.1 mg,
0.150 mmol) to afford the product (34.0 mg, 96%), identical in all
respects to the previously prepared racemic sample, with the exception
20
sample, with the exception of [α]D = −174.3 (c 0.11, CHCl3); SFC
20
(see Table S1).
of [α]D = +0.3 (c 1.38, CHCl3); SFC (see Table S1).
(S)-4-(Trifluoromethyl)-2-(2,4,6-trimethoxyphenyl)-1-indanone
((S)-2n). Prepared according to typical procedure E using α-aryl-β-
keto allyl ester 1n (67.6 mg, 0.150 mmol) to afford the product (41.9
mg, 76%), identical in all respects to the previously prepared racemic
sample, with the exception of [α]D = −48.1 (c 0.11, CHCl3); SFC
(see Table S1).
(R)-2-(2-(Methoxy)naphthalen-1-yl)-1-indanone ((R)-2f). Pre-
pared according to typical procedure F using α-aryl-β-keto allyl ester
1f (55.9 mg, 0.150 mmol) to afford the product (38.3 mg, 88%),
identical in all respects to the previously prepared racemic sample, with
the exception of [α]D20 = +22.9 (c 1.64, CHCl3); SFC (see Table S1).
(R)-2-(2,4-Dimethoxyphenyl)-1-indanone ((R)-2g). Prepared ac-
cording to typical procedure F using α-aryl-β-keto allyl ester 1g (52.9
mg, 0.150 mmol) to afford the product (37.8 mg, 94%), identical in all
respects to the previously prepared racemic sample, with the exception
20
(S)-2-Methyl-1-indanone ((S)-2o). Prepared according to typical
procedure E using α-methyl-β-keto allyl ester 1o (34.5 mg, 0.150
mmol) to afford the product (20.7 mg, 95%), identical in all respects
to the previously prepared racemic sample, with the exception of
20
of [α]D = +2.8 (c 2.36, CHCl3); SFC (see Table S1).
20
[α]D = +15.0 (c 0.05, CHCl3); SFC (see Table S1). The absolute
(R)-(2,3,4-Trimethoxyphenyl)-1-indanone ((R)-2h). Prepared ac-
cording to typical procedure F using α-aryl-β-keto allyl ester 1h (57.4
mg, 0.150 mmol) to afford the product (37.9 mg, 85%), identical in all
respects to the previously prepared racemic sample, with the exception
configuration was established by comparison of the optical rotation to
the literature value for (R)-2-methyl-1-indanone: [α]D22 − 42 (c 1.72,
p-dioxane).34
20
(S)-2-Allyl-1-indanone ((S)-2p). Prepared according to typical
procedure E using α-allyl-β-keto allyl ester 1p (38.4 mg, 0.150
mmol) to afford the product (19.2 mg, 74%), identical in all respects
to the previously prepared racemic sample, with the exception of
of [α]D = −1.7 (c 0.51, CHCl3); SFC (see Table S1).
(R)-2-(Benzo[d][1,3]dioxol-5-yl)-1-indanone ((R)-2i). Prepared
according to typical procedure F using α-aryl-β-keto allyl ester 1i
(50.5 mg, 0.150 mmol) to afford the product (32.0 mg, 85%), identical
in all respects to the previously prepared racemic sample, with the
20
[α]D = +6.6 (c 0.86, CHCl3); SFC (see Table S1). The absolute
20
configuration was established by comparison of the optical rotation to
the literature value for (R)-2-allyl-1-indanone: [α]D24 = +95.8 (c = 4.0,
CH2Cl2, 81% ee).32
exception of [α]D = −18.7 (c 0.82, CHCl3); SFC (see Table S1).
(R)-2-(4-Methoxyphenyl)-1-indanone ((R)-2j). Prepared according
to typical procedure F using α-aryl-β-keto allyl ester 1j (48.4 mg, 0.150
mmol) to afford the product (29.7 mg, 83%), identical in all respects
to the previously prepared racemic sample, with the exception of
(R)-2-Benzyl-1-indanone ((R)-2q). Prepared according to typical
procedure E using α-benzyl-β-keto allyl ester 1q (46.0 mg, 0.150
mmol) to afford the product (22.4 mg, 67%), identical in all respects
to the previously prepared racemic sample, with the exception of
20
[α]D = +4.0 (c 0.18, CHCl3); SFC (see Table S1).
(R)-2-(Phenyl)-1-indanone ((R)-2k). Prepared according to typical
procedure F using α-aryl-β-keto allyl ester 1k (43.9 mg, 0.150 mmol)
20
[α]D = −19.2 (c 0.89, CHCl3); SFC (see Table S1). The absolute
configuration was established by comparison of the optical rotation to
to afford the product (18.2 mg, 58%), identical in all respects to the
20
20
the literature value for (S)-2-benzyl-1-indanone: [α]D = +162 (c =
previously prepared racemic sample, with the exception of [α]D
=
0.1, CHCl3, 52% ee).35
+1.1 (c 0.97, CHCl3); SFC (see Table S1).
Typical Procedure F: Heterogeneous Decarboxylative
Asymmetric Protonation. Heterogeneous protonation of α-
substituted-β-keto allyl esters 1a−1q was adapted from the literature.8
Powdered 4 Å molecular sieves (270 mg) were added to a Schlenk
flask (25 mL). The flask and molecular sieves were flame-dried and
backfilled with N2 three times. Once the flask had cooled to ambient
temperature under N2, Pd(OAc)2 (3.4 mg, 0.015 mmol), (S)-(CF3)3-t-
(R)-5-Methyl-2-(2,4,6-trimethoxyphenyl)-1-indanone ((R)-2l).
Prepared according to typical procedure F using α-aryl-β-keto allyl
ester 1l (59.5 mg, 0.150 mmol) to afford the product (34.8 mg, 74%),
identical in all respects to the previously prepared racemic sample, with
the exception of [α]D20 = +13.8 (c 1.45, CHCl3); SFC (see Table S1).
(R)-5,7-Dichloro-2-(2,4,6-trimethoxyphenyl)-1-indanone ((R)-
2m). Prepared according to typical procedure F using α-aryl-β-keto
K
DOI: 10.1021/acs.joc.7b00303
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The Journal of Organic Chemistry
Article
1
allyl ester 1m (67.5 mg, 0.150 mmol) to afford the product (46.3 mg,
also isolated (7.4 mg, 42%). H NMR integration indicates 80−90%
deuterium incorporation at the methyl-position (observed at δ 1.90
ppm).
84%), identical in all respects to the previously prepared racemic
20
sample, with the exception of [α]D = +65.9 (c 0.32, CHCl3); SFC
(see Table S1).
Eq 2. Reaction performed using HCO2D. 2a was isolated (36.2 mg,
81%). H NMR integration indicates 49% deuterium incorporation at
the α-position (observed at δ 4.28 ppm). trans-β-Methylstyrene 4 was
also isolated (7.1 mg, 40%). 1H NMR integration indicates 0%
deuterium incorporation at the methyl-position (observed at δ 1.91
ppm).
1
(R)-4-(Trifluoromethyl)-2-(2,4,6-trimethoxyphenyl)-1-indanone
((R)-2n). Prepared according to typical procedure F using α-aryl-β-
keto allyl ester 1n (67.6 mg, 0.150 mmol) to afford the product (26.4
mg, 48%), identical in all respects to the previously prepared racemic
sample, with the exception of [α]D20 = +3.1 (c 0.81, CHCl3); SFC (see
Table S1).
Eq 3. Reaction performed using 3 Å molecular sieves and HCO2H.
2a was isolated (29.5 mg, 66%). H NMR integration indicates 0%
(S)-2-Methyl-1-indanone ((S)-2o). Prepared according to typical
procedure F using α-methyl-β-keto allyl ester 1o (34.5 mg, 0.150
mmol) to afford the product (15.6 mg, 71%), identical in all respects
to the previously prepared racemic sample, with the exception of
1
deuterium incorporation at the α-position (observed at δ 4.28 ppm).
Eq 4. Reaction performed with the addition of D2O (13.5 μL, 0.75
mmol) immediately prior to HCO2H. 2a was isolated (32.6 mg, 70%).
1H NMR integration indicates 8% deuterium incorporation at the α-
position (observed at δ 4.30−4.25 ppm).
20
[α]D = +6.3 (c 0.10, CHCl3); SFC (see Table S1).
(S)-2-Allyl-1-indanone ((S)-2p). Prepared according to typical
procedure F using α-allyl-β-keto allyl ester 1p (38.4 mg, 0.150
mmol) to afford the product (18.3 mg, 71%), identical in all respects
to the previously prepared racemic sample, with the exception of
Investigation of an Unidentified Proton Source. Eq 1.
Powdered 4 Å molecular sieves (180 mg) were added to a flame-
dried Schlenk flask (25 mL). The flask and molecular sieves were
flame-dried and backfilled with N2 three times. Once the flask had
cooled to ambient temperature under N2, Pd(OAc)2 (3.4 mg, 0.010
mmol), (S)-(CF3)3-t-Bu-PHOX (11.1 mg, 0.0125 mmol), and 1,4-
dioxane (2.5 mL) were added. The mixture was stirred at 40 °C for 30
min. Sodium formate (61.2 mg, 0.900 mmol) and α-aryl-β-keto allyl
ester 1a (57.4 mg, 0.150 mmol) were dried under vacuum for 1 h in a
flame-dried round-bottom flask (2-neck 25 mL), dissolved in 1,4-
dioxane (2.5 mL) and the solution transferred to the Schlenk flask via
a cannula. The reaction mixture was stirred at 40 °C for 18 h, filtered
through a plug of Celite and washed with Et2O. The filtrate was
concentrated in vacuo and purified by silica gel column chromatog-
raphy (pentane/Et2O, 95:5 to 80:20). 2a was isolated (13.0 mg, 29%)
with an ee of (S)-6%.
20
[α]D = +81.9 (c 0.80, CHCl3); SFC (see Table S1).
(S)-2-Benzyl-1-indanone ((S)-2q). Prepared according to typical
procedure F using α-benzyl-β-keto allyl ester 1q (46.0 mg, 0.150
mmol) to afford the product (30.1 mg, 90%), identical in all respects
to the previously prepared racemic sample, with the exception of
20
[α]D = +64.0 (c 1.12, CHCl3); SFC (see Table S1).
Identification of Divergent Byproducts. Eq 1. The reaction was
performed using α-aryl-β-keto allyl ester S4 (0.229 g, 0.500 mmol)
according to typical procedure F. 2a was isolated (109 mg, 73%) with
an ee of (R)-90%. trans-β-Methylstyrene 4 was isolated (0.038 g, 64%)
with spectroscopic analysis in good accordance to literature.36
Reaction without the Metal−Ligand Complex. The reaction was
performed using α-aryl-β-keto allyl ester S4 (69 mg, 0.15 mmol)
according to typical procedure F except no palladium or ligand was
added. As per the standard conditions, the reaction mixture was stirred
at 40 °C for 18 h, cooled to room temperature, and filtered through a
plug of Celite, and washed with Et2O. The crude product was analyzed
by SFC and no product 2a or trans-β-methylstyrene 4 formation was
observed. Subsequently, the solvent was removed in vacuo, and the
resulting residue was purified by silica gel column chromatography
(pentane/Et2O, 95:5 to 80:20) with α-aryl-β-keto allyl ester S4
isolated (26 mg, 0.057 mmol).
Eq 2. The reaction carried out as described for eq 1, except no
molecular sieves were included. 2a was isolated (13.2 mg, 29%) with
an ee of (S)-16%.
Investigation of a β-Keto Acid Intermediate. The reaction was
set up according to typical procedure F using α-aryl-β-keto allyl ester
1l (59.5 mg, 0.150 mmol). At 2.5 h the reaction was analyzed by TLC.
With evidence of some product formation, the reaction mixture was
cooled to 0 °C, filtered through a plug of Celite and washed with Et2O
(100 mL) into a 2-neck round-bottom flask. The filtrate was cooled to
0 °C and the flask flushed with N2. Trimethylsilyldiazomethane (1.5
mL, 2.0 M solution in ether, 3.0 mmol) was added dropwise and the
reaction mixture warmed to rt and stirred for 2 h. The solution was
cooled again to 0 °C and acetic acid (5 mL) added dropwise. The
reaction mixture was stirred for 2 h, washed with H2O (3 × 100 mL)
and then ether (100 mL). The organic layers were combined and
washed with saturated Na2CO3 solution (100 mL), dried over Na2SO4,
and concentrated in vacuo. No evidence of the formation of 6 was
Eq 2. The reaction was performed using α-aryl-β-keto allyl ester S4
(0.115 g, 0.250 mmol) as in eq 1 but Meldrum’s acid was added (with
the substrate as in typical procedure E) in place of formic acid. 2a was
isolated (0.033 g, 44%) with an ee of (S)-32%. 5,5-dicinnamyl-2,2-
dimethyl-1,3-dioxane-4,6-dione 5 was isolated (0.027 g, 57%) with
spectroscopic analysis in good accordance to literature.37
Deuterium-Labeling Studies. Prior to use, 4 Å molecular sieves
(270 mg) were heated in the microwave to 280 °C for 5 min (200 W)
then immediately transferred to a flame-dried Schlenk flask (25 mL)
containing a magnetic stir bar. The flask and molecular sieves were
then flame-dried and backfilled with N2 three times. Once the flask had
cooled to ambient temperature under N2, Pd(OAc)2 (3.4 mg, 0.015
mmol), (S)-(CF3)3-t-Bu-PHOX (11.1 mg, 0.01875 mmol), and 1,4-
dioxane (2.5 mL) were added. The mixture was stirred at 40 °C for 30
min prior to the addition of formic acid (34 μL, 0.90 mmol) followed
immediately by a solution of α-aryl-β-keto allyl ester S4 (68.8 mg,
0.150 mmol) in 1,4-dioxane (2.5 mL) from a round-bottom flask (25
mL, 2-neck). The reaction mixture was stirred at 40 °C for 18 h,
filtered through a plug of Celite and washed with Et2O. The filtrate
was concentrated in vacuo and purified by silica gel column
chromatography (pentane/Et2O, 100:0 to 90:10). The ee of the
product was determined by SFC under the standard conditions.
1
observed via TLC and H NMR spectroscopic analysis of the crude
reaction mixture.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.7b00303.
Full optimization results (Table S1, Figure S1); 1H
NMR, 13C NMR, and 19F NMR spectra of new
compounds; 1H NMR spectra for deuterium-labeling
studies; and the methods for the determination of
enantiomeric excess and SFC chromatograms of racemic
and enantioenriched compounds (PDF)
1
Deuterium incorporation was determined by comparison of the H
NMR integration to the previously isolated product 2a using unlabeled
formic acid as the proton source. Spectra were recorded using a 600
MHz spectrometer with a 25 s relaxation delay.
Eq 1. Reaction performed using DCO2H. 2a was isolated (23.9 mg,
1
X-ray crystallographic information for compound (S)-2a
53%). H NMR integration indicates 1% deuterium incorporation at
the α-position (observed at δ 4.31 ppm). trans-β-Methylstyrene 4 was
(CIF)
L
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To the best of our knowledge only one previous report of
enantiodivergent protonation exists wherein the switch in selectivity
is likely due to a change in mechanism based on the achiral protic
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: p.guiry@ucd.ie
ORCID
Patrick J. Guiry: 0000-0002-2612-8569
Notes
The authors declare no competing financial interest.
́
reagent utilized, see: (c) Concellon, C.; Duguet, N.; Smith, A. D. Adv.
Synth. Catal. 2009, 351, 3001−3009. (d) Wang, X.-N.; Lv, H.; Huang,
X.-L.; Ye, S. Org. Biomol. Chem. 2009, 7, 346−350.
(10) Doran, R.; Guiry, P. J. J. Org. Chem. 2014, 79, 9112−9124.
(11) (a) Yang, Y.; Philips, D.; Pan, S. J. Org. Chem. 2011, 76, 1902−
1905. (b) Zhong, C.; Liu, X.-H.; Chang, J.; Yu, J.-M.; Sun, X. Bioorg.
́
Med. Chem. Lett. 2013, 23, 4413−4418. (c) Mentre, F.; Pousset, F.;
ACKNOWLEDGMENTS
Comets, E.; Plaud, B.; Diquet, B.; Montalescot, G.; Ankri, A.; Mallet,
A.; Lechat, P. Clin. Pharmacol. Ther. 1998, 63, 64−78.
(12) Lee, C.-M.; Lee, K.-S.; Kim, J.; Jeong, E.-J. Photosensitive resin
composition for color filter and color filter using same. U.S. Patent
8158036 B2, April 17, 2012.
■
This publication has emanated from research conducted with
the financial support of the Synthesis and Solid State
Pharmaceutical Centre (SSPC), funded by Science Foundation
Ireland (SFI) under grant numbers 12\RC\2275. C.K. is
grateful for the award of a SSPC PhD Scholarship. Facilities
were provided by the Centre for Synthesis and Chemical
Biology (CSCB), funded by the Higher Education Authority’s
PRTLI. C.K. thanks Dr. Ramulu Akula (University College
Dublin) and David A. Petrone (University of Toronto) for
helpful advice and discussion. The authors wish to thank Dr.
Yannick Ortin for help with NMR spectroscopic studies, Dr.
́
(13) (a) Henin, F.; Muzart, J.; Pete, J.-P.; M’boungou-M’passi, A.;
Rau, H. Angew. Chem., Int. Ed. Engl. 1991, 30, 416−418. (b) Morita,
M.; Drouin, L.; Motoki, R.; Kimura, Y.; Fujimori, I.; Kanai, M.;
Shibasaki, M. J. Am. Chem. Soc. 2009, 131, 3858−3859. (c) Cheon, C.
H.; Kanno, O.; Toste, F. D. J. Am. Chem. Soc. 2011, 133, 13248−
13251. (d) Poisson, T.; Oudeyer, S.; Dalla, V.; Marsais, F.; Levacher,
V. Synlett 2008, 2008, 2447−2450.
(14) Phenyl and p-methoxybenzene substituted tertiary α−stereo-
centres were formed in 67% and 75% ee’s and 69% and 70% yields
respectively, see: Li, X.-H.; Zheng, B.-H.; Ding, C.-H.; Hou, X.-L. Org.
Lett. 2013, 15, 6086−6089.
(15) For a general review on organolead reagents see: Guiry, P. J.;
McCormack, P. Science of Synthesis; Moloney, M. G. Ed.; Thieme: New
York, 2003; Vol. 5, p 673.
(16) The absolute configuration of the product was unambiguously
determined to be (S) by X-ray crystallographic analysis, see the
Supporting Information for supplementary crystallographic data.
(17) Pinhey, J.; Rowe, B. Aust. J. Chem. 1980, 33, 113−120.
(18) Substrates 1o−1q were prepared via a procedure adapted from
the literature, see: Behenna, D. C.; Mohr, J. T.; Sherden, N. H.;
Marinescu, S. C.; Harned, A. M.; Tani, K.; Seto, M.; Ma, S.; Novak, Z.;
Krout, M. R.; McFadden, R. M.; Roizen, J. L.; Enquist, J. A., Jr.; White,
D. E.; Levine, S. R.; Petrova, K. V.; Iwashita, A.; Virgil, S. C.; Stoltz, B.
M. Chem. - Eur. J. 2011, 17, 14199−14223 and the Experimental
Section for further details.
Helge Muller-Bunz for X-ray crystal structure analysis, and
̈
Denise Moran and Chris Nottingham (University College
Dublin) for their help proofreading this manuscript.
REFERENCES
■
(1) (a) Tsuji, J.; Nisar, M.; Shimizu, I. J. Org. Chem. 1985, 50, 3416−
3417. (b) For a review on various applications of palladium and
formic acid, see: Guibe,
(2) Henin, F.; Muzart, J. Tetrahedron: Asymmetry 1992, 3, 1161−
1164.
(3) (a) Aboulhoda, S. J.; Henin, F.; Muzart, J.; Thorey, C.; Behnen,
W.; Martens, J.; Mehler, T. Tetrahedron: Asymmetry 1994, 5, 1321−
1326. (b) Muzart, J.; Henin, F.; Aboulhoda, S. J. Tetrahedron:
Asymmetry 1997, 8, 381−389. (c) Aboulhoda, S. J.; Reiners, I.; Wilken,
J.; Henin, F.; Martens, J.; Muzart, J. Tetrahedron: Asymmetry 1998, 9,
1847−1850. (d) Roy, O.; Diekmann, M.; Riahi, A.; Henin, F.; Muzart,
J. Chem. Commun. 2001, 6, 533−534. (e) Baur, M. A.; Riahi, A.;
Henin, F.; Muzart, J. Tetrahedron: Asymmetry 2003, 14, 2755−2761.
́
F. Tetrahedron 1998, 54, 2967−3042.
́
́
́
́
́
(19) Tsuji, J.; Mandai, T. Synthesis 1996, 1996, 1−24.
́
(20) Shimizu, I.; Ishii, H. Tetrahedron 1994, 50, 487−495.
(4) (a) Mohr, J. T.; Nishimata, T.; Behenna, D. C.; Stoltz, B. M. J.
Am. Chem. Soc. 2006, 128, 11348−11349. (b) For a general review on
enantioselective protonation, see: Mohr, J. T.; Hong, A. Y.; Stoltz, B.
M. Nat. Chem. 2009, 1, 359−369. (c) Fehr, C. Angew. Chem., Int. Ed.
Engl. 1996, 35, 2566−2587. (d) Oudeyer, S.; Brier
Eur. J. Org. Chem. 2014, 2014, 6103−6119.
́
(21) (a) Detalle, J.-F.; Riahi, A.; Steinmetz, V.; Henin, F.; Muzart, J. J.
Org. Chem. 2004, 69, 6528−6532. (b) Further investigation showed
the concentration of palladium influenced the rate but not the
enantioselectivity, indicating the asymmetric induction is purely
̀
e, J.-F.; Levacher, V.
organocatalysed, see: Kukula, P.; Matouse
Chem. - Eur. J. 2008, 14, 2699−2708.
̌
k, V.; Mallat, T.; Baiker, A.
(5) (a) Marinescu, S. C.; Nishimata, T.; Mohr, J. T.; Stoltz, B. M.
Org. Lett. 2008, 10, 1039−1042. (b) For an investigation into the
surprisingly high acidity of Meldrum’s acid, see: Nakamura, S.; Hirao,
H.; Ohwada, T. J. Org. Chem. 2004, 69, 4309−4316.
(22) The opposite sense of stereoinduction was observed for fused
and nonfused cycles in both the hetero- and homogeneous reactions.
(23) (a) Fragmentation of an allyl palladium formate complex to
produce propene and a catalytically active palladium species, has been
reported previously Oshima, M.; Shimizu, I.; Yamamoto, A.; Ozawa, F.
Organometallics 1991, 10, 1221−1223. (b) Decarboxylation/reductive
elimination may also be a concerted process, see: Mandai, T.;
Matsumoto, T.; Kawada, M.; Tsuji, J. Tetrahedron 1994, 50, 475−486.
(24) Oxidative addition of formic and acetic acid to palladium has
been previously reported, see Amatore, C.; Jutand, A.; Meyer, G.;
Carelli, I.; Chiarotto, I. Eur. J. Inorg. Chem. 2000, 2000, 1855−1859.
(25) Both carbon-bound and oxygen-bound arylpalladium enolate
complexes may be formed and undergo concerted intramolecular
reductive elimination. Regioselectivity is dependent upon the specific
stereoelectronic properties, see Culkin, D. A.; Hartwig, J. F.
Organometallics 2004, 23, 3398−3416.
(6) (a) Carroll, M. P.; Muller-Bunz, H.; Guiry, P. J. Chem. Commun.
̈
2012, 48, 11142−11144. (b) Recently we have extended this
approach to decarboxylative asymmetric allylic alkylation to prepare
quaternary α-allyl-α-aryl ketones and lactones, see: Akula, R.; Doran,
R.; Guiry, P. J. Chem. - Eur. J. 2016, 22, 9938−9942. (c) Akula, R.;
Guiry, P. J. Org. Lett. 2016, 18, 5472−5475.
(7) For selected examples of alternative approaches to tertiary α-aryl
ketones, see: (a) Bigot, A.; Williamson, A. E.; Gaunt, M. J. J. Am.
Chem. Soc. 2011, 133, 13778−13781. (b) Huang, Z.; Chen, Z.; Lim, L.
H.; Quang, G. C. P.; Hirao, H.; Zhou, J. Angew. Chem., Int. Ed. 2013,
52, 5807−5812. (c) Kang, B. C.; Nam, D. G.; Hwang, G.-S.; Ryu, D.
H. Org. Lett. 2015, 17, 4810−4813.
(8) Doran, R.; Carroll, M. P.; Akula, R.; Hogan, B. F.; Martins, M.;
Fanning, S.; Guiry, P. J. Chem. - Eur. J. 2014, 20, 15354−15359.
(9) For reviews on enantiodivergence see: (a) Zanoni, G.;
Castronovo, F.; Franzini, M.; Vidari, G.; Giannini, E. Chem. Soc. Rev.
(26) Zalesskiy, S. S.; Ananikov, V. P. Organometallics 2012, 31,
2302−2309.
(27) Craig, R. A.; Loskot, S. A.; Mohr, J. T.; Behenna, D. C.; Harned,
A. M.; Stoltz, B. M. Org. Lett. 2015, 17, 5160−5163.
́
2003, 32, 115−129. (b) Bartok, M. Chem. Rev. 2010, 110, 1663−1705.
M
DOI: 10.1021/acs.joc.7b00303
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(28) Morgan, J.; Pinhey, J. T. J. Chem. Soc., Perkin Trans. 1 1990,
715−720.
(29) Trost, B. M.; Xu, J. J. Org. Chem. 2007, 72, 9372−9375.
(30) Jagdale, A. R.; Youn, S. W. Eur. J. Org. Chem. 2011, 2011, 3904−
3910.
(31) Chen, P.-H.; Sieber, J.; Senanayake, C. H.; Dong, G. Chem. Sci.
2015, 6, 5440−5445.
(32) Trost, B. M.; Xu, J. J. Am. Chem. Soc. 2005, 127, 2846−2847.
(33) Poisson, T.; Dalla, V.; Marsais, F.; Dupas, G.; Oudeyer, S.;
Levacher, V. Angew. Chem., Int. Ed. 2007, 46, 7090−7093.
(34) Jaouen, G.; Meyer, A. J. Am. Chem. Soc. 1975, 97, 4667−4672.
(35) Pinedo-Rivilla, C.; Aleu, J.; Grande Benito, M.; Collado, I. G.
Org. Biomol. Chem. 2010, 8, 3784−3789.
(36) Compound is commercially available.
(37) Gan, K.-H.; Jhong, C.-J.; Yang, S.-C. Tetrahedron 2008, 64,
1204−1212.
N
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