α-Arylation of Esters and Ketones Enabled by a Bench-Stable Pd(I) Dimer Catalyst

Article abstract of DOI:10.1055/s-0037-1610087

A procedure for the α-arylation of α,α-disubstituted esters and ketones to generate quaternary carbon centers is described. The developed protocol is operationally simple and employs an air- and moisture-stable dinuclear Pd(I) complex [Pd(μ-I)(P t -Bu ₃)] ₂ to mediate selective α-arylation of aromatic C-I/Br bonds in the presence of aromatic C-Cl and/or C-OTf sites.

Full text of DOI:10.1055/s-0037-1610087

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–E
special topic
A
en
T. Sperger, F. Schoenebeck
Special Topic
Synthesis
α-Arylation of Esters and Ketones Enabled by a Bench-Stable Pd(I)
Dimer Catalyst
Theresa Sperger
1. LiTMP (1.2 equiv)
2. [Pd(μ-I)(Pt-Bu3)]2 (1 mol%),
ArX (1.0 equiv)
O
O
Franziska Schoenebeck*
0
0
0
0
0-
0
0
3
0-
0
4
7
0-
9
2
9
Ar
α
R'
(O)R
(O)R
Institute of Organic Chemistry, RWTH Aachen University,
Landoltweg 1, 52074 Aachen, Germany
franziska.schoenebeck@rwth-aachen.de
toluene
R''
R'
R''
• bench-stable catalyst
• versatile protocol
• high functional group tolerance
R = alkoxy, aryl
R', R'' = alkyl
X = I, Br
16 examples
up to 91% yield
Published as part of the Special Section dedicated to
Scott E. Denmark on the occasion of his 65th birthday
Received: 24.04.2018
Accepted after revision: 16.05.2018
Published online: 25.06.2018
on the bench.7 Therefore, we anticipated that its use as a
catalyst would greatly facilitate handling. Moreover, we en-
visioned that the greater overall robustness of the iodide-
bridged dimer might allow for a wider set of enolates or
bases to be compatible, and its recently demonstrated po-
tential in site-selective C–C bond formations8 might also be
transferrable towards the introduction of disubstituted es-
ters. As such we anticipated that in contrast to previous de-
velopments that primarily employed specific catalyst sys-
tems tailored to convert specific substrate classes, our dinu-
clear Pd(I)-based methodology might allow for a more
general protocol that operates efficiently for a variety of dif-
ferent substrates, such as esters and ketones (Scheme 1).
DOI: 10.1055/s-0037-1610087; Art ID: ss-2018-c0285-st
Abstract A procedure for the α-arylation of α,α-disubstituted esters
and ketones to generate quaternary carbon centers is described. The
developed protocol is operationally simple and employs an air- and
moisture-stable dinuclear Pd(I) complex [Pd(μ-I)(Pt-Bu3)]2 to mediate
selective α-arylation of aromatic C–I/Br bonds in the presence of aro-
matic C–Cl and/or C–OTf sites.
Key words Pd(I) dimer, air-stable Pd catalyst, quaternary carbon,
cross-coupling
α-Functionalized carbonyl compounds are a common
motif in natural products and are important building blocks
as well as target molecules in pharmaceutical research.1
Therefore, the α-arylation of carbonyl and related com-
pounds such as nitriles, sulfones, and sulfoximines via tran-
sition metal catalysis has been intensively investigated and
significant advances were made within the last decades.2
Although the vast majority of processes relies on Pd-cataly-
sis, Cu- and Ni-catalysis methodologies were also report-
ed.2a However, air- and moisture-sensitive catalysts are
commonly employed in these transformations, requiring
inert atmosphere in the reaction conditions and/or han-
dling of reagents.
• various Pd(0)-(pre)catalysts, ligands and bases
• specific catalyst system for specific
Hartwig (2000–2008):
substrate classes (esters, ketones, amides, etc.)
1. base
2. [Pd(μ-Br)(Pt-Bu3)]2 (1, 1 mol%),
ArX (1.0 equiv)
O
O
Ar
R'
OR
OR
X = Br: LiNCy2, r.t.
R' R''
R''
X = Cl: NaHMDS, 100 °C
R = alkyl, aryl
R', R'' = alkyl, H
Pd(OAc)2, ligand,
O
O
Ar
NaOt-Bu, ArX (1.0 equiv)
R'
R
R
X = Br: PCy3, THF, r.t. to 60 °C
X = Cl: phosphoramidite, 1,4-dioxane, 100 °C
R''
R'
R''
Seminal work in Pd-catalysis was done by Hartwig and
co-workers who developed a variety of catalytic conditions
to access α-arylated carbonyl compounds. This includes the
transformation of ester,3 ketone,4 and amide3c,5 substrates
under relatively mild conditions using a number of different
Pd catalysts (Scheme 1). They utilized the labile bromide-
bridged Pd(I) dimer [Pd(μ-Br)(Pt-Bu3)]2 (1) as a pre-catalyst
to Pd(0).6 While the bromide-bridged Pd(I) dimer is air-
sensitive, its iodide analogue [Pd(μ-I)(Pt-Bu3)]2 (2) is com-
pletely stable towards oxygen as a solid and can be stored
This work: one catalyst system efficiently converts esters and ketones
1. LiTMP (1.2 equiv)
2. [Pd(μ-I)(Pt-Bu3)]2 (2, 1 mol%),
ArX (1.0 equiv)
O
O
Ar
α
R'
(O)R
(O)R
toluene, r.t., 4–18 h
R' R''
R''
• bench-stable catalyst
• high functional group tolerance
• X = I, Br; tolerates Cl, OTf (selective)
α/β > 95:5
R = alkoxy, aryl
R', R'' = alkyl
Scheme 1 Seminal work in Pd-catalyzed α-arylation and outline of this
work employing a bench-stable dinuclear Pd(I) catalyst
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–E

B
T. Sperger, F. Schoenebeck
Special Topic
Synthesis
We recently utilized the bench-stable Pd(I) iodo dimer 2
as a catalyst in a number of cross-coupling reactions9 in-
cluding the chemoselective arylation and alkylation of aryl
bromides (via Negishi or Kumada cross-coupling),8,10 Heck
cross-coupling of acrylates and styrenes11 as well as for the
introduction of pharmaceutically relevant SCF3 and SeCF3
functionalities.12 In this context, we showcased that the
Pd(I) dimer 2 can act as a competent catalyst directly via di-
nuclear catalysis cycles.13 We also elucidated the require-
ments to activate the Pd(I) iodo dimer to Pd(0) and showed
that activating nucleophiles require (i) a certain nucleophil-
ic strength and (ii) should not be capable of forming a stabi-
lizing μ-bridge between the Pd atoms.10
With the optimized reaction conditions in hand, we em-
barked on exploring the scope of the reaction (Scheme 2). A
number of different aryl iodides could be coupled success-
fully and selectively even in the presence of potentially re-
active functionalities, such as aryl chloride (5aj) and triflate
(5ag). Pharmaceutically and agrochemically important het-
erocycles could also be efficiently transformed, and substit-
uents were better tolerated in meta- or para-position to the
coupling site than ortho. While aryl iodides react smoothly
at ambient temperature with low catalyst loading of 1 mol%
in 4–18 hours the use of aryl bromides as cross-coupling
partners required prolonged reaction times of 24 hours and
a higher catalyst loading of 5 mol% for high yields.
While our previous studies showed that a nucleophilici-
ty of 10.5 on Mayr’s scale14 is necessary to convert Pd(I)
bromo dimer 1 to Pd(0), much higher nucleophilicities of
16.1 were necessary to afford this conversion for the more
stable iodide analogue 2.10 Therefore, we anticipated that
careful choice of the employed base/enolate nucleophile is
essential to allow for an efficient catalytic cycle. Hence, we
commenced our study with the search for an appropriate
base to form the Li-enolate (Table 1) for the reaction of
methyl isobutyrate (3a) with 3-fluoroiodobenzene (4a).
1. LiTMP (1.2 equiv)
2. [Pd(μ-I)(Pt-Bu3)]2 (2; 1 mol%),
ArI 4 (1.0 equiv)
O
O
Ar
α
OMe
OMe
toluene, r.t., 4–18 h
3a
5a(i)
F
OMe
O
TfO
O
O
OMe
OMe
OMe
5ag(iii)
m-F (5aa): 53%
m-OMe (5ad): 81%
o-OMe (5ae): 25%(ii)
p-OMe (5af): 80%
(X = I): 75%
(X = Br): 68%(ii)
(X = Cl): 0% (<5%)(ii)
o-F (5ab): 26% (91%)(ii)
p-F (5ac): 81%
Table 1 Optimization of Reaction Conditionsa
N
N
Cl
F
O
O
O
1. Libase (1.6 equiv)
2. [Pd(μ-I)(Pt-Bu3)]2 (2, 5 mol%),
3-fluoro-iodobenzene (4a, 1.0 equiv)
O
O
N
OMe
OMe
OMe
OMe
OMe
5ah: 72%
5ai: 83%
5aj: 85%
toluene, r.t., 4 h
3a
5aa
O
N
F3C
19F NMR yield (%)b Selectivity (α/β)b
O
O
O
S
Entry Catalyst (mol%) Base
OMe
OMe
OMe
1
2
3
4
2 (5)
2 (5)
2 (5)
2 (5)
LiTMP
LiNCy2
LiHMDS
–
84
58
29
33:1
29:1
0.8:1c
n.d.
5ak: 46%
5al: 60%
5am: 88%
Scheme 2 Scope of aryl halides 4 in the arylation of methyl isobutyr-
ate (3a). Reagents and conditions: (i) methyl isobutyrate (3a; 0.48
mmol), LiTMP (0.48 mmol), aryl iodide 4 (0.40 mmol), Pd catalyst 2 (1
mol%, 0.004 mmol) in toluene (2.0 mL). Isolated yields are given. Val-
ues in parentheses refer to conversions determined by GC-MS; (ii) reac-
tion was conducted using Pd catalyst 2 (5 mol%) and prolonged
reaction time of 24 h; (iii) reaction was conducted using 4-halophenyl
triflate (X = I, Br, Cl).
0d
a Reactions were conducted using Pd(I) iodo dimer 2 (5 mol%), Li-base
(0.64 mmol), methyl isobutyrate (3a; 0.64 mmol), and 3-fluoroiodoben-
zene (4a; 0.4 mmol) in toluene (2 mL) at r.t.
b Yield and selectivity determined by quantitative 19F NMR after 4 h using
α,α,α-trifluorotoluene as an internal standard.
c Multiple species were detected in 19F NMR spectrum.
d Conversion after 24 h, determined by GC-MS.
Of the different tested Li-bases, the sterically more hin-
dered lithium 2,2,6,6-tetramethylpiperidide (LiTMP, Table
1, entry 1) afforded the product 5aa in good yield and selec-
tivity. The less bulky lithium dicyclohexylamide (LiNCy2,
entry 2) was not as efficient and lithium bis(trimethylsi-
lyl)amide (LiHMDS, entry 3) afforded a mixture of different
coupling products. Using LiTMP allowed for a decrease of
the amount of enolate from 1.6 equivalents to 1.2 equiva-
lents. Moreover, the catalyst loading could be lowered to 1
mol% without compromising the yield.
Notably, the developed protocol is also compatible with
various different α,α-disubstituted carbonyl compounds,
such as spirocycles 5ba and 5ca as well as indanone 5da
(Scheme 3). In particular, cyclopropyl ketones such as 5ca
are interesting pharmaceutical targets as they have been
shown to be present in a number of bioactive compounds.15
To the best of our knowledge, these medicinally privileged
building blocks have never been featured in α-arylations. As
such, the herein presented method is not only operationally
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–E

C
T. Sperger, F. Schoenebeck
Special Topic
Synthesis
simple (air-stable catalyst), but also more general in provid-
ing easy functionalization and access to new libraries of ac-
tive compounds.
namely activating C–I and C–Br over C–Cl and C–OTf, as
shown above. Given the change in reactivity, a difference in
mechanisms and/or active catalytic species also seems likely.16
While the Pd(I) iodo dimer catalyst system itself is very
robust and would not require an inert atmosphere,8 the Li-
enolate coupling partner decomposes within minutes in air.
However, test experiments have shown that no rigorous in-
ert conditions are required, thus the reagents can be
weighed in air and the reaction performed using standard
Schlenk techniques without the necessity for a glovebox.
In summary, we have showcased the α-arylation of es-
ters and ketones employing a bench-stable dinuclear Pd(I)-
catalyst. The developed method provides access to quater-
nary carbon centers and high levels of α/β-selectivity. The
utilized dinuclear Pd(I) catalyst is easily synthesized in a
one-pot procedure, completely air-stable and thus facile to
handle, while allowing for low catalyst loadings and fast re-
action times. A wide range of functional groups are tolerat-
ed and allow for the chemoselective activation of aryl io-
dides and bromides over other potentially reactive func-
tionalities such as aryl chlorides and triflates. Moreover, the
presented method allows for easy access to pharmaceuti-
cally relevant biologically active α-arylated cyclopropyl ke-
tones.
F
1. LiTMP (1.2 equiv)
2. [Pd(μ-I)(Pt-Bu3)]2 (2, 1 mol%),
O
O
3-fluoro-iodobenzene (4a, 1.0 equiv)
R'
R
R
toluene, r.t., 4–18 h
R' R''
5(i)
R''
3
biologically
active
F
F
F
O
O
O
5ba: 91%
5ca: 64%
5da: 20% (82%)
Scheme 3 Scope of carbonyls 3 in the arylation with 3-fluoroiodoben-
zene 4a. Reagents and conditions: (i) carbonyl 3 (0.48 mmol), LiTMP
(0.48 mmol), 4a (0.40 mmol), Pd catalyst 2 (1 mol%, 0.004 mmol) in
toluene (2.0 mL). Isolated yields are given. Values in parentheses refer
to conversions determined by GC-MS.
To gain further insight into the mechanism of the reac-
tion, a series of control experiments were performed to ex-
plore the likely catalytically active species (Table 2).
Table 2 Test Experiments to Elucidate the Catalytically Active Speciesa
Starting materials are all commercially available and were used with-
out further purification. Toluene was degassed and dried using an In-
novative Technology PS-MD-5 solvent purification system. Solvents
used in workup and purification were distilled prior to use. Pd(I) iodo
dimer 2 was prepared from Pd2(dba)3, Pt-Bu3 and PdI2 according to
1. LiTMP (1.2 equiv)
TfO
O
2. Pd-catalyst (5 mol% Pd),
O
4-halophenyl triflate (4g, 1.0 equiv)
OMe
OMe
toluene, r.t., 4 h
3a
5ag
1
the literature procedure.12a All H, 13C, 19F, and 31P NMR spectra were
recorded on Varian VNMRS 600, Varian VNMRS 400, or Varian Mercu-
ry 300 spectrometer at ambient temperature. Chemical shifts (δ) are
reported in parts per million (ppm) and were referenced either to re-
sidual solvent peak (CDCl3; for 1H and 13C spectra), α,α,α-trifluorotol-
uene PhCF3 (δ = –63.70 ppm, added as an internal standard for 19F), or
trimethyl phosphate O=P(OMe)3 (δ = 3.05 ppm, added as an internal
standard for 31P). Coupling constants (J) are given in hertz (Hz). Gas
chromatography coupled with mass spectrometry (GC-MS) was per-
formed on an Agilent Technologies 5975 series MSD mass spectrome-
ter coupled with an Agilent Technologies 7820A gas chromatograph.
Preparative HPLC was performed on a Gilson-Abimed HPLC (employ-
ing UV detector model 117) using a Merck LiChrosorb Si60 column
(porosity 7 μm, 250 × 25 mm). High-resolution mass spectrometry
(HRMS) was performed using a Thermo Scientific LTQ Orbitrap XL
spectrometer. IR spectra were recorded on a Spectrum 100 spectro-
photometer with an UATR Diamond/KRS-5 crystal with attenuated
total reflectance (ATR).
Entry Pd catalyst
Conversion of 4g Conversion of 4g
(X = I) (X = Cl)
1
2
3
[Pd(μ-I)(Pt-Bu3)]2 (2, 2.5 mol%)
35 (96)
0 (<1)
[Pd(μ-Br)(Pt-Bu3)]2 (1, 2.5 mol%)
95 (96)
59 (61)
Pd2(dba)3 (2.5 mol%), Pt-Bu3
(5 mol%)
100 (100)
100 (100)
a Reactions were conducted using Pd catalyst (5 mol% Pd), LiTMP (0.48
mmol), methyl isobutyrate (3a; 0.48 mmol), and 4-halophenyl triflate 4g
(0.4 mmol, X = I or Cl) in toluene (2 mL) at r.t. Conversions were determined
by GC-MS after 1 h. Values in parentheses refer to conversions after 4 h.
Historically, labile dinuclear Pd(I) complexes, such as
the bromo dimer 1, found application as precatalysts to
Pd(0). To assess whether the Pd(I) iodo dimer 2 might func-
tion as a precatalyst or even catalyst itself, the reactivities of
potential active species were compared. First, using Pd(I)
bromo dimer as a catalyst led to the functionalization of
aryl chlorides (Table 2, entry 2). Similar reactivity is also
obtained when employing Pd2(dba)3 and phosphine ligand
Pt-Bu3 in a 1:1 ratio of Pd:L (entry 3), which is generally as-
sumed to lead to the same active species as Pd(I) bromo di-
mer. In contrast, using Pd(I) iodo dimer 2 as a catalyst is dis-
tinct in not functionalizing the C–Cl bond (entry 1), thus re-
inforcing its selectivity in poly(pseudo)halogenated arenes,
The analytical and spectral data of six representative α-arylated prod-
ucts are listed below. The data for the remaining ten products are pro-
vided in the Supporting Information.
Enolate α-Arylation Reactions; General Procedure
Inside a glovebox, lithium 2,2,6,6-tetramethylpiperidide (LiTMP, 70.7
mg, 0.48 mmol, 1.2 equiv) was dissolved in toluene (1.5 mL) and car-
bonyl compound 3 (0.48 mmol, 1.2 equiv) was added. After stirring
for 15 min at r.t., a solution of Pd(I) iodo dimer 2 (3.5 mg, 0.004 mmol,
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–E

D
T. Sperger, F. Schoenebeck
Special Topic
Synthesis
1 mol%) and aryl halide (iodide or bromide, 0.4 mmol, 1.0 equiv) in
toluene (0.5 mL) was added. After 15 h of further stirring at r.t., the
crude reaction mixture was directly adsorbed onto silica gel and puri-
fied by flash column chromatography.
MS (EI): m/z (%) = 244 (5), 243 (28, [M+]), 185 (15), 184 (100), 169
(12), 168 (11), 167 (7), 156 (12), 143 (6), 141 (5), 115 (10), 78 (7).
HRMS (ESI): m/z [M + Na]+ calcd for C15H17NO2Na: 266.1152; found:
266.1151.
Methyl 2-Methyl-2-(4-{[(trifluoromethyl)sulfonyl]oxy}phe-
nyl)propanoate (5ag)
Methyl 2-Methyl-2-(4-morpholinophenyl)propanoate (5al)
The title compound was obtained according to the general procedure
from methyl isobutyrate (3a) and 4-(4-iodophenyl)morpholine (4l).
The crude mixture was purified by column chromatography [hex-
ane/EtOAc 5:1; Rf = 0.19 (hexane/EtOAc 5:1)] to afford the product as
a white solid in 60% yield (63.1 mg, 0.240 mmol); mp 53–54 °C.
The title compound was obtained according to the general procedure
from methyl isobutyrate (3a) and either 4-iodophenyl triflate or 4-
bromophenyl triflate (4g) using 5 mol% catalyst. The crude mixture
was purified by column chromatography [hexane/EtOAc 20:1; Rf =
0.30 (hexane/EtOAc 20:1)] to afford the product as a yellow oil in 75%
(97.3 mg, 0.298 mmol) and 68% yield (88.9 mg, 0.272 mmol) from
aryl iodide and bromide, respectively.
IR (neat): 2965, 2855, 1720, 1613, 1514, 1451, 1379, 1241, 1117, 926,
816, 770 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.29–7.18 (m, 2 H, ArH), 6.93–6.78 (m,
2 H, ArH), 3.87–3.77 (m, 4 H, OCH2), 3.62 (s, 3 H, OCH3), 3.19–3.05 (m,
4 H, NCH2), 1.54 (s, 6 H, 2 × CH3).
13C NMR (101 MHz, CDCl3): δ = 177.5 (C=O), 149.9 (C), 136.1 (C), 126.5
(CH), 115.5 (CH), 67.0 (CH2), 52.2 (d, J = 2.7 Hz, C), 49.3 (CH2), 45.8
(OCH3), 26.6 (CH3).
MS (EI): m/z (%) = 263 (19, [M+]), 205 (15), 204 (100), 146 (12), 145
(3), 131 (4), 130 (4), 118 (6), 117 (4), 91 (3), 77 (3).
HRMS (ESI): m/z [M + H]+ calcd for C15H22NO3: 264.1594; found:
264.1595.
IR (neat): 2982, 1732, 1500, 1419, 1208, 1138, 1015, 886, 844, 784,
698 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 7.44–7.40 (m, 2 H, ArH), 7.24–7.20 (m,
2 H, ArH), 3.66 (s, 3 H, OCH3), 1.58 (s, 6 H, 2 × CH3).
13C NMR (151 MHz, CDCl3): δ = 176.5 (C=O), 148.3 (C), 145.2 (C), 127.9
(CH), 121.3 (CH), 118.8 (q, J = 320.7 Hz, CF3), 52.5 (d, J = 2.0 Hz, C),
46.4 (OCH3), 26.6 (CH3).
19F NMR (564 MHz, CDCl3): δ = –72.98 (s, 3 F, SO2CF3).
MS (EI): m/z (%) = 326 (4, [M+]), 269 (6), 268 (12), 267 (100), 175 (13),
134 (10), 106 (6), 91 (10), 77 (3), 69 (6).
HRMS (ESI): m/z [M + Na]+ calcd for C12H13F3O5SNa: 349.0328; found:
349.0327.
[1-(3-Fluorophenyl)cyclobutyl](phenyl)methanone (5ba)
The title compound was obtained according to the general procedure
from cyclobutyl phenyl ketone (3b) and 3-fluoroiodobenzene (4a).
The crude mixture was purified by column chromatography [hex-
ane/EtOAc 20:1; Rf = 0.41 (hexane/EtOAc 15:1)] and preparative HPLC
(pentane/EtOAc 9:1) to afford the product as a colorless oil in 91%
yield (92.6 mg, 0.364 mmol).
Methyl 2-Methyl-2-(pyrazin-2-yl)propanoate (5ah)
The title compound was obtained according to the general procedure
from methyl isobutyrate (3a) and 2-iodopyrazine (4h). The crude
mixture was purified by column chromatography [(hexane/EtOAc
3:1; Rf = 0.29 (hexane/EtOAc 3:1)] to afford the product as a colorless
oil in 73% yield (52.8 mg, 0.293 mmol).
IR (neat): 3065, 2950, 2871, 1674, 1587, 1483, 1440, 1252, 1171, 927,
861, 783, 696 cm–1
.
IR (neat): 2985, 1734, 1527, 1467, 1397, 1256, 1120, 1015, 850, 771,
1H NMR (400 MHz, CDCl3): δ = 7.75–7.67 (m, 2 H, ArH), 7.45–7.37 (m,
1 H, ArH), 7.35–7.27 (m, 3 H, ArH), 7.19–7.11 (m, 2 H, ArH), 6.95–6.86
(m, 1 H, ArH), 3.02–2.87 (m, 2 H, 2 CHH′), 2.61–2.47 (m, 2 H, 2 CHH′),
2.15–2.00 (m, 1 H, CHH′), 2.01–1.84 (m, 1 H, CHH′).
676 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.61 (s, 1 H, ArH), 8.50 (br, 1 H, ArH),
8.44 (br, 1 H, ArH), 3.67 (s, 3 H, OCH3), 1.64 (s, 6 H, 2 × CH3).
13C NMR (101 MHz, CDCl3): δ = 175.9 (C=O), 159.2 (C), 143.6 (CH),
142.7 (CH), 142.4 (CH), 52.5 (C), 48.5 (OCH3), 25.4 (CH3).
MS (EI): m/z (%) = 180 (9, [M+]), 165 (7), 148 (12), 122 (9), 121 (100),
120 (17), 119 (21), 94 (5), 93 (18), 79 (6), 59 (6), 52 (8).
HRMS (ESI): m/z [M + H]+ calcd for C9H13N2O2: 181.0972; found:
181.0972.
13C NMR (101 MHz, CDCl3): δ = 200.6 (C=O), 163.4 (d, J = 246.3 Hz, C),
146.1 (d, J = 7.0 Hz, C), 134.1 (C), 132.6 (CH), 130.6 (d, J = 8.4 Hz, CH),
129.8 (CH), 128.4 (CH), 121.5 (d, J = 2.9 Hz, CH), 113.6 (d, J = 21.1 Hz,
CH), 112.9 (d, J = 21.9 Hz, CH), 57.1 (d, J = 1.9 Hz, C), 32.4 (CH2), 16.1
(CH2).
19F NMR (376 MHz, CDCl3): δ = –111.03 to –114.01 (m, 1 F, ArF).
MS (EI): m/z (%) = 254 (1, [M+]), 149 (8), 121 (8), 109 (7), 106 (8), 105
(100), 101 (6), 77 (24), 51 (5).
Methyl 2-[4-(1H-Pyrrol-1-yl)phenyl]-2-methylpropanoate (5ai)
HRMS (ESI): m/z [M + Na]+ calcd for C17H15FONa: 277.0999; found:
277.1000.
The title compound was obtained according to the general procedure
from methyl isobutyrate (3a) and 1-(4-iodophenyl)-1H-pyrrole (4i).
The crude mixture was purified by column chromatography [hex-
ane/EtOAc 20:1; Rf = 0.23 (hexane/EtOAc 20:1)] to afford the product
as an off-white low-melting solid in 83% yield (80.7 mg, 0.332 mmol).
1H NMR (400 MHz, CDCl3): δ = 7.43–7.31 (m, 4 H, ArH), 7.07 (dd,
J = 2.2, 2.2 Hz, 2 H, HetArH), 6.34 (dd, J = 2.1, 2.1 Hz, 2 H, HetArH), 3.68
(s, 3 H, OCH3), 1.61 (s, 6 H, 2 × CH3).
[1-(3-Fluorophenyl)cyclopropyl](phenyl)methanone (5ca)
The title compound was obtained according to the general procedure
from cyclopropyl phenyl ketone (3c) and 3-fluoroiodobenzene (4a).
The crude mixture was purified by column chromatography [hex-
ane/EtOAc 20:1; Rf = 0.39 (hexane/EtOAc 15:1)] and preparative HPLC
(pentane/EtOAc 95:5) to afford the product as a colorless oil in 64%
yield (61.7 mg, 0.257 mmol).
13C NMR (101 MHz, CDCl3): δ = 177.2 (C=O), 142.2 (C), 139.5 (C), 127.0
(CH), 120.6 (CH), 119.4 (CH), 110.5 (CH), 52.5 (C), 46.3 (OCH3), 26.7
(CH3).
IR (neat): 3066, 3014, 2328, 2095, 1818, 1672, 1586, 1487, 1439,
1299, 1197, 1034, 990, 925, 858, 782, 697 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–E

E
T. Sperger, F. Schoenebeck
Special Topic
Synthesis
1H NMR (400 MHz, CDCl3): δ = 7.80–7.72 (m, 2 H, ArH), 7.43–7.36 (m,
1 H, ArH), 7.33–7.25 (m, 2 H, ArH), 7.18 (ddd, J = 8.0, 8.0, 6.1 Hz, 1 H,
ArH), 6.97 (ddd, J = 7.8, 1.8, 0.9 Hz, 1 H, ArH), 6.90 (ddd, J = 10.1, 2.1,
2.1 Hz, 1 H, ArH), 6.85 (dddd, J = 8.4, 8.4, 2.5, 1.0 Hz, 1 H, ArH), 1.71–
1.65 (m, 2 H, 2 CHH′), 1.37–1.32 (m, 2 H, 2 CHH′).
(6) Proutière, F.; Aufiero, M.; Schoenebeck, F. J. Am. Chem. Soc.
2012, 134, 606.
(7) (a) Vilar, R.; Mingos, D. M. P.; Cardin, C. J. J. Chem. Soc., Dalton
Trans. 1996, 4313. (b) Colacot, T. Platinum Met. Rev. 2009, 53,
183.
(8) (a) Kalvet, I.; Magnin, G.; Schoenebeck, F. Angew. Chem. Int. Ed.
2017, 56, 1581. (b) Kalvet, I.; Sperger, T.; Scattolin, T.; Magnin,
G.; Schoenebeck, F. Angew. Chem. Int. Ed. 2017, 56, 7078.
(9) Sperger, T.; Sanhueza, I. A.; Schoenebeck, F. Acc. Chem. Res.
2016, 49, 1311.
13C NMR (101 MHz, CDCl3): δ = 199.6 (C=O), 163.0 (d, J = 246.3 Hz, C),
143.8 (d, J = 7.4 Hz, C), 136.8 (C), 132.3 (CH), 130.2 (d, J = 8.4 Hz, CH),
129.5 (CH), 128.2 (CH), 123.9 (d, J = 2.8 Hz, CH), 114.7 (d, J = 21.8 Hz,
CH), 113.7 (d, J = 21.0 Hz, CH), 35.0 (d, J = 1.8 Hz, C), 16.5 (CH2).
19F NMR (376 MHz, CDCl3): δ = –111.59 to –115.96 (m, 1 F, ArF).
MS (EI): m/z (%) = 241 (8), 240 (46, [M+]), 133 (10), 115 (5), 109 (5),
(10) Aufiero, M.; Scattolin, T.; Proutière, F.; Schoenebeck, F. Organo-
metallics 2015, 34, 5191.
106 (8), 105 (100), 77 (44), 51 (8).
HRMS (ESI): m/z [M + Na]+ calcd for C16H13FONa: 263.0843; found:
(11) Sperger, T.; Stirner, C. K.; Schoenebeck, F. Synthesis 2017, 49,
115.
(12) (a) Aufiero, M.; Sperger, T.; Tsang, A. S.; Schoenebeck, F. Angew.
Chem. Int. Ed. 2015, 54, 10322. (b) Yin, G.; Kalvet, I.;
Schoenebeck, F. Angew. Chem. Int. Ed. 2015, 54, 6809.
(13) (a) Bonney, K. J.; Proutiere, F.; Schoenebeck, F. Chem. Sci. 2013,
4, 4434. (b) Kalvet, I.; Bonney, K. J.; Schoenebeck, F. J. Org. Chem.
2014, 79, 12041.
(14) Mayr’s scale is based on the addition of nucleophiles to carbo-
cations and Michael acceptors; see: (a) Maji, B.; Stephenson, D.
S.; Mayr, H. ChemCatChem 2012, 4, 993. (b) Richter, D.; Mayr, H.
Angew. Chem. Int. Ed. 2009, 48, 1958. (c) Kempf, B.; Hampel, N.;
Ofial, A. R.; Mayr, H. Chem. Eur. J. 2003, 9, 2209.
263.0843.
Acknowledgment
We thank the RWTH Aachen University, the MIWF NRW, as well as
the Evonik Foundation (doctoral scholarship to T.S.) for financial sup-
port.
Supporting Information
(15) (a) Baumann, A. N.; Schüppel, F.; Eisold, M.; Kreppel, A.; de
Vivie-Riedle, R.; Didier, D. J. Org. Chem. 2018, 83, 4905. (b) Ries,
U. J.; Priepke, H. W. M.; Hauel, N. H.; Handschuh, S.; Mihm, G.;
Stassen, J. M.; Wienen, W.; Nar, H. Bioorg. Med. Chem. Lett. 2003,
13, 2297. (c) Peretto, I.; Radaelli, S.; Parini, C.; Zandi, M.;
Raveglia, L. F.; Dondio, G.; Fontanella, L.; Misiano, P.; Bigogno,
C.; Rizzi, A.; Riccardi, B.; Biscaioli, M.; Marchetti, S.; Puccini, P.;
Catinella, S.; Rondelli, I.; Cenacchi, V.; Bolzoni, P. T.; Caruso, P.;
Villetti, G.; Facchinetti, F.; Del Giudice, E.; Moretto, N.;
Imbimbo, B. P. J. Med. Chem. 2005, 48, 5705. (d) Qiao, J. X.; King,
S. R.; He, K.; Wong, P. C.; Rendina, A. R.; Luettgen, J. M.; Xin, B.;
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2009, 19, 462. (e) Vicker, N.; Su, X.; Pradaux-Caggiano, F.;
Potter, B. V. L. Patent PCT Int. Appl. WO2009106817 (A2), 2009.
(f) Bailey, S.; Barrett, S. D.; Bratton, L. D.; Fakhoury, S. A.;
Jennings, S. M.; Mitchell, L. H.; Raheja, R. K.;
Shanmugasundaram, V. Patent PCT Int. Appl. WO2007072164
(A2), 2007. (g) Li, J.; Kennedy, L. J.; Wang, H.; Li, J. J.; Walker, S. J.;
Hong, Z.; O’Connor, S. P.; Nayeem, A.; Camac, D. M.; Morin, P. E.;
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Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610087.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–E