Unraveling the C?H Arylation of Benzo-Fused Cycloalkanones: Combined Experimental and Computational Evidence

Article abstract of DOI:10.1002/adsc.202001349

The C?H functionalization of benzo-fused cycloalkanones represents a synthetic challenge, since such scaffolds display different activation sites, at sp² and sp³ carbons, a bicyclic structure, and various sizes of the cycloalkanone ring. Anticipating the outcome of C?H functionalization and the impact of the presence and size of the cycloalkanone ring would help to foresee synthetic routes to more complex molecular architectures. The mechanism of C?H arylation was studied using DFT calculations for tetralone, benzosuberone, and indanone and compared to acetophenone. Comparison of energetic profiles allowed identifying key steps of the process. Analysis of the topology of key intermediates allowed correlating the deformation of palladacycles to the potential reactivity of the benzo-fused cycloalkanone family members. The experimental results were in full agreement with the trend provided by the theoretical study. A wide panel of diversely substituted benzo-fused cycloalkanones has been successfully obtained using optimized conditions. Moreover, an approach towards polycyclic molecules has been illustrated featuring a C?H arylation and a second step taking advantage of the remaining ketone fragment and its ability to undergo diverse transformations leading to alternative pathways to more complex molecular architectures. (Figure presented.).

Full text of DOI:10.1002/adsc.202001349

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DOI: 10.1002/adsc.202001349
Very Important Publication
Unraveling the CÀ H Arylation of Benzo-Fused Cycloalkanones:
Combined Experimental and Computational Evidence
Benjamin Largea and Damien Prima,*
a
Université Paris-Saclay, UVSQ, CNRS, Institut Lavoisier de Versailles,
78035, Versailles, France
E-mail: damien.prim@uvsq.fr
Manuscript received: October 31, 2020; Revised manuscript received: January 12, 2021;
Version of record online: Februar 1, 2021
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202001349
Abstract: The CÀ H functionalization of benzo-fused cycloalkanones represents a synthetic challenge, since
such scaffolds display different activation sites, at sp2 and sp3 carbons, a bicyclic structure, and various sizes of
the cycloalkanone ring. Anticipating the outcome of CÀ H functionalization and the impact of the presence and
size of the cycloalkanone ring would help to foresee synthetic routes to more complex molecular architectures.
The mechanism of CÀ H arylation was studied using DFT calculations for tetralone, benzosuberone, and
indanone and compared to acetophenone. Comparison of energetic profiles allowed identifying key steps of
the process. Analysis of the topology of key intermediates allowed correlating the deformation of palladacycles
to the potential reactivity of the benzo-fused cycloalkanone family members. The experimental results were in
full agreement with the trend provided by the theoretical study. A wide panel of diversely substituted benzo-
fused cycloalkanones has been successfully obtained using optimized conditions. Moreover, an approach
towards polycyclic molecules has been illustrated featuring a CÀ H arylation and a second step taking
advantage of the remaining ketone fragment and its ability to undergo diverse transformations leading to
alternative pathways to more complex molecular architectures
Keywords: Tetralone; benzosuberone; indanone; CÀ H functionalization; Transient directing group
Introduction
(sp2 and sp3 carbons), a bicyclic benzo-annulated core,
a reactive carbonyl fragment and a partially hydro-
The functionalization of aromatic rings by selective genated ring of various sizes.
activation of CÀ H bonds has experienced an unprece-
Such structural features are likely to hamper the
dented growth allowing the construction of elaborate transposition of catalytic systems from simplest sub-
molecular architectures and the late stage installation strates to related homologues. Indeed, in the acetophe-
of substituents.[1–10] Although CÀ H activation has none (and benzaldehyde) series, Pd- and Ru-promoted
become a powerful synthetic tool to construct new Csp2À H as well as Pd-catalyzed Csp3À H functionaliza-
CÀ C or C-heteroatom bonds, and despite recent tions are well documented and high yielding
advances in the development of directing groups (DG), transformations.[11–18] (Figure 1)
site selection remains a significant challenge in
In contrast, Csp2À H functionalization of tetralone is
polycyclic substrates. The latter combine structural, almost exclusively described using Ru catalysis. If
electronic and steric effects within the same architec- palladium-based catalytic systems efficiently promote
ture. Thus, understanding the origin and/or predicting Csp3À H functionalization,[18] examples of Csp2À H func-
the selectivity of reactions using such DG requires tionalization of tetralone using a transient directing
gaining insights though related precursors or models group are scarce. In fact, CÀ H functionalization of
and/or combining experimental and computational benzo-fused cycloalkanones remains an underexplored
methods. Among bicyclic architectures, the benzo- transformation only exemplified with few or rare
fused cycloalkanone series represents a challenging examples
of
arylated
tetralones[19–22]
and
family of substrates displaying different activation sites benzosuberones[21,23,24] and restricted to aromatics bear-
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The reactivity trend within this series was confirmed
by experimental results and illustrated by the synthesis
of a broad family of aryl-benzo-cycloalkanones. Next,
our strategy towards polycyclic architectures from the
residual ketone fragment was also exemplified in the
tetrahydro-naphthalene and the naphthalene series.
Results and Discussion
DFT Study
We based our approach on the premise plausible
mechanism postulated by Jin in a recent paper dealing
with the arylation of acetophenone.[17] In the context of
the cornerstone tetralone substrate, key steps of this
mechanism (Scheme 1) could successively involve the
formation of the tDG (A), the coordination of the metal
(B), CÀ H activation (C), oxidative addition (D),
reductive elimination (E), regeneration of the catalytic
active species (F) and finally regeneration of the tDG
(G).
Figure 1. Acetophenone and alkanone functionalization sites
and catalytic systems.
Considering these steps, we first determined the
optimal energetic profile for the arylation of tetralone
ing electron withdrawing groups. In addition, the (full details are given in the ESI). As shown in
arylation of indanone has not been studied so far.
Figure 2, the coordination/CÀ H bond activation se-
General strategies allowing the selective installation quence is the first key issue of the mechanism. If
of substituents on benzo-fused cycloalkanones are of coordination of the Pd can be envisioned from both Z
current interest. Indeed, tetralones, indanones and and E imine of the tDG, calculations allowed a clear
benzosuberones, are important bicyclic scaffolds discrimination between pathways involving intermedi-
widely spread in natural products and display a broad ates INT2E.18E or INT2E.18Z (Figure 2).
array of biological properties. Further, as tetralones are
Notably, CÀ H activation step C is assumed to
considered as direct precursors of naphthalene proceed through carboxylate assisted CMD mechanism
derivatives,[25–29] the selective functionalization of
tetralone platform might (i) represent an alternative
route to diversely substituted naphthalenes.[30–33] (ii)
allow the modulation of the substitution pattern and
thus, of the properties of naphthalene derivatives in
materials and life science issues.[34,35] (iii) overcome
current hurdles in CÀ H activation chemistry of
naphthalene towards 1,2,8-trisubstituted naphthalenes
for examples.[36–38]
In this context, bare and fragmentary experimental
and theoretical data available in the CÀ H functionaliza-
tion of benzo-fused cycloalkanones, prompted us to
examine the CÀ H arylation of such substrates. Our
approach foresee the use of a transient directing groups
(tDG)[39–41] to promote the regioselective Cα,sp2À H bond
activation of benzo-fused cycloalkanones and to take
benefit from the intact ketone fragment to construct
polycyclic architectures. We first examined the impact
of the presence and the size of the condensed cyclo-
alkanone ring on the main key steps and intermediates
of the mechanism of the Cα,sp2À H bond activation
sequence by mean of theoretical calculations. The
energetic profiles of the Pd-catalyzed arylation process
of cyclic tetralone, indanone and suberone have been
Scheme 1. Jin’s postulated mechanism.
determined and compared to acyclic acetophenone.
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arising from the E imine. Since intermediate INT3
arising from the E imine is also thermodynamically
favored, by comparison with the Z imines analogues,
the overall Z path was not discussed further in the
paper and only INT3E was considered for the next
steps (the full calculated Z profile can be found in
ESI).
The following main mechanistic steps involve the
oxidative addition of aryl iodide (step D via TS2E)
followed by reductive elimination (step E via TS3E)
finally leading to the formation of a CÀ C bond at
position 8 of the tetralone platform (Figure 3). The key
intermediate INT5E.18 can by plausibly obtained from
two alternative pathways via TS2E.16 or TS2E.18
which only differ by the association/dissociation of
ligand L sequence from INT3E.16. Similarly, the
reductive elimination step leading to INT6E.16 could
occur directly from TS3E.17 or via TS3E.15 and
INT6E.14. Finally, INT6E.16 generates the expected
product (Prod) after release of the tDG and regener-
ation of the catalytic active species (steps F and G).
Including the dispersion in these calculations revealed
that the associative pathways (in green) could be
slightly favored against the dissociative ones (in blue).
This difference may suggest some uncertainty in the
Figure 2. Energetics of reaction coordinates for step C with the
starting material (benzo-fused cycloalkanone) as reference
(0 kcal.molÀ 1).
via TS1. Access to either INT3Z.18 or INT3Z.16 via exact mechanistic pathway (Figure 4).
TS1Z.15 or TS1Z.17 arising from the Z imine (barriers
The same approach was next applied to acetophe-
of 51.5 and 46.0 kcal.molÀ 1 respectively) are both none on one hand and to benzosuberone and indanone
strongly disfavored by comparison with the access to on another hand. In all cases energetic profiles have
INT3E.16 via TS1E.16 (barrier of 17.8 kcal.molÀ 1) been determined allowing the comparison of the
Figure 3. Energetics of reaction coordinates for steps D and E with tetralone as reference (0 kcal.molÀ 1).
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Figure 4. Energetics of reaction coordinates for steps D and E with tetralone as reference (0 kcal.molÀ 1). Dispersion included.
influence of the presence and the size of the aliphatic their respective TS: indanone and suberone with
ring on the outcome of the reaction. The results highest energy barriers and acetophenone and tetralone
obtained are gathered in Figure 5. Interestingly, the with lowest barriers. Finally, the formation of the CÀ C
early steps of the process leading to INT2E.16 bond followed by regeneration of the carbonyl moiety
evidence that the successive formation of the tDG and led to the arylation products. Small energetic differ-
the coordination to palladium required more energy in ences can be observed at this stage which take into
the case of tetralone (in green) than the corresponding account (i) the increase of the steric crowding around
acetophenone (blue) and benzo-fused cycloalkanones the newly created CÀ C bond (ii) the favorable energy
(orange and red). Each single step from the starting release occurring from the palladacycle ring opening
material highlights the particular behavior of tetralone. and thus favor the less crowded aryl indanone and aryl
The higher energy required in these steps potentially acetophenone rather than the tetralone and benzosuber-
indicates that the formation and the early reactivity of one analogues.
the tDG are crucial issues to address.
Our calculations and comparison of overall ener-
Further, activation of the C–H bond by Pd towards getic profiles within the benzo-fused cycloalkanone
INT3E.16 via TS1E.16 resulted in a contrasted assess- series show that the arylation is thermodynamically
ment. Indeed, indanone and benzosuberone required favored by 35.8 to 32.1 kcal.molÀ 1 from the starting
the highest amount of energy (barriers of 25.2 and materials to the products. Arylation of tetralone is the
23.8 kcal.molÀ 1 respectively). Tetralone and acetophe- most favored process in all critical steps from the CÀ H
none required less energy (barriers of 17.8 and activation (step C). The rather high energetic profile of
19.8 kcal.molÀ 1 respectively) for the corresponding early steps including formation of the tDG and
step. In addition, INT3E.16 appears the most favored coordination to Pd, might however hamper the prog-
for acetophenone and in decreasing order for tetralone, ress of the arylation of tetralone. Unless late stage of
benzosuberone and indanone likely as a consequence the process, the presence of a cycloalkanone ring
of less crowded metallacycle. The following main imparts additional stiffening in key intermediates and
intermediates and transition states until the reductive TS and thus results higher energetic profiles by
elimination TS3E.15, are illustrative of a similar trend comparison with acetophenone. Including the disper-
in which indanone intermediates are always the more sion in theses calculation did not change the overall
energetic, followed by benzosuberone, tetralone and conclusion of this study – The reaction is more favored
acetophenone.
when using acetophenone as substrate, followed by
The reductive elimination step via TS3E.15, allows benzotetralone, benzosuberone, and finally indanone,
splitting two sets of substrates based on the energy of which does not react in these conditions. The complete
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Figure 5. Comparison of energetic profiles for tetralone, acetophenone, benzosuberone and indanone.
energetic pathway, including this parameter, can be
found in ESI.
In fact, the mean relative deformation of pallada-
cycles within the benzo-fused cycloalkanones series
Careful examination of the topology of each allowed ranking indanone as the most distorted (2.4%
calculated intermediate or TS palladacycle showed that of relative deformation), followed by benzosuberone
the variation of the energetic profiles observed by (1.1% of relative deformation) and finally tetralone
comparing acetophenone and members of the benzo- (0.3% of relative deformation). The deformation trend
annulated cycloalkanone family is consistent with key observed further questioned about the structure-reac-
structural features such as bond distances and angles tivity relationship within this series of substrate. We
within the different palladacycles (from TS1E.16 to thus started to experimentally evaluate the propensity
TS3E.15). In our analysis, distances and angles of each member of the benzo-fused cycloalkanone
measured for the acetophenone-based intermediates family to undergo CÀ H arylation.
have been considered as standard (Figure 6 & ESI). As
exemplified in Figure 6, deviation and deformation
from these standard values have been calculated for
Optimization of the Reaction Conditions
INT3E.16tet, INT3E.16sub and INT3E.16ind which We started to examine the CÀ H arylation on tetralone.
stand for the corresponding intermediates in the First arylation attempts were based on experimental
profiles of tetralone, suberone and indanone derivatives conditions recently reported by Jin.[17] Unfortunately,
respectively (for a full analysis see ESI). For all bond under these conditions a poor conversion was observed
distances and angles, values related to the indanone and only 11% of the expected compound has been
analogue are the most strongly deviated. In contrast, isolated (Table 1 – Entry 1). A wide array of directing
values related to the tetralone analogues are closest to groups, palladium pre-catalysts, additives and solvents
standard.
have been thoroughly screened (see Table 1 and ESI
for full optimization tables) to determine the best
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Figure 6. Palladacycle deformation for INT3E.16.
Table 1. Optimization of the experimental conditions.
perform similar transformation on non-cyclic benzoal-
kanones. In addition, the arylation of tetralone
appeared very sensitive to pH variation. Indeed, both
the nature and the concentration of the acid co-solvent
used to promote the formation of the transient imine
were crucial parameters of this reaction (Table 1 –
Entry 4 & 5). Strong Bronsted acids completely inhibit
the reaction, and using weaker acid did not improve
the 1a/3aa ratio. The number of equivalents of glycine
was next carefully examined. Under our conditions the
use of a stoichiometric amount of glycine was essential
to ensure highest conversion of the starting material
(Table 1 – Entry 6), in good agreement with the
aforementioned theoretical calculations. Indeed, the
intermediates INT1, INT2E.18 and INT2E.16 were
found to be less stable in the tetralone series than in
the corresponding acetophenone series.
Entry tDG
[Pd]/
[Ag]
Solvent
3aa/1a
1
2
3
4
5
6
Gly (50%)
Pd(PPh3)2Cl2/ HFIP/AcOH (9/1) 1/4.6
AgOAc
Orthanilic acid Pd(PPh3)2Cl2/ HFIP/AcOH (9/1) 1/10.2
(50%)
Gly (50%)
AgOAc
Pd(TFA)2/
AgTFA
Pd(OAc)2/
AgOAc
Pd(OAc)2/
AgOAc
HFIP/AcOH (9/1) 1/1.2
HFIP/TFA (9/1) 1/7.0
Gly (50%)
Gly (50%)
Gly (1 eq)
AcOH
1/4.9
More importantly, attempts to use larger amount of
glycine inhibits the reaction. Performing this reaction
at a higher temperature or during an extended period
of time did not improve the conversion either. Finally,
the optimal conditions were defined as described in
Table 1 (Entry 6).
Pd(TFA)2/
AgTFA
HFIP/AcOH (9/1) 4.2/1
Ratio determined via NMR.
experimental procedure to perform this reaction. Our
tests concluded that glycine was the most efficient tDG
Scope of the Reaction
for this transformation (Table 1 – Entry 2). However, The next step was dedicated to the extension of the
the more electrophilic [Pd(TFA)2/AgTFA] catalytic scope of the reaction. We first applied the optimized
combination (Table 1 – Entry 3) revealed more adapted conditions to indanone, tetralone and benzosuberone
for the arylation of tetralones than the classical (Scheme 2).
[Pd(PPh3)2Cl2/AgOAc] combination usually used to
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Scheme 2. Influence of the cycloalkanone ring size on arylation
process.
While arylated tetralone 3ab could be isolated in
61% yield, benzosuberone derivative 3bb was ob-
tained in 9% yield and the expected arylated indanone
3cb was not observed. These results and the trend
observed experimentally are in complete adequacy
with the calculated energetic profiles and the degree of
deformation of key palladacycle intermediates.
To further widen the scope of this transformation,
we performed this reaction with various aryl iodides
(Scheme 3) on diverse tetralone derivatives
(Scheme 4).
As expected, aryl iodides bearing electro-withdraw-
ing groups were more easily coupled with tetralone Scheme 4. Scope of benzocycloalkanones.
derivatives under these conditions, as 61% of com-
pounds 3ab have been isolated. Nitro groups
(3ap&3aq) and esters (3ac&3ak) are also reasonably ao) when performed with iodo halogeno aryl deriva-
tolerated but the yield dropped when using an tives. The remaining halogen can be use in potential
unprotected carboxylic acid (3ae). Delightfully, the additional coupling reactions leading to extended
reaction leads to a halogeno aryl tetralone (3ad&3al– architectures. Unfortunately, the arylation does not
occur when using ortho substituted aryl iodides, or
activated iodides. Most likely overcrowding the reac-
tion site disfavors the formation of a PdIV intermediate
complex at the oxidative addition stage. The reaction
issue appears sensitive to the presence of a substituent
near the reacting site: the yield decreases from 57% to
35% when the methoxy group is moved from position
5 (3db) to position 6 (3eb), and drops to 10% when
this group is located on position 7 (3fb). Again, this
result is probably due to an increase of the steric
hindrance disfavoring the formation of the PdIV
intermediate (Figure 7).
Figure 7. Impact of the steric hindrance over the Z to E imine
Scheme 3. Scope of the aryl iodides.
intermediate.
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The presence of an additional substituent close to methylpent-enal afforded aryl naphthochromene 6ab
the ketone function at the cycloalkanone ring also in 56% yield using a known procedure (Scheme 6).[43]
impacted the reaction outcome: 54% yield was
obtained with a methyl group located at position 4
(3ib) against 12% at position 2 (3hb). The presence of
Conclusion
such substituent most likely favors the formation of a We explored the CÀ H arylation process of benzo-fused
Z-imine, which has been shown detrimental in the cycloalkanones through computational and experimen-
early stages of the process (Figure 7), according to our tal methods. Our theoretical study evidenced that both
calculations (Figure 2). When the benzoalkanone de- the presence and the size of the cycloalkanone ring
rivative bears strong electron-donating substituents, the deeply impact the outcome of the arylation sequence
expected product is not observed.
by comparison with classical acetophenone derivatives.
Energetic profiles undoubtedly showed that the for-
mation of imine derivatives to generate the tDG in
early stages of the process is crucial. First the E imine
is preferred over the Z imine in all cases. The
Application of the Methodology to the Synthesis of
Extended Polycyclic Architectures
Our next objective was to take advantage of the intact formation of the E imine as well as successive
ketone fragment after the arylation process. At this elementary steps before the CÀ H activation step
stage, the remaining ketone moiety offers an appealing required higher energy for tetralone by comparison to
and straightforward transformable organic platform. other substrates, which is in good agreement with the
We thus envision illustrating the development potential mandatory use of stoichiometric amount of glycine to
of our approach by an access to high value polycycles ensure high conversions. In contrast, in key oxidative
and naphthalene derivatives. The dihydronaphthtalene addition and reductive elimination steps, the tetralone
scaffold recently showed a strong ability to complex intermediates and transition states are clearly favored
ions due to its topology and synergistic contribution of by comparison with suberone and indanone analogues.
weak interactions.[42] Ketones 3aa, 3db and 3ib under- Our computational study also revealed that the top-
go alpha Csp2 arylation using o-iodobromobenzene and ology of palladacycles involved in each step of the
Pd-Xantphos as the catalytic system to afford in one mechanism is a crucial parameter for CÀ H arylation.
step new dihydronaphthobenzofuranes (Scheme 5).
Analysis of bond distances and angles allowed
Aryl ketones 3 can also be considered as advanced determining a mean deformation of palladacycles and
precursors of naphthalenes. CÀ H arylation of position ranking indanone, suberone and tetralone from the
8 of naphthalene substrates usually requires the most to the less distorted scaffold respectively. The
presence of elaborated directing groups. Our strategy deformation of intermediate palladacycles has been
represents an alternative to such methods and a new correlated to the reactivity trend within the benzo-
synthetic sequence towards polycyclic naphthalene- fused cycloalkanones series. Indeed, under an opti-
based derivatives. Oxidation of ketone 3ab into 8- mized set of conditions, using glycine to generate the
arylnaphthol 5ab, followed by condensation with tDG, arylation of tetralone was readily obtained. In
contrast, aryl benzosuberone was isolated with a poor
yield and aryl indanone could not be obtained. A wide
panel of diversely substituted aryl tetralones has been
successfully synthesized, isolated and characterized
with yields up to 61%. In addition, our strategy based
on the sequential CÀ H arylation and further beneficial
transformation of the residual ketone fragment, led to a
straightforward alternative access to polycyclic archi-
tectures including polysubstituted naphthalene-based
derivatives.
Scheme 5. Synthesis of dihydronaphthobenzofuranes & naph-
thochromenes.
Experimental Section
General Procedure for the Arylation of Tetralone
Derivatives
In a 2-dram screw glass tube, tetralone (1.0 eq) was added to a
solution of glycine (1.1 eq), silver trifluoroacetate (2.5 eq),
palladium acetate (0.1 eq) and aryl iodide (3.0 eq) and water
(4.0 eq) in a mixture of HFIP and AcOH (9/1–0.3 M). The
reaction mixture was stirred for 30 min at room temperature,
Scheme 6. Synthesis of aryl naphthochromene 6ab.
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°
and for 24 h at 130 C. After cooling to room temperature, the
crude mixture was filtered through a pad of Celite, and purified
using preparative TLC to obtain the desired product.
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General Procedure for the Synthesis of Hydrazone
Derivatives
In a round bottom flask, hydrazine (1.0 eq) was added to a
solution of indanone (1.0 eq) in ethanol (0.5 M) and then stirred
at room temperature for 17 h. The crude mixture was filtered
over a no 4 fritted glass. The resulting solid was washed with
ethanol to recover a part of the desired product. The combined
liquids were concentrated over reduced pressure and purified
using preparative TLC to retrieve the remaining desired
compound.
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General Procedure for the Synthesis of Dihydro-
naphthobenzofuranes Derivatives
Arylated tetralone (1.2 eq), Pd2dba3 (0.1 eq), cesium carbonate
(3.0 eq) and Xantphos (0.24 eq) were placed in a 2-dram screw
glass tube and left in a desiccator overnight. The tube was then
filled with argon and a solution of aryl iodide (1.0 eq) in
anhydrous toluene (0.7 M) was added. The resulting mixture
°
was stirred for 5 days at 120 C, diluted in AcOEt, filtered
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Acknowledgements
The Universities of Versailles St-Quentin and Paris-Saclay, the
French Ministry of Superior Education and Research (PhD
fellowship BL), and the CNRS are gratefully acknowledged for
their financial support. This work was also supported by the
French National Research Agency under the program
CHARMMMAT ANR-11-LABX-0039-grant. This work was
granted access to the computing resources of CINES (Mont-
pellier, allocation A0060810812 awarded by GENCI).
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