Sequential Catalytic Functionalization of Aryltriazenyl Aldehydes for the Synthesis of Complex Benzenes

Article abstract of DOI:10.1021/acscatal.1c01722

We demonstrate that aryltriazenes can promote three distinctive types of C-H functionalization reactions, allowing the preparation of complex benzene molecules with diverse substitution patterns. 2-Triazenylbenzaldehydes are shown to be efficient substrates for Rh(I)-catalyzed intermolecular alkyne hydroacylation reactions. The resulting triazene-substituted ketone products can then undergo either a Rh(III)-catalyzed C-H activation, or an electrophilic aromatic substitution reaction, achieving multifunctionalization of the benzene core. Subsequent triazene derivatization provides traceless products.

Full text of DOI:10.1021/acscatal.1c01722

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Letter
Sequential Catalytic Functionalization of Aryltriazenyl Aldehydes for
the Synthesis of Complex Benzenes
Sangwon Seo, Ming Gao, Eva Paffenholz, and Michael C. Willis*
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ABSTRACT: We demonstrate that aryltriazenes can promote
three distinctive types of C−H functionalization reactions, allowing
the preparation of complex benzene molecules with diverse
substitution patterns. 2-Triazenylbenzaldehydes are shown to be
efficient substrates for Rh(I)-catalyzed intermolecular alkyne
hydroacylation reactions. The resulting triazene-substituted ketone
products can then undergo either a Rh(III)-catalyzed C−H
activation, or an electrophilic aromatic substitution reaction,
achieving multifunctionalization of the benzene core. Subsequent
triazene derivatization provides traceless products.
KEYWORDS: hydroacylation, rhodium, triazene, benzene, sequential catalysis
iven the abundance of C−H bonds in organic molecules,
Gthe functionalization of these bonds represents an ideal
method for chemical manipulation.1 Transition-metal catalysis
has played a significant role in the advancement of this field,
providing powerful methods that are comparable to conven-
tional metal-catalyzed cross-coupling reactions.2 In particular,
the use of directing group strategies has been the dominant
approach to achieve regioselective reactions.3 A limitation of
such strategies is that the coordinating group, which, by design,
is present to direct the metal catalyst to specific C−H bonds of
the starting material, will also be present in the final product.
This limits synthetic flexibility, and, thus, the ability to remove
or transform the directing group to other useful functionalities
is advantageous. In addition, it would be beneficial if the
coordinating group was able to promote, not only one, but
multiple C−H functionalization reactions in a selective way.4,5
Metal-catalyzed hydroacylation reactions are examples of
C−H functionalizations in which the C−C multiple bond of an
alkene or alkyne inserts into the formyl C−H bond of an
aldehyde.6,7 Despite the advent of several non-chelation-
controlled methods for hydroacylation reactions,8 intermolec-
ular versions of these processes based on the use of some form
of substrate chelation remain the most common.9 Aldehydes
featuring P-,10 O-,11 N-,12 and S-based chelating groups,13 as
well as chelating alkenes,14 have all been used, and reactions
that proceed under mild reaction conditions and encompass
broad substrate scopes have been achieved. Regio-9e,f,12,15f and
enantioselective16 reactions have also been reported,15b,17 and
applications have been developed.11b,18 With these advances in
place, strategies to mitigate the issues associated with the
presence of chelating-substituents are needed. In this context,
approaches have been developed where the chelating group is
either incorporated into a target structure,18f,19 or transformed
to an alternate functionality.18g,20 For example, our laboratory
has shown that a chelating methyl sulfide employed in
hydroacylation reactions can be directly utilized in subsequent
Rh-catalyzed carbothiolation, arylation, or reduction reactions
(see Scheme 1a).21
Building on these prior reports, we aimed to develop an
alternative chelating group that would provide complementary
transformations and functionalization opportunities. We were
particularly interested in an approach in where the
coordinating group would be capable of promoting further
C−H functionalization reactions, allowing the use of simple
substrates, and access to a variety of substitution patterns. In
this context, Jun has reported a cascade strategy that uses in-
situ-generated picolyl imines for alkene hydroacylation and
ortho-alkylation of benzaldehydes (Scheme 1b).22 This double
C−H functionalization is assisted by a single chelating group.
However, the harsh reaction conditions (170 °C reaction
temperature) result in little regiocontrol, which, in turn, limits
the functionalization at both C−H sites to the same coupling
partner. The synthetic utility of this approach would be
significantly improved if the distinct C−H bonds could be
selectively functionalized using different coupling partners.4 To
achieve these aims, we selected aryl aldehydes substituted with
Received: April 15, 2021
Revised: April 29, 2021
Published: May 5, 2021
© 2021 The Authors. Published by
American Chemical Society
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further functionalization processes, allowing access to complex
benzene products.
Scheme 1. (a) Hydroacylation and Subsequent C−S
Functionalization,21 (b) Cascade Hydroacylation/ortho−C-
H Alkylation,22 (c) 2-Triazenyl-benzaldehydes in
Hydroacylation and Sequential C−H, Triazene
Functionalization, and E+ Substitution
2-Triazenylbenzaldehyde starting materials were prepared
from widely available anthranilic acids using simple proce-
dures.29 With the substrates in hand, we began our
investigation by evaluating a range of known hydroacylation
catalysts. It quickly became apparent that the combination of
[Rh(nbd)2]BF4 (nbd = norbornadiene) and bis(diphenylphos-
phinoethane) (dppe), in dichloromethane solvent at room
temperature, was the most efficient catalyst system for the
coupling reaction between the piperidine derivative 1a and a
selection of terminal alkynes (see the Supporting Information
for further details, as well as Scheme 2a). Excellent conversions
Scheme 2. (a) Intermolecular Hydroacylation of 2-
Triazenylbenzaldehyde 1a with Terminal Alkynes, and (b)
Removal of the Triazene Group under Acid Conditions
and yields were achieved with 1-octyne (2a), t-Bu-substituted
alkyne (2b), and phenylacetylene (2c), exclusively delivering
the linear isomers of the hydroacylation adducts 3a−3c.
We next explored how readily the triazene group could be
removed and replaced with a H-atom (see Scheme 2b). Initial
attempts using either known reducing (H-SiCl3)30 or acidic
conditions (TFA)25 were not successful. However, we found
that by using either BF3·OEt2 or triflic acid, the triazene group
could be efficiently removed (Scheme 2b).31 The use of a
THF/water solvent mixture was important for the success of
these reactions, because it presumably aids solubility of the
diazonium salt intermediate.
Next, we examined the scope of sequential hydroacylation/
triazene removal, with respect to different alkynes and 2-
triazenylbenzaldehydes (Scheme 3). The reaction was
generally effective, affording good to excellent yields of the
traceless hydroacylation products. Note that both trans-
formations were performed at ambient temperature. Aldehyde
1a could be combined with a range of terminal alkynes,
including those used in Scheme 2 (4a−4c), as well as
cycloalkyl-substituted alkynes (4d, 4e), enyne (4f), remote-aryl
alkyne (4g), and ferrocenyl (4h) substrates. The reactions also
proceeded well with a variety of different functional groups
positioned around the arene core of the aldehydes; 4-chloro
(4i), 4-trifluoromethyl (4j), 5-trifluoromethoxy (4k), and 5-
fluoro (4l) substituents were all well-tolerated.
2-triazenyl groups (Scheme 1c).23 The triazene group offers
many potential advantages: (1) although not previously
reported, the triazene group should be capable of acting as a
chelating group for metal-catalyzed intermolecular hydro-
acylation, with the first nitrogen atom positioned to form a
stable five-membered acyl-metal-hydride complex;7d (2)
catalyst coordination to the second nitrogen atom would
direct the metal center to the ortho−C−H bond;24 (3) the
electron-donating properties of the triazene would promote
electrophilic aromatic substitution reactions; (4) triazene
groups can be easily removed;25 and (5) triazenes can be
transformed to a wide range of alternative functional
groups.23,24,26 By exploiting just a selection of these activation
modes, it should be possible to access multisubstituted
benzenes; these are motifs that remain of considerable worth
to medicinal chemists.27 Despite the versatility of the triazene
group, its use as a directing group in metal-catalyzed C−H
functionalization is rare and remains challenging.24 This is
mainly due to the difficulty of controlling monofunctionaliza-
tion vs difunctionalization,24a,28 which, in turn, limits synthetic
applications. However, we were confident that our reaction
design, in which a variety of chemically distinct C−H bonds
are present, would alleviate these issues. Herein, we show that
it is indeed possible to use triazene groups in Rh-catalyzed
chelation-controlled alkyne hydroacylation, and in a variety of
The ability of the coordinating triazene group to facilitate
sequential C−H functionalization reactions was evaluated next.
Using the conditions developed by Huang for the ortho−C−H
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Scheme 3. Traceless Hydroacylation via Sequential Alkyne
Hydroacylation of 2-Triazenylbenzaldehydes/Removal of
the Triazene Group
Scheme 4. Sequential Hydroacylation/ortho−C−H
a
Functionalization Reactions
a
a
Reaction conditions: 1 (1 equiv), alkyne (1.5 equiv), [Rh(nbd)2]BF4
(5 mol %), dppe (5 mol %), CH2Cl2, 23 °C, 16 h; then, silica filtration
and BF3·OEt2 or TfOH (3.3−10 equiv), THF/H2O, 23 °C, 1 h.
Isolated yields over two steps.
olefination of aryltriazenes as a starting point,24a we found that
a Rh(III)-catalyst system could promote the C−H activation of
the initial hydroacylation products. Further optimization
showed that the original reaction conditions could be
simplified, allowing the reaction to proceed efficiently in the
absence of silver co-catalysts and at lower temperatures. With
the modified conditions in place, we performed the three-
component transformations in a sequential manner, with a
simple filtration through a silica pad separating the two steps
(see Scheme 4). Using two distinctive catalysts, the
combination of 2-triazenylbenzaldehyde 1a and t-Bu-substi-
tuted alkyne 2b, followed by the ortho-olefination with butyl
acrylate, gave the double C−H functionalization product 5a in
an excellent yield with absolute regiocontrol. A range of other
terminal alkynes could also be employed successfully, including
1-octyne (5b), and those substituted with alkyl chloride (5c),
phenyl (5d) and 3-thienyl (5e) groups. In addition, variation
of the aldehyde component was possible; 6-fluoro (5f), 5-
methyl (5g), 5-fluoro (5h), 4-chloro (5i), and 2-naphthyl (5j)
substrates all delivered the final products in good to excellent
yields. Importantly, the reaction could be performed on
increased scale, with the isolation of 1.2 g of benzene 5f
showcasing the excellent practicability of the developed
method.
a
Reaction conditions: 1 (1 equiv), alkyne (1.5 equiv), [Rh(nbd)2]BF4
(5 mol %), dppe (5 mol %), CH2Cl2, 23 °C, 16 h; then, silica filtration
and alkene (2.5 equiv), [RhCp*Cl2]2 (5 mol %), Cu(OAc)2·H2O (2
b
equiv), MeOH, 70 °C, 16 h. Isolated yields over two steps. TfOH
(3.3 equiv), THF/H2O, 23 °C, 1 h; Isolated yields.
noted, the triazene group could subsequently be removed using
triflic acid, providing the meta-substituted products (6a and
6b).
Having explored the utility of the triazene unit as a directing
group in metal-catalyzed sequential C−H functionalization
reactions, we next turned our attention to its potential use as a
controlling substituent in electrophilic aromatic substitution
reactions. We envisioned that the electron-donating ability of
the triazene should allow simple installation of electrophiles
onto the benzene core, which would, when combined with
hydroacylation and triazene removal, give access to additional
The scope, with respect to the alkene component, was also
examined. In addition to tert-butyl acrylate (5k), a selection of
alkenes absent from Huang’s report was also compatible with
the sequential process. These compounds included acrylamide
(5l), phenylsulfone (5m), and styrene (5n), which afforded
the corresponding products in good yields. As previously
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substitution patterns. Attracted by the versatility of aryl
bromides in organic synthesis, we selected bromination as
the transformation of choice. We found that one-pot addition
of NBS to the hydroacylation reaction mixture with stirring for
1 h at room temperature resulted in para-selective bromina-
tion, relative to the triazene substituent. In situ removal of the
triazene could be achieved as observed previously, to afford the
meta-substituted bromo enone products 7 (see Scheme 5).
substrates, establishing the high regioselectivity of this reaction.
2-Triazenylbenzaldehydes substituted with 4-fluoro (7f), 4-
chloro (7g), 4-methyl (7h), or 6-fluoro (7i) were also suitable
substrates, affording the meta-bromo products in good yields.
The 3-fluoro (7j) substrate was also well-tolerated for one-pot
hydroacylation/bromination, but triazene removal was in-
efficient. Chlorination could also be achieved if NBS was
replaced with 1-chloro-1,2-benziodoxol-3-one,32 with meta-
chloro-variant (7k) obtained in good yield. The mild reaction
conditions and high yields achieved for these meta-halogenated
products complements recent metal-catalyzed variants,33 which
often require forcing reaction conditions and specific electron-
poor substrates.
Scheme 5. Meta-selective One-Pot Hydroacylation/
a
Bromination, Followed by Removal of the Triazene Group
Until this point, functionalization of the triazene substituent
had only involved conversion to a H atom. However, the full
potential of this group was established by transformation to a
diverse set of products.23 For example, Pd-catalyzed cross-
coupling of triazene-containing hydroacylation adduct 3c with
an aryl boronic acid delivered the arylation product 8 in 88%
yield (Scheme 6).34 Alternatively, treatment of 3c with MeI
Scheme 6. Transformations of the Triazene Group Using
Hydroacylation Adduct 3c
provided the corresponding aryl iodide 9,28 which could either
be isolated, or reacted directly in a Pd-catalyzed Sonogashira-
coupling reaction to deliver alkyne 10. Reaction of 3c with
TMS-N3 afforded the azide-substituted enone 11 in excellent
yield.28 The triazene group could also be converted to a
deuterium atom via treatment with deuterated TFA and
deuterated THF (12).35
Having established a series of transformations that exploit
the triazene substituent of hydroacylation adducts, we then
combined several of these reactions with hydroacylation
(Scheme 7). Because of the importance of polyaromatic
compounds, the Pd-catalyzed detriazenative-arylation reaction
was further studied in a sequential manner (Scheme 7a). 4-
Methyl (13a), 2-methyl (13b), and 3-chloro-4-methoxy (13c)
aryl boronic acids were combined with 3-fluoro, 4-chloro, and
6-fluoro substrates, respectively, following hydroacylation,
giving the biaryl products in excellent yields. Although the
addition of a Pd catalyst is required for the arylation step, the
overall catalyst loading of the Rh(I) complex is reduced, no
oxidant is needed, less-costly reagents are used, and at a lower
temperature, when compared to the earlier reported cascade
a
Reaction conditions: (i) 1 (1 equiv), alkynes (1.5 equiv),
[Rh(nbd)2]BF4 (5 mol %), dppe (5 mol %), CH2Cl2, 23 °C, 16 h;
then NBS (1.5 equiv), 23 or 40 °C, 1−1.5 h, (ii) TfOH (3.3 equiv),
THF/H2O, 23 °C, 1 h; Sequential yields = yields over two steps,
obtained using one silica purification. b1-chloro-1,2-benziodoxol-3-
one used in place of NBS.
Bromination using an isolated hydroacylation product
confirmed that the process was not metal-catalyzed. In
addition, a control reaction established that a simple (E)-
chalcone was unreactive under these reaction conditions,
confirming the requirement for the triazene group. The scope
of the one-pot hydroacylation/bromination was general, and a
range of alkynes and aldehydes could be employed successfully.
tert-Butyl (7a), 1-octyne (7b), and cyclopentyl (7c) substrates
were efficiently transformed to the corresponding sequential
products. Phenyl- (7d) and phthalimide-substituted (7e) alkyl
examples were also compatible. Bromination of the non-
triazene-substituted aromatic rings was not observed in these
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of sequential transformations, including ortho-C−H olefina-
tion, para-bromination, and a range of detriazenative
functionalizations. Each class of sequential reaction utilizes
mild reaction conditions and tolerates a broad range of
functional groups, delivering traceless-, ortho- and meta-
substituted hydroacylation products. The ability to link
together multiple distinct transformations in a selective and
efficient manner demonstrates the versatility of triazenyl
aldehyde substrates for the preparation of complex benzenes,
which remain valuable motifs in drug discovery.27
Scheme 7. (a) Sequential Hydroacylation/Detriazenative
Arylation, (b) One-Pot Hydroacylation/1,4-Conjugate
Addition Followed by Arylation, and (c) Multiple C−H
Functionalizations Followed by Suzuki Coupling
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acscatal.1c01722.
■
sı
Experimental procedures and supporting characteriza-
tion data and spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Michael C. Willis − Department of Chemistry, Chemistry
Research Laboratory, University of Oxford, Oxford OX1
3TA, United Kingdom; orcid.org/0000-0002-0636-
6471; Email: michael.willis@chem.ox.ac.uk
Authors
Sangwon Seo − Department of Chemistry, Chemistry Research
Laboratory, University of Oxford, Oxford OX1 3TA, United
Kingdom; orcid.org/0000-0003-2281-9167
Ming Gao − Department of Chemistry, Chemistry Research
Laboratory, University of Oxford, Oxford OX1 3TA, United
Kingdom
Eva Paffenholz − Department of Chemistry, Chemistry
Research Laboratory, University of Oxford, Oxford OX1
3TA, United Kingdom
Complete contact information is available at:
https://pubs.acs.org/10.1021/acscatal.1c01722
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by the EPSRC (No. EP/K024205/
1).
■
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