NHC-Organocatalyzed CAr?O Bond Cleavage: Mild Access to 2-Hydroxybenzophenones

Article abstract of DOI:10.1002/anie.201610203

A Truce–Smiles rearrangement of acyl-anion equivalents generated by N-heterocyclic carbene (NHC) catalysis has been achieved. The developed method includes C_Ar?O, C_Ar?S, or C_Ar?N bond cleavage for the formation of a C_Ar?C bond and enables access to 2-hydroxybenzophenones, an important structural motif that is present in several bioactive natural products. By utilizing this procedure, the alkaloid taxilamine was synthesized in three steps. DFT calculations and control experiments support a classical S_NAr mechanism with a catalyst-bound Meisenheimer-type intermediate. The method features mild reaction conditions, excellent functional-group tolerance, and a broad substrate scope, including various classes of (hetero)arenes.

Full text of DOI:10.1002/anie.201610203

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201610203
German Edition: DOI: 10.1002/ange.201610203
Organocatalysis
Hot Paper
À
NHC-Organocatalyzed CAr O Bond Cleavage: Mild Access to
2-Hydroxybenzophenones
Daniel Janssen-Mꢀller+, Santanu Singha+, Fabian Lied, Karin Gottschalk, and Frank Glorius*
Dedicated to Professor Ronald Breslow on the occasion of his 85th birthday
Abstract: A Truce–Smiles rearrangement of acyl-anion equiv-
alents generated by N-heterocyclic carbene (NHC) catalysis
À
has been achieved. The developed method includes CAr O,
À
À
À
C
CAr S, or CAr N bond cleavage for the formation of a CAr
bond and enables access to 2-hydroxybenzophenones, an
important structural motif that is present in several bioactive
natural products. By utilizing this procedure, the alkaloid
taxilamine was synthesized in three steps. DFT calculations
and control experiments support a classical SNAr mechanism
with a catalyst-bound Meisenheimer-type intermediate. The
method features mild reaction conditions, excellent functional-
group tolerance, and a broad substrate scope, including various
classes of (hetero)arenes.
À
C
atalytic CAr O bond cleavage represents a difficult, but
emerging field that has a great impact on the sustainable use
of renewable chemical feedstocks, since these are rich in
hydroxy, ether, or ester groups. The field is dominated by
homogeneous nickel(0) catalysis for oxidative addition to
a range of CAr O bonds,[1] which has enabled several coupling
À
reactions to be developed and is especially useful with
unactivated, easily accessible substrates such as phenyl
esters and anisoles.[2]
À
À
Scheme 1. CAr O bond cleavage leads to aryl migration and C H
functionalization of the parent aldehyde.
An interesting, but underdeveloped example of an SNAr
À
reaction capable of cleaving CAr O bonds is the Truce–Smiles
rearrangement, a variation of the more general Smiles
À
rearrangement. The intramolecular substitution of a CAr
electronic activation of the arene because of the strength of
the employed carbon nucleophile. One drawback of this
reaction is normally the strong base required for generation of
the carbanion, such as BuLi or KOtBu, which results in harsh
reaction conditions. A catalytic method to generate the
required carbanion without the need for a strong base would
be highly desirable and could result in robust, mild, and more
economic reaction procedures. Pioneering work in 2011 by
Rao and Li on a rhodium-catalyzed Truce–Smiles rearrange-
ment involves an intramolecular SNAr reaction of an acyl-
rhodium species: Unfortunately, the novel procedure requires
10 mol% of the expensive rhodium catalyst, excess peroxide
oxidant, and the reported reaction temperature is 1608C, thus
making this transformation impractical.[5]
NHC organocatalysis has proven to be a reliable tool to
generate carbon nucleophiles.[6] Umpolung of aldehyde sub-
strates to provide an acyl-anion equivalent has led to several
important transformations, including the benzoin condensa-
tion,[7] Stetter reaction,[8] and hydroacylation of electron-
neutral and, more recently, electron-rich and heteroaromatic
olefins.[9] The SNAr reaction of the Breslow intermediate and
fluoro- or chloroarenes has been studied since the seminal
À
heteroatom bond (such as CAr O) by a tethered carbanion
nucleophile (Scheme 1) has been known since the initial
report by Truce et al. in 1958,[3] but stayed rather unexplored
until recently, when it caught the attention of some research-
ers and resulted in different applications with variations in
nucleophiles, linkers, and electrophiles.[4]
The Truce–Smiles rearrangement transforms readily
À
À
accessible CAr O bonds into synthetically valuable C C
bonds with high atom economy, often without the need for
[*] D. Janssen-Mꢀller,[+] S. Singha,[+] F. Lied, K. Gottschalk,
Prof. Dr. F. Glorius
Westfꢁlische Wilhelms-Universitꢁt Mꢀnster
Organisch-Chemisches Institut
Corrensstrasse 40, 48149 Mꢀnster (Germany)
E-mail: glorius@uni-muenster.de
Homepage: http://www.uni-muenster.de/Chemie.oc/glorius/
[+] These authors contributed equally to this work.
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
http://dx.doi.org/10.1002/anie.201610203.
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report by Suzuki and co-workers in 1998,[10] but, to date, this
À
chemistry could not be extended to the cleavage of CAr
bonds or rearrangement reactions.
O
Herein, we report an NHC-organocatalyzed Truce–Smiles
rearrangement, which operates through an intramolecular
SNAr reaction of a catalytically generated acyl-anion equiv-
alent under mild conditions and with high yields. The
obtained 2-hydroxybenzophenone moiety is present in many
highly important natural products and pharmaceuticals,
including many biologically active and antibiotic compounds
such as pyoluteorin,[11] acremonidin E,[12] the pyrrolomycin
family,[13] the marinopyrrole family,[14] and cercophorin A
(Figure 1).[15] The highly potent glucose-6-phosphate translo-
case inhibitor mumbaistatin[16] and the protein kinase A and
C inhibitor balanol (not shown)[17] also bear the 2-hydroxy-
benzophenone motif.
Figure 1. Members of a large group of biologically active natural
products containing the 2-hydroxybenzophenone moiety. All the com-
pounds shown are antibiotics.
Subjecting salicylaldehyde derivative 1a to NHC catalysis
afforded the rearrangement product 2a under a range of
conditions. The reaction was systematically optimized by
variation of the NHC catalyst, base, solvent, and temperature
by running reactions with substrate 1a on 0.1 mmol scale
Scheme 2. Substrate scope. Yields given are for the isolated products
following column chromatography. 2i and 2an were synthesized on
a 0.3 mmol scale. [a] Reaction at 808C.
1
reactions, with quantification by H NMR spectroscopy and
using CH2Br2 as an internal standard.[18] It was found that the
reaction is most efficient at room temperature in THF with
a weak base (NaOAc) and the use of highly nucleophilic
triazolium-NHC 3, which bears a N-dimethoxyphenyl sub-
stituent,[19] whereas different NHC precursors with less-
electron-donating N substituents or a thiazole or imidazole
core performed significantly worse. Benzophenone product
2a could be isolated from a 0.5 mmol scale reaction in
excellent yield (90%) under optimized conditions.
linker, with the products 2l and 2m obtained in yields of 81%
and 93%, respectively. We next investigated the scope of the
migrating aryl group. The 4-nitro group, which activates the
arene toward SNAr reactions, is also tolerated in the 2-
position (2aa). In addition to this, other electron-withdrawing
groups, such as nitriles and esters, were tolerated in the
reaction with no drop in yield (88% and 91%), however,
these less electron-poor substrates required the reaction be
heated to 808C.
With the optimized conditions in hand, we studied the
scope of the reaction. We first varied the substitution pattern
on the salicylaldehyde portion of the substrate (Scheme 2).
Electron-donating functional groups, such as methyl,
methoxy, ethoxy, and diethylamino (2b–2g), are tolerated,
and provided the products in very high yields of up to 99%.
Reactions of electron-deficient substrates also proceed in
high yields (2h–2j). Changing the benzaldehyde moiety to
naphthaldehyde gives the product 2k in 94% yield.
Next, various heteroarenes were tested in this reaction.
Pyridine derivatives (2ad–2af), as well as pyrazine (2ag),
quinoline (2ah), and isoquinoline (2ai) were all tolerated,
with yields above 90%. Substrates containing benzothiazoles
(2aj and 2ak) and thiazoles (2al and 2am) were tolerated as
well, with excellent yields obtained. Even pyrrole and furan
derivatives, normally highly nucleophilic arenes, could be
employed in this reaction when activated with electron-
À
withdrawing groups (2an and 2ao). Double CAr O bond
À
À
Of particular note is that C S and C N bond cleavage is
also possible when the substrate contains a thioether or amino
cleavage in a pyridine derivative was also achieved, which
afforded 2ap in 82% yield.
2
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To evaluate the reaction mechanism we performed DFT
calculations, which support the expected SNAr mechanism
proposed for the classical Truce–Smiles rearrangement.
Repeating the calculations with less-activated ester substrate
1ab provided the same mechanism, but with a notably higher
activation energy for the SNAr part of the mechanism (in line
with the need for a higher reaction temperature for the
formation of 2ab).[18]
A cross-over experiment was performed with substrates
1c and 1ad to investigate if the reaction could be proceeding
in an intermolecular fashion, but no cross-over products were
detected. To test if a benzyne SNAr mechanism or a NHC-
catalyzed hydroacylation/elimination mechanism is at work,
a deuterated substrate 4 was prepared. The deuteration on the
arene did not change over the course of the reaction, thereby
ruling out these two unlikely pathways (Scheme 3).
Scheme 4. Total synthesis of taxilamine in three steps.
In conclusion, we have developed a procedure for the
rearrangement of O-aryl salicylaldehydes to yield 2-hydroxy-
benzophenones. The reaction has a very broad substrate
scope, including various classes of (hetero)arenes, works
under mild conditions, and has enabled the three-step total
synthesis of taxilamine. Mechanistic experiments and DFT
calculations both support the same expected SNAr mecha-
nism.
Acknowledgements
Generous financial support by the Deutsche Forschungsge-
meinschaft (IRTG2027 Mꢀnster-Toronto, Leibniz Award) is
gratefully acknowledged. We thank Dr. Lisa Candish and Dr.
Chang Guo (WWU) for helpful discussions.
Conflict of interest
The authors declare no conflict of interest.
Scheme 3. Top: The cross-over experiment suggests a truly intramolec-
ular mechanism. The use of deuterated substrate 4 rules out a hydro-
acylation or benzyne mechanism. Bottom: Simplified catalytic cycle.[18]
Keywords: aromatic substitution · carbenes · natural products ·
organocatalysis · rearrangement
From the results of these mechanistic experiments and
DFT calculations[18] we propose the expected catalytic cycle:
The aldehyde substrate 1 forms the Breslow intermediate II,
which, after nucleophilic attack on the arene, forms Meisen-
heimer type complex III. Elimination of the oxygen linker to
give IV, followed by proton transfer, enables product
formation and regeneration of the NHC.
To demonstrate the synthetic utility of this reaction, we
synthesized the natural product taxilamine (Scheme 4),
a pseudobenzylisoquinoline alkaloid found in the Chinese
herb Berberis aristata, which is used in traditional and modern
medicine.[20] Taxilamine represents a tetramethoxy derivative
of our rearrangement product 2ai and, to the best of our
knowledge, a total synthesis of taxilamine has not yet been
reported. Substrate 8 could be synthesized in two steps from
commercially available 6,7-dimethoxy-1(2H)-isoquinolone
(6) and 3,4-dimethoxysalicylaldehyde, and gave the desired
alkaloid (9) in 99% yield.
À
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Manuscript received: October 18, 2016
Revised: January 3, 2017
Final Article published: && &&, &&&&
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Communications
Organocatalysis
D. Janssen-Mꢁller, S. Singha, F. Lied,
K. Gottschalk, F. Glorius*
&&& — &&&
À
NHC-Organocatalyzed CAr O Bond
Cleavage: Mild Access to 2-
Hydroxybenzophenones
À
Catalysis with Smiles: A Truce–Smiles
rearrangement of acyl-anion equivalents
generated by N-heterocyclic carbene
(NHC) catalysis has been achieved. The
or CAr N bond cleavage for the formation
À
of a CAr C bond and enables access to 2-
hydroxybenzophenones, an important
structural motif present in several bio-
active natural products.
À
À
developed method includes CAr O, CAr S,
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