CpRhIII-Catalyzed Allyl-Aryl Coupling of Olefins and Arylboron Reagents Enabled by C(sp3)-H Activation

Article abstract of DOI:10.1021/acscatal.8b04677

Herein, we present a mild CpRh^III-catalyzed Suzuki-Miyaura-type allyl-aryl coupling of readily accessible arylboron reagents with a broad range of olefins. Allylic arylation was achieved without the need for prefunctionalized alkenes, and the general Heck-type reactivity between olefins and arenes was not observed. Mechanistic studies indicate that the reaction was enabled through the fast generation of a Rh^III-allyl species via undirected C(sp³)-H activation. Moreover, the developed protocol was applied to the highly concise synthesis of the anti-inflammatory drug flurbiprofen.

Full text of DOI:10.1021/acscatal.8b04677

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Article
Cp*RhIII-Catalyzed Allyl–Aryl Coupling of Olefins and
Arylboron Reagents Enabled by C(sp3)–H Activation
Tobias Knecht, Tobias Pinkert, Toryn Dalton, Andreas Lerchen, and Frank Glorius
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b04677 • Publication Date (Web): 27 Dec 2018
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ACS Catalysis
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III
Cp*Rh -Catalyzed Allyl–Aryl Coupling of Olefins and
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Arylboron Reagents Enabled by C(sp )–H Activation
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‡
‡
Tobias Knecht, Tobias Pinkert, Toryn Dalton, Andreas Lerchen, and Frank Glorius*
Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Corrensstrasse 40, 48149 Münster, Germany
Supporting Information Placeholder
3
KEYWORDS C(sp )–H activation, rhodium, arylation, boroxines, allylic compounds
III
ABSTRACT: Herein, we present a mild Cp*Rh -catalyzed Suzuki-Miyaura-type allyl–aryl coupling of readily accessible arylboron
reagents with a broad range of olefins. Allylic arylation was achieved without the need for prefunctionalized alkenes and the general Heck-
type reactivity of olefins with arenes was not observed. Mechanistic studies indicate that the reaction was enabled through the fast generation
of a Rh -allyl species via undirected C(sp )–H activation. Moreover, the developed protocol was applied to the highly concise synthesis of
the anti-inflammatory drug flurbiprofen.
III
3
The Suzuki-Miyaura coupling is among the most commonly
applied organic transformations for the construction of aryl–aryl
bonds in organic synthesis. It has emerged as an indispensable
workhorse in agro- and pharmaceutical chemistry since it utilizes
bench stable, non-basic and broadly commercially available
arylboron compounds as nucleophilic reagents that can be coupled
A. Boron-Heck Reactivity
2
Well explored C(sp )-arylation without prefunctionalized olefins
H
TM, Oxidant
+
Ar BR2
R
Ar
R
1
reliably with a variety of electrophiles. Beyond arene cross-
coupling, organoboron compounds could be further applied to the
B. Substrate-Controlled Allylic Arylation
Prefunctionalized olefins enable formation of allyl metal species
arylation of olefins, also known as the boron Heck reaction
LG
Ar
2
(Scheme 1A).
Pd, Ir, Rh, Cu, Ni
+
Ar BR2
2
2
R
R
In contrast to the well explored C(sp )–C(sp ) bond forming
reactions, the Suzuki-Miyaura-type construction of C(sp )–C(sp )
bonds has been rarely described due to the tendency of alkyl–metal
species to undergo -hydride elimination. The arylation of allylic
sp -hybridized carbon atoms is among those coupling reactions of
particular interest since the alkyl metal complex is stabilized
through the isomerization to an allyl metal species and allylic
arylation generates a stereogenic sp -hybridized center while
preserving the olefin moiety. Thus, space for further
functionalization remains. However, achieving allylic arylation is
often difficult owing to the intrinsic Heck-type reactivity of olefins
2
3
LG = OAc, OPh, Br, etc...
3
C. This Work: Catalyst-Controlled Allylic Arylation via CH Activation
3
3
No prefunctionalized olefins: Direct arylation of allylic C(sp )H bonds
H
Cp*RhIII, Oxidant
Ar
+
Ar BR2
3
R
R
4
3
fast C(sp )-H activation
reductive elimination
2
in transition metal catalysis. Diverse approaches have been
Ar
Cp*
X
Cp*
transmetalation
investigated to allow allylic arylation utilizing arylboron reagents.
With the use of prefunctionalized olefins bearing suitable leaving
groups (LGs), such as halides, ethers or acetates in the allylic
position, the formation of metal–allyl species can be induced by the
Rh
Rh
+
Ar BR2
R
R
Scheme 1. Allylic vs. vinylic functionalization of olefins.
5
substrate (Scheme 1B). Therefore, typical Heck-reactivity of
With regard to the significant synthetic value of allyl groups and
inspired by Nakamura’s fundamental work on transition metal
olefins can be overridden and allylic arylation products can be
obtained instead. In addition, Sigman and coworkers elegantly
achieved the formation of products bearing arenes in the allylic
position through palladium-catalyzed hydroarylation of 1,3-dienes
using boronic esters. However, the Suzuki-Miyaura-type
construction of aryl–allyl bonds without the use of
prefunctionalized olefins remains elusive.
4a
catalyzed allylic arylation , we became motivated to develop a
mild and broadly applicable strategy for the formation of allylic
2
3
C(sp )–C(sp ) bonds that obviates the need of prefunctionalized
olefins which have to be prepared in multi-step procedures. Our
design aimed to enable the allylic coupling of the vast number of
commercially available arylboron reagents with the petrochemical
feedstock of terminal and internal olefins by using catalyst-
controlled allylic C–H activation instead of substrate-controlled
formation of allyl-metal species (Scheme 1C).
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III
III 9,10
Based on our experience, we envisaged that high valent Cp*Rh -
reaction using Cp*Rh .
To achieve the desired reactivity the
-
3
III
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catalysts (Cp*=C
5
Me
5
) might be capable to enable the direct
arylation of allylic C–H bonds since they have not only shown their
potential in allylic C–H activation reactions but also in the
arylation of C(sp )–H bonds utilizing organoboron reagents.
However, this transformation presents several intrinsic challenges:
i) The utilization of a transition metal (TM), a transmetalating
reagent, an olefin and an oxidant typically results in the formation
of Heck-type products. Additionally, a variety of transformations
C(sp )–H activation/Rh –allyl formation must be favoured over
arene transmetalation/migratory insertion (Scheme 1A); (ii) in
order to avoid the formation of large quantities of arene
homocoupling, the allylic arylation reaction must be faster than
7
3
8
2
2
twofold arene transmetalation/C(sp )–C(sp ) reductive elimination;
iii) the catalyst must distinguish between the formation of syn- and
anti--allyl species to guarantee
(
(
a
high degree of
2
diastereoselectivity.
has been described for the directing group assisted oxidative Heck
0
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9
0
[Cp*RhCl2]2 (5 mol%)
AgSbF6 (30 mol%)
AgOAc (3.0 equiv.)
R
R'
R
R'
+
(ArBO)3
H
DCE, 60 °C, 4 h
Ar
1
.0 equiv.
1.0 equiv.
1
2
3
Arene scope using internal olefinsa
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
F
F
Br
3ab
59%
E/Z: 8/1
CF3
O
O
Ph
3ag
CF3
O
O
3aa
0%
E/Z: 11/1
3ac
3ad
3ae
70%d
3af
62%
E/Z: >20/1
6
64% E/Z: 3/1
6% E/Z: >20:1b
3%c
76%
E/Z: 13/1
5
4
E/Z: 12/1
E/Z: 10/1
Et
nPr
Et
nPr
Et
nPr
Et
nPr
Et
nPr
Et
nPr
Et
nPr
F
F
F
O
F
O
O
3
ah
3ai
44%c
3aj
45%c
3ak
49%c
3al
68%c
3am
76%
3an
61%
1%c
5
E/Z: >20/1
E/Z: >20/1
E/Z: >20/1
E/Z: >12/1
E/Z: >20/1
E/Z: >20/1
E/Z: >20/1
Olefin scopee
O
O
O
Ar
O
O
H
nPent
7
O
O
5
5
Ar
H
Ar
Ar
Ar
3ba
3bb
3bc
3bd
50%
3be
76%
72%
77%
51%
E/Z: 20/1, b/l: 2/1
E/Z: >20/1, b/l: 2/1
E/Z: >20:1, b/l: 2/1
E/Z: >20/1, b/l: 3/1
E/Z: >20/1, b/l: 1/1
H
H
H
O
Ar
O
N
S
O
O
O
R
3
O
O
NH
Ar
O
3
bf, R=H, 77%, E/Z: 20/1, l/b: >20/1
bg, R=Ph, 93%, E/Z: 20/1, l/b:>20/1
Ar
6
3
Ar
O
Ar
6
3bh, R=F, 88%, E/Z: 20/1, l/b: >20/1
3
bk
3bl
50%
3bm
61%
E/Z: >20/1, b/l: 1/1
3bn
44%
E/Z: 1/1
3
bi, R=Ac, 57%, E/Z: 20/1, l/b: >20/1
bj, R=OTf, 65%, E/Z: 20/1, l/b: >20/1
54%d
3
E/Z: >20/1, b/l: 2/1
E/Z: >20:1, b/l: 2/1
ABC
III
Scheme 2. Scope of the Rh -catalyzed allylic arylation. Reactions performed on a 0.3 mmol scale in 1.5 mL of 1,2-dichloroethane (DCE).
a
Isolated yields are stated for isomeric mixtures unless otherwise noted. Products were obtained as a single regioisomer using (E)-2-pentene
b
c
and in a ~1.4:1 ratio using (E)-4-octene (see supporting information). AgO
2
Cnpent was used instead of AgOAc. 20 mol% AgSbF
6
was
d
1
e
used. Yield determined by H-NMR using 1,3,5-trimethoxybenzene as internal standard. Ar = 2-fluorobenzene; AgO
2
Cnpent was used
instead of AgOAc for all terminal olefins except allylarenes.
We began our studies using (E)-2-pentene as the substrate. The
catalyst would have to distinguish between the activation of the
internal versus the terminal C–H bonds. Additionally we were
arylated product in 72% GC- and 60% isolated yield, noting the
volatility of the product. The diastereoselectivity was determined
to be 11:1. Interestingly, with the use of the slightly more sterically
III
iPr
iPr
aware of the formation of syn- and an anti-Rh –allyl species
demanding
Cp -ligand
(Cp =isopropyl-tetramethyl-
possibly leading to (E)- or (Z)-isomers, respectively. 4-
Fluorophenylboronic acid was chosen to be the coupling partner
cyclopentadienyl) we could obtain 3aa in 60% yield and excellent
diastereoselectivity (>20:1 ) (see supporting information). With the
optimized reaction conditions in hand, we began to investigate the
scope using triarylboroxines, internal olefins as coupling partners
and the reaction was carried out with [Cp*RhCl
AgSbF (20 mol%) and AgOAc (2.0 equiv.) in DCE (0.2 M) at
0 °C (see Table S1, supporting information). Unfortunately, only
traces of homo-coupled arene and no desired product formation
3aa) were observed. Upon switching from the boronic acid to its
2 2
] (5.0 mol%),
6
6
2 2
and the commercially available [Cp*RhCl ] as the catalyst
(Scheme 2). The para substituted bromophenyl boroxine 2b
reacted smoothly to provide 3ab in 59% yield. A strongly electron-
withdrawing trifluoromethyl substituent gave a 64% yield of 3ac
with a poor diastereomeric ractio of 3:1. Intriguingly, by a simple
switch of the Ag-carboxylate from acetate to n-hexanoate we could
(
anhydride the tris(4-fluorophenyl)boroxine, we were delighted to
obtain product 3aa in 59% GC-yield. By a slight increase of the
oxidant to 3.0 equivalents and AgSbF to 30 mol% we obtained the
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ACS Catalysis
increase the diastereoselectivity to >20:1 (see supporting
ozonolysis and subsequent oxidative workup to yield 75% of
flurbiprofen in overall 3 straightforward steps (Scheme 3).
1
2
1
2
3
4
5
6
7
8
9
information). Other electron-withdrawing groups such as
trifluoromethoxy (2d), ester (2e) or formyl (2f) substituents in the
para or meta positions delivered the desired products in good yields
and moderate to excellent diastereoselectivies. We observed that
E/Z selectivities are dependent on the electronics of the arylboron
reagent and speculate that electron-rich arylboroxines tend to
undergo transmetalation faster than electron-poor arylboroxines,
thus leading to higher E/Z selectivities since the Rh-allyl species
has less time to isomerize. Notably, by switching from (E)-2-
A. KIE-Experiments
C7H15
C7H15
standard conditions
parallel experiment
C7H15 KIE = 1.1
or
H
H
D
D
Ar H/D
1d
1d-D2
3bo / 3bo-D
B. Deuterium-Scrambling
C H
4
9
4 9
C H
[
Cp*RhCl2]2 (5 mol%)
(ArBO)3 (1.0 equiv.)
AgSbF6 (30 mol%)
H
H
Ar
H
1
c / 1c-D
3bp / 3bp-D
C H
4
9
C H
[<1%]
[2%]
7
15 AgOAc (3.0 equiv.)
III
D D
(1.0 equiv.)
1d-D2
pentene to (E)-4-octene the Rh catalyst can hardly distinguish
DCE, 60 °C, 1h
C7H15
C7H15
(
1.0 equiv.)
1ci
D
1d-D2
D
Ar
D
between the reductive elimination in the 3- or 4- positions
delivering a roughly 1.4:1 regioisomeric ratio (see supporting
information). Triphenylboroxine (3ah) gave 51% product
formation and >20:1 diastereoselectivity using (E)-4-octene (1b) as
the coupling partner. Sterically more demanding tris(1-naphthyl)-
boroxine (2i) resulted in 44% product formation. Electron-donating
substituents such as tert-butyl (2j) or methoxy (2k) led to moderate
yields and excellent E/Z ratios. An ortho-fluoro substituted arene
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
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5
5
5
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0
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0
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9
0
1
2
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0
1
2
3
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0
1
2
3
4
5
6
7
8
9
0
3bo / 3bo-D
[
<1%]
[95%]
[
97%]
[95%]
C. Effect of Additives
[Rh], additive
yield
[
Rh] (10 mol%)
[Cp*RhCl2]2, AgSbF6
[Cp*RhCl ] , AgBF
[Cp*RhCl2]2, AgClO4
[Cp*RhCl2]2, NaSbF6
72%2
9%2
Additive (30 mol%)
AgOAc (3.0 equiv.)
Ar
2
2
4
(ArBO)3
37%2
52%2
68%
DCE, 60 °C, 4h
(1.0 equiv.) (1.0 equiv.)
1a
2a
3a
[Cp*Rh(OAc)2(H2O)], NaSbF6
(2m) led to 76% product formation. Multi-substituted arenes could
D. Reaction Kinetics
be also utilized and delivered 3ag and 3an in high yields. We
proceeded to evaluate the scope of the reaction using different
unactivated terminal olefins. Interestingly, even though we only
observed the internal arylation product using (E)-2-pentene we
were likewise able to functionalize a variety of terminal olefins. 1-
Octene could be arylated in 73% yield, excellent
diastereoselectivity and a 2:1 regiosiomeric ratio favouring the
branched product. The regioisomeric ratio could be inversed to 1:2
when a sterically less demanding tetramethylcyclopentadienyl
ligand was used (see supporting information). An olefin attached to
a methyl ester gave a similar result as 1-octene (3bb) and an
aliphatic aldehyde resulted in 50% product formation (3bd). A
lithocholic acid derivate delivered 76% of the corresponding
product (3be). Furthermore, a variety of allylarenes could be
functionalized. To our delight, exclusively linear products were
obtained with perfect diastereoselectivites and good to excellent
yields (3bf–3bj). We assume that the formation of linear products
is favoured owing to conjugation of the double bond. Product 3bm,
bearing the Probenecid drug scaffold, was obtained in 61% yield.
Additionally, we were able to obtain the arylated product derived
from phenylalanine (3bk) in 54% yield. Interestingly, cyclic olefins
could be used as substrates. Cyclododecene was converted to 3bn
in a moderate yield and a roughly 1:1 E/Z mixture. Selective
functionalization at the terminal olefin was obtained even when the
molecules contained a terminal-branched (3bc) or a cis double
bond (3bl).
[
Cp*Rh(OAc)2(H2O)] (10 mol%)
AgOAc (3.0 equiv.)
Ar
3bq
b) without addition of NaSbF6
(
ArBO)3
Ar Ar
DCE, 60 °C
(
1.0 equiv.)
(1.0 equiv.)
5
1b
2a
a) with addition of 30 mol% NaSbF6
E. Arene Homocoupling
[Cp*Rh(OAc) (H O)] (10 mol%)
2
2
kinit / [mol/(L•s)]
Additive
NaSbF6 (30 mol%)
AgOAc (3.0 equiv.)
1.74•10-5
2.14•10-6
no additive
NaSbF6
(ArBO)3
Ar Ar
DCE, 60 °C
2a
5
Scheme 4. Mechanism studies. Yields determined by GC-FID.
Deuterium incorporation indicated in square brackets; Ar = 4-
fluorophenyl. Structures of major isomers given.
We were intrigued by the reaction mechanism and started its
investigation by kinetic isotope effect (KIE) studies. In a parallel
experiment with deuterated and undeuterated 1-undecene (1d, 1d-
2
D ) no significant KIE was observed, suggesting that the C–H
activation is unlikely to be occurring during the rate limiting step
(Scheme 4A, for further details see supporting information).
OH
13
1
2
) O3, Aceton, -78°C
) Jones Oxidation
O
Subsequently deuterium scrambling experiments were conducted,
F
F
2
in which deuterated 1d-D and undeuterated 1c were submitted to
7
5%
4
the standard reaction conditions for just 1 h to prevent full
conversion of the olefins (Scheme 4B). Neither in the remaining
3ag
Flurbiprofen
starting materials (1c, 1d-D
2
) nor in the corresponding products
(
3bp, 3bo-D) were significant amounts of deuterium/hydrogen
Scheme 3. Concise synthesis of flurbiprofen.
-Arylpropionic acids are a highly important class of nonsteroidal
exchange detected. This is indicating that presumably either the
nature of the C–H activation step or the olefin coordination to the
metal center is irreversible under the reaction conditions. Low
coordinating silver salts are typically added in Rh -catalyzed C–H
activation protocols to guarantee fast halogen abstraction from the
2
anti-inflammatory drugs, however, the synthesis of -arylated
carboxylic acids is still synthetically challenging. By applying our
developed reaction protocol we were able to prepare flurbiprofen
III
1
1
in a highly concise synthetic sequence. Starting from the cheap
and commercially available boronic acid we prepared the boroxine
[
Cp*RhCl
reaction optimization we found that an increased AgSbF
from 20% to 30% led to higher yields even though 20% AgSbF
2
]
2
pre-catalyst rendering it more reactive. During the
6
loading
2
g quantitatively by refluxing under Dean-Stark conditions and
6
coupled it with E-2-pentene by our standard protocol. The
allylically arylated product 3ag was further converted by
should be sufficient to abstract all halogen ions. Subsequently, we
probed this effect by the addition of different additives (Scheme
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Page 4 of 6
4
C). By employing AgSbF
only 9% product was formed when AgBF
was observed by applying AgClO . We would expect the anion to
6
3a was obtained in 72% yield whereas
scientific discussions as well as Roman Kleinmans and Grete
Hoffmann for experimental support. We gratefully acknowledge
Dr. Klaus Bergander for NMR assistance.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
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4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
4
was used and 37% of 3a
4
exhibit minor or no effects if the role of the salt is limited to halogen
abstraction. Spurred by this observation we opted to determine if
the Ag -ion is indispensable for the reaction outcome. To our
REFERENCES
+
(1) (a) Miyaura, N.; Suzuki, M. Palladium-Catalyzed Cross-Coupling
6
surprise, with the addition of NaSbF we could obtain 3a in 52%
Reactions of Organoboron Compounds. Chem. Rev. 1995, 95, 2457–2483.
(b) Martin, R.; Buchwald, S. L. Palladium-Catalyzed Suzuki-Miyaura
Cross-Coupling Reactions Employing Dialkylbiaryl Phosphine Ligands.
Acc. Chem. Res. 2008, 41, 1461–1473. (c) Lennox, A. J. J.; Lloyd-Jones, G.
C. Selection of boron reagents for Suzuki–Miyaura coupling. Chem. Soc.
Rev. 2014, 43, 412-443.
(2) (a) Fagnou, K.; Lautens, M. Rhodium-Catalyzed Carbon−Carbon Bond
Forming Reactions of Organometallic Compounds. Chem. Rev. 2003, 103,
169–196. (b) Karimi, B.; Behzadnia, H.; Elhamifar, D.; Akhavan, P. F.;
Esfahani, F. K.; Zamani, A. Transition-Metal-Catalyzed Oxidative Heck
Reactions. Synthesis 2010, 9, 1399-1427. (c) Lee, A.-L. Enantioselective
oxidative boron Heck reactions. Org. Biomol. Chem. 2016, 14, 5357-5366.
(d) Delcamp, J. H.; Brucks, A. P.; White, M. C. A General and Highly
Selective Chelate-Controlled Intermolecular Oxidative Heck Reaction. J.
Am. Chem. Soc. 2008, 130, 11270–11271. (e) Werner, E. W.; Sigman, M.
S. A Highly Selective and General Palladium Catalyst for the Oxidative
Heck Reaction of Electronically Nonbiased Olefins. J. Am. Chem. Soc.
2010, 132, 13981–13983.
yield (Scheme 4C). When compared to our standard catalytic
III
system, the combination of a Cp*Rh acetate pre-catalyst and
NaSbF
6
led to an almost identical amount of product (68%).
is playing a bifunctional role,
Therefore, it is likely that AgSbF
6
guaranteeing a fast halogen abstraction owing to the weakly
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+
coordinated Ag and additionally facilitating the reaction. The
addition of non-coordinating anions can lead to ion pair partitioning
and thus forming a more cationic catalyst as it has been described
for palladium catalysed allylic substitution.14 We decided to record
reaction kinetics using [Cp*Rh(OAc)
and NaSbF as the additive to exclude influences of the halogen
abstraction (Scheme 4d, for a full reaction profile see supporting
information S3). With the addition of NaSbF (Scheme 4D-a)
2 2
(H O)] as the pre-catalyst
6
6
product formation is initially faster than arene homocoupling. With
a decreasing olefin concentration (1b) homocoupling (5) begins to
override cross-coupling (3bq) and similar amounts of both
products are formed after 2 h reaction time. In contrast, without the
(3) (a) Chemler, S. R.; Trauner, D.; Danishefsky, S. J. The B-Alkyl Suzuki–
Miyaura Cross-Coupling Reaction: Development, Mechanistic Study, and
Applications in Natural Product Synthesis. Angew. Chem. Int. Ed. 2001, 40,
4544–4568. (b) Rudolph, A.; Lautens, M. Secondary Alkyl Halides in
Transition‐Metal‐Catalyzed Cross‐Coupling Reactions. Angew. Chem. Int.
Ed. 2009, 48, 2656–2670. (c) Jana, R.; Pathak, T. P.; Sigman, M. S.
Advances in Transition Metal (Pd,Ni,Fe)-Catalyzed Cross-Coupling
Reactions Using Alkyl-organometallics as Reaction Partners. Chem. Rev.
addition of NaSbF
formed and homocoupling proceeded until triarylboroxine 2a was
consumed. The SbF –anion is presumably either decreasing the
6
only traces of cross-coupled product 3bq were
6
transmetalation rate, allowing the formation of Rh-allyl species that
can further react to the corresponding arylated products, or
accelerating the allylic C–H activation. Investigation of the initial
rates of the arene homocoupling revealed that the addition of
2
011, 111, 1417–1492. (d) Choi, J.; Fu, G. C. Transition metal–catalyzed
alkyl-alkyl bond formation: Another dimension in cross-coupling
chemistry. Science 2017, 356, 152–160.
NaSbF
Similar results were obtained with [Cp*RhCl
with AgBF /AgSbF (see supporting information). Thus, we
6
tremendously slows down the reaction (Scheme 4E).
2 2
]
in combination
(4) (a) Sekine, M.; Illies, L.; Nakamura, E. Iron-Catalyzed Allylic Arylation
4
6
3
of Olefins via C(sp )–H Activation under Mild Conditions. Org.
Lett. 2013, 15, 714–717. (b) Cuthbertson, J. D.; MacMillan, D. W. C. The
direct arylation of allylic sp C–H bonds via organic and photoredox
catalysis. Nature 2015, 519, 74–77. (c) Huang, L.; Rueping, M. Direct
Cross-Coupling of Allylic C(sp )–H Bonds with Aryl- and Vinylbromides
assume that allylic arylation is enabled when C–H activation is
maintained faster than transmetalation.
3
In conclusion we have developed the first Suzuki-Miyaura-type
allylic coupling of unactivated terminal and internal olefins with
both electron-rich and -deficient arylboroxines. Further, the
reaction could be applied to the efficient synthesis of the anti-
inflammatory drug flurbiprofen. Mechanistic investigations were
3
by Combined Nickel and Visible-Light Catalysis. Angew. Chem. Int. Ed.
2
018, 57, 10333–10337.
(5) (a) Pigge, F. C. Metal-Catalyzed Allylation of Organoboranes and
Organoboronic Acids. Synthesis 2010, 11, 1745–1762. (b) Miura, T.;
Takahashi, Y.; Murakami, M. Rhodium-catalysed substitutive arylation of
cis-allylic diols with arylboroxines. Chem. Commun. 2007, 595–597. (c)
Nishikata, T.; Lipshutz, B. H. Allylic Ethers as Educts for Suzuki−Miyaura
Couplings in Water at Room Temperature. J. Am. Chem. Soc. 2009, 131,
12103–12105. (d) Ohmiya, H.; Makida, Y.; Li, D.; Tanabe, M.; Sawamura,
M. Palladium-Catalyzed γ-Selective and Stereospecific Allyl−Aryl
Coupling between Acyclic Allylic Esters and Arylboronic Acids. J. Am.
Chem. Soc. 2010, 132¸879–889. (d) Sidera, M.; Fletcher, S. P. Rhodium-
catalysed asymmetric allylic arylation of racemic halides with arylboronic
acids. Nat. Chem. 2015, 7, 935–939. (e) Nallasivam, J. K.; Fernandes, R. A.
Pd-Catalyzed Site-Selective Mono-allylic Substitution and Bis-arylation by
Directed Allylic C–H Activation: Synthesis of anti-γ-(Aryl,Styryl)-β-
hydroxy Acids and Highly Substituted Tetrahydrofurans. J. Am. Chem. Soc.
conducted to give insights into the reaction mechanism and an
-
unexpected role of the SbF
6
counter-ion was observed.
AUTHOR INFORMATION
Corresponding Author
*E-mail: glorius@uni-muenster.de
Author Contributions
‡
These authors contributed equally.
Notes
2
016, 138, 13238–13245. (f) Schäfer, M.; Palacin, T.; Sidera, M.; Fletcher,
The authors declare no competing financial interest.
S. P. Asymmetric Suzuki-Miyaura coupling of heterocycles via Rhodium-
catalysed allylic arylation of racemates. Nat. Commun. 2017, 8, 15762–
15770.
(6) Liao, L.; Sigman, M. S. Palladium-Catalyzed Hydroarylation of 1,3-
Dienes with Boronic Esters via Reductive Formation of π-Allyl Palladium
Intermediates under Oxidative Conditions. J. Am. Chem. Soc. 2010, 132,
ASSOCIATED CONTENT
Supporting Information. Experimental procedures and
spectroscopic data. This material is available free of charge via the
Internet at http://pubs.acs.org website at DOI:
1
0209–10211.
(7) (a) Rakshit, S.; Patureau, F. W.; Glorius, F. Pyrrole Synthesis via Allylic
ACKNOWLEDGMENT
3
sp C−H Activation of Enamines Followed by Intermolecular Coupling
We thank the Deutsche Forschungsgemeinschaft (SFB 858,
Leibniz Award) for generous financial support. We are grateful to
Felix Klauck, Steffen Greßies and Michael Teders for helpful
with Unactivated Alkynes J. Am. Chem. Soc. 2010, 132, 9585–9587. (b)
Cochet, T.; Bellosta, V.; Roche, D.; Ortholand, J.-Y.; Greiner, A.; Cossy, J.
Rhodium(III)-catalyzed allylic C–H bond amination. Synthesis of cyclic
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amines from -unsaturated N-sulfonylamines. Chem. Commun. 2012, 48,
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Murray, P.; Guy Orpen, A.; Osborne, R.; Owen-Smith, G. J. J.; Purdie, M.
Counterintuitive Kinetics in Tsuji-Trost Allylation: Ion-Pair Partitioning
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2
3
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10745–10747. (c) Archambeau, A.; Rovis, T. Rhodium(III)‐Catalyzed
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Allylic C(sp )–H Activation of Alkenyl Sulfonamides: Unexpected
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Ernst, J. B.; Bergander, K.; Daniliuc, C.; Glorius, F. Non-Directed Cross-
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Dehydrogenative (Hetero)arylation of Allylic C(sp )–H bonds enabled by
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C–H Activation. Angew. Chem. Int. Ed. 2018, 57, 15248. (g) Nelson, T. A.
F.; Blakey, S. B. Intermolecular Allylic C−H Etherification of Internal
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8) Wang, X.; Yu, D.-G.; Glorius, F. Cp*Rh -Catalyzed Arylation of
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C(sp )–H Bonds. Angew. Chem. Int. Ed. 2015, 54, 10280–10283.
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Coupling of Aromatic Substrates with Alkynes and Alkenes under Rhodium
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Li, X. C–C, C–O and C–N bond formation via rhodium(III)-catalyzed
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Cp*Rh-Catalyzed C–H Activations: Versatile Dehydrogenative Cross-
Couplings of Csp2 C–H Positions with Olefins, Alkynes, and Arenes.
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Formal
N
S -Type Reactions in Rhodium(III)-Catalyzed C–H Bond
Activation. Adv. Synth. Catal. 2014, 356, 1443–1460. (g) Song, G.; Li, X.
Substrate Activation Strategies in Rhodium(III)-Catalyzed Selective
Functionalization of Arenes. Acc. Chem. Res. 2015, 48, 1007–1020. (h) Ye,
B.; Cramer, N. Chiral Cyclopentadienyls: Enabling Ligands for
Asymmetric Rh(III)-Catalyzed C–H Functionalizations. Acc. Chem. Res.
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Vinylation of Unactivated Acetanilides. J. Am. Chem. Soc. 2010, 132, 9982-
9983. (b) Tsai, A. S.; Brasse, M.; Bergman, R. G.; Ellman, J. A. Rh(III)-
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Ph
F
O
B
H
Ar
Cp*RhIII
Application:
1 step
+ R
3
R = Me
R
Ar
O
R
R
R
OH
Flurbiprofen
3
+
+
Undirected C(sp )H Activation
Mild and Versatile Allylic Arylation
+ Substrates Readily Available
+ Highly Important Product Motifs
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