Palladium-Catalyzed C8-Arylation of Naphthalenes through C?H Activation: A Combined Experimental and Computational Study

Article abstract of DOI:10.1002/chem.201903500

Herein, a direct C8-arylation reaction of 1-amidonaphthalenes is described. By using diaryliodonium salts as arylating agents, the palladium-catalyzed C?H activation reaction showed perfect C8 regioselectivity and a wide functional group tolerance. In most cases, the desired polyaromatic compounds were isolated in good to excellent yields. To explain the observed regioselectivity, DFT calculations were performed and highlighted the crucial role of the amide directing group. Finally, the utility of this method is showcased by the synthesis of benzanthrone derivatives.

Full text of DOI:10.1002/chem.201903500

DOI: 10.1002/chem.201903500
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Synthesis Design |Hot Paper|
Palladium-Catalyzed C8-Arylation of Naphthalenes through CꢀH
Activation: A Combined Experimental and Computational Study
Julian Garrec,[b] Marie Cordier,[c, d] Gilles Frison,[c] and Sꢀbastien Prꢀvost*[a]
Abstract: Herein, a direct C8-arylation reaction of 1-amido-
naphthalenes is described. By using diaryliodonium salts as
arylating agents, the palladium-catalyzed CꢀH activation re-
action showed perfect C8 regioselectivity and a wide func-
tional group tolerance. In most cases, the desired polyaro-
matic compounds were isolated in good to excellent yields.
To explain the observed regioselectivity, DFT calculations
were performed and highlighted the crucial role of the
amide directing group. Finally, the utility of this method is
showcased by the synthesis of benzanthrone derivatives.
Introduction
able conditions, this strategy could allow access to substituted
naphthalenes more easily than going through a prefunctional-
ization step and is, of course, very interesting from an atom-
economy point of view. Traditionally, this kind of reaction has
been accomplished by using a directing group containing ni-
trogen, sulfur, or phosphorus atoms to form a stable metallacy-
cle, which then reacts to obtain the desired compound.[3] How-
ever, this strategy, based on strongly coordinating directing
group, suffers from a drawback: the further use or removal of
the directing group. Indeed, most of the time, this directing
group cannot be transformed. However, the use of a weakly
coordinating directing group, such as carbonyl derivatives, has
recently started to emerge.[4] In this case, the resulting metalla-
cycle is less thermodynamically stable, so the reactions can be
more difficult to achieve. On the other hand, carbonyl deriva-
tives can be easily transformed and used for the further con-
struction of complex structures.
Naphthalene is a key building block for the synthesis of more
complex aromatic structures with many interesting properties,
such as optical and electronic properties.[1] Naphthalene is also
a commonly found skeleton in natural products that exhibits
various biological activities (Figure 1).[2]
Figure 1. Naphthalene core in active products. PDE=phosphodiesterase.
Regarding arylation reactions of 1-carbonylnaphthalenes
through a CꢀH activation strategy, several research groups re-
ported C2 regioselectivity with different transition metals as
catalysts, such as Pd,[5] Ru,[6] Ir,[7] Ni,[8] or Co,[9] and carboxylic
acid, ketones, or amides as the directing group (Scheme 1a).
Whereas C2 arylation of 1-carbonylnaphthalenes has been
widely observed, the same is not true for C8 regioselectivity.
Considering all kinds of CꢀH functionalization of 1-carbonyl-
In this context, the synthesis of polysubstituted naphtha-
lenes is of considerable interest. Even if their synthesis through
a classical cross-coupling reaction is widely used by the com-
munity, naphthalene is a structure of choice to develop new
arylation reactions through CꢀH activation. By choosing suit-
[a] Dr. S. Prꢀvost
Laboratoire de Synthꢁse Organique, Ecole Polytechnique
ENSTA, CNRS, Institut Polytechnique de Paris, 91128 Palaiseau (France)
E-mail: sebastien.prevost@ensta-paris.fr
[b] Dr. J. Garrec
Unitꢀ Chimie et Procꢀdꢀs
ENSTA, Institut Polytechnique de Paris, 91128 Palaiseau (France)
[c] M. Cordier, Dr. G. Frison
Laboratoire de Chimie Molꢀculaire, Ecole Polytechnique
CNRS, Institut Polytechnique de Paris, 91128 Palaiseau (France)
[d] M. Cordier
Present address: Institut des Sciences Chimiques de Rennes
Universitꢀ de Rennes, Campus de Baulieu, 35042 Rennes Cedex (France)
Supporting information and the ORCID identification number(s) for the
author(s) of this article can be found under:
https://doi.org/10.1002/chem.201903500.
Scheme 1. C2 versus C8 arylation of naphthalene derivatives.
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naphthalene derivatives, few examples of C8 regioselectivity
have been reported,[10] although a mixture of C2 and C8 re-
gioisomers have been observed in certain cases.[11] However,
with respect to C8 regioselectivity, there is a lack of methods
to achieve this. Only a study by the group of Fu focused on
C8-triflation of naphthalenes by using ketones and disubstitut-
ed amides as directing groups.[12] With this in mind, we were
keen to develop the first general method for the C8-arylation
of 1-carbonylnaphthalenes to open the door to the short syn-
thesis of polyaromatic structures (Scheme 1b).
ed compound was not detected. Encouraged by this prelimina-
ry result and taking into account that the addition of triflic
acid (TfOH) could enhance the electrophilicity of PdII,[16] differ-
ent quantities of TfOH were added to the reaction (Table 1, en-
tries 2 and 3) and the use of one equivalent of TfOH allowed a
yield of 50%, as determined by NMR spectroscopy, to be
reached. After extensive screening of the solvents, concentra-
tions, temperatures, and directing groups (see the Supporting
Information), we turned our attention to the diaryliodonium
salt (Table 1, entries 7–10). Diphenyliodonium trifluorometh-
anesulfonate was found to be a better reagent for the reaction
(Table 1, entry 8), whereas diphenyliodonium bromide did not
show any conversion (Table 1, entry 9). Finally, the optimal re-
action conditions involved 3 equivalents of iodonium salt and
1 equivalent of TfOH in DCE as a solvent at 808C. After 24 h,
80% yield, as determined by NMR spectroscopy, was observed
(Table 1, entry 10).
Diaryliodonium salts are known as electrophilic reagents for
the introduction of aryl substituents.[13] Since the work of San-
ford’s group,[14] they have been widely used for the synthesis
of biaryl compounds.[15] The oxidative character of iodonium
salts make them very interesting candidates for palladium-cata-
lyzed CꢀH activation reactions for which a PdII/PdIV catalytic
pathway has been proposed.[14] Herein, we report the palladi-
um-catalyzed C8-arylation of 1-amidonaphthalenes by using di-
aryliodonium salts as the arylating agent and a computational
study of the reaction to explain the observed regioselectivity.
With the optimized conditions in hand, we investigated the
scope of the reaction and tested different naphthalene deriva-
tives (Table 2). (8-Phenylnaphthalen-1-yl)(pyrrolidin-1-yl)metha-
none (2aa) was isolated in 78% yield, which was in line with
the yield previously observed by NMR spectroscopy. The reac-
tion proved to be remarkably general. 1-Amidonaphthalenes
1b–d, substituted in position 4 with a methyl, fluorine, or me-
thoxy group, respectively, were compatible with the reaction
conditions and delivered the desired products in very good
yields (65–86%). Amides 1e–j, with an aryl group in position 5,
were engaged in the reaction. Whether with electron-donating
or -withdrawing substituents, desired phenylated naphthalenes
Results and Discussion
At the outset, we focused our attention on the C8-phenylation
of naphthalen-1-yl(pyrrolidin-1-yl)methanone (1a) by using di-
phenyliodonium tetrafluoroborate as an arylating agent. From
reports in the literature,[12] we anticipated that disubstituted
amides would be suitable directing groups to induce C8-regio-
selectivity. Pleasingly, desired product 2aa could be obtained
in 26% yield, as determined by means of NMR spectroscopy,
with palladium diacetate as the catalyst and 1,2-dichloroethane
(DCE) as a solvent after 24 h at 1008C (Table 1, entry 1). The re-
gioselectivity of the reaction was confirmed by X-ray character-
ization of 2aa. It is worth noting that a large amount of start-
ing material was not converted and the C8-phenylated product
was the only one formed during the reaction; the C2-phenylat-
Table 2. Scope of the naphthalene derivatives.[a,b]
Table 1. Selected optimization results.[a]
Entry Ph2IX
([equiv])
Solvent
(C=mol Lꢀ1
T
TfOH
Yield[b]
[%]
)
[8C] [equiv]
1
2
3
4
5
6
7
8
9
PhI2BF4 (2)
PhI2BF4 (2)
PhI2BF4 (2)
PhI2BF4 (2)
PhI2BF4 (2)
PhI2BF4 (2)
PhI2BF4 (2)
PhI2OTf (2)
PhI2Br (2)
DCE (0.1)
DCE (0.1)
DCE (0.1)
toluene (0.1)
THF (0.1)
100
100
100
100
100
80
80
80
80
80
0
1
2
1
1
1
1
1
1
1
26
47
30
23
40
50
53
66
0
DCE (0.1)
DCE (0.05)
DCE (0.05)
DCE (0.05)
DCE (0.05)
10
PhI2OTf (3)
80
[a] Reactions were carried out by using 1 (0.2 mmol), Ph2IOTf (0.6 mmol),
TfOH (0.2 mmol), and Pd(OAc)2 (0.02 mmol) in DCE (4 mL) for 24 h at
808C. [b] Yields of products isolated were reported.
[a] Reactions were run on 0.1 mmol scale. [b] NMR yield determined
using 1,3,5-trimethoxybenzene as internal standard.
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2ea–ja were isolated in excellent yields (66–86%). To extend
the scope of our reaction, naphthalenes substituted in posi-
tions 2 or 6 by a methoxy group were tested and showed reac-
tivity under the optimal conditions with moderate isolated
yields (48 and 44%, respectively). Finally, we wondered if differ-
ent directing groups could be used in the reaction. From the
optimization results,[17] we knew that esters and carboxylic
acids were not suitable for the reaction. However, noncyclic
amides, such as N,N-diethylamide, were able to direct the phe-
nylation reaction, even if phenylated compound 2ma was ob-
tained in a moderate yield of 41%. Interestingly, a Weinreb
amide could also be used as a directing group and 2na was
synthesized in 62% yield. This last reaction was scaled up to
2 mmol and the yield reached 67%. This latter example offers
interesting transformation opportunities thanks to all known
chemistry related to Weinreb amide derivatives.[18]
introduced into the C8 position of naphthalene 1g, despite a
moderate yield for the last derivative (26%). Then, ortho-meth-
ylated diaryliodonium was tested in the reaction and product
2gi was isolated in 68% yield, even if the conversion was not
complete, probably due to steric hindrance induced by the
methyl group. Finally, the reaction was tested with the dimesi-
tyliodonium trifluoromethanesulfonate, but no reaction was
observed because of steric hindrance. In the literature,[19] many
nonsymmetrical diaryliodonium derivatives with one mesityl
group are described, so this negative result is very promising
to extend our scope because it means that [arylꢀIꢀMes]OTf
(Mes=mesityl) could probably be used to transfer the aryl
group selectively thanks to steric difference between the aryl
and Mes groups.
With this last result in mind, different [arylꢀIꢀMes]OTf deriva-
tives were engaged in the reaction with naphthalene 1g
(Table 4). The obtained results confirmed our hypothesis.
After that, we turned our attention to the transferred aryl
group and naphthalenes 1a and 1g were used as model sub-
strates. Several symmetrical diaryliodonium derivatives were
synthesized and tested under our reaction conditions (Table 3).
Table 4. Naphthalene functionalization with [arylꢀIꢀMes]OTf.[a,b]
Table 3. Naphthalene functionalization with symmetrical diaryliodonium
salts.[a,b]
[a] Reactions were carried out by using 1 (0.2 mmol), [arylꢀIꢀMes]OTf
(0.6 mmol), TfOH (0.2 mmol), and Pd(OAc)2 (0.02 mmol) in DCE (4 mL) for
24 h at 808C. [b] Yields of products isolated were reported.
[a] Reactions were carried out by using 1 (0.2 mmol), Ar2IOTf (0.6 mmol),
TfOH (0.2 mmol), and Pd(OAc)2 (0.02 mmol) in DCE (4 mL) for 24 h at
808C. [b] Yields of products isolated were reported.
Indeed, several aryl groups substituted at the para and meta
positions were successfully transferred. Naphthalenes 2gk–
2gm, with electron-withdrawing substituents (CO2Et, F, CF3) in
the para position, were isolated in moderate to good yields
(17–69%). Product 2gn, into which a biphenyl group was in-
serted, was obtained in excellent yield (91%). Naphthalenes
2go and 2gp, with meta-substituted aryl groups were also ob-
tained in very good yield. 3,5-Dimethylphenyl was transferred
in 89% yield, whereas 3-methoxyphenyl was inserted in 69%
yield. [arylꢀIꢀMes]OTf derivatives were also reacted with naph-
thalene 1n, which included the Weinreb amide as a directing
group. Desired products 2nn and 2no were obtained in good
yields (71 and 53%, respectively).
First, aryls with a para substituent were introduced, with suc-
cess, under our standard conditions. Products 2ab–ae, bearing
bromine, chlorine, methoxy, or tert-butyl groups in the para
position, were obtained in good yields (55–80%). Compounds
2ab and 2ac, with an halogenated aryl group, open the door
to further coupling reactions to synthesize more complex poly-
aromatic derivatives. The reaction also worked very well on
naphthalene 1g with different para-substituted diaryliodonium
derivatives (products 2gc–2gh). Indeed, aryls substituted with
chlorine, methoxy, methyl, or acetyl groups were successfully
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To shed some light on the observed C8-regioselectivity, we
explored both C2- and C8-arylation pathways by using DFT cal-
culations. N,N-Dimethyl-1-naphthamide was used as a model
substrate to prevent conformational difficulties on the pyrrol-
idine moiety. Due to literature precedents in which the palladi-
um catalyst was first oxidized by the diaryliodonium salt
before the CꢀH activation step,[20] we checked that the prelimi-
nary formation of PdIV was not favorable under our reaction
conditions.[21] Then, taking into account that cyclopalladation is
typically the rate-limiting step of palladium-catalyzed CꢀH
functionalization,[22] a comparison of the free energy profiles of
palladium addition at the two different positions was per-
formed. It turns out that initial palladium addition, during
which the CꢀPd bond is formed prior to the arylation step, is
clearly more favorable at position C8 than that at position C2
(Figure 2). Both reaction pathways start from the reactants at
points toward the C8ꢀH bond. Indeed, the amide group is not
coplanar with the naphthalene p system, probably due to
steric interactions between the alkyl groups of the amide and
the C2ꢀH and C8ꢀH bonds. The naphthalene skeleton implies
that the steric interaction with C2ꢀH is weaker, so partial con-
jugation of the amide is observed (dihedral angle C2-C1-C-O=
122.98), with the N(Me)2 moiety pointing towards the C2ꢀH
bond. This conformation is well adapted to establish a stabiliz-
ing interaction between the catalyst and carbonyl oxygen
atom in the RC-C8 complex (Pd···O=2.04 ꢂ, see also Figure S2
in the Supporting Information). On the other hand, the posi-
tioning of the catalyst above C2 does not allow this interaction
(Pd···O=3.17 ꢂ, see also Figure S1 in the Supporting Informa-
tion), which explains the lower energy of RC-C8. This DFT study
shows that a disubstituted amide directing group allows con-
trol over the regioselectivity of palladium insertion and ex-
plains our experimental observations.
To demonstrate the synthetic utility of our arylation reaction,
amide 2gp was heated at 1008C in phosphoryl chloride
(Scheme 2a) and, through amide activation, benzanthrone 3
Figure 2. Free energy profiles of palladium addition at the C2- (red) and C8-
positions (blue) of N,N-dimethyl-1-naphthamide. Optimized molecular struc-
tures for each stationary state, namely, reactants at infinite separation (R1),
reactant complexes (RCs), transition states (TSs), and reaction intermediates
with a CꢀPd bond (I) are shown. Molecules in the R1 state are represented
with a surrounding dotted ellipse to highlight the fact that they were mod-
eled independently, in their own solvation cavity. For the sake of clarity,
most hydrogen atoms of 1-amidonaphthalene are hidden. Only (C2)H and
(C8)H atoms are shown, if necessary. Additional molecular representations
and all XYZ coordinates of each stationary point are provided in the Sup-
porting Information. Energy variation along the formation of the RCs and
the chemical steps are represented with dashed and solid lines, respectively.
Scheme 2. Product transformations to demonstrate the synthetic utility of
our arylation reaction.
was synthesized in 79% yield. This method offers a facile
access to the benzanthrone moiety, the fluorescent probe ap-
plications,[23] as well as biological properties, of which are well
known.[24] Moreover, the arylation reaction was possible by
using the Weinreb amide as a directing group, which allowed
classical transformations known for this functional group. For
instance, the methoxy group of the Weinreb amide could be
deprotected to deliver secondary amide 4 in 76% yield from
2na (Scheme 2b). Interestingly, Weinreb amide 2na was re-
infinite separation (R1), namely, palladium(II) triflate (formed
from palladium diacetate and TfOH) and N,N-dimethyl-1-naph-
thamide in their respective solvent cages. The first stage of the
reaction is the formation of a RC, the geometry of which de-
pends on whether the palladium catalyst approaches the C2ꢀ duced into aldehyde 5 by lithium aluminum hydride, which
H or C8ꢀH bond. Then the reaction proceeds through the
actual chemical step, passing through a TS, and leading to the
reaction intermediate (I) that contains a newly created C2ꢀPd
or C8ꢀPd bond.
gave access to another versatile functional group.
Conclusion
A comparison of the two free energy profiles reveals that
the main difference lies in the relative stability of RC-C8 versus
RC-C2. The former is indeed 11 kcalmolꢀ1 lower in free energy
than that of the latter. This preference seems to originate from
the structure of the free substrate, in which the amide group
We developed a palladium-catalyzed C8-arylation reaction of
1-amidonaphthalenes based on a CꢀH activation strategy. This
methodology gives efficient access to polyaromatic structures
by using diaryliodonium salts as arylating agents. The perfect
C8-regioselectivity observed in our reaction was explained
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thanks to DFT calculations. Indeed, we showed that, due to the
weakly coordinating tertiary amide directing group, approach
of the palladium catalyst was more favorable in the C8 posi-
tion than that at C2. Our method represents an effective way
to functionalize 1-amidonaphthalenes in position 8 and its util-
ity was demonstrated by the synthesis of the benzanthrone
scaffold. Further explorations of CꢀH activation reactions with
naphthalene derivatives are currently in progress in our labora-
tory.
Acknowledgements
We thank T. T. Thuan for the synthesis of compound 1k. The
CNRS, ENSTA, and Ecole Polytechnique are acknowledged for
financial support.
Conflict of interest
The authors declare no conflict of interest.
Keywords: arylation
homogeneous catalysis · palladium · synthesis design
·
density functional calculations
·
Experimental Section
For a detailed description of the synthesis of starting material, the
arylation reaction, and product transformations, see the Supporting
Information.
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General procedure for naphthalene amide 1a–l formation
thionyl chloride (1.5 equiv) was added dropwise at 08C to a solu-
tion of 1-naphthoic acid (1 equiv) in dry CH2Cl2 (C=0.15m) and the
mixture was stirred at RT for 1 h. At 08C, Et3N (3 equiv) and pyrrol-
idine (1.2 equiv) were added dropwise and the mixture was stirred
at RT for 16 h. At RT, H2O was added and the layers were separat-
ed. The aqueous layer was extracted with Et2O and the combined
organic layers were dried over MgSO4 and concentrated in vacuo.
The residue was purified by flash chromatography to deliver amide
1.
General procedure for C8-arylation
Naphthalene amide 1 (0.2 mmol, 1 equiv), palladium diacetate
(4.5 mg, 0.02 mmol, 0.1 equiv), and the desired diaryliodonium salt
(0.6 mmol, 3 equiv) were placed in a tube. DCE (4 mL) and TfOH
(18 mL, 0.2 mmol, 1 equiv) were added and the tube was closed
with a screw cap. The mixture was stirred at 808C for 24 h. The
mixture was filtered through a pad of Celite and washed with
CH2Cl2. The organic phase was washed with a saturated aqueous
solution of NaHCO3, dried over MgSO4, and concentrated in vacuo.
The residue was purified by flash chromatography to give com-
pound 2.
Computational methods
All electronic structure calculations were performed by means of
DFT with the M062X functional,[25] as implemented in the Gaussian
09 suite of programs.[26] All atoms except palladium were repre-
sented with the 6-31G(d,p) basis set,[27–29] whereas the LANL2DZ
basis set, together with the corresponding effective core poten-
tial,[30] were used for palladium. The molecular system was embed-
ded in a dielectric cavity that mimicked the DCE solvent (polariz-
able continuum model (PCM)[31]). All relevant reactants, products,
and TS geometries were optimized, including solvent effects, and
then validated by means of normal mode analysis. For each TS, the
single mode corresponding to an imaginary frequency was used to
define an intrinsic reaction coordinate[32]+and proceeded downhill
toward the reactants and products of the elementary step. Graph-
ical representations of the molecules were made with the software
VMD.[33]
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Manuscript received: July 31, 2019
Accepted manuscript online: September 3, 2019
Version of record online: && &&, 0000
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FULL PAPER
&
Synthesis Design
J. Garrec, M. Cordier, G. Frison, S. Prꢀvost*
&& – &&
Palladium-Catalyzed C8-Arylation of
Naphthalenes through CꢀH
Directing reactions: The development
of direct palladium-catalyzed C8-aryla-
tion of naphthalene derivatives was
achieved by using diaryliodonium deriv-
atives as arylating agents (see scheme).
The regioselectivity of the reaction (C8
vs. C2) was studied by DFT calculations
and the important role of the tertiary
amide directing group was explained.
Activation: A Combined Experimental
and Computational Study
Chem. Eur. J. 2019, 25, 1 – 7
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ꢁ 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers! ÞÞ