Palladium-Catalysed Construction of All-Carbon Quaternary Centres with Propargylic Electrophiles: Challenges in the Simultaneous Control of Regio-, Chemo- and Enantioselectivity

Article abstract of DOI:10.1055/s-0036-1591957

This article describes the palladium-catalysed three-component coupling of 1,3-dicarbonyl compounds with nucleophiles and propargylic electrophiles for the generation of quaternary all-carbon centres in a single step, which necessitates the simultaneous control of regio-, chemo- and enantioselectivity. The use of propargyl enol carbonates, the source of two of the components, was found to be essential in maintaining high levels of regiocontrol and chemoselectivity, whereas a careful analysis of p K _a trends of O-, C- and N-nucleophiles as the other coupling partner indicates that the highest levels of selectivity are likely to be obtained with relatively acidic species, such as phenols, 1,3-dicarbonyl compounds and aromatic N-heterocycles. Finally, studies towards the development of the catalytic enantioselective construction of quaternary all-carbon centres by means of alkenylation and allylic alkylation are disclosed.

Full text of DOI:10.1055/s-0036-1591957

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–S
feature
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en
M. Kenny et al.
Feature
Synthesis
Palladium-Catalysed Construction of All-Carbon Quaternary
Centres with Propargylic Electrophiles: Challenges in the
Simultaneous Control of Regio-, Chemo- and Enantioselectivity
Miles Kennya
Sybrin P. Schröderb
Nicholas J. Taylorb
Paula Jacksonb
Daniel J. Kitsona
Vilius Franckevičius*a
O
Challenges:
The simultaneous control of
• regioselectivity
O
R3
*
O
O
R3
NuH
Nu
R1
R1
• chemoselectivity
• enantioselectivity
Pd catalysis
– CO2
R2
O
R2
O
0
0
0
0
0-
0
0
2
4-
3
8
6
8-
4
6
2
a Department of Chemistry, Lancaster University, Lancaster,
LA1 4YB, UK
v.franckevicius@lancaster.ac.uk
b Department of Chemistry, University of York, Heslington,
York, YO10 5DD, UK
Received: 15.01.2018
Accepted after revision: 20.02.2018
Published online: 27.03.2018
However, quaternary all-carbon centres are severely steri-
cally crowded, making the catalytic enantioselective con-
struction of such centres a formidable synthetic challenge
and an active area of research.6 As such, the development of
new catalytic methodologies for the installation of quater-
nary centres remains essential towards enabling access to
novel 3D building blocks for drug discovery.
DOI: 10.1055/s-0036-1591957; Art ID: ss-2018-z0026-fa
Abstract This article describes the palladium-catalysed three-compo-
nent coupling of 1,3-dicarbonyl compounds with nucleophiles and
propargylic electrophiles for the generation of quaternary all-carbon
centres in a single step, which necessitates the simultaneous control of
regio-, chemo- and enantioselectivity. The use of propargyl enol car-
bonates, the source of two of the components, was found to be essen-
tial in maintaining high levels of regiocontrol and chemoselectivity,
whereas a careful analysis of pKa trends of O-, C- and N-nucleophiles as
the other coupling partner indicates that the highest levels of selectivity
are likely to be obtained with relatively acidic species, such as phenols,
1,3-dicarbonyl compounds and aromatic N-heterocycles. Finally, stud-
ies towards the development of the catalytic enantioselective construc-
tion of quaternary all-carbon centres by means of alkenylation and allyl-
ic alkylation are disclosed.
Our group has had a long-standing interest in the reac-
tivity of propargylic electrophiles under palladium cataly-
sis, the broad reactivity profiles that propargylic electro-
philes exhibit, and the opportunities to exploit this type of
reactivity in the construction of quaternary all-carbon cen-
tres. In reactions with a palladium(0) catalyst (Scheme 1, A),
propargylic electrophiles, such as carbonate 1, lead to the
formation of η3-π-propargylpalladium(II) intermediate 2
via oxidative addition and subsequent decarboxylation.7 Al-
though species 2 can take part in propargylation and alle-
nylation reactions,8 the process generating the most com-
plexity is one that allows the coupling of two nucleophiles
with 2.9 Such a process typically requires the use of soft
nucleophiles,10 the first of which undergoes addition at the
central carbon atom in 2 and affords transient pallada-
cyclobutene species 3.11 Protonation of 3 by the conjugate
acid of the second nucleophile gives rise to η3-π-allylpalla-
dium(II) intermediate 4, where the initial palladacyclo-
butene 3 formation and protonation may be synchronous.7b
In the final mechanistic step, allylic alkylation at one of the
termini in 4 affords product 5, in which one nucleophile has
undergone alkenylation and the second, allylic alkylation.
Unfortunately, the direct one-pot coupling of η3-π-prop-
argylpalladium(II) intermediate 2 with two independent
nucleophiles is extremely challenging owing to several
selectivity issues (Scheme 1, B).12 Firstly, the order of addi-
tion of the two nucleophiles must be controlled so that only
one of the two cross-coupled products 5 or 6 is made (regio-
Key words palladium, enantioselective catalysis, quaternary centres,
propargylic electrophiles, 1,3-dicarbonyl compounds
To facilitate drug discovery programmes, the pharma-
ceutical industry has historically relied upon tapping into
compound screening libraries which are strongly biased to-
wards molecules that are rich in aromatic character and flat
structural features.1 These properties are associated with
low shape diversity, poorer solubility, higher toxicity and,
therefore, higher levels of attrition during drug develop-
ment.2 To alleviate this effect, there is currently a strong
drive to enhance the efficiency of drug discovery processes
by utilising molecules with greater 3D complexity, in-
creased levels of saturation and more chiral centres.3 These
changes can result in better solubility profiles, higher selec-
tivity of binding and lower toxicity,4 as well as more effi-
cient sampling of larger areas of chemical space.5 Quaterna-
ry all-carbon centres inherently offer scope for maximum
exploration of 3D chemical space through chain growth in
all four directions from the sp3 tetrahedral carbon atom.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–S

B
M. Kenny et al.
Feature
Synthesis
Biographical Sketches
Miles Kenny was born in Milton
Keynes, UK, in 1991. After receiving
his MChem degree from the Uni-
versity of East Anglia, UK, Miles em-
barked on a PhD in the group of Dr
Vilius Franckevičius at Lancaster
University, UK, working on the de-
velopment of new palladium-cata-
lysed methodologies for the
generation of quaternary carbon
centres. Miles successfully complet-
ed his PhD in 2017.
Sybrin P. Schröder was born in
the Netherlands in 1989. He re-
ceived his BSc degree in chemistry
from Radboud University Nijme-
gen, the Netherlands, in 2010,
where he also obtained his MSc de-
gree in organic chemistry, in 2012,
working in the group of Prof. Floris
Rutjes. As part of his master’s stud-
ies, Sybrin undertook an Erasmus
placement at the University of
York, UK, working with Dr. Vilius
Franckevičius on the development
of new methodologies for the palla-
dium-catalysed intermolecular cou-
propargylic electrophiles. He is cur-
rently a PhD student in the group
of Prof. Hermen Overkleeft in
Leiden, the Netherlands, focusing
on the development of activity-
based probes for carbohydrate-pro-
cessing enzymes.
pling
of
nucleophiles
with
Nicholas J. Taylor was born in
Macclesfield, UK, in 1990. He com-
pleted his MChem in chemistry at
the University of York, UK, during
which he undertook a final year
project working with Dr. Vilius
Franckevičius on the palladium-cat-
alysed coupling of propargylic elec-
trophiles with enolate nucleophiles.
He then moved to the University of
Oxford, UK, for his DPhil studies,
where he worked in the group of
Professor Véronique Gouverneur on
the copper-mediated nucleophilic
18F-radiolabelling of (hetero)arenes
for applications in positron emis-
sion tomography. He is currently a
postdoctoral research chemist in her-
bicide chemistry at Syngenta, UK.
Paula Jackson was born in Liver-
pool, UK, in 1991. She received an
integrated MChem degree from the
University of York, UK, in 2014,
working in the group of Prof. Rich-
ard Taylor under the supervision of
Dr. William Unsworth. During her
studies, Paula successfully secured
a Royal Society of Chemistry Un-
dergraduate Research Bursary to
undertake a summer placement
with Dr. Vilius Franckevičius focus-
ing on the development of new de-
carboxylative palladium-catalysed
coupling methodologies. She is cur-
rently a scientist at Redx Pharma
Plc., UK, working on the develop-
ment of novel small-molecule ther-
apies for cancer and fibrosis.
Daniel J. Kitson was born in Man-
chester, UK, in 1995. In 2015, Dan-
ny was awarded a Royal Society of
Chemistry Undergraduate Research
Bursary, exploring palladium-cata-
lysed methodologies for quaternary
carbon centre generation in the
group of Dr. Vilius Franckevičius at
Lancaster University, UK. Danny
graduated with an MChem degree
from Lancaster University, UK, in
2017, having undertaken a final
year research project in the area of
photochemistry under the supervi-
sion of Dr. Susannah Coote.
Vilius Franckevičius was born in
Lithuania in 1983. Since 2013, he
has been a lecturer at the Depart-
ment of Chemistry at Lancaster
University, UK, and has research
interests in new synthetic method-
ology development and enantio-
selective catalysis. Prior to this,
Vilius completed his PhD under the
supervision of Prof. Steven V. Ley at
the University of Cambridge, UK.
This was followed by a postdoctoral
position in the group of Prof. Dirk
Trauner at Ludwig Maximilians Uni-
versity of Munich, Germany, and a
Research and Teaching Fellowship
with Prof. Richard Taylor at the Uni-
versity of York, UK.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–S

C
M. Kenny et al.
Feature
Synthesis
A. Reactivity of soft nucleophiles with propargylic
electrophiles under palladium catalysis:
B. Selectivity issues:
C. Control of selectivity by tethering:
MeO2CO
Nu2
2
LnPd(0)
Nu2H
O
Nu2
Pd(II)Ln
1
Nu1
Nu2
or
Nu1
O
OMe
CO2 + MeO
Nu1
intramolecular
alkenylation
5
Nu1H
Nu2H
one-pot
reaction
Nu1H
LnPd(0)
n
n
n
9
10
OCO2Me
11
Cross-coupling (regioselectivity):
Nu1
1
Nu2H
Nu2
LnPd(0)
Pd(II)Ln
Nu1H
Nu2
Nu1
Nu1
Pd(II)Ln
Nu2
Nu1
promote initial
addition of Nu1
n
+ Nu2
n
4
2
5
6
12
13
Homo-coupling (chemoselectivity):
E. Control of enantioselectivity in the
intermolecular coupling of nucleophiles:
Nu1H + MeO
MeOH
Nu1
Nu2
Pd(II)Ln
R4
*
R1
R2
Nu2H
Nu2
R5
R6
Nu1
R1
*
Nu2
R1
R2
*
Nu1
R3
3
7
8
Nu1
*
R2
R3
17
18
R3
19
D. Control of regio- and chemoselectivity in the intermolecular coupling of nucleophiles:
enantioselective enantioselective
enantioselective
alkenylation/
allylic alkylation
R2
O
alkenylation
allylic alkylation
O
via
O
LnPd(0)
NuH
PdLn
O
O
O
O
Nu
16
Key challenge:
R1
O
• The simultaneous control of
- regioselectivity
- chemoselectivity
- enantioselectivity
R1
R2
R3
chemo- and
R1
R2
15
– CO2
R3
R3
regioselective
14
Scheme 1 Control of selectivity in palladium-catalysed coupling reactions of nucleophiles with propargylic electrophiles
selectivity). Secondly, homo-coupling of just one nucleo-
phile, leading to 7 and 8, must also be prevented (chemo-
selectivity).
maintaining high levels of regiocontrol and chemoselectivi-
ty. This approach involves the use of propargylic enol car-
bonates 14 (Scheme 1, D), derived from 1,3-dicarbonyl
compounds. The palladium-catalysed reaction proceeds via
intermediate 15 following oxidative addition and decarbox-
ylation, in which the η3-π-propargylpalladium(II) electro-
phile remains tightly associated with the enolate nucleo-
phile.15 This process results in the selective intramolecular
alkenylation of the enolate and intermolecular allylic
alkylation of the external nucleophile to afford linear prod-
ucts of type 16 with high regio- and chemoselectivity, in
which a quaternary all-carbon centre has been installed.
We surmised that, in the presence of a chiral ligand on pal-
ladium, the use of a non-symmetrical enolate could result
in the enantioselective construction of a quaternary all-car-
bon centre in 17 via alkenylation (Scheme 1, E). Similarly,
the use of a non-symmetrical external carbon-based nucle-
ophile could lead to the enantioselective installation of a
quaternary carbon centre by means of allylic alkylation
(18). Finally, the use of two non-symmetrical carbon-based
nucleophiles could, in principle, pave the way to the enantio-
selective construction of two all-carbon quaternary centres
in a single step (19). However, to achieve both high efficien-
cy and stereoselectivity in any of the above enantioselective
processes, all control elements, namely, regio-, chemo- and
enantioselectivity, must be simultaneously controlled. In-
deed, there are very few examples reported of the enantio-
selective construction of quaternary all-carbon centres by
means of alkenylation using the palladium-catalysed cou-
pling reaction of propargylic electrophiles with nucleo-
Typically, these selectivity challenges can be overcome
by employing tethering strategies in cyclisation reactions
(Scheme 1, C). For example, if one of the nucleophiles is
tethered to the propargylic electrophile in 9,13 then alke-
nylation of the tethered nucleophile is likely to occur prior
to alkenylation of the external nucleophile due to the intra-
molecular nature of the cyclisation reaction. Allylic alkyla-
tion of the second nucleophile then follows at either the
less or the more substituted position to afford 10 or 11, re-
spectively. An alternative approach is the use of tethered
bis-nucleophiles 12.14 In such a process, a clear differentia-
tion between the two nucleophiles in 12 must be achieved
if the order of addition is to be accurately controlled. If one
of the nucleophiles is more acidic than the other, then it
should preferentially undergo the initial deprotonation and,
therefore, alkenylation, followed by intramolecular allylic
alkylation of the second nucleophile to afford 13. Alterna-
tively, if the acidity is similar, a strong steric bias between
the two nucleophiles or a distinct difference in nucleo-
philicity could favour the initial addition of one nucleophile
over the other. Both approaches enable the control of regi-
oselectivity, whereas homo-coupling is prevented through
intramolecularity.
To exploit the use of palladium catalysis in the genera-
tion of quaternary all-carbon centres from propargylic elec-
trophiles, our group discovered a method that enables the
coupling of nucleophiles to afford linear products whilst
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–S

D
M. Kenny et al.
Feature
Synthesis
philes,16 typically affording only moderate levels of enanti-
oselectivity. The induction of enantioselectivity at the allyl-
ic alkylation step of the mechanism has been studied using
catechol,17 and β-ketoester nucleophiles;18 however, there
are no examples in which a quaternary all-carbon centre
had been installed enantioselectively.
This article describes our investigations into the utility
of this methodology and the challenges involved in con-
trolling selectivity in the palladium-catalysed coupling of
nucleophiles with propargylic electrophiles.
we found that Xantphos, a large-bite-angle ligand, was
most suitable in this reaction and, in all cases, no homo-
coupling of nucleophiles was observed. The use of
monodentate or smaller bite-angle bidentate ligands leads
to severe erosion of both reaction efficiency and selectivi-
ty.15 In the presence of phenols, 1,3-cyclohexanedione
products 20a and 20b were formed with moderate to good
regioselectivity; however, the reaction with 2-naphthol as
the nucleophile was not selective (20c). The coupling of
five-membered 1,3-diketones with phenol to afford 20d
and 20e also gave different levels of regioselectivity. It can
be reasoned that the highly stabilised nature of cyclic 1,3-
diketone enolates can result in lower levels of regioselectiv-
ity, either due to the lower nucleophilicity of the enolate in-
hibiting the required intramolecular alkenylation process in
15 (vide supra, Scheme 1), or dissociation of the palladium
complex from the highly stabilised enolate, paving the way
to an uncontrolled order of addition of the two nucleo-
Phenol Nucleophiles
Our investigation began with the coupling of highly sta-
bilised enolates, derived from cyclic 1,3-diketones (1,3-
cyclohexanedione, pKa 10 in DMSO),19 with phenols as nuc-
leophiles (phenol, pKa 18 in DMSO),19 to afford the desired
product 20 and/or its regioisomer 21 (Scheme 2). In this
one-pot process, an all-carbon quaternary centre is formed
along with new C–C and C–O bonds.15 Upon optimisation,
Pd2(dba)3 (5 mol%)
Xantphos (10 mol%)
1,4-dioxane, 80 °C, 2 h
O
O
O
R3
R3
O
O
R3
O
O
R1
R1
O
PPh2
+
R1
R
R
HO
PPh2
R2
O
R2
O
O
R
21
14
20
R2
O
Xantphos
O
O
O
O
O
O
O
O
O
O
Ph
O
O
O
O
20a (77%)a
20b (72%)a
20d (85%)
rr >19:1
20c (67%)a
rr 1.1:1
20e (58%)a
rr 2.0:1
rr 3.6:1
rr 8.0:1
O
O
Ph
O
O
O
O
Ph
O
O
Ph
O
O
OPh
OPh
OPh
OPh
OPh
OPh
O
O
20k (35%)a
20i (66%)
20j (70%)
20f (76%)
20g (52%)
20h (77%)
rr >19:1
rr >19:1
rr >19:1
rr 7.0:1
rr >19:1
rr 3.3:1
O
O
O
O
O
O
O
O
O
O
OMe
O
NH2
O
OMe
OH
20m (79%)
rr >19:1
20l (87%)
rr >19:1
20n (91%)
rr >19:1
20o (72%)
rr >19:1
O
O
O
O
O
O
O
O
O
O
O
O
NO2
NO2
20p (25%)
21p (41%)
rr 1:1.6
20q (28%)
21q (22%)
rr 1:1.1
20r (41%)
21r (44%)
rr 1:1.9
20s (32%)
21s (25%)
rr 1.4:1
CF3
NO2
O
O
O
O
O
O
O
O
O
Cl
Br
O
O
O
Cl
O
O
O
N
20t (32%)
21t (14%)
rr 1.9:1
20u (46%)
21u (18%)
rr 3.3:1
20v (53%)
21v (16%)
rr 2.6:1
20w (49%)
21w (11%)
rr 3.1:1
F
20x (68%)
rr >19:1
Scheme 2 Regio- and chemoselective coupling of 1,3-dicarbonyl compounds with phenols. Yields of isolated product in parentheses. Isomer 20
shown. Regioselectivity (rr) ratios of 20:21 were determined by 1H NMR analysis of the crude product mixtures. a Combined yield of 20 and 21 isolated
as a mixture
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–S

E
M. Kenny et al.
Feature
Synthesis
philes. In contrast, the use of propargyl carbonates, derived
from less acidic acyclic 1,3-dicarbonyls (pKa 13–16 in
DMSO),19 gave excellent regioselectivity in most cases (20f–k)
in the coupling with phenol, presumably due to the tighter
association of the enolate with the intermediate palladium
complex following decarboxylation. Excellent regioselectiv-
ity was maintained with electron-rich phenols (20l and
20m), and no chemoselectivity issues were observed in the
presence of other unprotected nucleophiles (20n and 20o),
whereby allylic alkylation of the phenol functionality takes
place exclusively owing to its higher acidity. In contrast,
regioselectivity was low when electron-deficient phenols
were utilised. For example, nitro-, trifluoromethyl- and
pyridyl-substituted phenols afforded 20p–t with low regio-
selectivity. Similarly, halogenated phenols gave rise to 20u–
w with moderate selectivity, with the surprising exception
of fluorine-substituted 20x, which was isolated with com-
plete regioselectivity. Given that electron-poor phenols are
more acidic than their electron-rich counterparts (4-nitro-
phenol, pKa 11 in DMSO),20 and as acidic as, if not more
than, acyclic 1,3-dicarbonyl compounds, it is likely that the
enolate formed in situ after decarboxylation undergoes pro-
tonation by the phenol nucleophile, which leads to the dis-
sociation of the palladium complex and, thus, loss of regio-
control.
ence of an acidic proton in the product structure. This pro-
cess was extended to the use of 1,3-dicarbonyl compounds
other than 1,3-diketones, and all products 23s–w were
formed with complete regioselectivity. Since the 1,3-dicar-
bonyls tested are less acidic than 1,3-diketones, this process
is analogous to the use of electron-rich phenols as nucleo-
philes, which had also afforded products with complete
regioselectivity (vide supra, Scheme 2). Excellent selectivity
was obtained in the formation of regioisomers 23x–aa,
with the exception of 23ab, which resulted in a complex
mixture of products.
N-Nucleophiles
In addition to O- and C-nucleophiles, we discovered that
indole, an aromatic N-heterocycle, can also be readily
deprotonated and alkylated as a coupling partner to afford
24a with complete regio- and chemoselectivity (Scheme
4).22 However, given that aromatic N-heterocycles are typi-
cally less acidic than phenols (indole, pKa 21; pyrrole, pKa
23, both in DMSO),19 a higher reaction temperature was re-
quired to facilitate deprotonation. Indeed, product 24b was
obtained in relatively high yield, presumably due to the
higher acidity of the indole nucleophile which bears an
electron-withdrawing ester substituent. In contrast, elec-
tron-donating substitution on the indole unit negatively
impacted on the efficiency of the reaction (24c). The use of
carbazole as the nucleophile was successful (24d), and the
reaction scope could also be extended to the use of propar-
gyl enol carbonates derived from β-ketoesters (24e). The
coupling process was broadened to the use of pyrrole as an
analogue to indole (24f), albeit an electron-withdrawing
substituent was essential to obtain a high yield of product
(24g–j). Crucially, all reactions proceeded with complete
regio- and chemoselectivity owing to both the tight associ-
ation of the η3-π-propargylpalladium(II) intermediate with
the enolate following decarboxylation of 14 and the lack of
protonation of the enolate by the N-heterocyclic nucleo-
phile given the substantial difference in pKa. This methodol-
ogy was readily extended to other aromatic N-heterocycles,
including azaindole, imidazole, benzimidazole and pyra-
zole, affording 24k–n, respectively, with complete regio-
control. Unfortunately, a much less acidic saturated cyclic
amine as nucleophile failed to couple (24o).
1,3-Dicarbonyl Nucleophiles
Given the success in controlling the regioselectivity in
the coupling of acyclic 1,3-diketones with relatively elec-
tron-rich phenols, we sought to explore whether the analo-
gous coupling could be extended by replacing the phenol
nucleophile with a 1,3-dicarbonyl compound (Scheme 3).21
Indeed, this reaction process was found to be very efficient
using DPEphos as the large-bite-angle ligand, enabling the
formation of two all-carbon quaternary carbon centres and
two new C–C bonds in a single step with complete regio-
control and good chemoselectivity (23a–d) despite the
structural similarities between the two nucleophiles. Given
that high levels of regiocontrol are imparted by the tight as-
sociation of the η3-π-propargylpalladium(II) intermediate
with the enolate after decarboxylation of 14, this reaction
process becomes regioswitchable by utilising an enol car-
bonate of 1,3-dicarbonyl nucleophile 22, thus paving the
way to regioisomeric products 23e–h. Substitution of the
1,3-diketone nucleophile was tolerated to afford coupled
products 23i–k, as well as regioisomers 23n and 23o; only a
complex mixture of products was obtained in the formation
of 23p. By analogy to electron-deficient phenols, the use of
a significantly more acidic 1,3-cyclohexanedione nucleo-
phile in the formation of 23l afforded a mixture of products,
with nucleophile homo-coupling being the major pathway.
However, the selectivity in the formation of regioisomer
23q in the regioswitched process was higher. When an un-
substituted 1,3-diketone was utilised as a nucleophile, 23m
was isolated in 56% yield, but the synthesis of its regio-
isomer 23r was not successful, presumably due to the pres-
Acidity Trends
The palladium-catalysed coupling of propargyl enol car-
bonates derived from 1,3-dicarbonyls relied upon the use of
phenols (phenol, pKa 18 in DMSO),19 1,3-dicarbonyl com-
pounds (pKa 13–16),19 and aromatic N-heterocyclic nucleo-
philes (pKa 19–23, in DMSO)19 to obtain high levels of regio-
control. As such, we set out to investigate the utility of nuc-
leophiles outside of this pKa range. Based on the previous
cases of low regioselectivity, where the external nucleop-
hile was more acidic than the conjugate acid of the enolate,
such as electron-deficient phenols (vide supra, Scheme 2),
several other acidic species were tested as nucleophiles
(Scheme 5). In this context, carboxylic acids as nucleop-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–S

F
M. Kenny et al.
Feature
Synthesis
hiles, which display similar acidity to electron-deficient
phenols (pKa 11–12 in DMSO),19 did afford products 25a–c,
however, regioselectivity was again low and in line with the
previous observation that undesired protonation of the
enolate occurs prior to the alkenylation step. By increasing
the acidity of the external nucleophile further, such as us-
ing p-toluenesulfonic acid, the reaction process was even
more difficult to control (25d), leading to a complex mix-
ture of products. On the other side of the pKa range, the
reactivity of C-nucleophiles 27–30, all less acidic than
O
R4
O
O
O
O
Pd2(dba)3 (5 mol%)
DPEphos (10 mol%)
R3
O
O
R3
O
R4
R5
R1
O
PPh2
R6
+
R1
O
R6
1,4-dioxane, 80 °C, 2 h
R5
PPh2
R2
O
O
14
22
23
DPEphos
R2
O
O
O
O
O
O
O
O
O
O
O
Bn
O
O
O
O
23a (85%)
rr >19:1
chemo 6.1:1a
23b (47%)
rr >19:1
23c (79%)
rr >19:1
23d (73%)
rr >19:1
chemo 6.9:1a
chemo 5.2:1.1a:1b
chemo 10:1.2a:1b
O
O
O
O
O
O
O
O
O
O
O
O
Bn
O
O
O
O
23e (70%)
rr >19:1
chemo 5.0:1b
23g (71%)
rr >19:1
chemo >19:1
23h (21%)
rr >19:1
chemo 1:1a
23f (61%)
rr >19:1
chemo 10:2.0a:1b
O
O
O
O
O
OH
O
O
O
O
O
O
O
O
O
O
Ph
Ph
O
O
O
O
CO2Et
O
O
23l (27% of 23lb)c
rr 1.3:1
chemo 6.2b:2.6:1.3:1a
23i (54%)
rr >19:1
23j (60%)
rr >19:1
23k (36%)
rr n.d.
chemo n.d.
23m (56%)
rr n.d.
chemo n.d.
chemo 4.6:1a
chemo 10:1.2a:1b
O
CO2Et
O
O
O
O
O
O
O
O
Ph
O
O
O
O
O
Ph
O
O
O
O
O
23n (63%)
rr >19:1
23o (41%)
rr 3.5:1
23p
23q (43%)
rr 4.0:1
chemo 4.3:1.6a:1b
23r
complex mixture
complex mixture
chemo 4.4:1a
chemo 10:2.0a:1b
O
O
O
O
O
O
EtO
O
O
O
O
S
O
O
O
O
OEt
O
O
NBoc
Me
O
O
O
O
O
23s (38%)
rr >19:1
chemo >19:1
23t (54%)
rr >19:1
chemo 6.9:1a
23u (58%)
rr >19:1
chemo 7.4:1b
23v (81%)
rr >19:1
chemo 11:1b
23w (34%)
rr >19:1
chemo 6.5:2.2a:1b
O
O
O
O
OEt
O
O
O
O
O
O
O
O
O
O
O
S
O
O
O
BocN
O
O
EtO
O
O
23x (42%)
rr >19:1
chemo 14:6.7b:1a
23y (21%)
rr >19:1
chemo 5.0:1b
23z (58%)
rr >19:1
chemo 10:2.0b:1a
23aa (53%)
rr >19:1
chemo 7.8:1a
23ab
complex mixture
Scheme 3 Regioswitchable coupling of 1,3-dicarbonyl compounds. Yields of isolated isomer 23 in parentheses. Isomer 23 shown. Regioselectivity (rr)
and chemoselectivity (chemo) ratios were determined by 1H NMR analysis of the crude product mixtures. n.d. = not determined due to overlapping
signals. a Refers to homo-coupling of 14. b Refers to homo-coupling of 22. c Homo-coupled 22 was the major product isolated in 27% yield (23lb, see the
experimental section)
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–S

G
M. Kenny et al.
Feature
Synthesis
O
Pd2(dba)3 (5 mol%)
Xantphos (10 mol%)
O
O
O
R3
R3
Nu
R1
R1
toluene, 120 °C, 2 h
NuH
14
24
R2
O
O
R2
O
N
CO2Me
CO2Me
O
O
O
O
O
OEt
O
O
O
O
N
N
N
N
OMe
24a (55%)
24b (70%)
24c (27%)
24d (53%)
24e (81%)
rr >19:1
rr >19:1
rr >19:1
rr >19:1
rr >19:1
Ph
MeO2C
O
O
O
O
O
O
O
O
O
O
O
O
N
N
N
N
O
N
CO2Me
CO2Me
CO2Me
CO2Me
24f (21%)
rr >19:1
24g (81%)
rr >19:1
24h (57%)
rr >19:1
24i (95%)
24j (99%)
rr >19:1
rr >19:1
O
O
O
O
O
N
N
N
O
N
O
O
O
O
N
N
N
N
N
24k (73%)
24l (49%)
24m (42%)
24n (51%)
24o
rr >19:1
rr >19:1
rr >19:1
rr >19:1
complex mixture
Scheme 4 Regio- and chemoselective coupling of 1,3-dicarbonyl compounds with N-nucleophiles. Yields of isolated isomer 24. Regioselectivity (rr)
ratios were determined by 1H NMR analysis of the crude product mixtures. No homo-coupling (chemoselectivity) of 14 or the N-nucleophile was
observed in all cases
phenols and 1,3-dicarbonyl compounds (e.g., cyclohexa-
none, pKa 26 in DMSO),19 was tested. If the reaction were to
O
proceed through the previously postulated mechanism
(vide supra, Scheme 1), then deprotonation of a much less
acidic nucleophile would be required. Unfortunately, the re-
action with ketone 27 was unsuccessful and a complex mix-
ture of products was obtained. To enhance the acidity of the
carbonyl functionality and attempt to facilitate deprotona-
tion, we explored cyclohexenone (28), which had been
shown to participate in an intramolecular coupling reac-
tion,14c furanone 29, which would give an aromatic anion
upon deprotonation that would be more stable than an
enolate of a saturated lactone, and α-difluorinated ester 30,
which is more acidic than a simple ester due to the
electron-withdrawing nature of the fluorine atoms. In all
three cases, only a complex mixture of products was
observed. It was therefore apparent that, overall, in the
coupling of 1,3-dicarbonyl compounds with nucleophiles,
high reaction efficiency and selectivity is most likely to be
achieved with relatively acidic nucleophiles (pKa ~13–23 in
DMSO).
R3
Nu
O
R1
Pd2(dba)3 (5 mol%)
Xantphos (10 mol%)
25
O
O
O
R2
O
O
O
R3
1,4-dioxane
80 °C, 2 h
NuH
Nu
R1
26
R2
O
31
O
O
O
O
O
Ph
O
O
25a (44%)a
rr 1.5:1
25b (43%)a
rr 1.8:1
O
O
O
O
O
O
N
OTs
Boc
25c (49%, dr 1:1)
26c (15%, dr 1:1)
rr n.d.
25d
complex mixture
Unsuccessful C-nucleophiles:
O
O
O
O
Diastereoselective Synthesis
F
MeO
O
A crucial aspect of this project was the construction of
quaternary all-carbon centres in a stereoselective manner.
By utilising propargyl enol carbonate 31 and β-ketoester
32, two stereogenic quaternary centres were installed in a
single step (Scheme 6). However, while the reaction condi-
tions enabled the concerted control of regio- and chemo-
selectivity in the formation of 33, no induction of diastereo-
selectivity was observed, potentially due to the remoteness
F
27
28
29
30
Scheme 5 Investigation of acidity trends. Isomer 25 shown. Regio-
selectivity (rr) and diastereoselectivity (dr) ratios were determined by
1H NMR analysis of the crude product mixtures. n.d. = not determined
due to overlapping signals. No homo-coupling (chemoselectivity) of 31
or the external nucleophile was observed in all cases. a Combined yield
of 25 and 26 isolated as a mixture
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–S

H
M. Kenny et al.
Feature
Synthesis
of the two chiral centres and the acyclic nature of 1,3-dicar-
bonyl compound 32. This observation gave an indication
that the enantioselective installation of a stereogenic centre
during the alkenylation step of the mechanism while rely-
ing on diastereocontrol to construct the second stereogenic
centre at the allylic alkylation stage was likely to pose chal-
lenges. To avoid this difficulty, the next stage of the investi-
gation focused on the enantioselective installation of a sin-
gle stereogenic centre, either by means of alkenylation or
allylic alkylation. Notwithstanding, such a process was still
likely to be extremely demanding because to achieve both
high levels of enantioselectivity and yield of the desired
product, the simultaneous control of not only stereoselec-
tivity, but also regio- and chemoselectivity is required.
fied as the optimum ligand in terms of yield and selectivity.
Although 23g was formed in 57% yield, the enantioselectiv-
ity was low (21% ee). Similar levels of enantioselectivity
were observed in the formation of 23n and 34a, but the
product yields were low due to inadequate levels of control
of either regio- or chemoselectivity. In addition to the use
of 1,3-dicarbonyls, phenol and pyrrole nucleophiles were
utilised, both of which afforded 20h and 24g in 19% ee
whilst maintaining full regio- and chemoselectivity.
Enantioselective Allylic Alkylation
The enantioselective construction of a quaternary all-
carbon centre via the allylic alkylation of intermediate 38
was developed in a fashion analogous to the enantioselec-
tive alkenylation process (Scheme 8), where again the si-
multaneous control of regio-, chemo- and stereoselectivity
was essential. Following a screen of chiral ligands for palla-
dium (see the Supporting Information for ligand structures
and full optimisation details), (R)-Tol-BINAP (37) was found
to give the best balance of reaction efficiency and enantio-
selectivity. Using this ligand and 1,3-diketone 22 with a de-
fined enolate geometry upon deprotonation, product 23c
was formed in a good yield owing to complete regiocontrol
and good chemoselectivity; however, the enantioselectivity
was low (27% ee).
O
O
O
O
O
O
32
OEt
O
O
O
O
F
F
Pd2(dba)3 (5 mol%)
DPEphos (10 mol%)
OEt
33 (63%), dr 1:1
rr >19:1
chemo 8.2:1a
1,4-dioxane
80 °C, 2 h
31
Scheme 6 Diastereoselective coupling. a Refers to homo-coupling of 32
Enantioselective Alkenylation
When a β-ketoester was employed as a nucleophile, 36a
was formed with complete regiocontrol, but the yield was
low due to modest chemoselectivity; additionally, the
enantioselectivity was poor. All attempts to extend this
process to a broader range of substrates by exploring substi-
tution led to disappointing results: the attempted forma-
tion of 36b afforded a complex mixture of products, indi-
cating low levels of selectivity, whereas 36c and 23i were
not formed due to the corresponding propargyl enol car-
bonates only undergoing decarboxylation and failing to take
part in the desired reaction process. Based on these results,
it is apparent that the contemporaneous control of regio-,
The enantioselective construction of a stereogenic all-
carbon quaternary centre in 34 by means of a chiral ligand
sphere around the palladium centre necessitates stereocon-
trol at the alkenylation step of enolate 15 following decar-
boxylation (Scheme 7). In this context, 30 chiral bisphos-
phines were screened, including the BINAP, SEGPHOS,
BIPHEP, P-PHOS, PhanePhos, Trost, PHOX and phosphoramid-
ite ligand families, and reaction parameters, including
solvent, time and temperature, were carefully optimised
(see the Supporting Information for ligand structures and
full optimisation details). (R)-Xylyl-P-PHOS (35) was identi-
via
MeO
O
N
O
P
Pd2(dba)3 (5 mol%)
R3
PdLn
O
O
R3
(R)-Xylyl-P-PHOS (6 mol%)
MeO
MeO
Nu
R1
O
*
R1
R3
O
THF, 60 °C, 2 h
NuH
P
R1
R2
O
N
14
R2
O
R2
MeO
34
15
(R)-Xylyl-P-PHOS (35)
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
N
O
O
Ph
*
*
*
*
Bn
*
CO2Me
23g (57%), 21% ee
rr n.d.
23n (34%), 19% ee
34a (29%), 19% ee
20h (44%), 19% ee
24g (80%), 19% ee
rr >19:1
rr n.d.
rr >19:1
rr >19:1
chemo 1.4:1a
chemo >19:1
chemo >19:1
chemo 16:3.4a:1b
chemo n.d.
Scheme 7 Enantioselective alkenylation. Yields of isolated isomer 34. Isomer 34 shown. Enantiomeric excess (ee) values were determined by
chiral HPLC. Regioselectivity (rr) and chemoselectivity (chemo) ratios were determined by 1H NMR analysis of the crude product mixtures. n.d. = not
determined due to overlapping signals. a Refers to homo-coupling of 14. b Refers to homo-coupling of external NuH
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–S

I
M. Kenny et al.
Feature
Synthesis
via
O
R1
O
O
Pd2(dba)3 (5 mol%)
O
O
O
O
O
O
P
P
PdLn
Nu
(R)-Tol-BINAP (6 mol%)
*
R3
O
+
R1
R2
1,4-dioxane
r.t. to 80 °C, 2–16 h
R3
R2
14
O
O
O
22
36
38
(R)-Tol-BINAP (37)
O
O
O
EtO
O
O
O
O
CO2Et
O
O
O
O
O
O
O
Bn
*
*
*
O
*
*
Ph
O
O
O
O
O
decarboxylation only
23c (68%), 27% ee
rr >19:1
36a (35%), 11% ee
36b
36c
23i
complex mixture
decarboxylation only
rr >19:1
chemo 4.0:1a
chemo 7.9:1.3a:1b
Scheme 8 Enantioselective allylic alkylation. Yields of isolated isomer 36. Isomer 36 shown. Enantiomeric excess (ee) values were determined by chiral
HPLC. Regioselectivity (rr) and chemoselectivity (chemo) ratios were determined by 1H NMR analysis of the crude product mixtures. a Refers to homo-
coupling of 14. b Refers to homo-coupling of 22
chemo- and stereoselectivity in the palladium-catalysed in-
termolecular coupling of nucleophiles in the presence of
propargylic electrophiles remains notoriously difficult.
In conclusion, this research programme has enabled us
to identify and explore the utility of propargyl enol carbon-
ates, derived from 1,3-dicarbonyls, in the palladium-
catalysed cross-coupling with nucleophiles for the con-
struction of quaternary all-carbon centres. We have suc-
cessfully developed chemical processes for the decarboxyl-
ative coupling of enolates with a range of nucleophiles with
high levels of regio- and chemoselectivity owing to the
tight association of the η3-π-propargylpalladium(II) inter-
mediate with the enolate following decarboxylation. A care-
ful analysis of acidity trends of nucleophiles has indicated
that relatively acidic nucleophiles (pKa ~13–23 in DMSO),
such as phenols, 1,3-dicarbonyl compounds and aromatic
N-heterocycles, give rise to excellent levels of regiocontrol.
The use of more acidic nucleophiles, such as electron-
deficient phenols, cyclic 1,3-diketones and carboxylic acids,
results in low regioselectivity, presumably owing to the
premature protonation of the intermediate enolate and,
thus, dissociation of the palladium metal centre from the
resulting neutral enol. Similarly, less acidic carbon-based
nucleophiles, such as unstabilised enolates derived from
ketones and esters, failed to take part in the desired cou-
pling process. Crucially, this approach has enabled us to ex-
plore the opportunities for the catalytic enantioselective
construction of quaternary all-carbon stereogenic centres.
Both enantioselective alkenylation and allylic alkylation
processes were explored; however, despite extensive
screens of chiral ligands, the need for simultaneous control
of regio-, chemo- and stereoselectivity was a formidable
challenge to overcome. While it was possible to retain high
levels of regiocontrol and chemoselectivity in many cases,
the levels of enantioselectivity were generally low. The
stereoselective installation of quaternary carbon centres by
means of palladium-catalysed coupling of nucleophiles
with propargylic electrophiles remains a major challenge
for synthetic chemists, yet at the same time offers ample
opportunities for its broader development and application.
All commercially available starting materials were used as received
without further purification. Solvents were of reagent grade and
dried prior to use. Petrol (PE) refers to the fraction of petroleum ether
that boils between 40 and 60 °C. All reactions were performed under
an argon atmosphere in oven dry glassware. Reactions were moni-
tored by thin-layer chromatography using Fluka precoated silica gel
plates with a fluorescent indicator (254 nm) and visualised by UV
light (254 nm) and by staining with potassium permanganate or
aqueous acidic ammonium molybdate(IV) solutions. Flash column
chromatography was carried out using Fisher silica gel (60 Å particle
size, 230–400 mesh). Melting points were determined using a Gallen-
kamp melting point instrument and are uncorrected. Optical rota-
tions were recorded using a Optical Active AA-65 Automatic Polari-
meter polarimeter. IR spectra were recorded on a Agilent Technolo-
gies Cary 630 FTIR spectrometer as a neat film. NMR spectra were
recorded on either Bruker Ultra Shield Plus 400 or 300 MHz instru-
ments (1H NMR at 400 and 300 MHz, respectively, and 13C{1H} NMR at
100 and 75 MHz, respectively) in CDCl3. Residual solvent CHCl3 was
referenced at 7.26 ppm for 1H NMR spectra, and the central resonance
of CDCl3 was referenced at 77.0 ppm for 13C{1H} NMR spectra. High-
resolution mass spectrometry data were recorded using electron
spray ionisation on a Shimadzu LCMS-IT-TOF mass spectrometer.
The following compounds have been previously reported in reactions
using phenols:15 20a, 20d, 20f, 20h–j, 20l–p and 20x; 1,3-dicarbonyl
compounds:21 23a, 23c–g, 23i, 23j, 23n, 23t–v, 23z, 23aa, 33 and 36a;
N-heterocycles:22 24a–n. With the exception of 39, 41 and 43–45,
syntheses of all propargyl enol carbonates 14 and 31 have been re-
ported and appropriate references are provided in each case below.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–S

J
M. Kenny et al.
Feature
Synthesis
Palladium-Catalysed Cross-Coupling; Method A
13C NMR (100 MHz, CDCl3): δ (resonances due to 20b quoted) = 207.9,
156.2, 143.8, 136.8, 130.7, 123.9, 122.0, 116.6, 113.0, 70.0, 68.7, 38.7,
21.4, 19.5, 17.7, 16.0.
HRMS (ESI): m/z [M + Na]+ calcd for C18H22O3Na: 309.1461; found:
309.1448.
Carbonate 14 (0.24 mmol), Pd2(dba)3 (11 mg, 0.012 mmol), Xantphos
(13.9 mg, 0.024 mmol) and the phenol nucleophile (0.26 mmol) were
added to a dried tube under argon. The tube was fitted with a septum
and purged further with argon. 1,4-Dioxane (1.5 mL) was added and
the sealed tube was placed in an oil bath preheated to 80 °C. The mix-
ture was stirred at 80 °C for 2 h, then cooled to room temperature,
concentrated in vacuo and purified by flash column chromatography.
The ratio of 20:21 was determined by 1H NMR spectroscopy of the
crude product mixture prior to purification.
2-Methyl-2-[3-(naphthalen-1-yloxy)prop-1-en-2-yl]cyclohexane-
1,3-dione (20c) and 2-Methyl-2-[2-(naphthalen-1-yloxy)allyl]cy-
clohexane-1,3-dione (21c)
Following method A, carbonate 1415 (50 mg, 0.24 mmol) was reacted
with 2-naphthol (37 mg, 0.26 mmol). Flash column chromatography
(PE/EtOAc, 19:1) afforded an inseparable mixture of 20c and 21c in a
1.6:1 ratio (50 mg, 67%) as an orange oil.
Palladium-Catalysed Cross-Coupling; Method B
Carbonate 14 (0.24 mmol), Pd2(dba)3 (11 mg, 0.012 mmol), DPEphos
(13.1 mg, 0.024 mmol) and the 1,3-dicarbonyl nucleophile (0.24
mmol) were added to a dried tube under argon. The tube was fitted
with a septum and purged further with argon. 1,4-Dioxane (1.5 mL)
was added and the sealed tube was placed in an oil bath preheated to
80 °C. The mixture was stirred at 80 °C for 2 h, then cooled to room
temperature, concentrated in vacuo and purified by flash column
chromatography. Regioselectivity and chemoselectivity ratios were
determined by 1H NMR spectroscopy of the crude product mixture
prior to purification.
Rf = 0.25 (PE/EtOAc, 3:1).
IR (film): 3348, 1669, 1554 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.26–6.75 (m, 7 H and 7 H*), 5.63 (t,
J = 1.3 Hz, 1 H*), 5.26 (s, 1 H*), 4.62 (s, 2 H*), 4.12 (dd, J = 2.3, 1.0 Hz, 1
H), 3.74 (d, J = 2.5 Hz, 1 H), 3.16 (s, 2 H), 2.86–2.65 (m, 4 H and 2 H*),
2.65–2.56 (m, 2 H*), 2.13–2.00 (m, 1 H*), 1.99–1.86 (m, 2 H), 1.87–
1.77 (m, 1 H*), 1.51 (s, 3 H*), 1.39 (s, 3 H); isomer 21c annotated by an
asterisk.
13C NMR (100 MHz, CDCl3): δ (mixture of 20c and 21c) = 210.4, 208.4,
158.6, 151.9, 150.3, 143.3, 135.0, 134.9, 127.9, 127.7, 126.6 (2 C),
126.4, 126.4, 126.0, 125.9, 125.2, 125.0, 122.1, 121.9, 120.4, 117.5,
117.2, 108.6, 105.8, 89.4, 69.4, 69.2, 62.4, 40.1, 38.7, 38.0, 22.2, 20.1,
17.8, 17.5.
HRMS (ESI): m/z [M + H]+ calcd for C20H21O3: 309.1485; found:
309.1474.
Palladium-Catalysed Cross-Coupling; Method C
Carbonate 14 (0.24 mmol), Pd2(dba)3 (11 mg, 0.012 mmol), Xantphos
(13.9 mg, 0.024 mmol) and the N-heterocyclic nucleophile (0.24
mmol) were added to a dried tube under argon. The tube was fitted
with a septum and purged further with argon. Toluene (1.5 mL) was
added and the sealed tube was placed in an oil bath preheated to
120 °C. The mixture was stirred at 120 °C for 2 h, then cooled to room
temperature, concentrated in vacuo and purified by flash column
chromatography.
O
O
O
O
Palladium-Catalysed Cross-Coupling; Method D
Carbonate 14 (0.24 mmol), Pd2(dba)3 (11 mg, 0.012 mmol), Xantphos
(13.9 mg, 0.024 mmol) and the carboxylic acid nucleophile (0.24
mmol) were added to a dried tube under argon. The tube was fitted
with a septum and purged further with argon. 1,4-Dioxane (1.5 mL)
was added and the sealed tube was placed in an oil bath preheated to
80 °C. The mixture was stirred at 80 °C for 2 h, then cooled to room
temperature, concentrated in vacuo and purified by flash column
chromatography. The ratio of 25:26 was determined by 1H NMR spec-
troscopy of the crude product mixture prior to purification.
39
3-Oxo-2-methylcyclopent-1-enyl prop-2-ynyl Carbonate (39)
A suspension of sodium hydride (60 wt%, 220 mg, 5.5 mmol) in min-
eral oil was washed with PE (2 mL). Tetrahydrofuran (25 mL) was add-
ed and the mixture was cooled to 0 °C. 2-Methyl-1,3-cyclopentadione
(560 mg, 5.0 mmol) was added as a solid. After stirring at 0 °C for 10
min, propargyl chloroformate (539 μL, 5.5 mmol) was added drop-
wise. The mixture was allowed to warm to room temperature and
stirred at this temperature for 1.5 h. The reaction was quenched by
addition of aq HCl (10%, 50 mL) and the mixture was extracted with
EtOAc (3 × 50 mL). The combined organic phases were washed with
aq NaHCO3 (3 × 50 mL), brine (100 mL), dried (MgSO4) and concen-
trated in vacuo. Flash column chromatography (PE/EtOAc, 4:1) afford-
ed carbonate 39 (590 mg, 61%) as a pale yellow oil.
2-[3-(2,5-Dimethylphenoxy)prop-1-en-2-yl]-2-methylcyclohex-
ane-1,3-dione (20b)
Following method A, carbonate 1415 (50 mg, 0.24 mmol) was reacted
with 2,5-dimethylphenol (32 mg, 0.26 mmol). Flash column chroma-
tography (PE/EtOAc, 19:1) afforded an inseparable mixture of 20b and
21b in a 13:1 ratio (48 mg, 72%) as an orange oil.
Rf = 0.17 (PE/EtOAc, 4:1).
IR (film): 3353, 2883, 2097, 1750, 1642 cm–1
Rf = 0.36 (PE/EtOAc, 3:1).
IR (film): 2878, 1703, 1673 cm–1
.
.
1H NMR (400 MHz, CDCl3): δ = 4.81 (d, J = 2.8 Hz, 2 H), 2.87 (ddd,
J = 9.2, 4.0, 2.0 Hz, 2 H), 2.61 (t, J = 2.4 Hz, 1 H), 2.53–2.48 (m, 2 H),
1.63 (t, J = 2.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 205.5, 174.7, 149.9, 125.8, 76.7, 75.8,
56.3, 34.2, 26.4, 6.3.
1H NMR (400 MHz, CDCl3): δ (resonances due to 20b quoted) = 7.00
(d, J = 7.4 Hz, 1 H), 6.70 (d, J = 7.5 Hz, 1 H), 6.59 (s, 1 H), 5.52 (t, J = 1.3
Hz, 1 H), 5.13 (s, 1 H), 4.39 (s, 2 H), 2.86 (ddd, J = 16.5, 8.5, 5.4 Hz, 2 H),
2.60 (ddd, J = 16.6, 8.0, 5.0 Hz, 2 H), 2.30 (s, 3 H), 2.19–2.09 (m, 1 H),
2.16 (s, 3 H), 1.90–1.77 (m, 1 H), 1.45 (s, 3 H).
HRMS (ESI): m/z [M + H]+ calcd for C10H11O4: 195.0652; found:
195.0654.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–S

K
M. Kenny et al.
Feature
Synthesis
2-Methyl-2-(3-phenoxyprop-1-en-2-yl)cyclopentane-1,3-dione
(20e) and 2-Methyl-2-(2-phenoxyallyl)cyclopentane-1,3-dione
(21e)
2-Benzoylcyclopent-1-en-1-yl Prop-2-yn-1-yl Carbonate (41)
A suspension of sodium hydride (60 wt%, 117 mg, 2.93 mmol) in min-
eral oil was washed with PE (2 mL). Tetrahydrofuran (20 mL) was add-
ed and the mixture was cooled to 0 °C. A solution of 2-benzoylcyclo-
pentanone (40) (500 mg, 2.66 mmol) in tetrahydrofuran (2 mL) was
added dropwise. After stirring at 0 °C for 10 min, propargyl chlorofor-
mate (286 μL, 2.93 mmol) was added dropwise. The mixture was al-
lowed to warm to room temperature and stirred at this temperature
for 1 h. The reaction was quenched by addition of aq HCl (10%, 20 mL)
and the mixture was extracted with EtOAc (3 × 20 mL). The combined
organic phases were washed with brine (50 mL), dried (MgSO4) and
concentrated in vacuo. Flash column chromatography (PE/EtOAc,
19:1–4:1) afforded carbonate 41 (320 mg, 10% from cyclopentanone)
as a brown oil.
Following method A, carbonate 39 (47 mg, 0.24 mmol) was reacted
with phenol (25 mg, 0.26 mmol). Flash column chromatography
(PE/EtOAc, 9:1) afforded an inseparable mixture of 20e and 21e in a
2.0:1 ratio (34 mg, 58%) as a clear oil.
Rf = 0.25 (PE/EtOAc, 4:1).
IR (film): 3017, 2883, 2828, 1739, 1698, 1623, 1572 cm–1
.
1H NMR (400 MHz, CDCl3,): δ = 7.30 (t, J = 7.6 Hz, 1 H), 7.25–7.21 (m, 2
H), 7.12 (tt, J = 7.2, 1.2 Hz, 1 H*), 6.95 (tt, J = 7.2, 1.2 Hz, 2 H*), 6.90–
6.86 (m, 2 H*), 6.78–6.73 (m, 2 H), 5.48 (t, J = 1.6 Hz, 1 H), 5.32 (t,
J = 0.8 Hz, 1 H), 4.46 (t, J = 1.2 Hz, 2 H), 4.15–4.12 (m, 1 H*), 3.82 (d,
J = 2.4 Hz, 1 H*), 2.85 (s, 4 H), 2.82 (s, 2 H*), 2.75 (dt, J = 10.0, 2.4 Hz, 4
H*), 1.32 (s, 3 H), 1.15 (s, 3 H*); isomer 21e annotated by an asterisk.
13C NMR (100 MHz, CDCl3): δ = 215.8*, 213.3, 157.7*, 157.3, 153.9*,
141.5, 129.7, 129.6, 124.8*, 121.7*, 120.8*, 116.6, 114.2, 89.5*, 68.9,
59.5, 53.9*, 39.6*, 34.8*, 34.7, 20.7*, 18.7; isomer 21e annotated by an
asterisk.
Rf = 0.34 (PE/EtOAc, 4:1).
IR (film): 3287, 2967, 2130, 1766, 1715, 1619 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.60–7.56 (m, 2 H), 7.44–7.41 (m, 3 H),
4.83 (d, J = 2.5 Hz, 2 H), 2.94 (t, J = 7.1 Hz, 2 H), 2.57 (t, J = 2.5 Hz, 1 H),
2.40 (t, J = 7.8 Hz, 2 H), 1.95 (quin, J = 7.4 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 204.9, 151.7, 147.6, 133.5, 130.4,
128.4, 128.1, 124.7, 76.6, 76.0, 56.0, 39.2, 30.3, 20.5.
HRMS (ESI): m/z [M + Na]+ calcd for C15H16O3Na: 267.0992; found:
267.0989.
O
2-Benzoyl-2-(3-phenoxyprop-1-en-2-yl)cyclopentanone (20g)
Following method A, carbonate 41 (64.8 mg, 0.24 mmol) was reacted
with phenol (25 mg, 0.26 mmol). Flash column chromatography
(PE/EtOAc, 49:1) afforded an inseparable mixture of 20g and diben-
zylideneacetone (dba) (42 mg, ratio 20g:dba 13:1, corresponding to
40.0 mg of 20g, 52%) as a yellow oil.
O
O
O
O
O
O
Ph
Ph
40
41
Rf = 0.66 (PE/EtOAc, 3:1).
IR (film): 3078, 2967, 2926, 2891, 1748, 1667, 1597, 1495 cm–1
2-Benzoylcyclopentanone (40)23
.
To a stirred solution of cyclopentanone (4.42 mL, 50 mmol) and p-tol-
uenesulfonic acid (476 mg, 2.5 mmol) in toluene (100 mL) was added
pyrrolidine (6.15 mL, 75 mmol). The mixture was heated to reflux at
110 °C under Dean–Stark conditions for 16 h, then allowed to cool to
room temperature. The mixture was concentrated in vacuo to afford
the crude enamine (6.31 g) as a dark orange oil.
1H NMR (400 MHz, CDCl3): δ = 8.08 (dd, J = 8.5, 1.3 Hz, 2 H), 7.54 (tt,
J = 7.4, 1.3 Hz, 1 H), 7.42 (t, J = 7.7 Hz, 2 H), 7.24 (dd, J = 8.8, 7.4 Hz, 2
H), 6.94 (tt, J = 7.4, 1.0 Hz, 1 H), 6.80 (dd, J = 8.8, 1.0 Hz, 2 H), 5.54 (t,
J = 1.4 Hz, 1 H), 5.24 (s, 1 H), 4.77 (d, J = 12.7 Hz, 1 H), 4.57 (d, J = 12.7
Hz, 1 H), 2.86–2.79 (m, 1 H), 2.53–2.43 (m, 2 H), 2.41–2.30 (m, 1 H),
2.08–1.97 (m, 1 H), 1.95–1.82 (m, 1 H).
To a stirred solution of the crude enamine (4.17 g, 30 mmol) in tolu-
ene (80 mL) were added triethylamine (5.82 mL, 42 mmol) and ben-
zoyl chloride (4.88 mL, 42 mmol). The mixture was heated to reflux at
110 °C for 1.5 h, then allowed to cool to room temperature. Aq HCl
(10%, 30 mL) was added and the mixture was heated to reflux at
110 °C for 30 min, then allowed to cool to room temperature. Another
portion of aq HCl (10%, 20 mL) was added and the mixture was ex-
tracted with EtOAc (3 × 50 mL). The combined organic phases were
washed with brine (100 mL), dried (MgSO4) and concentrated in vac-
uo. Flash column chromatography (PE/EtOAc, 49:1–9:1) afforded a
mixture of three compounds as a yellow solid. The major component
was the enol tautomer of diketone 40.
13C NMR (100 MHz, CDCl3): δ = 212.3, 196.8, 158.0, 142.2, 134.6,
133.0, 130.1, 129.4, 128.1, 121.1, 116.8, 114.4, 70.4, 69.0, 37.8, 34.3,
19.4.
HRMS (ESI): m/z [M + Na]+ calcd for C21H20O3Na: 343.1305; found:
343.1293.
2-Acetyl-2-(3-phenoxyprop-1-en-2-yl)cyclohexanone (20h)15
Following method A, carbonate 3115 (53.3 mg, 0.24 mmol) was react-
ed with phenol (25 mg, 0.26 mmol). Flash column chromatography
(PE/EtOAc, 19:1) afforded 20h (50 mg, 77%) as a clear oil.
Rf = 0.39 (PE/EtOAc, 4:1).
Rf = 0.66 (PE/EtOAc, 3:1).
Enantioselective Catalysis: carbonate 1415 (35.5 mg, 0.16 mmol),
Pd2(dba)3 (7.3 mg, 0.008 mmol), (R)-Xylyl-P-PHOS (35) (7.3 mg,
0.0096 mmol) and phenol (15 mg, 0.16 mmol) were added to a dried
tube under argon. The tube was fitted with a septum and purged fur-
ther with argon. Tetrahydrofuran (1 mL) was added and the mixture
was stirred at 60 °C for 2 h, then concentrated in vacuo. Flash column
chromatography (PE/EtOAc, 19:1–9:1) afforded 20h (19 mg, 44%).
IR (film): 2985, 2938, 1717, 1624 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.12 (dd, J = 8.3, 1.4 Hz, 2 H), 7.79–7.75
(m, 1 H), 7.48–7.44 (m, 2 H), 2.87 (t, J = 7.1 Hz, 2 H), 2.50 (t, J = 7.9 Hz,
2 H), 2.01–1.92 (m, 2 H), (signal due to OH not observed).
13C NMR (100 MHz, CDCl3): δ = 210.6, 171.8, 133.8, 130.7, 128.6,
128.4, 109.4, 37.7, 28.4, 21.4.
HRMS (ESI): m/z [M + Na]+ calcd for C12H12O2Na: 211.0730; found:
211.0730.
Chiral HPLC: AD-H column, 1 mL/min, (hexane/IPA, 9:1), tA (major) =
6.0 min, tB (minor) = 6.5 min, 19% ee.
[α]D25 +0.8 (c 0.1, CHCl3, 19% ee).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–S

L
M. Kenny et al.
Feature
Synthesis
20q
O
Rf = 0.23 (PE/EtOAc, 4:1).
O
O
O
IR (film): 3335, 2896, 2829, 1687, 1569 cm–1
.
Ph
O
Ph
1H NMR (400 MHz, CDCl3): δ = 8.19 (d, J = 9.3 Hz, 2 H), 7.00 (d, J = 9.3
Hz, 2 H), 5.65 (t, J = 1.4 Hz, 1 H), 5.27 (s, 1 H), 4.70 (dt, J = 12.9 Hz, 1.3
Hz, 1 H), 4.49 (d, J = 12.9 Hz, 1 H), 3.05 (sept, J = 6.7 Hz, 1 H), 2.60 (dt,
J = 14.0, 6.8 Hz, 1 H), 2.54–2.43 (m, 2 H), 2.16–2.08 (m, 1 H), 1.95–1.79
(m, 3 H), 1.79–1.68 (m, 1 H), 1.11 (d, J = 6.7 Hz, 3 H), 1.06 (d, J = 6.7 Hz,
3 H).
13C NMR (100 MHz, CDCl3): δ = 213.5, 209.4, 163.3, 141.7, 140.3,
125.9, 118.9, 114.7, 72.5, 69.4, 41.2, 36.7, 32.7, 26.8, 22.1, 20.8, 20.7.
HRMS (ESI): m/z [M + Na]+ calcd for C19H23NO5Na: 368.1468; found:
368.1464.
42
O
43
4-Oxo-3-phenylpent-2-en-2-yl Prop-2-ynyl Carbonate (43)
A suspension of sodium hydride (60 wt% in mineral oil, 74.8 mg, 1.87
mmol) in tetrahydrofuran (15 mL) was cooled to 0 °C. A solution of
4224 (300 mg, 1.70 mmol) in tetrahydrofuran (5 mL) was added drop-
wise and the mixture was stirred at 0 °C for 10 min. Propargyl chloro-
formate (182 μL, 1.87 mmol) was added dropwise and the mixture
was allowed to warm to room temperature and then stirred at room
temperature for 1.5 h. The reaction was quenched by the addition of
aq HCl (1 M, 10 mL) and the mixture was extracted with EtOAc (3 × 25
mL). The combined organic phases were washed with brine (30 mL),
dried (MgSO4) and concentrated in vacuo. Flash column chromatogra-
phy (PE/EtOAc, 4:1) afforded 43 (279 mg, 57%) as a pale green solid.
21q
Rf = 0.35 (PE/EtOAc, 4:1).
IR (film): 2895, 2828, 1669, 1622, 1586, 1567 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.22 (d, J = 9.3 Hz, 2 H), 7.09 (d, J = 9.2
Hz, 2 H), 4.40 (d, J = 2.4 Hz, 1 H), 4.18 (d, J = 2.5 Hz, 1 H), 3.07 (d,
J = 15.0 Hz, 1 H), 2.97 (sept, J = 6.7 Hz, 1 H), 2.73 (d, J = 15.0 Hz, 1 H),
2.67 (dtd, J = 13.9, 4.0, 2.5 Hz, 1 H), 2.54 (dtd, J = 13.9, 4.3, 1.0 Hz, 1 H),
2.31 (ddd, J = 14.4, 12.0, 5.7 Hz, 1 H), 2.05–1.96 (m, 1 H), 1.86–1.77
(m, 2 H), 1.75–1.64 (m, 1 H), 1.55–1.45 (m, 1 H), 1.05 (d, J = 6.6 Hz, 3
H), 0.99 (d, J = 6.7 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 210.8, 208.9, 160.0, 157.4, 143.8,
125.7, 120.5, 95.4, 66.6, 42.3, 38.7, 36.4, 33.7, 26.9, 22.2, 21.2, 20.1.
HRMS (ESI): m/z [M + Na]+ calcd for C19H23NO5Na: 368.1468; found:
Rf = 0.16 (PE/EtOAc, 2:1); mp 46–48 °C.
IR (film): 3270, 2989, 2126, 1763, 1686, 1612 cm–1
1H NMR (400 MHz, CDCl3): δ = 7.41–7.30 (m, 3 H), 7.25–7.21 (m, 2 H),
4.81 (d, J = 2.8 Hz, 2 H), 2.58 (t, J = 2.1 Hz, 1 H), 2.11 (s, 3 H), 1.91 (s, 3
.
H).
13C NMR (100 MHz, CDCl3): δ = 198.2, 151.1, 150.7, 134.8, 131.1,
129.3, 128.8, 128.0, 76.4, 76.1, 55.9, 30.6, 18.4.
HRMS (ESI): m/z [M + H]+ calcd for C15H15O4: 259.0962; found:
259.0965.
368.1461.
3-(3-Phenoxyprop-1-en-2-yl)-3-phenylpentane-2,4-dione (20k)
and 3-(2-Phenoxyallyl)-3-phenylpentane-2,4-dione (21k)
2-Acetyl-2-[3-(4-nitrophenoxy)prop-1-en-2-yl]-3,4-dihydronaph-
thalen-1(2H)-one (20r) and 2-Acetyl-2-[2-(4-nitrophenoxy)allyl]-
3,4-dihydronaphthalen-1(2H)-one (21r)
Following method A, carbonate 1415 (65 mg, 0.24 mmol) was reacted
with 4-nitrophenol (36 mg, 0.26 mmol). Flash column chromatogra-
phy (PE/EtOAc, 19:1–9:1–4:1) afforded 20r (35.5 mg, 41%) as a dark
yellow solid and 21r (38.5 mg, 44%) as a clear oil.
Following method A, carbonate 43 (62 mg, 0.24 mmol) was reacted
with phenol (25 mg, 0.26 mmol). Flash column chromatography
(PE/EtOAc, 19:1) afforded an inseparable mixture of 20k, dba and 21k
in a 4.0:1.5:1 ratio (29 mg, corresponding to 25.5 mg of 20k and 21k,
35%) as a yellow oil.
Rf = 0.48 (PE/EtOAc, 4:1).
IR (film): 3014, 2983, 1681, 1627, 1573 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.44–7.18 (m), 6.94 (tt, J = 7.6, 1.2 Hz),
6.89–6.84 (m) (10 H and 10 H*), 5.85 (t, J = 1.6 Hz, 1 H), 5.32 (s, 1 H),
4.66 (t, J = 0.8 Hz, 2 H), 4.00 (d, J = 2.4 Hz, 1 H*), 3.83 (d, J = 2.4 Hz, 1
H*), 3.35 (s, 2 H*), 2.21 (s, 6 H and 6 H*); resonances due to 21k anno-
tated by an asterisk.
13C NMR (100 MHz, CDCl3): δ = 205.1, 204.9, 158.8, 158.2, 143.3,
142.9, 135.6, 134.7, 130.5, 129.5, 129.4, 128.9, 128.4, 128.23, 128.20,
127.5, 125.4, 124.5, 121.5, 121.2, 121.1, 114.6, 74.1, 72.7, 68.9, 38.9,
29.7, 28.1.
20r
Rf = 0.15 (PE/EtOAc, 4:1); mp 124–126 °C.
IR (film): 3009, 2908, 1685, 1647, 1571, 1492, 1477, 1320 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.16 (d, J = 9.6 Hz, 2 H), 8.12 (d, J = 9.2
Hz, 1 H), 7.51 (td, J = 5.7, 1.6 Hz, 1 H), 7.32 (td, J = 7.6, 0.8 Hz, 1 H), 7.24
(d, J = 7.6 Hz, 1 H), 6.87 (d, J = 9.2 Hz, 2 H), 5.59 (s, 1 H), 5.21 (s, 1 H),
4.77 (d, J = 12.0 Hz, 1 H), 4.69 (dd, J = 12.4, 0.8 Hz, 1 H), 3.00 (t, J = 13.6
Hz, 2 H), 2.73 (dd, J = 14.0, 6.4 Hz, 1 H), 2.43–2.37 (m, 1 H), 2.36 (s, 3
H).
13C NMR (100 MHz, CDCl3): δ = 205.6, 195.8, 162.9, 143.0, 141.8,
140.2, 134.0, 131.9, 128.7, 127.9, 127.0, 125.9, 119.8, 114.6, 70.2, 67.9,
29.6, 28.2, 25.8.
HRMS (ESI): m/z [M + Na]+ calcd for C20H20O3Na: 331.1305; found:
331.1292.
2-Isobutyryl-2-[3-(4-nitrophenoxy)prop-1-en-2-yl]cyclohexa-
none (20q) and 2-Isobutyryl-2-[2-(4-nitrophenoxy)allyl]cyclohex-
anone (21q)
HRMS (ESI): m/z [M + H]+ calcd for C21H20NO5: 366.1336; found:
366.1333.
Following method A, carbonate 1415 (60 mg, 0.24 mmol) was reacted
with 4-nitrophenol (36 mg, 0.26 mmol). Flash column chromatogra-
phy (PE/EtOAc, 49:1–19:1) afforded 20q (23 mg, 28%) and 21q (18.5
mg, 22%) as clear oils.
21r
Rf = 0.30 (PE/EtOAc, 4:1).
IR (film): 3029, 2888, 2807, 1683, 1648, 1567, 1495, 1467, 1431 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–S

M
M. Kenny et al.
Feature
Synthesis
1H NMR (400 MHz, CDCl3): δ = 8.21 (d, J = 8.4 Hz, 2 H), 8.03 (d, J = 8.0
Hz, 1 H), 7.50 (t, J = 7.6 Hz, 1 H), 7.32 (t, J = 7.6 Hz, 1 H), 7.23 (d, J = 7.6
Hz, 1 H), 7.07 (d, J = 9.2 Hz, 2 H), 4.52 (d, J = 2.4 Hz, 1 H), 4.30 (d, J = 2.4
Hz, 1 H), 3.27–3.14 (m, 2 H), 2.93 (dt, J = 17.6, 4.0 Hz, 1 H), 2.85 (d,
J = 14.8 Hz, 1 H), 2.80 (dt, J = 14.0, 4.0 Hz, 1 H), 2.14 (s, 3 H), 2.08 (ddd,
J = 16.4, 11.2, 5.2 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 204.2, 196.2, 160.1, 157.1, 143.8,
143.7, 134.1, 131.8, 129.0, 127.9, 126.8, 125.7, 120.0, 96.8, 62.8, 39.3,
29.4, 27.1, 25.8.
20t
Rf = 0.16 (PE/EtOAc, 1:1).
IR (film): 2894, 2822, 1687, 1669, 1550 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.32–8.24 (m, 1 H), 8.21 (dd, J = 3.6, 2.4
Hz, 1 H), 7.26–7.21 (m, 2 H), 5.64 (t, J = 1.2 Hz, 1 H), 5.27 (s, 1 H), 4.63
(d, J = 12.4 Hz, 1 H), 4.49 (dd, J = 12.4, 1.2 Hz, 1 H), 2.61–2.50 (m, 2 H),
2.46 (ddq, J = 14.0, 6.8, 1.2 Hz, 1 H), 2.23 (s, 3 H), 2.06 (dddd, J = 14.4,
9.6, 4.0, 0.8 Hz, 1 H), 1.97–1.86 (m, 1 H), 1.86–1.74 (m, 2 H), 1.72–1.60
(m, 1 H).
HRMS (ESI): m/z [M + Na]+ calcd for C21H19NO5Na: 388.1155; found:
388.1148.
13C NMR (100 MHz, CDCl3): δ = 209.1, 206.8, 154.6, 142.1, 141.4,
137.8, 124.5, 121.5, 119.4, 71.7, 69.5, 40.9, 32.8, 27.0, 26.9, 21.9.
HRMS (ESI): m/z [M + H]+ calcd for C16H20NO3: 274.1438; found:
274.1429.
2-Acetyl-2-{3-[4-(trifluoromethyl)phenoxy]prop-1-en-2-yl}cyclo-
hexan-1-one (20s) and 2-Acetyl-2-{2-[4-(trifluoromethyl)phe-
noxy]allyl}cyclohexan-1-one (21s)
Following method A, carbonate 3115 (53.3 mg, 0.24 mmol) was react-
ed with 4-(trifluoromethyl)phenol (42 mg, 0.26 mmol). Flash column
chromatography (PE/EtOAc, 19:1–9:1) afforded 20s (26.5 mg, 32%) as
a clear oil and an inseparable mixture of 21s and dba in a 9.4:1 ratio
(21.5 mg, corresponding to 20 mg of 21s, 25%) as a pale yellow oil.
21t
Rf = 0.34 (PE/EtOAc, 1:1); mp 61–63 °C.
IR (film): 2898, 2824, 1672, 1618 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.41 (br s, 1 H), 8.32 (br s, 1 H), 7.33
(ddd, J = 8.4, 2.8, 1.6 Hz, 1 H), 7.30–7.26 (m, 1 H), 4.17 (d, J = 2.4 Hz, 1
H), 3.87 (d, J = 2.4 Hz, 1 H), 3.21 (d, J = 14.8 Hz, 1 H), 2.76 (dq, J = 14.0,
3.6 Hz, 1 H), 2.53 (dtd, J = 13.6, 4.0, 1.6 Hz, 1 H), 2.51 (d, J = 14.8 Hz, 1
H), 2.24 (ddd, J = 14.0, 13.2, 6.4 Hz, 1 H), 2.14 (s, 3 H), 2.09–1.99 (m, 1
H), 1.92–1.74 (m, 2 H), 1.68 (qt, J = 12.8, 4.0 Hz, 1 H), 1.43 (ddd,
J = 14.0, 12.0, 4.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 209.0, 204.2, 159.0, 150.9, 145.9,
143.8, 128.8, 124.1, 91.7, 66.7, 41.9, 39.5, 34.3, 27.4, 26.7, 22.2.
HRMS (ESI): m/z [M + H]+ calcd for C16H20NO3: 274.1438; found:
274.1436.
20s
Rf = 0.39 (PE/EtOAc, 4:1).
IR (film): 3037, 2902, 2824, 1687, 1617, 1589, 1566 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.53 (d, J = 8.4 Hz, 2 H), 6.95 (d, J = 8.4
Hz, 2 H), 5.64 (t, J = 1.2 Hz, 1 H), 5.26 (s, 1 H), 4.62 (d, J = 12.0 Hz, 1 H),
4.49 (dd, J = 12.4, 1.2 Hz, 1 H), 2.63–2.49 (m, 2 H), 2.45 (dddd, J = 14.8,
7.2, 3.2, 1.6 Hz, 1 H), 2.24 (s, 3 H), 2.11–2.02 (m, 1 H), 1.98–1.74 (m, 3
H), 1.73–1.61 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 209.2, 206.7, 160.6, 141.5, 126.9 (q,
J = 3.7 Hz), 123.3 (q, J = 32.6 Hz), 119.4, 114.6, 71.6, 69.4, 40.9, 32.8,
27.1, 27.0, 21.8, (signal due to CF3 not observed).
HRMS (ESI): m/z [M + Na]+ calcd for C18H19F3O3Na: 363.1179; found:
363.1175.
2-Acetyl-2-[3-(3-chlorophenoxy)prop-1-en-2-yl]cyclohexan-1-
one (20u) and 2-Acetyl-2-[2-(3-chlorophenoxy)allyl]cyclohexan-
1-one (21u)
Following method A, carbonate 3115 (53.3 mg, 0.24 mmol) was react-
ed with 3-chlorophenol (33.4 mg, 0.26 mmol). Flash column chroma-
tography (PE/EtOAc, 19:1–9:1) afforded 20u (34 mg, 46%) as a pale
yellow oil and an inseparable mixture of 21u and dba in a 1.6:1 ratio
(19 mg, corresponding to 13 mg of 21u, 18%) as a yellow oil.
21s
Rf = 0.50 (PE/EtOAc, 4:1).
IR (film): 3070, 3018, 2900, 2827, 1670, 1619, 1589 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.59 (d, J = 8.4 Hz, 2 H), 7.07 (d, J = 8.0
Hz, 2 H), 4.23 (d, J = 2.4 Hz, 1 H), 4.00 (d, J = 2.4 Hz, 1 H), 3.19 (d,
J = 14.8 Hz, 1 H), 2.76 (dq, J = 14.0, 3.6 Hz, 1 H), 2.52 (dtd, J = 13.6, 4.0,
1.6 Hz, 1 H), 2.50 (d, J = 14.8 Hz, 1 H), 2.24 (td, J = 12.8, 5.6 Hz, 1 H),
2.13 (s, 3 H), 2.09–1.98 (m, 1 H), 1.89–1.74 (m, 2 H), 1.68 (tt, J = 12.8,
4.0 Hz, 1 H), 1.43 (ddd, J = 13.6, 12.0, 4.4 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 209.0, 204.3, 158.2, 157.2, 127.0 (q,
J = 3.8 Hz), 126.5 (q, J = 32.5 Hz), 121.1, 93.0, 66.7, 41.9, 39.2, 34.3,
27.4, 26.7, 22.2, (signal due to CF3 not observed).
20u
Rf = 0.36 (PE/EtOAc, 4:1).
IR (film): 3024, 2899, 2823, 1687, 1618, 1570 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.17 (t, J = 8.4 Hz, 1 H), 6.92 (ddd,
J = 7.6, 1.6, 0.8 Hz, 1 H), 6.87 (t, J = 2.0 Hz, 1 H), 6.76 (ddd, J = 8.4, 2.4,
0.8 Hz, 1 H), 5.64 (t, J = 0.8 Hz, 1 H), 5.24 (s, 1 H), 4.55 (d, J = 12.0 Hz, 1
H), 4.44 (dd, J = 12.0, 0.8 Hz, 1 H), 2.65–2.47 (m, 2 H), 2.43 (dddd,
J = 14.4, 7.6, 3.2, 1.2 Hz, 1 H), 2.32 (s, 3 H), 2.06 (dddd, J = 14.4, 8.8, 3.2,
1.2 Hz, 1 H), 1.95–1.61 (m, 4 H).
HRMS (ESI): m/z [M + Na]+ calcd for C18H19F3O3Na: 363.1179; found:
363.1169.
13C NMR (100 MHz, CDCl3): δ = 209.3, 206.7, 158.8, 141.6, 134.8,
130.2, 121.3, 119.5, 115.0, 113.0, 71.6, 69.4, 40.8, 32.6, 27.1 (2 C), 21.8.
HRMS (ESI): m/z [M + H]+ calcd for C17H20ClO3: 307.1095; found:
307.1094.
2-Acetyl-2-[3-(pyridin-3-yloxy)prop-1-en-2-yl]cyclohexan-1-one
(20t) and 2-Acetyl-2-[2-(pyridin-3-yloxy)allyl]cyclohexan-1-one
(21t)
Following method A, carbonate 3115 (53.3 mg, 0.24 mmol) was react-
ed with 3-hydroxypyridine (25 mg, 0.26 mmol). Flash column chro-
matography (PE/EtOAc, 2:1–1:1) afforded 20t (21 mg, 32%) as a brown
oil and 21t (9 mg, 14%) as a dark orange solid.
21u
Rf = 0.46 (PE/EtOAc, 4:1).
IR (film): 2890, 2806, 1671, 1626, 1566 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–S

N
M. Kenny et al.
Feature
Synthesis
1H NMR (400 MHz, CDCl3): δ = 7.25 (t, J = 8.4 Hz, 1 H), 7.11 (ddd,
J = 8.0, 2.0, 1.2 Hz, 1 H), 6.98 (t, J = 2.0 Hz, 1 H), 6.87 (ddd, J = 8.0, 2.4,
0.8 Hz, 1 H), 4.15 (d, J = 2.4 Hz, 1 H), 3.93 (d, J = 2.4 Hz, 1 H), 3.18 (d,
J = 14.8 Hz, 1 H), 2.75 (dq, J = 14.0, 3.6 Hz, 1 H), 2.52 (dtd, J = 13.6, 3.6,
1.2 Hz, 1 H), 2.47 (d, J = 14.8 Hz, 1 H), 2.24 (td, J = 13.6, 5.6 Hz, 1 H),
2.13 (s, 3 H), 2.08–1.99 (m, 1 H), 1.90–1.73 (m, 2 H), 1.67 (tt, J = 12.8,
4.0 Hz, 1 H), 1.42 (ddd, J = 14.0, 12.4, 4.4 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 209.1, 204.2, 158.6, 155.0, 134.8,
130.4, 124.8, 121.7, 119.6, 91.8, 66.7, 41.9, 39.2, 34.2, 27.4, 26.7, 22.2.
HRMS (ESI): m/z [M + Na]+ calcd for C17H19ClO3Na: 329.0915; found:
329.0911.
20w
Rf = 0.29 (PE/EtOAc, 4:1).
IR (film): 2898, 2822, 1673 cm–1
1H NMR (400 MHz, CDCl3): δ = 7.51 (dd, J = 8.0, 1.6 Hz, 1 H), 7.24 (ddd,
J = 8.4, 7.6, 1.6 Hz, 1 H), 6.93 (dd, J = 8.4, 1.6 Hz, 1 H), 6.83 (td, J = 7.6,
1.6 Hz, 1 H), 5.76 (t, J = 1.2 Hz, 1 H), 5.26 (s, 1 H), 4.63 (d, J = 12.4 Hz, 1
H), 4.45 (d, J = 12.4 Hz, 1 H), 2.64–2.44 (m, 3 H), 2.27 (s, 3 H), 2.17–
2.07 (m, 1 H), 1.96–1.75 (m, 3 H), 1.73–1.60 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 209.1, 206.9, 154.6, 141.1, 133.3,
128.4, 122.1, 119.6, 113.3, 111.9, 71.8, 69.6, 40.9, 32.8, 27.1, 27.0,
21.9.
.
HRMS (ESI): m/z [M + H]+ calcd for C17H20BrO3: 351.0590; found:
351.0580.
2-Acetyl-2-[3-(2-chlorophenoxy)prop-1-en-2-yl]cyclohexan-1-one
(20v) and 2-Acetyl-2-[2-(2-chlorophenoxy)allyl]cyclohexan-1-one
(21v)
Following method A, carbonate 3115 (53.3 mg, 0.24 mmol) was react-
ed with 2-chlorophenol (27 μL, 0.26 mmol). Flash column chromatog-
raphy (PE/EtOAc, 19:1–9:1) afforded 20v (39 mg, 53%) as a yellow oil
and an inseparable mixture of 21v and dba in a 1.2:1 ratio (23 mg,
corresponding to 12 mg of 21v, 16%) as a yellow oil.
21w
Rf = 0.40 (PE/EtOAc, 4:1); mp 46–49 °C.
IR (film): 2895, 1672, 1596 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.55 (dd, J = 8.0, 1.6 Hz, 1 H), 7.30–7.25
(m, 1 H), 7.06–6.99 (m, 2 H), 4.13 (d, J = 2.4 Hz, 1 H), 3.77 (d, J = 2.4 Hz,
1 H), 3.26 (d, J = 14.8 Hz, 1 H), 2.81 (dq, J = 14.0, 3.6 Hz, 1 H), 2.57 (d,
J = 14.8 Hz, 1 H), 2.52 (dtd, J = 14.0, 4.0, 1.6 Hz, 1 H), 2.31–2.19 (m, 1
H), 2.19 (s, 3 H), 2.10–1.98 (m, 1 H), 1.95–1.61 (m, 3 H), 1.51 (ddd,
J = 14.0, 12.4, 4.4 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 209.0, 204.6, 157.8, 151.4, 133.5,
128.7, 126.1, 123.3, 116.2, 90.8, 66.8, 41.7, 39.2, 34.2, 27.3, 26.8, 22.2.
HRMS (ESI): m/z [M + Na]+ calcd for C17H19BrO3Na: 373.0410; found:
373.0399.
20v
Rf = 0.28 (PE/EtOAc, 4:1).
IR (film): 3020, 2900, 2822, 1673, 1564 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.33 (dd, J = 8.0, 1.6 Hz, 1 H), 7.19 (ddd,
J = 8.4, 7.6, 1.6 Hz, 1 H), 6.96 (dd, J = 8.4, 1.6 Hz, 1 H), 6.88 (td, J = 7.6,
1.2 Hz, 1 H), 5.73 (t, J = 1.2 Hz, 1 H), 5.26 (s, 1 H), 4.64 (d, J = 12.4 Hz, 1
H), 4.47 (dd, J = 12.4, 0.8 Hz, 1 H), 2.64–2.43 (m, 3 H), 2.27 (s, 3 H),
2.16–2.07 (m, 1 H), 1.96–1.75 (m, 3 H), 1.73–1.61 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 209.2, 206.8, 153.7, 141.3, 130.2,
127.7, 122.7, 121.6, 119.7, 113.4, 71.8, 69.7, 40.9, 32.7, 27.1, 27.0,
21.9.
HRMS (ESI): m/z [M + H]+ calcd for C17H20ClO3: 307.1095; found:
307.1088.
3-[3-(1-Isobutyryl-2-oxocyclohexyl)prop-1-en-2-yl]-3-methyl-
pentane-2,4-dione (23b)
Following method B, carbonate 1421 (47.1 mg, 0.24 mmol) was react-
ed with 2-isobutyrylcyclohexanone (40 μL, 0.24 mmol). Flash column
chromatography (PE/EtOAc, 9:1) afforded 23b (36 mg, 47%) as a yel-
low solid.
Rf = 0.25 (PE/EtOAc, 4:1); mp 40–42 °C.
21v
Rf = 0.40 (PE/EtOAc, 4:1).
IR (film): 2972, 2931, 2875, 1694, 1641 cm–1
.
IR (film): 3015, 2897, 2824, 1672, 1626, 1596, 1567 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 5.02 (q, J = 1.2 Hz, 1 H), 4.87 (q, J = 1.4
Hz, 1 H), 3.01 (sept, J = 6.6 Hz, 1 H), 2.54–2.39 (m, 5 H), 2.18 (s, 3 H),
2.17 (s, 3 H), 1.79–1.60 (m, 5 H), 1.55 (s, 3 H), 1.10 (d, J = 7.1 Hz, 3 H),
0.98 (d, J = 6.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 214.8, 209.9, 207.6, 207.4, 141.4,
116.9, 71.9, 67.6, 41.5, 36.0, 35.7, 34.3, 27.2, 27.06, 27.05, 22.0, 21.0,
20.6, 18.8.
1H NMR (400 MHz, CDCl3): δ = 7.38 (dd, J = 8.0, 1.6 Hz, 1 H), 7.23 (ddd,
J = 8.0, 7.6, 1.6 Hz, 1 H), 7.12–7.06 (m, 1 H), 7.03 (dd, J = 8.0, 1.6 Hz, 1
H), 4.11 (d, J = 2.4 Hz, 1 H), 3.76 (d, J = 2.4 Hz, 1 H), 3.24 (d, J = 15.2 Hz,
1 H), 2.80 (dq, J = 14.0, 4.0 Hz, 1 H), 2.57 (d, J = 14.8 Hz, 1 H), 2.52 (dtd,
J = 14.0, 4.0, 1.6 Hz, 1 H), 2.25 (ddd, J = 13.6, 12.8, 5.6 Hz, 1 H), 2.18 (s,
3 H), 2.08–1.98 (m, 1 H), 1.95–1.75 (m, 2 H), 1.68 (qt, J = 12.8, 4.0 Hz,
1 H), 1.50 (ddd, J = 14.0, 12.4, 4.4 Hz, 1 H).
HRMS (ESI): m/z [M + H]+ calcd for C19H29O4: 321.2060; found:
321.2047.
13C NMR (100 MHz, CDCl3): δ = 209.0, 204.6, 157.8, 150.2, 130.5,
128.0, 127.0, 125.8, 123.3, 90.6, 66.7, 41.7, 39.1, 34.1, 27.3, 26.7, 22.2.
HRMS (ESI): m/z [M + Na]+ calcd for C17H19ClO3Na: 329.0915; found:
329.0905.
3-[3-(2-Acetyl-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)prop-1-
en-2-yl]-3-methylpentane-2,4-dione (23c)21
Carbonate 1421 (23.5 mg, 0.12 mmol), Pd2(dba)3 (5.5 mg, 0.006
mmol), DPEphos (6.5 mg, 0.012 mmol) and 2-acetyl-1-tetralone (26.7
mg, 0.12 mmol) were added to a dried tube under argon. The tube
was fitted with a septum and purged further with argon. 1,4-Dioxane
(1.5 mL) was added and the sealed tube was placed in an oil bath pre-
heated to 80 °C. The mixture was stirred at 80 °C for 2 h, then cooled
to room temperature and concentrated in vacuo. Flash column chro-
matography (PE/EtOAc, 4:1) afforded an inseparable mixture of 23c
2-Acetyl-2-[3-(2-bromophenoxy)prop-1-en-2-yl]cyclohexan-1-
one (20w) and 2-Acetyl-2-[2-(2-bromophenoxy)allyl]cyclohexan-
1-one (21w)
Following method A, carbonate 3115 (53.3 mg, 0.24 mmol) was react-
ed with 2-bromophenol (30 μL, 0.26 mmol). Flash column chroma-
tography (PE/EtOAc, 19:1–9:1) afforded 20w (41 mg, 49%) as a pale
yellow oil and an inseparable mixture of 21w and dba in a 1.8:1 ratio
(21 mg, corresponding to 9.5 mg of 21w, 11%) as a yellow solid.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–S

O
M. Kenny et al.
Feature
Synthesis
and homo-coupled 14 in a 14:1 ratio (34.8 mg, corresponding to 32
mg of 23c, 79%) as a yellow oil.
Rf = 0.22 (PE/EtOAc, 4:1).
IR (film): 3058, 2983, 2926, 1692, 1641, 1500 cm–1
.
Rf = 0.33 (PE/EtOAc, 4:1).
1H NMR (400 MHz, CDCl3): δ = 7.36–7.27 (m, 5 H), 5.08 (q, J = 1.7 Hz, 1
H), 4.89 (q, J = 1.9 Hz, 1 H), 3.03 (t, J = 2.0 Hz, 2 H), 2.21 (s, 6 H), 2.20 (s,
6 H), 1.61 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 207.5, 205.8, 141.1, 136.1, 129.0,
128.2, 128.0, 117.1, 72.8, 71.8, 35.2, 28.1, 27.0, 19.0.
Enantioselective Catalysis: carbonate 1421 (31.3 mg, 0.16 mmol),
Pd2(dba)3 (7.3 mg, 0.008 mmol), (R)-Tol-BINAP (37) (6.5 mg, 0.0096
mmol) and 2-acetyl-1-tetralone (30 mg, 0.16 mmol) were added to a
dried tube under argon. The tube was fitted with a septum and
purged further with argon. 1,4-Dioxane (1 mL) was added and the
mixture was stirred at room temperature for 16 h, then concentrated
in vacuo. Flash column chromatography (PE/EtOAc, 9:1–4:1) afforded
23c (37 mg, 68%).
HRMS (ESI): m/z [M + H]+ calcd for C20H25O4: 329.1747; found:
329.1750.
O
O
Chiral HPLC: OD-H column, 1 mL/min, (hexane/IPA, 9:1), tA (minor) =
11.2 min, tB (minor) = 12.9 min, 27% ee.
[α]D25 +1.4 (c 0.1, CHCl3, 27% ee).
O
O
23lb
3-[2-(2-Acetyl-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)allyl]-3-
methylpentane-2,4-dione (23g)21
Following method B, carbonate 1421 (64.8 mg, 0.24 mmol) was react-
ed with 3-methyl-2,4-pentanedione (28 μL, 0.24 mmol). Flash col-
umn chromatography (PE/EtOAc, 4:1) afforded 23g (58 mg, 71%) as a
yellow oil.
2,2′-(Prop-2-ene-1,2-diyl)bis(2-methylcyclohexane-1,3-dione)
(23lb)
Following method B, carbonate 1421 (47.1 mg, 0.24 mmol) was react-
ed with 2-methyl-1,3-cyclohexadione (30.2 mg, 0.24 mmol). Flash
column chromatography (PE/EtOAc, 4:1) afforded an inseparable mix-
ture of homo-coupled 22 (23lb), 23l, its regioisomer 23q, and homo-
coupled 14 in a 9.0:4.0:1.2:1 ratio (39 mg, corresponding to 20 mg of
23lb, 27%) as an orange solid.
Rf = 0.34 (PE/EtOAc, 4:1).
Enantioselective Catalysis: carbonate 1421 (43.2 mg, 0.16 mmol),
Pd2(dba)3 (7.3 mg, 0.008 mmol), (R)-Xylyl-P-PHOS (35) (7.3 mg,
0.0096 mmol) and 3-methyl-2,4-pentanedione (19 μL, 0.16 mmol)
were added to a dried tube under argon. The tube was fitted with a
septum and purged further with argon. Tetrahydrofuran (1 mL) was
added and the mixture was stirred at 60 °C for 2 h, then concentrated
in vacuo. Flash column chromatography (PE/EtOAc, 9:1–4:1) afforded
23g (30 mg, 57%).
Rf = 0.29 (PE/EtOAc, 9:1–4:1); mp 63–65 °C.
IR (film): 3368, 2939, 1723, 1686, 1638 cm–1
.
1H NMR (400 MHz, CDCl3): δ (resonances due to 23lb quoted) = 4.67
(q, J = 1.5 Hz, 1 H), 4.11 (q, J = 1.5 Hz, 1 H), 2.96–2.87 (m, 2 H), 2.84–
2.75 (m, 2 H), 2.72–2.57 (m, 3 H), 2.54–2.50 (m, 1 H), 2.48 (t, J = 1.5
Hz, 2 H), 2.18–2.13 (m, 2 H), 1.60–1.58 (m, 2 H), 1.33–1.31 (m, 6 H).
13C NMR (100 MHz, CDCl3): δ (resonances due to 23lb quoted) =
209.1, 208.1, 144.9, 113.0, 73.5, 63.2, 38.7, 37.5, 36.0, 26.7, 17.46,
17.45, 17.4.
Chiral HPLC: AD-H column, 1 mL/min, (hexane/IPA, 9:1), tA (minor) =
10.7 min, tB (major) = 12.6 min, 21% ee.
[α]D25 –1.3 (c 0.1, CHCl3, 21% ee).
HRMS (ESI): m/z [M + H]+ calcd for C17H23O4: 291.1591; found:
291.1580.
3,6-Diacetyl-3-benzyl-6-methyl-4-methyleneoctane-2,7-dione
(23h)
Following method B, carbonate 1415 (65.3 mg, 0.24 mmol) was react-
ed with 3-methyl-2,4-pentanedione (28 μL, 0.24 mmol). Flash col-
umn chromatography (PE/EtOAc, 9:1–4:1) afforded an inseparable
mixture of 23h and homo-coupled 14 in a 6.5:1 ratio (21 mg, corre-
sponding to 17.5 mg of 23h, 21%) as a yellow solid.
3-Acetyl-6-(1-hydroxyethylidene)-3-methyl-4-methyleneoctane-
2,7-dione (23m)
Following method B, carbonate 1421 (47.1 mg, 0.24 mmol) was react-
ed with acetylacetone (25 μL, 0.24 mmol). Flash column chromatogra-
phy (PE/EtOAc, 4:1) afforded an inseparable mixture of 23m and
homo-coupled 14 in a 10:1 ratio (37 mg, corresponding to 33.6 mg of
23m, 56%) as a yellow solid.
Rf = 0.37 (PE/EtOAc, 4:1); mp 70–72 °C.
IR (film): 3384, 2993, 2927, 1692, 1641, 1500 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.24–7.17 (m, 3 H), 7.06 (dd, J = 7.7, 1.5
Hz, 2 H), 5.18 (q, J = 1.4 Hz, 1 H), 4.91 (q, J = 1.9 Hz, 1 H), 3.47 (s, 2 H),
2.64 (t, J = 1.7 Hz, 2 H), 2.15 (s, 6 H), 2.11 (s, 6 H), 1.41 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 206.9, 205.8, 141.2, 136.1, 129.7,
128.4, 127.0, 117.5, 78.0, 66.0, 37.8, 35.6, 28.4, 26.2, 18.0.
Rf = 0.27 (PE/EtOAc, 9:1–4:1); mp 63–65 °C.
IR (film): 2983, 2926, 1704, 1639, 1562 cm–1
1H NMR (400 MHz, CDCl3): δ = 16.88 (s, 1 H), 5.08 (t, J = 2.2 Hz, 1 H),
5.01 (t, J = 1.9 Hz, 1 H), 2.83 (t, J = 2.0 Hz, 2 H), 2.21 (s, 6 H), 2.06 (s, 6
H), 1.64 (s, 3 H).
.
HRMS (ESI): m/z [M + H]+ calcd for C21H27O4: 343.1904; found:
343.1898.
13C NMR (100 MHz, CDCl3): δ = 207.1, 192.3, 144.5, 114.5, 106.0, 71.0,
30.7, 26.9, 22.7, 18.9.
HRMS (ESI): m/z [M + H]+ calcd for C14H21O4: 253.1456; found:
253.1442.
3,6-Diacetyl-3-methyl-4-methylene-6-phenyloctane-2,7-dione
(23k)
Following method B, carbonate 1421 (47.1 mg, 0.24 mmol) was react-
ed with 3-phenyl-2,4-pentanedione (42 mg, 0.24 mmol). Flash col-
umn chromatography (PE/EtOAc, 9:1–4:1) afforded an inseparable
mixture of 23k and homo-coupled 14 in a 4.8:1 ratio (35 mg, corre-
sponding to 28.2 mg of 23k, 36%) as a red oil.
6-Acetyl-3-benzoyl-3,6-dimethyl-4-methyleneoctane-2,7-dione
(23n)21
Following method B, carbonate 1421 (61.9 mg, 0.24 mmol) was react-
ed with 3-methyl-2,4-pentanedione (28 μL, 0.24 mmol). Flash col-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–S

P
M. Kenny et al.
Feature
Synthesis
umn chromatography (PE/EtOAc, 4:1) afforded an inseparable mix-
ture of 23n and homo-coupled 14 in a 5.3:1 ratio (61 mg, correspond-
ing to 50 mg of 23n, 63%) as a red solid.
IR (film): 2983, 2931, 1701, 1653 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 5.01–4.99 (m, 2 H), 4.18 (q, J = 7.1 Hz, 1
H), 4.18 (q, J = 7.1 Hz, 1 H), 2.69 (dt, J = 18.1, 1.8 Hz, 1 H), 2.49 (dt,
J = 17.7, 1.5 Hz, 1 H), 2.19 (s, 3 H), 2.11 (s, 3 H), 2.10 (s, 3 H), 1.43 (s, 3
H), 1.39 (s, 3 H), 1.19 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 207.2, 207.1, 205.0, 172.7, 142.4,
116.0, 72.0, 61.8, 58.7, 36.2, 27.3, 27.0, 26.0, 19.0, 18.6, 13.9.
Rf = 0.26 (PE/EtOAc, 4:1); mp 73–76 °C.
Enantioselective Catalysis: carbonate 1421 (45.8 mg, 0.16 mmol),
Pd2(dba)3 (7.3 mg, 0.008 mmol), (R)-Xylyl-P-PHOS (35) (7.3 mg,
0.0096 mmol) and 3-methyl-2,4-pentanedione (19 μL, 0.16 mmol)
were added to a dried tube under argon. The tube was fitted with a
septum and purged further with argon. Tetrahydrofuran (1 mL) was
added and the mixture was stirred at 60 °C for 2 h, then concentrated
in vacuo. Flash column chromatography (PE/EtOAc, 9:1–4:1) afforded
23n (18 mg, 34%).
HRMS (ESI): m/z [M + H]+ calcd for C16H25O5: 297.1697; found:
297.1684.
3-[3-(3-Acetyl-2-oxotetrahydrofuran-3-yl)prop-1-en-2-yl]-3-
methylpentane-2,4-dione (23w)
Chiral HPLC: OD-H column, 1 mL/min, (hexane/IPA, 9:1), tA (major) =
7.7 min, tB (minor) = 8.5 min, 19% ee.
[α]D25 +1.3 (c 0.1, CHCl3, 19% ee).
Following method B, carbonate 1421 (47.1 mg, 0.24 mmol) was react-
ed with α-acetylbutyrolactone (30.8 mg, 0.24 mmol). Flash column
chromatography (PE/EtOAc, 9:1–4:1) afforded an inseparable mixture
of 23w, homo-coupled 14 and homo-coupled 22 in a 6.8:2.2:1 ratio
(35 mg, corresponding to 23.0 mg of 23w, 34%) as a yellow oil.
Ethyl 3,3,6-Triacetyl-6-methyl-4-methylene-7-oxooctanoate (23o)
Following method B, carbonate 1415 (50 mg, 0.24 mmol) was reacted
with 3-methyl-2,4-pentanedione (28 μL, 0.24 mmol). Flash column
chromatography (PE/EtOAc, 4:1) afforded an inseparable mixture of
23o, homo-coupled 22, and the regioisomer of 23o in a 16:1.2:1 ratio
(38 mg, corresponding to 33.5 mg of 23o, 41%) as a green oil.
Rf = 0.15 (PE/EtOAc, 4:1).
IR (film): 2981, 2924, 2855, 1759, 1701 cm–1
1H NMR (300 MHz, CDCl3): δ = 5.02 (q, J = 1.4 Hz, 1 H), 4.89 (q, J = 1.8
Hz, 1 H), 4.38–4.24 (m, 2 H), 3.13–3.00 (m, 2 H), 3.01 (dt, J = 18.2, 1.6
Hz, 1 H), 2.43–2.33 (m, 1 H), 2.36 (s, 3 H), 2.17 (s, 3 H), 2.16 (s, 3 H),
1.59 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 206.6, 206.4, 203.3, 174.7, 142.1, 115.6,
71.5, 66.9, 60.5, 37.7, 29.7, 27.04, 27.00, 25.7, 18.9.
HRMS (ESI): m/z [M + H]+ calcd for C15H21O5: 281.1384; found:
281.1348.
.
Rf = 0.31 (PE/EtOAc, 4:1).
IR (film): 2983, 2935, 1697, 1638 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 5.09 (q, J = 1.8 Hz, 1 H), 4.87 (q, J = 1.9
Hz, 1 H), 4.13 (q, J = 4.1 Hz, 2 H), 3.05 (s, 2 H), 2.54 (t, J = 1.6 Hz, 2 H),
2.25 (s, 6 H), 2.11 (s, 6 H), 1.40 (s, 3 H), 1.25 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 206.4, 204.8, 170.6, 140.2, 117.2, 73.5,
65.3, 61.2, 37.7, 36.0, 28.1, 26.2, 18.0, 14.0.
O
HRMS (ESI): m/z [M + Na]+ calcd for C18H26O6Na: 361.1622; found:
361.1606.
O
O
O
EtO
44
2-(4-Acetyl-4-methyl-5-oxohex-1-en-2-yl)-2-methylcyclohexane-
1,3-dione (23q)
Following method B, carbonate 1415 (50 mg, 0.24 mmol) was reacted
with 3-methyl-2,4-pentanedione (28 μL, 0.24 mmol). Flash column
chromatography (PE/EtOAc, 9:1–4:1) afforded 23q (29 mg, 43%) as a
yellow solid.
Ethyl 2-Methyl-3-[(prop-2-ynyloxy)carbonyloxy]but-2-enoate (44)
A suspension of sodium hydride (60 wt% in mineral oil, 92.3 mg, 2.31
mmol) in tetrahydrofuran (10 mL) was cooled to 0 °C. A solution of 2-
methyl ethyl acetoacetate (300 μL, 2.1 mmol) in tetrahydrofuran (5
mL) was added dropwise and the mixture was stirred at 0 °C for 10
min. Propargyl chloroformate (225 μL, 2.31 mmol) was added drop-
wise and the mixture was allowed to warm to room temperature and
stirred at room temperature for 1.5 h. The reaction was quenched by
the addition of aq HCl (1 M, 20 mL) and the mixture was extracted
with EtOAc (3 × 15 mL). The combined organic phases were washed
with brine (20 mL), dried (MgSO4) and concentrated in vacuo. Flash
column chromatography (PE/EtOAc, 19:1) afforded 44 (200 mg, 45%)
as a clear oil.
Rf = 0.31 (PE/EtOAc, 4:1); mp 42–44 °C.
IR (film): 3382, 2994, 2950, 2942, 1722, 1692, 1634 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 4.89 (q, J = 1.7 Hz, 1 H), 4.73 (q, J = 1.7
Hz, 1 H), 2.85–2.74 (m, 2 H), 2.62–2.53 (m, 2 H), 2.47 (t, J = 1.2 Hz, 2
H), 2.15–2.12 (m, 1 H), 2.10 (s, 6 H), 1.83–1.80 (m, 1 H), 1.42 (s, 3 H),
1.31 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 208.0, 206.6, 142.8, 114.8, 73.2, 65.9,
38.5, 36.2, 26.2, 18.9, 18.2, 17.4.
HRMS (ESI): m/z [M + H]+ calcd for C16H23O4: 279.1591; found:
Rf = 0.65 (PE/EtOAc, 7:1).
IR (film): 3368, 2939, 2122, 1723, 1686, 1638 cm–1
.
279.1585.
1H NMR (400 MHz, CDCl3): δ = 4.79 (d, J = 2.4 Hz, 2 H), 4.18 (q, J = 7.3
Hz, 2 H), 2.55 (t, J = 2.4 Hz, 1 H), 2.05 (q, J = 1.2 Hz, 3 H), 1.90 (q, J = 1.2
Hz, 3 H), 1.27 (t, J = 6.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 166.2, 152.1, 151.3, 117.0, 76.6, 76.0,
60.9, 55.8, 18.1, 14.5, 14.0.
Ethyl 2,5-Diacetyl-2,5-dimethyl-4-methylene-6-oxoheptanoate
(23s)
Following method B, carbonate 1421 (47.1 mg, 0.24 mmol) was react-
ed with ethyl 2-methyl acetoacetate (34 μL, 0.24 mmol). Flash column
chromatography (PE/EtOAc, 9:1–4:1) afforded 23s (27 mg, 38%) as a
brown oil.
HRMS (ESI): m/z [M + H]+ calcd for C11H15O5: 227.0914; found:
227.0916.
Rf = 0.29 (PE/EtOAc, 4:1).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–S

Q
M. Kenny et al.
Feature
Synthesis
Ethyl 2,5-Diacetyl-2,5-dimethyl-3-methylene-6-oxoheptanoate
(23x)
13C NMR (100 MHz, CDCl3): δ = 207.1, 207.0, 202.7, 137.2, 121.1, 80.2,
65.7, 37.8, 35.7, 27.2, 26.7, 26.2, 18.9, 15.6.
LRMS (ESI): m/z [M + H]+ calcd for C14H23SO5: 303.1261; found:
303.0790.
Following method B, carbonate 44 (54.3 mg, 0.24 mmol) was reacted
with 3-methyl-2,4-pentanedione (28 μL, 0.24 mmol). Flash column
chromatography (PE/EtOAc, 9:1–4:1) afforded an inseparable mixture
of 23x, homo-coupled 22 and homo-coupled 14 in a 16:1.3:1 ratio (34
mg, corresponding to 30 mg of 23x, 42%) as a yellow oil.
Methyl 1-[2-(1-Acetyl-2-oxocyclohexyl)allyl]-1H-pyrrole-2-car-
boxylate (24g)22
Following method C, carbonate 3115 (53 mg, 0.24 mmol) was reacted
with methyl 1H-pyrrole-2-carboxylate (30 mg, 0.24 mmol). Flash col-
umn chromatography (PE/EtOAc, 9:1–4:1) afforded 24g (59 mg, 81%)
as a yellow solid.
Rf = 0.35 (PE/EtOAc, 4:1).
IR (film): 2935, 2873, 1694, 1641, 1556 cm–1
1H NMR (400 MHz, CDCl3): δ = 5.00 (q, J = 1.2 Hz, 1 H), 4.76 (q, J = 1.4
Hz, 1 H), 4.21 (q, J = 7.1 Hz, 2 H), 2.70 (d, J = 6.2 Hz, 2 H), 2.21 (s, 3 H),
2.13 (s, 3 H), 2.12 (s, 3 H), 1.55 (s, 3 H), 1.43 (s, 3 H), 1.27 (t, J = 7.1 Hz,
3 H).
13C NMR (100 MHz, CDCl3): δ = 207.1, 206.9, 204.8, 171.4, 142.0,
114.7, 66.4, 66.3, 61.6, 36.1, 27.0, 26.3, 26.2, 19.9, 17.8, 14.0.
HRMS (ESI): m/z [M + Na]+ calcd for C16H24O5Na: 319.1516; found:
319.1524.
.
Rf = 0.43 (PE/EtOAc, 4:1); mp 104–106 °C.
Enantioselective Catalysis: carbonate 3115 (35.5 mg, 0.16 mmol),
Pd2(dba)3 (7.3 mg, 0.008 mmol), (R)-Xylyl-P-PHOS (35) (7.3 mg,
0.0096 mmol) and methyl 1H-pyrrole-2-carboxylate (20 mg, 0.16
mmol) were added to a dried tube under argon. The tube was fitted
with a septum and purged further with argon. Tetrahydrofuran (1
mL) was added and the mixture was stirred at 60 °C for 2 h, then con-
centrated in vacuo. Flash column chromatography (PE/EtOAc, 9:1–
4:1) afforded 24g (39 mg, 80%).
O
O
O
O
O
Chiral HPLC: OD-H column, 1 mL/min, (hexane/IPA, 19:1), tA (minor) =
8.7 min, tB (major) = 9.1 min, 19% ee.
S
45
[α]D25 –0.5 (c 0.1, CHCl3, 19% ee).
3-(Methylsulfonyl)but-2-en-2-yl Prop-2-ynyl Carbonate (45)
2-(1-Acetyl-2-oxocyclohexyl)allyl Benzoate (25a) and 3-(1-Acetyl-
2-oxocyclohexyl)prop-1-en-2-yl Benzoate (26a)
A suspension of sodium hydride (60 wt% in mineral oil, 30.4 mg, 0.76
mmol) in tetrahydrofuran (30 mL) was cooled to 0 °C. A solution of 3-
(methylsulfonyl)butan-2-one25 (104 mg, 0.69 mmol) in tetrahydrofu-
ran (5 mL) was added dropwise and the mixture was stirred at 0 °C for
10 min. Propargyl chloroformate (74 μL, 0.76 mmol) was added drop-
wise and the mixture allowed to warm to room temperature and
stirred at room temperature for 1.5 h. The reaction was quenched by
the addition of aq HCl (1 M, 10 mL) and the mixture was extracted
with EtOAc (3 × 10 mL). The combined organic phases were washed
with brine (10 mL), dried (MgSO4) and concentrated in vacuo. Flash
column chromatography (PE/EtOAc, 4:1–1:1) afforded 45 (101 mg,
64%) as a white solid.
Following method D, carbonate 31 (53.3 mg, 0.24 mmol) was reacted
with benzoic acid (29.3 mg, 0.24 mmol). Flash column chromatogra-
phy (PE/EtOAc, 19:1–9:1) afforded an inseparable mixture of 25a and
26a in a 1.7:1 ratio (32 mg, 44%) as a clear oil.
Rf = 0.26 (PE/EtOAc, 9:1).
IR (film): 2931, 2866, 17171, 1698 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.03–7.92 (m, 2 H and 2 H*), 7.62–7.51
(m, 1 H and 1 H*), 7.50–7.38 (m, 2 H and 2 H*), 5.67 (s, 1 H), 5.21 (s, 1
H), 4.96 (s, 1 H*), 4.90 (s, 1 H*), 4.89 (d, J = 13.6 Hz, 1 H), 4.83 (d,
J = 13.6 Hz, 1 H), 3.07 (d, J = 15.6 Hz, 1 H*), 2.76 (d, J = 15.2 Hz, 1 H*),
2.71–2.57 (m, 1 H and 1 H*), 2.54–2.34 (m, 2 H and 1 H*), 2.23 (s, 3 H),
2.22–2.08 (m, 1 H and 1 H*), 2.03 (s, 3 H*), 2.03–1.93 (m, 1 H*), 1.92–
1.57 (m, 4 H and 3 H*), 1.56–1.43 (m, 1 H*); isomer 26a annotated by
an asterisk.
13C NMR (75 MHz, CDCl3): δ = 209.2, 208.4, 206.5, 204.6, 165.9, 164.4,
151.4, 141.4, 133.5, 133.2, 129.9, 129.6, 129.5, 129.3, 128.5, 128.4,
120.0, 106.4, 71.8, 66.6, 65.4, 41.6, 40.6, 38.8, 33.8, 32.3, 27.3, 27.14,
27.08, 26.4, 22.1, 21.7.
Rf = 0.10 (PE/EtOAc, 1:1); mp 75–77 °C.
IR (film): 3293, 2929, 2137, 1763, 1668 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 4.78 (d, J = 2.7 Hz, 2 H), 2.99 (s, 3 H),
2.58 (t, J = 2.3 Hz, 1 H), 2.13 (q, J = 1.2 Hz, 3 H), 2.03 (q, J = 1.7 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 152.7, 150.8, 127.7, 76.4, 76.0, 56.3,
42.6, 18.3, 13.5.
HRMS (ESI): m/z [M + Na]+ calcd for C9H12SO5Na: 255.0298; found:
255.0291.
HRMS (ESI): m/z [M + Na]+ calcd for C18H20O4Na: 323.1254; found:
323.1251.
6-Acetyl-3,6-dimethyl-4-methylene-3-(methylsulfonyl)octane-
2,7-dione (23y)
2-(1-Acetyl-2-oxocyclohexyl)allyl Pivalate (25b) and 3-(1-Acetyl-2-
oxocyclohexyl)prop-1-en-2-yl Pivalate (26b)
Following method B, carbonate 45 (55.7 mg, 0.24 mmol) was reacted
with 3-methyl-2,4-pentanedione (28 μL, 0.24 mmol). Flash column
chromatography (PE/EtOAc, 9:1–1:1) afforded 23y (15 mg, 21%) as a
green oil.
Following method D, carbonate 31 (53.3 mg, 0.24 mmol) was reacted
with pivalic acid (24.5 mg, 0.24 mmol). Flash column chromatography
(PE/EtOAc, 19:1–9:1) afforded an inseparable mixture of 25b and 26b
in a 1.7:1 ratio (29 mg, 43%) as clear oily crystals.
Rf = 0.10 (PE/EtOAc, 4:1).
IR (film): 2927, 2855, 1712, 1695, 1634 cm–1
.
Rf = 0.62 (PE/EtOAc, 4:1).
1H NMR (400 MHz, CDCl3): δ = 5.23 (q, J = 1.6 Hz, 1 H), 5.07 (q, J = 1.9
Hz, 1 H), 3.07 (s, 3 H), 2.96–2.94 (m, 1 H), 2.93–2.91 (m, 1 H), 2.25 (s, 3
H), 2.18 (s, 3 H), 2.17 (s, 3 H), 1.86 (s, 3 H), 1.48 (s, 3 H).
IR (film): 2956, 2874, 1732, 1717, 1696 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 5.54 (s, 1 H), 5.14 (s, 1 H), 4.76 (d,
J = 1.8 Hz, 1 H*), 4.73 (d, J = 1.5 Hz, 1 H*), 4.63 (d, J = 13.5 Hz, 1 H), 4.50
(d, J = 13.5 Hz, 1 H), 2.81 (d, J = 15.3 Hz, 1 H*), 2.70 (d, J = 15.3 Hz, 1
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–S

R
M. Kenny et al.
Feature
Synthesis
H*), 2.67–2.21 (m, 3 H and 4 H*), 2.21 (s, 3 H), 2.10 (s, 3 H*), 2.09–1.92
(m, 1 H and 1 H*), 1.92–1.77 (m, 2 H), 1.77–1.57 (m, 2 H and 3 H*),
1.20 (s, 9 H*), 1.16 (s, 9 H); isomer 26b annotated by an asterisk.
13C NMR (75 MHz, CDCl3): δ = 209.3, 208.4, 206.3, 204.7, 177.9, 176.5,
151.8, 141.7, 120.8, 105.4, 71.6, 66.6, 65.2, 41.7, 40.5, 39.0, 38.7, 38.3,
33.7, 32.0, 27.5, 27.2, 27.01, 26.97, 26.94, 26.5, 22.1, 21.6.
3-[2-(1-Acetyl-2-oxocyclohexyl)allyl]-3-benzylpentane-2,4-dione
(34a)
Enantioselective Catalysis: carbonate 3115 (35.5 mg, 0.16 mmol),
Pd2(dba)3 (7.3 mg, 0.008 mmol), (R)-Xylyl-P-PHOS (35) (7.3 mg,
0.0096 mmol) and 3-benzylpentane-2,4-dione (30.5 mg, 0.16 mmol)
were added to a dried tube under argon. The tube was fitted with a
septum and purged further with argon. Tetrahydrofuran (1 mL) was
added and the mixture was stirred at 60 °C for 2 h, then concentrated
in vacuo. Flash column chromatography (PE/EtOAc, 9:1–4:1) afforded
34a (17 mg, 29%) as a clear oil.
HRMS (ESI): m/z [M + Na]+ calcd for C16H24O4Na: 303.1567; found:
303.1558.
2-[2-(1-Acetyl-2-oxocyclohexyl)allyl] 1-(tert-Butyl) (2S)-Pyrroli-
dine-1,2-dicarboxylate (25c) and 2-[3-(1-Acetyl-2-oxocyclohex-
yl)prop-1-en-2-yl] 1-(tert-Butyl) (2S)-Pyrrolidine-1,2-
dicarboxylate (26c)
Rf = 0.44 (PE/EtOAc, 4:1).
Chiral HPLC: AD-H column, 1 mL/min, (hexane/IPA, 9:1), tA (minor) =
8.4 min, tB (major) = 9.5 min, 19% ee.
[α]D25 +1.0 (c 0.1, CHCl3, 19% ee).
Following method D, carbonate 31 (53.3 mg, 0.24 mmol) was reacted
with N-Boc-L-proline (52 mg, 0.24 mmol). Flash column chromatog-
raphy (PE/EtOAc, 9:1–4:1) afforded 25c (46 mg, 49%) as a 1:1 mixture
of diastereoisomers as a sticky pale yellow oil, and 26c (14 mg, 15%)
as a 1:1 mixture of diastereoisomers as a sticky pale yellow oil.
IR (film): 2942, 2206, 1694 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.25–7.19 (m, 3 H), 6.99–6.93 (m, 2 H),
5.04 (q, J = 1.7 Hz, 1 H), 4.97 (q, J = 1.5 Hz, 1 H), 3.40 (dd, J = 19.3, 15.0
Hz, 2 H), 2.56 (dt, J = 19.1, 1.6 Hz, 1 H), 2.52–2.36 (m, 3 H), 2.24 (s, 3
H), 2.22 (s, 3 H), 2.17–2.13 (m, 1 H), 2.07 (s, 3 H), 2.07–2.00 (m, 1 H),
1.90–1.80 (m, 1 H), 1.77–1.66 (m, 1 H), 1.57–1.46 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 209.1, 207.4, 206.9, 206.6, 141.2,
135.9, 129.6, 128.4, 127.2, 115.8, 73.4, 70.2, 41.0, 38.0, 33.6, 33.0,
27.7, 27.4, 27.1, 26.7, 21.7.
25c
Rf = 0.06 (PE/EtOAc, 9:1).
IR (film): 2974, 1752, 1696 cm–1
.
1H NMR (400 MHz, CDCl3): δ (mixture of diastereoisomers and rota-
mers) = 5.61–5.49 (m, 1 H), 5.19–5.10 (m, 1 H), 4.78–4.48 (m, 2 H),
4.39–4.15 (m, 1 H), 3.60–3.30 (m, 2 H), 2.68–2.52 (m, 1 H), 2.52–2.40
(m, 1 H), 2.40–2.29 (m, 1 H), 2.27–2.09 (m, 4 H), 2.07–1.78 (m, 6 H),
1.78–1.61 (m, 2 H), 1.47–1.40 (m, 9 H).
13C NMR (100 MHz, CDCl3): δ (mixture of diastereoisomers and rota-
mers) = 209.3, 209.2, 209.0, 208.9, 206.7, 206.45, 206.37, 172.39,
172.36, 172.3, 171.0, 170.9, 154.33, 154.28, 153.7, 153.6, 141.4, 141.3,
141.1, 141.0, 120.0, 119.8, 119.7, 119.2, 78.0, 79.8, 71.8, 71.7, 71.6,
59.14, 59.06, 59.01, 58.95, 58.85, 58.78, 46.6, 46.3, 40.8, 40.64, 40.60,
32.5, 32.3, 32.0, 30.8, 30.74, 30.70, 29.8, 29.7, 28.4, 28.3, 27.4, 27.2,
27.15, 27.12, 27.07, 27.00, 26.95, 24.39, 24.37, 24.30, 23.7, 23.6, 21.7,
21.64, 21.58.
HRMS (ESI): m/z [M + H]+ calcd for C23H29O4: 369.2060; found:
369.2050.
Ethyl 3-(3-Acetyl-3-methyl-2-methylene-4-oxopentyl)-4-oxochro-
man-3-carboxylate (36a)21
Enantioselective Catalysis: carbonate 1421 (31.3 mg, 0.16 mmol),
Pd2(dba)3 (7.3 mg, 0.008 mmol), (R)-Tol-BINAP (37) (6.5 mg, 0.0096
mmol) and ethyl 4-oxochroman-3-carboxylate26 (35 mg, 0.16 mmol)
were added to a dried tube under argon. The tube was fitted with a
septum and purged further with argon. 1,4-Dioxane (1 mL) was add-
ed and the mixture was stirred at room temperature for 16 h, then
concentrated in vacuo. Flash column chromatography (PE/EtOAc, 9:1–
4:1) afforded 36a (21 mg, 35%).
HRMS (ESI): m/z [M + Na]+ calcd for C21H31NO6Na: 416.2044; found:
416.2029.
Rf = 0.42 (PE/EtOAc, 5:1).
Chiral HPLC: OD-H column, 1 mL/min, (hexane/IPA, 9:1), tA (major) =
10.1 min, tB (minor) = 11.2 min, 11% ee.
[α]D25 +0.8 (c 0.1, CHCl3, 11% ee).
26c
Rf = 0.07 (PE/EtOAc, 9:1).
IR (film): 2942, 2874, 1760, 1696 cm–1
.
1H NMR (400 MHz, CDCl3): δ (mixture of diastereoisomers and rota-
mers) = 4.99–4.91 (m, 1 H), 4.77 (s, 1 H), 4.29–4.14 (m, 1 H), 3.60–
3.32 (m, 2 H), 2.93–2.78 (m, 1 H), 2.72–2.43 (m, 4 H), 2.30–2.17 (m, 2
H), 2.17–2.09 (m, 3 H), 2.07–1.81 (m, 4 H), 1.81–1.57 (m, 3 H), 1.51–
1.38 (m, 9 H).
13C NMR (100 MHz, CDCl3): δ (mixture of diastereoisomers and rota-
mers) = 208.6, 208.4, 205.4, 204.6, 170.9, 170.7, 170.6, 154.3, 153.71,
153.67, 151.2, 151.14, 151.07, 105.6, 105.14, 105.11, 80.1, 79.8, 66.7,
66.6, 59.21, 59.17, 59.0, 46.6, 46.4, 41.7, 41.6, 38.8, 38.7, 38.4, 38.2,
33.80, 33.77, 33.6, 30.5, 29.5, 28.40, 28.36, 27.0, 26.5, 26.4, 24.4, 23.6,
22.1.
Funding Information
We gratefully acknowledge the Royal Society (RG150189, V.F.), the
University of York (N.J.T. and V.F.), Lancaster University (M.K. and V.F.),
the EU (Erasmus Exchange Programme to S.P.S.), and the Royal Society
of Chemistry (Undergraduate Research Bursaries to P.J. and D.J.K.) for
financial support.
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9)
Acknowledgment
HRMS (ESI): m/z [M + Na]+ calcd for C21H31NO6Na: 416.2044; found:
416.2045.
We are grateful to Prof. Richard Taylor for the generous donation of
chemicals and consumables as well as useful discussions. We thank
Dr. K. Heaton (University of York), Dr. D. Rochester (Lancaster Univer-
sity), as well as the EPSRC Mass Spectrometry Service (Swansea, UK)
for mass measurements. We also gratefully acknowledge Dr. D. Roch-
ester (Lancaster University) for help with HPLC analysis.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–S

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M. Kenny et al.
Feature
Synthesis
Supporting Information
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Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1591957.
S
u
p
p
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S
u
p
p
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–S