Pd-Catalyzed Decarboxylative Asymmetric Protonation of Sterically Hindered α-Aryl Lactones and Dihydrocoumarins

Article abstract of DOI:10.1002/adsc.201800724

Pd-catalyzed decarboxylative asymmetric protonation (DAP) has been developed for sterically hindered α-aryl lactone and dihydrocoumarin substrates. Optimization studies were conducted using δ-lactone- and dihydrocoumarin-derived α-aryl, β-oxo-allyl esters with 2,4,6-trimethoxyphenyl as the aryl substituent. In the absence of a chiral P,N-ligand, (1R,2S)-(?)ephedrine, a cheap and readily available chiral proton donor, induced enantioselectivities of up to 92% ee and 88% ee with lactone and dihydrocoumarin substrates, respectively. Bulky aryl groups containing di-ortho substitutions and naphthyl groups gave the highest enantioselectivities of up to 92% and 86%, respectively. A stereochemical rationale is proposed to explain the preferred sense of asymmetric induction. (Figure presented.).

Full text of DOI:10.1002/adsc.201800724

Title: Pd-Catalyzed Decarboxylative Asymmetric Protonation of
Sterically Hindered α-Aryl Lactones and Dihydrocoumarins
Authors: Jinju James, Ramulu Akula, and Patrick Guiry
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10.1002/adsc.201800724
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Pd-Catalyzed Decarboxylative Asymmetric Protonation of
Sterically Hindered α-Aryl Lactones and Dihydrocoumarins
Jinju James a, Ramulu Akulab, Patrick J. Guirya,b*
a
Centre for Synthesis and Chemical Biology, School of Chemistry, University College Dublin, Belfield, Dublin 4,
Ireland
b
Synthesis & Solid State Pharmaceutical Centre (SSPC), School of Chemistry, University College Dublin, Belfield,
Dublin 4, Ireland
E-mail: p.guiry@ucd.ie
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. Pd-catalyzed decarboxylative asymmetric and dihydrocoumarin substrates, respectively. Bulky aryl
protonation (DAP) has been developed for sterically groups containing di-ortho substitutions and naphthyl
hindered α-aryl lactone and dihydrocoumarin substrates. groups gave the highest enantioselectivities of up to 92%
Optimization studies were conducted using δ-lactone- and and 86%, respectively. A stereochemical rationale is
dihydrocoumarin-derived α-aryl, β-oxo-allyl esters with proposed to explain the preferred sense of asymmetric
2,4,6-trimethoxyphenyl as the aryl substituent. In the induction.
absence of a chiral P,N-ligand, (1R,2S)-(−)ephedrine, a
cheap and readily available chiral proton donor, induced
enantioselectivities of up to 92% ee and 88% ee with lactone
Keywords: Decarboxylation; Enantioselective protonation;
Palladium Catalysis; Lactones; Dihydrocoumarins
Introduction
Lactone and dihyrocoumarin derivatives have a
structural framework that is commonly found in
natural products and pharmaceuticals.[1] They exhibit
important biological activities and have been
employed
as
antihypertensive,
antitumor,
antiinflamatory and antiplatelet aggregation agents.[2]
In addition, ring opening reactions result in hydroxy
groups that are easily transformed to new
functionalities.[3] It is therefore useful to probe
different ways to synthesize and derivatize this class of
compounds. While there has been extensive research
on the enantioselective formation of carbonyl groups
with quaternary[4] and tertiary[5] stereocentres, there
have only been limited reports of the enantioselective
construction of α-substituted lactones. Asymmetric
metal-catalysed α-arylation of enolates, in particular
those derived from ketones, aldehydes, oxindoles,
esters etc., has been well developed.[6] However, most
of these methods for the introduction of aryl groups are
limited to the asymmetric formation of quaternary
centres. The basic conditions needed to effect the α-
arylation are often unsuitable to form tertiary centres
stereoselectively, due to fast product racemization.
Scheme 1. Approaches for the enantioselective synthesis of
α-tertiary lactones and dihydrocoumarins.
1
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10.1002/adsc.201800724
Advanced Synthesis & Catalysis
The groups of MacMillan and Gaunt simultaneously report our investigations into the Pd-catalyzed DAP for
developed the enantioselective α-arylation of sterically hindered α-aryl β-oxo-allyl ester lactone and
enolsilane derivatives using a combination of copper dihydrocoumarin substrates to form tertiary
7]
catalysis and diaryliodonium salts.[ MacMillan also stereocentres with high levels of enantioselectivity.
reported three examples (Scheme 1, Eq 1) where α-
arylated δ-lactones were formed in high
7b]
enantioselectivities (up to 91% ee).[ Zhou developed
Results and Discussion
the first general method for the α-arylation of silyl
enolates (Scheme 1, Eq 2) derived from lactones to
The α-aryl, β-oxo-allylester substrates (1a-i and 3a-
i) for the study were synthesized by known methods
previously reported by our group.[19b, 19d] The lack of
literature precedents for the synthesis of α-aryl
lactones or dihydrocoumarins with sterically hindered
di-ortho substitutions prompted us to examine the
2,4,6-trimethoxyphenylated substrates (1a and 3a) for
DAP.
generate
tertiary
stereocentres
with
high
8]
enantioselectivities (up to 98% ee).[ The use of new
chiral phosphine ligands in particular was key to the
high stereosectivities observed. Recently Hyster
developed
a
highly enantioselective radical
dehalogenation of α-aryl α-halo lactones (Scheme 1,
Eq 3) using a ketoreductase nicotinimide-dependent
9]
enzyme (up to 96% ee).[
Table 1. Preliminary optimization results for substrates 1a
and 3a.
Despite the prevalence of the dihydrocoumarin
scaffold in many biologically active molecules, the
synthesis of non-racemic α-aryl dihydrocoumarins was
only first reported by List in 2012 (Scheme 1, Eq.
10]
4).[
Their synthesis of enantioenriched α-aryl
dihydrocoumarins was achieved via an effective de-
racemization strategy using catalytic amounts of chiral
phosphoric acid.
A
recent strategy for the
enantioselective construction of the dihydrocoumarin
core has mainly revolved around the N-hetrocyclic
carbene (NHC)-catalyzed [4+2] cycloadditon of o-
quinone methides (Scheme 1, Eq 5) with silyl ketene
11]
12]
13]
acetals,[ acyl imidazoles,[ carboxylic acids[ and
Entry
Pd Source
Ligand
Proton
donor
Time
(h)
Product
ee (S)
14]
α-chloro aldehydes.[
(%)b)
1a)
2
Pd2(dba)3·CHCl3
Pd2(dba)3·CHCl3
Pd2(dba)3·CHCl3
L1
L2
L2
MA (3 equiv.)
MA (2 equiv.)
1
1
3
2a
2a
2a
6
11
41
Decarboxylative asymmetric protonation (DAP) offers
3
ECC (2 equiv.)
a direct route for constructing tertiary centres adjacent
5c]
to a carbonyl group.[
The first Pd-catalyzed
4
Pd2(dba)3·CHCl3
L2
3
2a
43
TBA (2equiv.)
FA (2 equiv.)
FA (5 equiv.)
FA (6 equiv.)
MA (2.5
5c)
6c)
7 c)
8 d)
Pd(OAc)2
Pd(OAc)2
L2
L2
L2
L1
20
20
20
3
2a
2a
4a
4a
16
50
31
7
decarboxylative protonation was developed by Tsuji
and co-workers as a benign alternative to the harsh
conditions that were required for decarboxylation and
Pd(OAc)2
15]
hydrolysis.[
Muzart
first
reported
the
Pd2(dba)3·CHCl3
enantioselective variant employing a chiral proton
equiv.)
16]
source.[ Subsequent reports by the Stoltz and Shao
9 d)
Pd2(dba)3·CHCl3
L2
MA (2.5
1
4a
4a
35
groups greatly improved the enantioselectivities for β-
equiv.)
keto allyl esters by using chiral PHOX
10 c)
Pd(OAc)2
L2
FA (4 equiv.)
24
12
17]
(phosphinooxazoline)
ligands[
independently
18]
introduced by Pfaltz, Helmchen and Williams.[
For the full optimization results, see Supporting information; Tables S1 – S4; MA = Meldrum’s acid;
FA = Formic acid; ECC = Ethyl cyclopentanone-2-carboxylate; TBA = Tert-Butylacetoacetate; a)
80% conversion determined by 1H-NMR spectroscopy of crude product. All other entries gave >99%
conversion to product. b) Determined by chiral SFC (Chiralcel IC-3, scCO2:Acetonitrile, 70:30, 3
ml/min): 2a Rt = 5.23 and 7.60 (major) min, 4a Rt = 4.02 and 4.49 (major) min. c) Reaction carried
out in the presence of 4Å molecular sieves. [d] Reaction carried out in THF instead of 1,4-dioxane.
Previous work in our group has focused on developing
decarboxylative asymmetric catalysis for a range of β-
19]
keto allyl esters to generate quaternary[
and
20]
tertiary[ stereocentres with excellent stereocontrol.
19d]
We
had
also
examined
lactones[
and
19b]
dihydrocoumarins[
as substrates for the generation
Chiral phosphinooxazoline (P,N)-ligands exemplified
by the parent t-Bu-PHOX L1 and the electronically
deficient analogue L2 have been very successful for a
range of DAP reactions both within our group and for
other research groups.[17, 20a-c] With this in mind, we
began our investigations with L1 and L2 using a
variety of achiral proton donors. Examining a range of
of quaternary stereocentres with enantioselectivities of
up to 99.5% and 96%, respectively. In view of the
prevalence of lactone and dihydrocoumarins as chiral
building blocks we decided to examine whether the
decarboxylative asymmetric protonation strategy could
also be successfully developed for these important
molecular scaffolds (Scheme 1, Eq 6). Herein, we
2
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10.1002/adsc.201800724
Advanced Synthesis & Catalysis
organic proton donors (Table 1, entries 1-4), only previously successful in the work of Muzart for
moderate levels of enantioselectivity (43% ee) could asymmetric protonations in other systems such as
be achieved for lactone substrate 1a. Switching to indanones (up to 43% ee) and tetralones (up to 41%
heterogenous conditions by using formic acid in the ee).[22] Chiral phosphoric acid (A) led to full recovery
presence of 4Å molecular sieves, gave the highest ee of unreacted starting material (Table 2, entry 1), while
of 50% for 1a (Table 1, entry 6). We then examined using (1R,2S)-(−)-ephedrine (B) as the chiral proton
dihydrocoumarin substrate 3a using similar source and L2 as the chiral ligand gave the desired
protonation conditions (Table 1, entries 7-10). Despite product 4a in an increased 74% ee (Table 2, entry 2).
testing a range of reaction parameters such as chiral Surprisingly, replacing L2 with achiral ligands such as
ligand, proton donor, solvent, temperature etc.[21] the dppe and PPh3 did not have a negative effect on the ee
enantioselectivities obtained for 3a were lower than values (Table 2, entries 4, 11-13). Other amino
the ones obtained for the lactone substrate 1a. A large alcohols D and E gave moderate enantioselectivities
excess of the proton donor (up to 6 equiv.) was but poor conversion to protonated product 4a (Table 2,
required for both substrates 1a and 3a to prevent the entries 6-7). Quinine (G) gave 35% ee with full
competitive α-allylation.
conversion to the desired product (Table 2, entry 9),
whereas Quinidine (H) furnished the product in only
2% ee under similar reaction conditions (Table 2, entry
10). We observed a further jump in ee values to 82 %
when using Pd(PPh3)4 was employed as the catalyst
instead of generating the active Pd-complex in-situ
(Table 2, entry 14).
Table 2. Optimization of DAP for 3a using chiral proton
sources.
Table 3. Optimization of DAP for 3a using (1R,2S)-(−)-
ephedrine as the chiral proton source.
Entry
Deviation from standard conditions
Conv.
(%)a)
ee
(%)b)
86
1
2
none
>99 [96]
>99
Pd(PPh3)4 5 mol%, B: 2.5 equiv., 40 °C
Pd(PPh3)4 5 mol%, B: 2.5 equiv., 25 °C
Pd(PPh3)4 5 mol%, B: 2.5 equiv., 10 °C, 1h
Pd(PPh3)4 5 mol%, B: 2.5 equiv., 0 °C, 48 h
1,4-dioxane
75
3
>99 [92]
>99
82
4
85
Entry
Pd source
Ligand
AH*
Time
(h)
Conv.
(%)a)
ee
5
90
83
(equiv.)
(%)b)
6
>99
85
7
Acetonitrile
>99
85
1
2
Pd2(dba)3·CHCl3
Pd2(dba)3·CHCl3
Pd2(dba)3·CHCl3
Pd2(dba)3·CHCl3
Pd2(dba)3·CHCl3
Pd2(dba)3·CHCl3
Pd2(dba)3·CHCl3
Pd2(dba)3·CHCl3
Pd2(dba)3·CHCl3
Pd2(dba)3CHCl3
Pd2(dba)3CHCl3
Pd(OAc)2
L2
A (1.1)
24
0.5
0.5
0.5
24
24
24
24
2
-
>99 [96]
>99 [91]
>99 [95]
18
-
8
2-MeTHF
>99
2
L2
B (2.5)
B (2.5)
74
71
75
6
9
4Å molecular sieves added
>99
>99 [94]c)
83
86 [91]d
3
L1
10
Pd(PPh3)4 1.2 mol%
B (2.5)
4
dppe
dppe
dppe
dppe
dppe
dppe
dppe
PPh3
PPh3
dppe
-
For the full optimization results, see Supporting information; Table S6 a) Determined
by 1H-NMR spectroscopy of crude product; Yields in parenthesis b) Determined by
chiral SFC (Chiralcel IC-3, scCO :Acetonitrile, 70:30, 3 mL/min): R = 4.02 and 4.50
5
C (1.25)
D (1.25)
E (1.25)
F (1.25)
G (2.5)
H (2.5)
B (2.5)
B (2.5)
B (2.5)
B (2.5)
6
21
20
30
2
2
t
7
65
(major) min. c) By-product 4-BP isolated in 91% yield. d) ee after one
8
>99
recrystallization from diethyl ether in parenthesis, 82 % yield.
9
>99
35
2
10
11
12
13c)
14
2
>99
0.5
0.5
0.5
0.5
>99
74
73
75
82
Encouraged by this result we decided to optimize
>99
other reaction parameters as summarized in Table 3.[23
]
Pd2(dba)3·CHCl3
Pd(PPh3)4
>99 [96]
>99
It was found that temperatures above 25 °C led to an
erosion of enantioselectivity (Table 3, entry 2), while
lower temperatures gave higher levels of
enantioselectivity (Table 1, entries 3-5). The reactivity
is however much slower at low temperatures as
demonstrated by the increased times needed for
reaction completion and low conversions to the
protonated product. Among the solvents screened, 1,4-
dioxane, acetonitrile and THF gave the best levels of
enantioselectivities (85% ee). The addition of activated
For full solvent screen, see supporting information; Table S5 a) Determined by 1H-NMR
spectroscopy of crude product; Yields in parenthesis b) Determined by chiral SFC (Chiralcel
IC-3, scCO :Acetonitrile, 70:30, 3 mL/min): R = 4.02 and 4.50 (major) min. c) Reaction
2
t
carried out in THF.
Disappointed with the moderate enantioselectivities
for the model substrates, we decided to screen a range
of weakly acidic chiral proton donors, (Table 2, A-H)
3
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10.1002/adsc.201800724
Advanced Synthesis & Catalysis
4Å molecular sieves to sequester any trace moisture moderate levels of enantioselectivities were obtained
did not have any effect on ee (Table 3, entry 9). with substrates containing mono-ortho substitution (1d,
Lowering the catalyst loadings from 5 mol% of 1e, 3d and 3e), we found that carrying out the
Pd(PPh3)4 to 2.5 mol% and (1R,2S)-(−)-ephedrine to reactions at −40 °C in THF led to the formation of the
1.2 equivalents gave our highest level of protonated lactone products 2d and 2e with higher
enantioselectivity (86% ee, Table 3, Entry 1). enantioselectivities of 65% and 70% respectively. The
Surprisingly, a large excess of proton donor was not bulky naphthyl-substituted lactone substrates also gave
required to circumvent the formation of α-allylated high enantioselectivities (1f – 86% ee and 1g – 73%
product (5a) indicating that the protonation was much ee), while lower levels of enantioselectivities were
faster. The catalyst loading could be further lowered to observed for the corresponding dihydrocoumarin
1.2 mol% by increasing the scale of the reaction to substrates (3f – 30% ee and 3g – 35% ee).
0.15 mmol, giving the protonated product 4a in 91% Disappointingly, the lack of ortho-substitution
ee after one recrystallization from diethyl ether (Table significantly reduced the enantioselectivity (<10% ee)
3, Entry 10). Additionally, we were able to isolate the with substrates 1h, 1i, 3h-3j undergoing DAP. In fact,
N-allylated ephedrine (4-BP) in 91% yield as a by- the lack of ortho-substitution on the aryl groups (1h
product from the reaction. Muzart and Hénin first and 1i; 3h and 3i) led instead to the formation of the α-
reported the isolation of the enantiomeric by-product allylated products (5h and 5i; 6h and 6i) through the
(4-BP) in their DAP study in 1992 in 93% yield.[16a
competitive decarboxylative allylation process.
Increasing the number of equivalents of (1R,2S)-(−)-
ephedrine (2.5 equiv.) and lowering the temperature
(10 °C) led to an increase in the formation of the
protonated product for 2h (78%) and 4h (38%) but
could not entirely suppress the unwanted α-allylation.
Lowering the temperature further to −40 °C
completely suppressed the unwanted allylation in all
cases except for dihydrocoumarin substrate 3h which
formed the allylated product 6h in a low 9% yield and
the DAP product 4h in 87% yield. It was also found
that carrying out the reaction at temperatures below
−50 °C led to the formation of the allylated product
exclusively, as (1R,2S)-(−)-ephedrine was observed to
be insoluble in THF at such low temperatures.
]
Scheme 2. Substrate scope of lactones (1a-i) and
dihydrocoumarins (3a-j) in DAP.
Figure 1. X-ray crystal structures of products 2b and 4c.
The optimized conditions (Table 3, Entry 1) were
then applied in a substrate scope study giving a range
of protonated lactone (2a-i) and dihydrocoumarin (4a-
j) products with low to excellent levels of yields and
enantioselectivities (Scheme 2). The DAP reactions for
dihydrocoumarin substrates (3a-j) were carried out in
THF, while 1,4-dioxane was found to be marginally
better for the lactone substrates (2a-i). Complete
conversion of starting material was observed within
15-30 min in all cases using optimized conditions with
no measurable racemization if the reactions were left
for longer times. Aryl groups with 2,6-dimethoxy
substitutions gave the best enantioselectivites (up to
92% ee) as observed for products 2a-c and 4a-c. While
The absolute configurations (R) of the stereocentres
of lactone 2b and dihydrocoumarin 4c were confirmed
24
by X-ray crystallographic analysis (Figure 1).[ ] Based
16d, 22, 25
]
on extensive studies by Muzart[
on DAP with
chiral proton donors and our group’s experience with
electron-rich, sterically hindered aryl groups in DAP
and DAAA reactions, we propose a mechanistic
rationale for the above stereochemical outcome and the
product distribution, Scheme 3. We surmize that
(1R,2S)-(−)-ephedrine has
a
dual role in the
protonation, acting first as the nucleophile towards the
cationic η3-[allyl]-Pd complex followed by protonation
4
This article is protected by copyright. All rights reserved.

10.1002/adsc.201800724
Advanced Synthesis & Catalysis
Conclusion
of the in-situ generated pro-chiral enolate. This would
also account for the formation of the N-allylated
ephedrine by-product (4-BP).
In conclusion, we have described the first DAP strategy
for lactones and dihydrocoumarins. This methodology
provides a route for the highly enantioselective construction
of sterically hindered α-aryl lactones and dihydrocoumarins.
These compounds containing aryl groups with di-ortho-
substituents
were
not
previously
reported
via
complementary routes such as α-arylation. This DAP
protocol is successful for substrates in which the aryl groups
have been installed at the α-carbon prior to the
enantioselective protonation. A screen of the different
reaction parameters in the absence of a chiral P,N-ligand
revealed, the superiority of (1R,2S)-(−)-ephedrine as the
chiral protonating agent for DAP of lactone and
dihydrocoumarins. This protonating agent is cheap[26] and
commercially available in both enantiomeric forms
eliminating the need for an expensive chiral ligand. A
limitation of the strategy is the competitive α-allylation,
which proceeded faster for aryl groups without ortho-
substitutions. However this could almost entirely be
suppressed by carrying out the reaction at low temperatures
(−40 °C) in THF, without a significant change in ee.
Analyzing the product distribution (decarboxylative
allylation vs. decarboxylative protonation) led to
a
Scheme 3. Rationalizing the stereochemical outcome.
mechanistic rationale that highlighted how subtle changes in
reaction parameters can lead to selectivity. A stereochemical
rationale is also proposed to account for the sense of
stereoinduction observed. We believe the novel DAP
strategy can be used as a complementary method with other
existing methodologies for generating enantioenriched α-
tertiary centres in important lactone and dihydrocoumarin
scaffolds. Additional explorations on expanding the scope
and applications of this methodology are currently underway.
For enolates bearing bulky di-ortho methoxy
substituents, it can be reasoned that maximum
stereoelectronic hindrance would arise between the
enolate oxygen and the methoxy groups. This would
prevent free rotation around the single bond between
the C-enolate and the aryl group prohibiting co-
planarity, thereby leading to conformational rigidity in
the transition state. Since approach of the proton would
be vertical to the plane defined by the π-bond of the
enolate, there can be two pathways: approach of the
proton from the front (Pathway 1) or from the back
Experimental Section
(Pathway 2). The unfavorable steric interactions in General Information
Materials and Methods
Pathway 1 between bulky groups of the aryl group and
the phenyl and methyl substituents of (1R,2S)-(−)-
ephedrine would mean that the proton approaches
selectively from the Si-face of the enolate (Pathway 2),
explaining the high ees observed. In contrast, aryl
groups without sufficient steric bulk on the ortho-
position can rotate more freely around the single bond,
possibly adopting a co-planar conformation. This
offers little enantiodiscrimination in the transition state,
leaving the protonating agent (I) to approach from
either side without significant bias. We propose that
the formation of α-allylated products (5h and 5i; 6h
and 6i) indicates that stabilized enolates react faster
with the cationic Pd-allyl than with (1R,2S)-(−)-
ephedrine. For unstabilized enolates we believe, the
rate of reactivity towards the cationic Pd-allyl is
significantly reduced leaving (1R,2S)-(−)-ephedrine to
become allylated. This in turn generates the
ammonium salt (I), which protonates the enolate to
afford the tertiary products observed.
Reagents were obtained from Sigma Aldrich and were used
without further purification unless otherwise stated.
Reactions were carried out with rigorous exclusion of air
and moisture under an inert atmosphere of nitrogen in
flame-dried glassware with magnetic stirring unless
otherwise stated. N2-flushed plastic syringes were used to
transfer air and moisture sensitive reagents. Oxygen-free
nitrogen was obtained from BOC gases. Anhydrous
tetrahydrofuran (THF) was freshly distilled under N2 from
sodium/benzophenone ketyl and stored over 3Å molecular
sieves. All other anhydrous solvents were obtained from
commercial
sources
and
used
as
received.
Tris(dibenzylideneacetone) palladium(0) chloroform adduct
was prepared via the method of Zalesskiy et al.[27]
Tetrakis(triphenylphosphine) palladium(0) was prepared by
the method of Grim et al.[28] The bright yellow Pd(PPh3)4
was stored in the freezer and washed with methanol, diethyl
ether and dried thoughroughly under vaccum before use in
catalysis. Pd(OAc)2 was purchased from Sigma Aldrich and
used as received. L1 and L2 were prepared according to
previously reported methods.[29] L3 and L4 were purchased
from Sigma Aldrich and used as received. In vacuo refers to
5
This article is protected by copyright. All rights reserved.

10.1002/adsc.201800724
Advanced Synthesis & Catalysis
the evaporation of solvent under reduced pressure on a 3-(2,4,6-Trimethoxyphenyl)tetrahydro-2H-pyran-2-one
rotary evaporator. Thin-layer chromatography was (2a) The title compound was prepared according to general
performed on silica coated aluminium sheets (60 F254
)
procedure I using α-aryl-β-oxo allyl ester 1a (34 mg, 0.096
supplied by Merck. Compounds were visualised with UV mmol) to afford the product as a white solid (17.4 mg, 68%).
light (254 nm) fluorescence quenching, or by charring with Rf = 0.16 (cyclohexane : EtOAc, 7:3); IR (neat) νmax 2924,
an acidic vanillin solution (vanillin, H2SO4 in ethanol). Flash 1713, 1590, 1120 cm-1; M.P. = 125–127 °C; 1H NMR (400
column chromatography was performed using 40-63 μm, MHz, CDCl3) δ 6.15 (s, 2H), 4.52 – 4.45 (m, 1H), 4.44 –
230-400 mesh silica gel.
Instrumentation
4.35 (m, 1H), 4.19 – 4.09 (m, 1H), 3.80 (s, 9H), 2.08 – 1.97
(m, 1H), 1.96 – 1.84 (m, 3H); 13C NMR (101 MHz, CDCl3)
1H NMR spectra were recorded on Varian Unity 600, 500, δ 173.1, 160.5, 158.0, 110.8, 91.3, 70.1, 55.9, 55.5, 36.7,
400 and 300 MHz system spectrometers. 13C NMR spectra 27.5, 23.8; HRMS: (ESI-TOF) Calculated for C14H19O5 [M
were recorded on 400, 500 or 600 MHz spectrometers at 101, + H+] 267.1232, found 267.1233.
126 or 151 MHz. Chemical shifts (δ) are quoted in parts per
million (ppm) downfield from tetramethylsilane (TMS) and
referenced to residual solvent peaks in the NMR solvent
3-(2,6-Dimethoxyphenyl)tetrahydro-2H-pyran-2-one (2b)
The title compound was prepared according to general
procedure I using α-aryl-β-oxo allyl ester 1b (31 mg, 0.096
mmol) to give the product as an off-white solid (18.8 mg,
83%). Rf = 0.39 (pentane : EtOAc, 1:1); IR (neat) νmax 2956,
1
(CDCl3 = δ 7.26 ppm; δ 77.16 ppm). H and 13C NMR
chemical shift assignments are based on two-dimensional
1
NMR experiments including H-gCOSY, DEPT, HSQC and
1
HMBC. All 13C spectra are H decoupled. NMR data are
1
1719, 1593, 1105 cm-1; M.P. = 111–113 °C; H NMR (400
represented as follows: chemical shift (δ ppm), multiplicity
(s = singlet, d = doublet, t = triplet, q = quartet, dd = double
doublet, m = multiplet, app. dd, = apparent doublet of
doublets, br = broad peak), coupling constant (J) in Hertz
(Hz), integration. Infrared spectra were recorded on a Varian
Instrument Excalibur series FT-IR 3100 spectrometer or
were recorded on a Bruker Platinum ATR spectrometer and
are reported as wavenumbers with units of reciprocal
centimetres (cm -1). Samples were prepared neat between
NaCl discs as oils or as KBr discs for Varian Instrument
Excalibur series FT-IR 3100 spectrometer. Melting points
were determined in open capillary tubes using a Barnstead
electrothermal melting point apparatus. Optical rotation data
were obtained with a Perkin Elmer Model 343 polarimeter
with the sample solvent and values quoted in units of 10-
1deg cm2 g-1. High resolution mass spectra [electrospray
ionization (ESI-TOF)] (HRMS) were measured on a
MHz, CDCl3) δ 7.19 (t, J = 8.3 Hz, 1H), 6.57 (d, J = 8.3 Hz,
2H), 4.52 – 4.37 (m, 2H), 4.24 (t, J = 7.5 Hz, 1H), 3.81 (s,
6H), 2.09 – 1.96 (m, 2H), 1.96 – 1.86 (m, 2H); 13C NMR
(101 MHz, CDCl3) δ 172.7, 157.2, 128.3, 118.0, 104.3, 70.0,
55.8, 36.8, 27.2, 23.6; HRMS: (ESI-TOF) Calculated for
C13H16O4Na [M + Na+] 259.0946, found 259.0940.
3-(2,3,6-Trimethoxyphenyl)tetrahydro-2H-pyran-2-one
(2c) The title compound was prepared according to general
procedure I using α-aryl-β-oxo allyl ester 1c (34 mg, 0.096
mmol) to yield the product as a viscous oil (19.9 mg, 78%).
Rf = 0.34 (cyclohexane : EtOAc, 6:4); IR (neat) νmax 1722,
1
1487, 1251, 1083 cm-1; H NMR (400 MHz, CDCl3) δ 6.78
(d, J = 9.0 Hz, 1H), 6.58 (d, J = 9.0 Hz, 1H), 4.47 – 4.40 (m,
1H), 4.20 – 4.13 (m, 1H), 4.20 – 4.13 (m, 1H), 3.85 (s, 3H),
3.82 (s, 3H), 3.77 (s, 3H), 2.09 – 1.97 (m, 2H), 1.96 – 1.86
(m, 2H); 13C NMR (101 MHz, CDCl3) δ 172.7, 151.0, 147.2,
147.1, 124.5, 111.5, 106.2, 70.2, 60.6, 56.3, 56.2, 37.8, 27.9,
23.6; HRMS: (ESI-TOF) Calculated for C14H18O3Na [M +
Na+] 289.1052, found 289.1059.
micromass
LCT
orthogonal
time-of-flight
mass
spectrometer with leucine encephalin (Tyr-Gly-Phe-Leu) as
an internal lock mass. Supercritical fluid chromatography
(SFC) was performed on a Waters UPC2 using Chiralpak-
IA3, IB3, IC3 or ID3 columns to determine the enantiomeric
excess. Products 5h, 5i, 6h and 6i obtained from the
competitive decarboxylative allylation process have been
characterized previously and reported by our group.[19b, 19d]
3-(2,4-Dimethoxyphenyl)tetrahydro-2H-pyran-2-one (2d)
The title compound was prepared according to general
procedure I using α-aryl-β-oxo allyl ester 1d (0.31 mg,
0.096 mmol) to afford the product as a clear oil (21.9 mg,
96%). Rf = 0.18 (cyclohexane : EtOAc, 7:3); IR (neat) νmax
1726, 1455, 1153, 1031 cm-1; 1H NMR (400 MHz, CDCl3) δ
7.06 (d, J = 8.2 Hz, 1H), 6.50 – 6.43 (m, 2H), 4.51 – 4.44 (m,
1H), 4.44 – 4.38 (m, 1H), 3.81 (s, 3H), 3.79 (s, 3H), 3.76 –
3.70 (m, 1H), 2.16 – 2.06 (m, 1H), 2.06 – 2.00 (m, 1H), 1.99
– 1.88 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 172.7, 160.4,
157.4, 130.3, 121.5, 104.5, 99.4, 69.8, 55.6, 55.5, 43.3, 28.0,
23.2; HRMS: (ESI-TOF) Calculated for C13H17O4 [M + H+]
237.1127, found 237.1128.
General procedure I for Racemic Decarboxylative
Protonation
Pd(OAc)2 (0.8 mg, 0.004 mmol) and dppe (1.5 mg, 0.004
mmol) were added to a flame dried Schlenk flask (10 mL)
and THF (1 mL) was added. The suspension was stirred at
40 °C for 60 min and formic acid (12μL, 0.3 mmol) was
added followed immediately by α-aryl-β-oxo-allyl ester in
1,4-dioxane for lactone substrates (1a-i) and THF for
dihydrocoumarin substrates (3a-j). The substrates (1a-i and
3a-i) for catalysis studies were prepared by previously
reported methods.[19b, 19d] The reaction mixture was stirred at
40 °C for 18 h after which the solvent was removed in vacuo
and the resulting residue purified by flash column
chromatography (cyclohexane/EtOAc or pentane/EtOAc).
3-(2,3,4-Trimethoxyphenyl)tetrahydro-2H-pyran-2-one
(2e) The title compound was prepared according to general
procedure I using α-aryl-β-oxo allyl ester 1e (34.0 mg, 0.096
mmol) to yield the product as a clear oil (23.3 mg, 91%). Rf
= 0.12 (cyclohexane : EtOAc, 7:3); IR (neat) νmax 1720,
6
This article is protected by copyright. All rights reserved.

10.1002/adsc.201800724
Advanced Synthesis & Catalysis
1
1465, 1155, 1096 cm-1; H NMR (400 MHz, CDCl3) δ 6.84 yield the product as a colourless oil (10.5 mg, 53%). Rf
=
(d, J = 8.5 Hz, 1H), 6.61 (d, J = 8.5 Hz, 1H), 4.54 – 4.40 (m, 0.16 (cyclohexane : EtOAc, 7:3); IR (neat) νmax 1725, 1510,
1
2H), 3.91 (s, 3H), 3.86 (s, 3H), 3.84 (s, 3H), 3.68 (dd, J = 1246, 1160, 1033 cm-1; H NMR (400 MHz, CDCl3) δ 7.19
10.5, 7.8 Hz, 1H), 2.18 – 2.06 (m, 1H), 2.06 – 1.98 (m, 1H), – 7.13 (m, 2H), 6.91 – 6.86 (m, 2H), 4.49 – 4.39 (m, 2H),
1.98 – 1.91 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 172.8, 3.79 (s, 3H), 3.73 (dd, J = 10.0, 7.1 Hz, 1H), 2.32 – 2.22 (m,
153.5, 150.8, 142.3, 126.9, 123.8, 107.0, 70.0, 60.7, 60.4, 1H), 2.12 – 2.04 (m, 1H), 2.04 – 1.94 (m, 2H); 13C NMR
56.1, 44.0, 28.9, 23.2; HRMS: (ESI-TOF) Calculated for (101 MHz, CDCl3) δ 172.8, 158.7, 130.8, 129.2, 114.1, 69.1,
C14H19O5 [M + H+] 267.1232, found 267.1239.
55.3, 46.2, 28.1, 22.0; All other physical data were identical
to those previously reported.[30]
3-(2-Methoxynaphthalen-1-yl)tetrahydro-2H-pyran-2-one
(2f) The title compound was prepared according to general 3-(2,4,6-Trimethoxyphenyl)chroman-2-one (4a) The title
procedure I using α-aryl-β-oxo allyl ester 1f (33.0 mg, 0.096 compound was prepared according to general procedure I
mmol) to give the product as white solid (16.7 mg, 68%). Rf using α-aryl-β-oxo allyl ester 3a (30 mg, 0.075 mmol) to
= 0.44 (cyclohexane : EtOAc, 6:4); IR (neat) νmax 1722, afford the product as a white solid (17.2 mg, 73%). Rf
=
1470, 1259, 1158, 1083 cm-1; M.P. = 158–168 °C; 1H NMR 0.26 (cyclohexane : EtOAc, 8:2); IR (neat) νmax 1753, 1589,
1
(400 MHz, CDCl3) δ 7.85 – 7.83 (m, 1H), 7.81 (d, J = 9.0 1133, 1107 cm-1; M.P. = 179–185 °C; H NMR (400 MHz,
Hz, 2H), 7.50 (ddd, J = 8.0, 6.7, 1.0 Hz, 1H), 7.36 (ddd, J = CDCl3) δ 7.28 – 7.22 (m, 1H), 7.18 – 7.13 (m, 1H), 7.11 –
8.0, 6.7, 1.0 Hz, 1H), 7.30 (d, J = 9.0 Hz, 1H), 4.63 – 4.50 7.04 (m, 2H), 6.18 (s, 2H), 4.49 (dd, J = 13.5, 6.9 Hz, 1H),
(m, 2H), 4.49 – 4.39 (m, 1H), 3.96 (s, 3H), 2.28 – 2.14 (m, 3.82 (s, 3H), 3.78 (s, 6H), 3.58 (dd, J = 15.0, 13.5 Hz, 1H),
1H), 2.11 – 1.94 (m, 3H); 13C NMR (101 MHz, CDCl3) δ 2.82 (dd, J = 15.0, 6.9 Hz, 1H); 13C NMR (101 MHz,
172.6, 153.6, 132.1, 129.6, 129.3, 129.0, 127.1, 123.7, 123.3, CDCl3) δ 170.0, 161.0, 158.8, 152.2, 128.0, 127.9, 124.1,
122.1, 114.0, 70.2, 56.5, 39.5, 28.1, 23.7; HRMS: (ESI- 124.0, 116.9, 107.1, 91.3, 55.9, 55.5, 35.5, 29.6; HRMS:
TOF) Calculated for C16H17O3 [M + H+] 257.1178, found (ESI-TOF) Calculated for C18H18O5Na [M + Na+] 337.1052,
257.1171.
found 337.1040.
3-(2-(Benzyloxy)naphthalen-1-yl)tetrahydro-2H-pyran-2-
3-(2,6-Dimethoxyphenyl)chroman-2-one (4b) The title
one (2g) The title compound was prepared according to compound was prepared according to general procedure I
general procedure I using α-aryl-β-oxo allyl ester 1g (41.0 using α-aryl-β-oxo allyl ester 3b (27.6 mg, 0.075 mmol) to
mg, 0.096 mmol) to afford the product as white solid (24.6 give the product as a white solid (17.1 mg, 62%). Rf = 0.55
mg, 79%). Rf = 0.46 (pentane : EtOAc, 7:3); IR (neat) νmax (cyclohexane : EtOAc, 6:4); IR (neat) νmax 1764, 1593, 1131,
1720, 1256, 1155, 1081 cm-1; M.P. = 120–123 °C; 1H NMR 1100 cm-1; M.P. = 113–117 °C; 1H NMR (400 MHz, CDCl3)
(400 MHz, CDCl3) δ 7.89 – 7.79 (m, 3H), 7.55 – 7.46 (m, δ 7.30 – 7.21 (m, 2H), 7.19 – 7.13 (m, 1H), 7.12 – 7.04 (m,
3H), 7.46 – 7.40 (m, 2H), 7.40 – 7.34 (m, 3H), 5.20 (s, 2H), 2H), 6.61 (d, J = 8.4 Hz, 2H), 4.59 (dd, J = 13.4, 6.9 Hz,
4.51 – 4.38 (m, 1H), 4.30 (d, J = 10.6 Hz, 1H), 3.94 (br, 1H), 1H), 3.80 (s, 6H), 3.61 (dd, J = 15.7, 13.4 Hz, 1H), 2.85 (dd,
2.19 – 2.08 (m, 1H), 2.08 – 1.92 (m, 2H), 1.90 – 1.77 (m, J = 15.7, 6.9 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 69.6,
1H); 13C NMR (101 MHz, CDCl3) δ 172.5, 153.0, 136.6, 158.0, 152.0, 129.0, 127.9, 127.9, 124.0, 123.7, 116.8, 114.4,
132.3, 129.6, 129.3, 129.0, 128.7, 128.6, 128.4, 127.1, 123.7, 104.4, 55.8, 35.5, 29.2; HRMS: (ESI-TOF) Calculated for
123.1, 122.1, 114.5, 71.5, 69.8, 39.7, 27.8, 23.6; HRMS: C17H17O4 [M + H+] 285.1127, found 285.1136.
(ESI-TOF) Calculated for C22H21O3 [M + H+] 333.1491,
found 333.1486.
3-(2,3,6-Trimethoxyphenyl)chroman-2-one (4c) The title
compound was prepared according to general procedure I
using α-aryl-β-oxo allyl ester 3c (30 mg, 0.075 mmol) to
3-(Benzo[d][1,3]dioxol-5-yl)tetrahydro-2H-pyran-2-one
(2h) The title compound was prepared according to general yield the product as a white solid (19.2 mg, 81%). Rf = 0.49
procedure I using α-aryl-β-oxo allyl ester 1h (29.2 mg, (cyclohexane : EtOAc, 6:4); IR (neat) νmax 1763, 1589, 1488,
1
0.096 mmol) to give the product as a white solid (20.03 mg, 1133, 1089 cm-1; M.P. = 116–122 °C; H NMR (400 MHz,
96%). Rf = 0.3 (cyclohexane : EtOAc, 7:3); IR (neat) νmax CDCl3) δ 7.30 – 7.24 (m, 1H), 7.18 – 7.15 (m, 1H), 7.12 –
1
1720, 1488, 1239, 1144, 1033 cm-1; M.P. = 129–131 °C; H 7.08 (m, 2H), 6.85 (d, J = 9.0 Hz, 1H), 6.64 (d, J = 9.0 Hz,
NMR (400 MHz, CDCl3) δ 6.77 (d, J = 7.9 Hz, 1H), 6.73 (d, 1H), 4.52 (dd, J = 13.5, 6.9 Hz, 1H), 3.84 (s, Hz, 6H), 3.76
J = 1.8 Hz, 1H), 6.68 (dd, J = 7.9, 1.8 Hz, 1H), 5.94 (s, 2H), (s, 3H), 3.64 (dd, J = 15.7, 13.5, 1.2 Hz, 1H), 2.86 (dd, J =
4.49 – 4.38 (m, 2H), 3.72 – 3.66 (m, 1H), 2.32 – 2.21 (m, 15.7, 6.9 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 169.9,
1H), 2.09 – 2.03 (m, 1H), 2.03 – 1.96 (m, 2H); ); 13C NMR 152.1, 151.7, 148.0, 147.2, 128.1, 127.99, 124.3, 123.6,
(101 MHz, CDCl3) δ 172.7, 148.0, 146.9, 132.6, 121.6, 120.8, 116.9, 112.3, 106.3, 61.0, 56.4, 56.2, 36.6, 29.9;
108.8, 108.5, 101.2, 69.2, 46.9, 28.4, 22.2; HRMS: (ESI- HRMS: (ESI-TOF) Calculated for C18H18O5Na [M + Na+]
TOF) Calculated for C12H13O4 [M + H+] 221.0814, found 337.1052, found 337.1046.
221.0812.
3-(2,4-Dimethoxyphenyl)chroman-2-one (4d) The title
3-(4-Methoxyphenyl)tetrahydro-2H-pyran-2-one (2i) The compound was prepared according to general procedure I
title compound was prepared according to general procedure using α-aryl-β-oxo allyl ester 3d (28 mg, 0.075 mmol) to
I using α-aryl-β-oxo allyl ester 1i (27.9 mg, 0.096 mmol) to afford the product as white crystals (17.0 mg, 80%). Rf
=
7
This article is protected by copyright. All rights reserved.

10.1002/adsc.201800724
Advanced Synthesis & Catalysis
0.46 (cyclohexane : EtOAc, 6:4); IR (neat) νmax 1758, 1585, 3-(Benzo[d][1,3]dioxol-5-yl)chroman-2-one (4h) The title
1
1490, 1131, 1089 cm-1; M.P. = 130–133 °C; H NMR (400 compound was prepared according to general procedure I
MHz, CDCl3) δ 7.33 – 7.22 (m, 1H), 7.22 – 7.14 (m, 1H), using α-aryl-β-oxo allyl ester 3h (26 mg, 0.075 mmol) to
7.14 – 7.05 (m, 3H), 6.55 – 6.45 (m, 2H), 4.16 (dd, J = 13.1, give the product as a white solid (17.9 mg, 89%). Rf = 0.5
6.3 Hz, 1H), 3.81 (s, 3H), 3.80 (s, 3H), 3.45 (dd, J = 15.7, (cyclohexane : EtOAc, 7:3); IR (neat) νmax 1768, 1585, 1455,
1
13.1 Hz, 1H), 3.01 (dd, J = 15.7, 6.3 Hz, 1H); 13C NMR 1279, 1056 cm-1; M.P. = 165–170 °C; H NMR (400 MHz,
(101 MHz, CDCl3) δ 169.7, 160.7, 158.2, 152.0, 129.7, CDCl3) δ 7.31 – 7.25 (m, 1H), 7.20 (dd, J = 8.0, 1.3 Hz, 1H),
128.3, 128.1, 124.3, 123.6, 118.0, 116.9, 104.7, 99.3, 55.7, 7.12 (dd, J = 7.4, 1.2 Hz, 1H), 7.11 – 7.06 (m, 1H), 6.79 –
55.5, 40.6, 30.8; HRMS: (ESI-TOF) Calculated for 6.74 (m, 2H), 6.70 (dd, J = 8.0, 1.8 Hz, 1H), 5.95 (s, 2H),
C17H17O4 [M + H+] 285.1127, found 285.1119.
3.89 (dd, J = 11.3, 6.3 Hz, 1H), 3.30 (dd, J = 15.9, 11.3 Hz,
1H), 3.18 (dd, J = 15.9, 6.3 Hz, 1H); 13C NMR (101 MHz,
CDCl3) δ 169.5, 151.8, 148.2, 147.4, 130.2, 128.6, 128.1,
124.6, 122.7, 121.6, 116.9, 108.62, 108.59, 101.3, 45.5,
31.9; HRMS: (ESI-TOF) Calculated for C16H13O4 [M + H+]
269.0814, found 269.0809.
3-(2,3,4-Trimethoxyphenyl)chroman-2-one (4e) The title
compound was prepared according to general procedure I
using α-aryl-β-oxo allyl ester 3e (30 mg, 0.075 mmol) to
give the product as a white solid (15.5 mg, 66%). Rf = 0.49
(cyclohexane : EtOAc, 6:4); IR (neat) νmax 1758, 1585, 1490,
1
1131, 1089 cm-1; M.P. = 125–129 °C; H NMR (400 MHz, 3-(4-Methoxyphenyl)chroman-2-one
(4i)
The
title
CDCl3) δ 7.32 – 7.24 (m, 1H), 7.20 – 7.15 (m, 1H), 7.13 – compound was prepared according to general procedure I
7.07 (m, 2H), 6.87 (d, J = 8.6 Hz, 1H), 6.66 (d, J = 8.6 Hz, using α-aryl-β-oxo allyl ester 3i (25 mg, 0.075 mmol) to
1H), 4.11 (dd, J = 13.3, 6.3 Hz, 1H), 3.92 (s, 3H), 3.88 (s, afford the product as a white solid (18.6 mg, 97%). Rf
=
3H), 3.86 (s, 3H), 3.44 (dd, J = 15.7, 13.3 Hz, 1H), 3.01 (dd, 0.61 (cyclohexane : EtOAc, 7:3); IR (neat) νmax 1769, 1585,
1
J = 15.7, 6.3 Hz, 1H).; 13C NMR (101 MHz, CDCl3) δ 169.8, 1487, 1122, 1028 cm-1; H NMR (400 MHz, CDCl3) δ 7.32
153.6, 151.8, 151.7, 142.2, 128.2, 127.9, 124.3, 123.3, 123.1, – 7.23 (m, 1H), 7.23 – 7.15 (m, 3H), 7.15 – 7.05 (m, 2H),
123.1, 116.8, 107.2, 60.9, 60.7, 56.0, 41.0, 31.2; HRMS: 6.93 – 6.84 (m, 2H), 3.93 (dd, J = 11.0, 6.3 Hz, 1H), 3.79 (s,
(ESI-TOF) Calculated for C18H19O5 [M + H+] 315.1232, 3H), 3.32 (dd, J = 15.9, 11.0 Hz, 1H), 3.20 (dd, J = 15.9, 6.3
found 315.1220.
Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 169.8, 159.3, 151.8,
129.3, 128.6, 128.5, 128.2, 124.6, 122.9, 116.9, 114.4, 55.4,
44.9, 31.9; HRMS: (ESI-TOF) All other physical data were
identical to those previously reported.[10]
3-(2-Methoxynaphthalen-1-yl)chroman-2-one (4f) The title
compound was prepared according to general procedure I
using α-aryl-β-oxo allyl ester 3f (29.1 mg, 0.075 mmol) to
afford the product as a white solid (16.7 mg, 73%). Rf
=
3-Benzylchroman-2-one (4j) The title compound was
0.63 (cyclohexane : EtOAc, 6:4); IR (neat) νmax 1763, 1594, prepared according to general procedure I using α-aryl-β-
1
1489, 1124, 1021 cm-1; M.P. = 178–182 °C; H NMR (400 oxo allyl ester 3j (24 mg, 0.075 mmol) to yield the product
MHz, CDCl3) δ 7.90 – 7.79 (m, 3H), 7.52 – 7.46 (m, 1H), as a white solid (15.3 mg, 86%). Rf = 0.53 (cyclohexane :
7.40 – 7.29 (m, 3H), 7.21 – 7.10 (m, 3H), 4.85 (br, 1H), 3.94 EtOAc, 7:3); IR (neat) νmax 2955, 1760, 1585, 1487, 1263
1
(s, 3H), 3.76 – 3.66 (m, 1H), 3.02 (dd, J = 16.0, 7.1 Hz, 1H); cm-1; H NMR (400 MHz, CDCl3) δ7.36 – 7.29 (m, 2H),
13C NMR (101 MHz, CDCl3) δ 169.6, 154.9, 152.2, 132.1, 7.29 – 7.17 (m, 4H), 7.11 – 7.02 (m, 3H), 3.40 (dd, J = 13.9,
130.1, 129.7, 129.2, 128.3, 128.2, 127.1, 124.4, 123.7, 123.3, 5.9 Hz, 1H), 2.99 – 2.89 (m, 1H), 2.85 (dd, J = 15.8, 5.9 Hz,
122.3, 119.4, 117.1, 113.9, 56.6, 37.9, 30.2; HRMS: (ESI- 1H), 2.79 – 2.67 (m, 2H); 13C NMR (101 MHz, CDCl3) δ
TOF) Calculated for C20H16O3Na [M + Na+] 327.0097, 170.7, 151.7, 138.1, 129.3, 128.8, 128.42, 128.37, 126.9,
found 327.0984.
124.5, 122.5, 116.7, 41.0, 35.7, 28.4; HRMS: (ESI-TOF)
Calculated for C16H15O2 [M + H+] 239.1072, found
239.1075. These spectroscopic data correspond to those
previously reported.[31]
3-(2-(Benzyloxy)naphthalen-1-yl)chroman-2-one (4g) The
title compound was prepared according to general procedure
I using α-aryl-β-oxo allyl ester 3g (35 mg, 0.075 mmol) to
yield the product as an off-white solid (23.4 mg, 82%). Rf = General procedure II for catalytic decarboxylative
0.4 (cyclohexane : EtOAc, 6:4); IR (neat) νmax 1761, 1594, asymmetric protonation
1
1488, 1127, 1025 cm-1; M.P. = 157–162 °C; H NMR (400
MHz, CDCl3) δ 7.86 – 7.78 (m, 3H), 7.48 (ddd, J = 8.5, 6.8,
1.4 Hz, 1H), 7.43 – 7.23 (m, 8H), 7.16 – 7.06 (m, 3H), 5.24
(s, 2H), 4.87 (br, 1H), 3.72 (dd, J = 16.0, 13.2 Hz, 1H), 2.96
(dd, J = 16.0, 7.2 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ
169.6, 154.1, 152.1, 136.9, 132.1, 130.0, 129.8, 129.2, 128.7,
128.3, 128.13, 128.08, 127.5, 127.2, 124.4, 123.8, 123.1,
122.4, 119.8, 117.1, 115.1, 71.7, 38.0, 30.1; HRMS: (ESI-
TOF) Calculated for C26H21O3 [M + H+] 381.1491, found
381.1505.
Pd(PPh3)4 (1a-i : 2.8 mg, 0.0024 mmol; 3a-j : 2.2 mg,
0.0019 mmol; [5 mol %]), (1R,2S)-(−)-ephedrine (1a-i : 19.0
mg, 0.115 mmol; 3a-j : 14.9 mg, 0.09 mmol; [ 1.2 equiv.])
and substrates 1a-i (0.075 mmol) or 3a-j (0.0096 mmol)
were added to a flame dried Schlenk flask (10 mL) followed
by anhydrous THF (1a-i : 3.2 mL; 3a-j : 2.5 mL). The
reaction mixture was stirred at 25 °C for 30 min after which
the solvent was removed in vacuo and the resulting residue
purified
by
flash
column
chromatography
(cyclohexane/EtOAc or pentane/EtOAc).
8
This article is protected by copyright. All rights reserved.

10.1002/adsc.201800724
Advanced Synthesis & Catalysis
Note 1: Substrates 2c, 2d, 2h and 2i are oils and these were (21.7 mg, 96%, 65% ee), identical in all respects to the
dissolved in 1,4-dioxane or THF in a flame-dried 2-neck previously prepared racemic sample, with the exception of
20
round bottom flask under N2 and transferred to the Schlenk [α]D = -23.76 (c 1.04, CH2Cl2); SFC: (Chiralcel IC-3,
flask containing Pd(PPh3)4 and (1R,2S)-(−)-ephedrine.
scCO2/MeCN, 99/1 to 70/30 gradient over 5 min, 3
mL/min): Rt = 5.25 (major) and 5.73 min.
Note 2: For low temperature reactions (-40 °C) involving
substrates 2d, 2e, 2h, 2i and 4h the solvents used were (R)-3-(2,3,4-Trimethoxyphenyl)tetrahydro-2H-pyran-2-one
cooled to -40 °C before adding it carefully into the Schlenk (2e) The title compound was prepared according to general
flask containing Pd(PPh3)4 and (1R,2S)-(−)-ephedrine and procedure II using α-aryl-β-oxo allyl ester 1e (0.34 mg,
allowed to stir at -40 °C until complete consumption of 0.096 mmol) to yield the product as a clear oil (24.4 mg,
starting material.
96%, 65% ee), identical in all respects to the previously
prepared racemic sample, with the exception of [α]D = -
20
15.03 (c 1.21, CH2Cl2); SFC: (Chiralcel IC-3, scCO2/MeCN,
99/1 to 70/30 gradient over 5 min, 3 mL/min): Rt = 6.35 and
7.80 (major) min.
(R)-3-(2,4,6-Trimethoxyphenyl)tetrahydro-2H-pyran-2-one
(2a) The title compound was prepared according to general
procedure II using α-aryl-β-oxo allyl ester 1a (34 mg, 0.096
mmol) to yield the product as a viscous oil (21.7 mg, 82%,
86% ee), identical in all respects to the previously prepared (R)-3-(2-Methoxynaphthalen-1-yl)tetrahydro-2H-pyran-2-
racemic sample, with the exception of [α]D20 = 46.25 (c 1.00, one (2f) The title compound was prepared according to
CH2Cl2); SFC: (Chiralcel IC-3, scCO2/MeCN, 99/1 to 70/30 general procedure II using α-aryl-β-oxo allyl ester 1f (33.0
gradient over 5 min, 3 mL/min): Rt = 5.20 and 7.54 (major) mg, 0.096 mmol) to yield the product as a white solid (23.4
min.
mg, 95%, 86% ee), identical in all respects to the previously
prepared racemic sample, with the exception of [α]D = -
20
26.72 (c 0.78, CH2Cl2); SFC: (Chiralcel IC-3, scCO2/MeCN,
99/1 to 70/30 gradient over 5 min, 3 mL/min): Rt = 6.26
(major) and 7.69 min.
(R)-3-(2,6-Dimethoxyphenyl)tetrahydro-2H-pyran-2-one
(2b) The title compound was prepared according to general
procedure II using α-aryl-β-oxo allyl ester 1b (31 mg, 0.096
mmol) to afford the product as an off white solid (21.2 mg,
93%, 85% ee), identical in all respects to the previously (R)-3-(2-(Benzyloxy)naphthalen-1-yl)tetrahydro-2H-
20
prepared racemic sample, with the exception of [α]D = - pyran-2-one (2g) The title compound was prepared
49.66 (c 1.25, CH2Cl2); SFC: (Chiralcel IC-3, scCO2/MeCN, according to general procedure II using α-aryl-β-oxo allyl
99/1 to 70/30 gradient over 5 min, 3 mL/min): Rt = 4.77 ester 1g (41.0 mg, 0.096 mmol) to give the product as a
(major) and 6.03 min.
white solid (23.2 mg, 97%, 73% ee), identical in all respects
to the previously prepared racemic sample, with the
exception of [α]D20 = -47.5 (c 1.03, CH2Cl2); SFC: (Chiralcel
ID-3, scCO2/MeCN, 99/1 to 70/30 gradient over 5 min, 3
mL/min): Rt = 5.10 (major) and 5.71 min.
Crystals suitable for X-ray analysis were grown by
dissolving 2b in Et2O (1 mL), and the Et2O layer was
carefully layered with pentane (2 mL) followed by slow
evaporation of solvents in the fridge (0 - 4° C): C13H16O4, M
= 236.26, orthothrombic, a = 6.52790(7) Å, b = 12.4590(2) (R)-3-(Benzo[d][1,3]dioxol-5-yl)tetrahydro-2H-pyran-2-
Å, c = 14.9339(2) Å, U = 1214.59(3) Å3, T = 100 K, space one (2h) The title compound was prepared according to
group P212121 (no. 19), Z = 4, 25439 reflections measured, general procedure II at -40 °C, using α-aryl-β-oxo allyl ester
2558 unique (Rint = 0.0285) which were used in all 1h (29.2 mg, 0.096 mmol) to yield the product as a white
calculations. The final wR(F2) was 0.0656 (all data).
solid (19.4 mg, 92%, 27% ee), identical in all respects to the
previously prepared racemic sample, with the exception of
20
[α]D = +5.97 (c 1.00, CH2Cl2); SFC: (Chiralcel IC-3,
scCO2/MeCN, 99/1 to 70/30 gradient over 5 min, 3
mL/min): Rt = 4.94 (major) and 5.16 min.
(R)-3-(2,3,6-trimethoxyphenyl)tetrahydro-2H-pyran-2-one
(2c) The title compound was prepared according to general
procedure II using α-aryl-β-oxo allyl ester 1c (34 mg, 0.096
mmol) to give the product as a viscous oil (24.6 mg, 96%,
92% ee), identical in all respects to the previously prepared (R)-3-(Benzo[d][1,3]dioxol-5-yl)tetrahydro-2H-pyran-2-
racemic sample, with the exception of [α]D20 = -51.8 (c 1.26, one (2i) The title compound was prepared according to
CH2Cl2); SFC: (Chiralcel IC-3, scCO2/MeCN, 99/1 to 70/30 general procedure II at -40 °C, using α-aryl-β-oxo allyl ester
gradient over 5 min, 3 mL/min): Rt = 9.04 (major) and 9.78 1i (27.9 mg, 0.096 mmol) to afford the product as a
min.
colourless oil (18.5 mg, 94%, 30% ee), identical in all
respects to the previously prepared racemic sample, with the
20
exception of [α]D = +10.30 (c 1.08, CH2Cl2); SFC:
(Chiralcel IA-3, scCO2/IPA, 99/1 to 80/20 gradient over 5
min, 3 mL/min): Rt = 3.93 (major) and 4.04 min.
(R)-3-(2,4-Dimethoxyphenyl)tetrahydro-2H-pyran-2-one
(2d) The title compound was prepared according to general
procedure II at -40 °C, using α-aryl-β-oxo allyl ester 1d
(0.31 mg, 0.096 mmol) to afford the product as a clear oil
9
This article is protected by copyright. All rights reserved.

10.1002/adsc.201800724
Advanced Synthesis & Catalysis
(R)-3-(2,4,6-Trimethoxyphenyl)chroman-2-one (4a) The CH2Cl2); SFC: (Chiralcel IC-3, scCO2/MeCN, 99/1 to 70/30
title compound was prepared according to general procedure gradient over 5 min, 3 mL/min): Rt = 4.82 and 5.58 (major)
II using α-aryl-β-oxo allyl ester 3a (30 mg, 0.075 mmol) to min.
give the product as a white solid (22.6 mg, 96%, 86% ee).
The product was recrystallized from diethyl ether 0.5 mL
and washed with pentane to afford the product in 82 % yield
(R)-3-(2-Methoxynaphthalen-1-yl)chroman-2-one (4f) The
title compound was prepared according to general procedure
II using α-aryl-β-oxo allyl ester 3f (29 mg, 0.075 mmol) to
give the product as a white solid (21.6 mg, 95%, 30% ee),
identical in all respects to the previously prepared racemic
and 91% ee, identical in all respects to the previously
20
prepared racemic sample, with the exception of [α]D
=
+36.13 (c 1.0, CH2Cl2); SFC: (Chiralcel IC-3, scCO2/MeCN,
99/1 to 70/30 gradient over 5 min, 3 mL/min): Rt = 4.02
(major) and 4.50 min.
20
sample, with the exception of [α]D = +30.37 (c 1.0,
CH2Cl2); SFC: (Chiralcel IC-3, scCO2/MeCN, 99/1 to 70/30
gradient over 5 min, 3 mL/min): Rt = 4.83 and 4.97 (major)
(R)-3-(2,6-Dimethoxyphenyl)chroman-2-one (4b) The title min.
compound was prepared according to general procedure II
using α-aryl-β-oxo allyl ester 3b (27.6 mg, 0.096 mmol) to
yield the product as a white solid (17.9 mg, 84%, 86% ee),
(R)-3-(2-(Benzyloxy)naphthalen-1-yl)chroman-2-one (4g)
The title compound was prepared according to general
procedure II using α-aryl-β-oxo allyl ester 3g (35 mg, 0.075
mmol) to yield the product as an off white solid (23.7 mg,
identical in all respects to the previously prepared racemic
20
sample, with the exception of [α]D = +44.53 (c 1.0,
CH2Cl2); SFC: (Chiralcel IC-3, scCO2/MeCN, 99/1 to 70/30
gradient over 5 min, 3 mL/min): Rt = 3.61 (major) and 3.92
min.
83%, 35% ee), identical in all respects to the previously
20
prepared racemic sample, with the exception of [α]D
=
+32.25 (c 1.1, CH2Cl2); SFC: (Chiralcel IC-3, scCO2/MeCN,
99/1 to 70/30 gradient over 5 min, 3 mL/min): Rt = 5.51 and
(R)-3-(2,3,6-Trimethoxyphenyl)chroman-2-one (4c) The 5.81 (major) min.
title compound was prepared according to general procedure
II using α-aryl-β-oxo allyl ester 3c (30 mg, 0.075 mmol) to
afford the product as a white solid (22.7 mg, 96%, 88% ee),
(R)-3-(Benzo[d][1,3]dioxol-5-yl)chroman-2-one (4h) The
title compound was prepared according to general procedure
II using α-aryl-β-oxo allyl ester 3h (26 mg, 0.075 mmol) to
afford the product as an off white solid (18.5 mg, 92%, 29%
ee), identical in all respects to the previously prepared
identical in all respects to the previously prepared racemic
20
sample, with the exception of [α]D = +45.58 (c 1.0,
CH2Cl2); SFC: (Chiralcel IC-3, scCO2/MeCN, 99/1 to 70/30
gradient over 5 min, 3 mL/min): Rt = 4.73 and 4.92 (major)
min.
20
racemic sample, with the exception of [α]D = +8.92 (c 1.0,
CH2Cl2); SFC: (Chiralcel IA-3, scCO2/IPA, 99/1 to 70/30
gradient over 5 min, 3 mL/min): Rt = 4.22 and 4.40 (major)
Crystals suitable for X-ray analysis were grown by min.
dissolving 4c in Et2O (1 mL), and the Et2O layer was
carefully layered with pentane (2 mL) followed by slow
evaporation of solvents at room temperature: C18H18O5, M =
314.32, orthothrombic, a = 7.1206(2) Å, b = 8.6539(2) Å, c
= 25.7065(4) Å, U = 1584.06(6) Å3, T = 100 K, space group
P212121 (no. 19), Z = 4, 26367 reflections measured, 3311
unique (Rint = 0.0413) which were used in all calculations.
The final wR(F2) was 0.0705 (all data).
(S)-3-Benzylchroman-2-one (4j) The title compound was
prepared according to general procedure II using α-aryl-β-
oxo allyl ester 3j (24 mg, 0.075 mmol) to give the product
as an off white solid (14.6 mg, 82%, 14% ee), identical in all
respects to the previously prepared racemic sample, with the
exception of [α]D20 = +5.97 (c 1.0, CH2Cl2); SFC: (Chiralcel
IA-3, scCO2/IPA, 99/1 to 70/30 gradient over 5 min, 3
mL/min): Rt = 2.55 and 2.70 (major) min.
(R)-3-(2,4-Dimethoxyphenyl)chroman-2-one (4d) The title
compound was prepared according to general procedure II
using α-aryl-β-oxo allyl ester 3d (28 mg, 0.075 mmol) to
yield the product as white crystals (17.5 mg, 82%, 70% ee),
identical in all respects to the previously prepared racemic
sample, with the exception of [α]D20 = -3.30 (c 1.0, CH2Cl2);
SFC: (Chiralcel IC-3, scCO2/MeCN, 99/1 to 70/30 gradient
over 5 min, 3 mL/min): Rt = 4.19 (major) and 4.36 min.
Acknowledgements
J. J. is grateful for the award of an Irish Research Council
Enterprise
Partnership
Scheme
PhD
Scholarship
(EPSPG/2014/110) with Enterprise Partner APC Ltd. 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 number 12\RC\2275 (postdoctoral fellowship for R.A.). We
acknowledge facilities provided by the Centre for Synthesis and
Chemical Biology (CSCB), funded by the Higher Education
Authority’s PRTLI. We would like to thank Dr. Helge Müller-Bunz
for X-ray crystal structure analysis and Dr. Yannick Ortin for help
with the NMR spectroscopic studies.
(R)-3-(2,3,4-Trimethoxyphenyl)chroman-2-one (4e) The
title compound was prepared according to general procedure
II using α-aryl-β-oxo allyl ester 3e (30 mg, 0.075 mmol) to
afford the product as a white solid (22.4 mg, 95%, 65% ee),
identical in all respects to the previously prepared racemic
20
sample, with the exception of [α]D = -3.25 (c 1.23,
10
This article is protected by copyright. All rights reserved.

10.1002/adsc.201800724
Advanced Synthesis & Catalysis
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Advanced Synthesis & Catalysis
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10.1002/adsc.201800724
Advanced Synthesis & Catalysis
FULL PAPER
Pd-Catalysed Decarboxylative Asymmetric
Protonation of Sterically Hindered α-Aryl
Lactones and Dihydrocoumarins
Adv. Synth. Catal. Year, Volume, Page – Page
Jinju James a, Ramulu Akulab, Patrick J. Guirya,b*
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