Non-Directed Cross-Dehydrogenative (Hetero)arylation of Allylic C(sp3)?H bonds enabled by C?H Activation

Article abstract of DOI:10.1002/anie.201807047

Herein, we report the selective, non-directed and cross-dehydrogenative coupling of allylic C(sp³)?H bonds with C(sp²)?H bonds of (hetero)arenes. The methodology employs olefins and (hetero)arenes which are abundantly available chemical feedstocks, and could be applied in late-stage functionalization reactions of pharmaceuticals. Furthermore, the system exclusively delivers the allylic C?C coupling products highlighting the preservation of the olefin substitution pattern for further derivatization.

Full text of DOI:10.1002/anie.201807047

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Accepted Article
Title: Non-Directed Cross-Dehydrogenative (Hetero)arylation of Allylic
C(sp3)-H bonds enabled by C-H activation
Authors: Andreas Lerchen, Tobias Knecht, Maximilian Koy, Johannes
Bruno Ernst, Klaus Bergander, Constantin Daniliuc, and Frank
Glorius
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201807047
Angew. Chem. 10.1002/ange.201807047
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Non-Directed Cross-Dehydrogenative (Hetero)arylation of Allylic
C(sp3)–H bonds enabled by C–H activation
Andreas Lerchen, Tobias Knecht, Maximilian Koy, Johannes B. Ernst, Klaus Bergander, Constantin G.
Daniliuc, and Frank Glorius*
Dedicated to Professor Helmut Schwarz on the occasion of his 75th birthday
Abstract: Herein, we report the selective, non-directed and cross-
dehydrogenative coupling of allylic C(sp3)–H bonds with C(sp2)–H
bonds of (hetero)arenes. The developed methodology employs the
abundant chemical feedstocks of olefins and (hetero)arenes and
could be applied in late-stage functionalization reactions of
pharmaceuticals. Furthermore, the discovered system exclusively
delivers the allylic C–C coupling products highlighting the preservation
of the olefin substitution pattern for further derivatization.
literature.[8] However, the successful tackling of this desired
approach could be realized by the coupling of allylic C(sp3)–H
bonds with C(sp2)–H bonds of heteroarenes. Considering this
reaction design, a second challenge needs to solved: While for
instance the amination,[9] oxygenation[10] and alkylation[11] of allylic
C(sp3)–H bonds belong to established reactions in C–H activation
approaches (Scheme 1a) the allylic C(sp3)–H arylation is rarely
explored and strongly limited in applicability.[12] So far only pre-
functionalized (cyanoarenes/aryl-Grignards) or multifluorinated
arenes can be employed. Given the lack of reports adressing
these challenges by incorporating the selective coupling of
abundant and unfunctionalized starting materials, clearly
indicates the considerable need for research in this area.
The direct catalytic formation of C–C bonds through the selective
activation of a specific C(sp3)–H bond in organic molecules is an
elementary goal of synthetic chemists in the pursuit of generating
valuable and complex target molecules. To date, stoichiometric
directing groups (DGs) have been used to enable such
processes,[1] but the need to install and eliminate these DGs
results in an overall tenuous atom-economy.[2] Significant
improvements to this approach have been made by the groups of
Yu and Ge, who independently reported the use of catalytic
transient DGs.[3] However, the portfolio of reactions that avoid
permanently installed or transient DGs remains underrepresented.
Nevertheless, such challenging non-directed approaches are
highly attractive in medicinal and materials chemistry because of
their applicability in late-stage functionalization reactions.[4]
Analogous to removing DGs to improve atom- and step-economy,
the ideal (non-directed) coupling reaction should also not require
wasteful pre-functionalization of the coupling partner and utilize
only C–H bonds. However, there are other challenges associated
with such a cross-dehydrogenative coupling (CDC) approach.[5]
For example, the selectivity of a CDC reaction requires both the
coupling partner and substrate to undergo either a catalyst- or
substrate-controlled C–H activation event.[6] Furthermore, an
inversion of catalyst reactivity is typically necessary after the first
C–H activation event to prevent homo-coupling and to switch
selectivity to the other coupling partner.[7]
Scheme 1: Dehydrogenative coupling reactions. Cp*
=
1,2,3,4,5-
pentamethylcyclopentadienyl.
To achieve such a challenging reaction, the competing cross-
dehydrogenative Heck-type coupling of the arene C(sp2)–H bond
and the olefin C(sp2)–H bond that is also known as Fujiwara-
Moritani reaction needs to be overcome (Scheme 1b).[13]
Therefore, an effective catalyst-controlled differentiation in
between the activation of the allylic C(sp3)–H bond, the
heteroarene C(sp2)–H bond and the olefinic C(sp2)–H bond is
necessary. This means for our desired scenario that a catalyst is
needed which selectively activates the allylic C(sp3)–H bond first
(Scheme 1c). Then, a selective activation of the heteroarene
C(sp2)–H bond needs to be guaranteed at the electronically
activated site and therefore a dichotomous behavior of the
catalyst needs to be ensured. This means, that the activation of
the heteroarene is less favored by the initial catalyst, whereby a
high affinity is needed of the rhodium-allyl intermediate for the
heteroarene activation. In this way, complementary reactivity to
Considering the above, we envisaged a combined non-directed
CDC approach that solves two long-sought challenges. First, we
wanted to investigate the selective non-directed coupling of a
specific C(sp3)–H bond with a C(sp2)–H bond, that is enabled by
a transition-metal catalyzed C–H activation approach. To the best
of our knowledge this type of coupling is rarely explored in the
[*]
A. Lerchen, T. Knecht, M. Koy, Dr. J. B. Ernst, Dr. K. Bergander, Dr.
C. G. Daniliuc, Prof. Dr. F. Glorius
Organisch-Chemisches Institut
Westfälische Wilhelms-Universität Münster
Corrensstrasse 40, 48149 Münster (Germany)
E-mail: glorius@uni-muenster.de
Supporting information for this article is given via a link at the end of
the document.
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previously reported dehydrogenative Heck-type reactions can be
achieved.
excellent yield, demonstrating a broad functional group tolerance.
Moreover, a C2-alkylated thiophene was also well tolerated under
the reaction conditions (3ak). For thiophenes bearing an aryl
substituent at the C3-position we were able to promote either
mono-substitution at the C2-position (3al, 3an) or di-substitution
at both the C2- and C5-position (3am, 3ao). Additionally, the furan
and the thiophene bearing an estrone moiety at the C2-position,
reacted with the standard substrate in moderate yield (3ap, 3aq).
Next, other heteroarenes were investigated (Scheme 2b).
Arylated and alkylated furans all delivered the corresponding
products in moderate to high yield (3ba–3bd). Pleasingly, aza-
heterocycles could also be readily functionalized under the
reaction conditions (3be–3bg). Whilst, benzofuran was primarily
functionalized in the C2-position (3bh), benzothiophene afforded
the corresponding product with a 1:1 selectivity for the C2:C3
positions (3bi). Finally, 1,3,5-trimethoxybenzene could also be
reacted to afford the corresponding product (3bj).
To begin our studies towards this goal, we selected [Cp*RhCl2]2
as catalyst of choice as this catalyst has already shown reactivity
in all of the above activation scenarios.[14] Next, after brief
optimization studies (see the Supporting Information) we selected
to use (E)-prop-1-ene-1,3-diyldibenzene as a substrate for allylic
C(sp3)–H bond activation to obviate selectivity and potential
homo-coupling issues and arylated thiophenes were chosen as
coupling partners. Then, we investigated the scope (Scheme 2a),
which revealed that several 2-aryl substituted thiophenes could
be tolerated and did not influence the selectivity (3aa–3ad).
Additionally, compound 3ac was unambiguously confirmed by X-
ray crystallographic analysis (see the Supporting Information).
Thiophenes bearing electron-withdrawing (3ae, 3af, 3ah, 3ai) or
electron-donating substituents (3ag, 3aj) were then examined,
which all afforded reliably the desired products in good to
Scheme 2: Substrate scope of the cross-dehydrogenative (hetero)arylation of allylic C(sp3)–H bonds. General conditions: 2 (0.2 mmol), 1 (1.50 equiv), [Cp*RhCl2]2
(5 mol%), AgBF4 (20 mol%), AgOAc (2.20 equiv) in 1,2-dichloroethane (1.0 mL) were used. (a) 1 (0.2 mmol) and 2 (4.00 equiv) were used. (b) 1 (4.00 equiv),
2 (0.2 mmol) and AgOAc (4.40 equiv) were used. (c) Reaction was stirred for 48 hours. (d) 1 (2.00 equiv) were used. (e) 1 (4.00 equiv) were used. (f) Reaction was run
at room temperature. DCE = 1,2-dichloroethane, Boc = tert-butyloxycarbonyl, Ac = Acetyl.
Furthermore, a variety of internal olefins were tested under the
optimized conditions (Scheme 2c). Trans-β-alkyl styrenes, all
underwent selective heteroarylation at the allylic C(sp3)–H bond
and the styrenyl-moiety remained untouched (3ca–3cd). Then,
the internal olefins 4-octene and 5-decene were tested, which
both delivered the corresponding heteroarylation products as 1:1
regioisomers (3ce, 3cf). However, the unsymmetrical internal
olefin 2-pentene delivered the desired product as a single
regioisomer (3cg), indicating that the catalyst favors the formation
of an internal rhodium-allyl species versus the terminal.
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Afterwards, allylbenzene was employed as an example for
terminal alkenes and coupled with each, benzothiophene as well
as 5-fluorobenzothiophene to afford the corresponding linear
functionalized products in moderate yield (3ci, 3cj). Next,
allylbenzene was reacted with 2-pentylfuran and the coupling
product 3ck was isolated in 46% yield. However, in this reaction
a regioisomeric mixture of 1.9:1 was obtained while the branched
functionalization was favored over the linear. A similar result was
observed when 2-(p-tolyl)thiophene and 2-allylnaphthalene were
reacted. Under the optimized conditions the corresponding
product 3ch was isolated in 41% as a mixture of regioisomers
(1.5:1 branched/linear).
Recently, the use of naturally occurring carboxylic acids in
decarboxylative olefination reactions has received significant
attention from the chemical community.[15] The highly
functionalized products resulting from those reactions generally
bear an allylic C(sp3)–H bond adjacent to the olefin. Therefore, we
wanted to investigate whether our developed methodology could
be employed for further functionalization of those motifs
(Scheme 2d). Indeed, acetyl-protected lithocholic acid could be
coupled with 4-methoxystyrene and the resulting olefin could be
derivatized with 2-(m-tolyl)thiophene at the allylic C(sp3)–H
position in 65% (3da). In a similar manner, acetyl-protected
aleuritic acid could be employed and the corresponding product
3db was isolated in 68% yield. Finally, stearic acid was coupled
first with styrene and further derivatization with 2-(m-
tolyl)thiophene delivered 3dc in high yield. Moreover, the furan
substituted at the C2-position with an estrone unit could also be
reacted with an olefin arising from stearic acid and the desired
product was obtained in 53% yield (3dd).
reason, either allylbenzene or trans-β-methylstyrene were
reacted together with benzothiophene under the general reaction
conditions and both reactions delivered exactly the same
products with identical selectivity (3ci-I, 3ci-II). Based on these
results two crucial hypotheses can be postulated: first, a Heck-
type carbometalation pathway can be excluded[12b] and therefore
second, the generation of either a η3-π-allyl, a η3-σ-allyl or a
η1-σ-allyl species can be proposed in the reaction medium
(Scheme 4b).[16] Although it is known that these species can
undergo a σ-π-σ-isomerization[16,17] we then attempted to isolate
one of these proposed intermediates. Pleasingly, we were indeed
successful in isolating a Rh-π-allyl complex (3fa) from C–H
activation conditions when 2-allylnaphthalene was employed
(Scheme 4c). The solid-state structure of the complex was
confirmed by X-Ray crystallography showing that a η3-π-allyl-
complex was obtained.[18] Then, the reactivity of this rhodium-η3-
π-allyl complex (3fa) was investigated in a stoichiometric
experiment. The branched product of the arylated
allylnaphthalene (3ce), that is supposed to be the major isomer in
its corresponding catalytic reaction, was exclusively observed by
NMR-spectroscopy, suggesting that a rhodium-π-allyl complex is
an active intermediate in this transformation. However, the
formation of the linear isomer was not observed. It could be
reasoned that the η3-π-allyl-intermediate is not the most reactive
species that is generated in the catalytic medium. Even though a
η3-σ-allyl or a η1-σ-allyl species could be more reactive, we were
already able to demonstrate that the allylic moiety can be
isomerized by the catalyst (Scheme 4a). Considering a η3-π-allyl-
species is very likely to be an intermediate in this
σ-π-σ-isomerization process, we can therefore conclude that this
species is indeed present in the catalytic cycle.[17b]
To further establish the broad applicability of this protocol and
considering its potential applications in late-stage modification,
we sought to apply our methodology to pharmaceuticals
(Scheme 3). Ticlopidine, an antiplatelet drug, reacted with (E)-
prop-1-ene-1,3-diyldibenzene to form the desired product (3ea) in
69% yield and with >20:1 selectivity (C2:C3). Similar reactivity
was also obtained when using clopidrogel as substrate (3eb). To
our delight, the methyl-protected drug gemfibrozil bearing an
electron-rich arene scaffold also reacted in combination with
allylbenzene to afford the product (3ec) in modest yield.
Scheme 4: Mechanistic investigations.
Scheme 3: Late-stage functionalization of pharmaceuticals. General conditions:
2 (0.2 mmol) and 1 (1.50 equiv) were used. (a) 1 (2.00 equiv) were used.
Finally, we investigated the substrate-activation and the
subsequent coupling-selectivity of the Cp*Rh(III)-catalyst for the
heteroarenes, since the homo-coupling reactivity has already
been observed for this catalyst.[7c] When only benzofuran or
2(o-tolyl)thiophene were employed under the standard conditions,
To gain crucial mechanistic understanding of the developed
transformation, several experiments were conducted (Scheme 4).
First, we performed two independent reactions to investigate the
activation mechanism of the allylic moiety (Scheme 4a). For this
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the homo-coupling products (4a, 4b) were not observed (see the
Supporting Information). This result indicates that the homo-
coupling of the heteroarenes is less favored by the Cp*Rh(III)-
catalyst than the functionalization of the allylic moiety. Further
mechanistic investigations and the development of either racemic
or enantioselective Cp*Rh(III)-catalyzed allylic functionalization
reactions are on-going in our laboratory.
In summary, a new concept of methodology is developed for the
non-directed, selective and predictable cross-dehydrogenative
coupling of allylic C(sp3)–H bonds and (hetero)arene C(sp2)–H
bonds. This C–H activation methodology employs the abundant
chemical feedstocks of olefins and (hetero)arenes without the
need for pre-functionalization of both, substrate and coupling
partner. Moreover, the discovered system exclusively delivers the
allylic C–C coupling products preserving the substitution pattern
of the olefin. Additionally, we demonstrated the excellent
functional group tolerance of this mild reaction protocol and its
application in late-stage functionalization.
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Acknowledgements
We gratefully acknowledge the Deutsche Forschungs-
gemeinschaft (Leibniz Award) and the Fonds der Chemischen
Industrie (J.B.E) for financial support. We thank Dr. Michael J.
James, Mario Wiesenfeldt, and Dr. M. van Gemmeren for fruitful
discussions and we thank Steffen Greßies for technical support.
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Keywords: rhodium • cross-dehydrogenative coupling • CDC •
allylic arylation • heteroarenes
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Entry for the Table of Contents (Please choose one layout)
Layout 2:
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Andreas Lerchen, Tobias Knecht,
Maximilian Koy, Johannes B. Ernst,
Klaus Bergander, Constantin G.
Daniliuc, and Frank Glorius*
Page No. – Page No.
Non-Directed Cross-Dehydrogenative
(Hetero)arylation of Allylic C(sp3)–H
bonds enabled by C–H activation
Catch Desired Couplings: The non-directed cross-dehydrogenative coupling of
allylic C(sp3)–H bonds with (hetero)arene C(sp2)–H bonds is developed. This
desired approach is enabled by C–H activation and employs the abundant chemical
feedstocks of olefins and (hetero)arenes. A particular highlight of this mild reaction
protocol is the applicability in late-stage functionalization reactions. Moreover, the
discovered system exclusively delivers the allylic C–C coupling products preserving
the substitution pattern of the olefin.
This article is protected by copyright. All rights reserved.