Palladium-Catalyzed C8-Oxygenation of Naphthalene Derivatives: Direct Access to Naphtholactone Skeleton

Article abstract of DOI:10.1002/adsc.202100317

Herein, a direct C8-oxygenation of naphthalene derivatives is described. Different carbonyl groups were used as directing group to deliver corresponding naphthols via a palladium-catalyzed oxidation reaction using PhI(OAc)₂ in a TFA/TFAA mixture. Interestingly, when Weinreb amide was employed as the directing group, the naphtholactone skeleton was directly obtained. This methodology was applied to the synthesis of variously substituted naphtholactones. (Figure presented.).

Full text of DOI:10.1002/adsc.202100317

UPDATES
doi.org/10.1002/adsc.202100317
Palladium-Catalyzed C8-Oxygenation of Naphthalene
Derivatives: Direct Access to Naphtholactone Skeleton
Caroline Berroua and Sébastien Prévosta,*
a
Laboratoire de Synthèse Organique, Ecole Polytechnique, ENSTA Paris, CNRS, Institut Polytechnique de Paris, Palaiseau 91128
Cedex, France
E-mail: sebastien.prevost@ensta-paris.fr
Manuscript received: March 12, 2021; Revised manuscript received: June 21, 2021;
Version of record online: ■■■, ■■■■
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202100317
reported but generally requiring a large number of
Abstract: Herein,
a direct C8-oxygenation of
steps and harsh conditions.[4]
naphthalene derivatives is described. Different
carbonyl groups were used as directing group to
deliver corresponding naphthols via a palladium-
catalyzed oxidation reaction using PhI(OAc)2 in a
TFA/TFAA mixture. Interestingly, when Weinreb
amide was employed as the directing group, the
naphtholactone skeleton was directly obtained. This
methodology was applied to the synthesis of
variously substituted naphtholactones.
In this context, the development of a direct oxygen-
ation method of naphthalenes to easily obtain naph-
tholactone is of considerable interest. In order to form
the lactone moiety, a suitable strategy would be based
on naphthalene oxygenation via a carbonyl directed
CÀ H activation of the peri-position. Indeed, this
strategy would allow the introduction of the oxygen
atom of the lactone while using the carbonyl group as
directing group and then as lactone precursor.
In recent years, many advances have been made on
direct CÀ H oxygenation of arenes.[5] The importance of
phenols incited chemists to develop straightforward
synthetic methods with high atom- and step-economy
so that different transition metals, combined or not
with photochemistry or electrochemistry, have been
Keywords: CÀ H oxygenation; naphtholactone; 1-
carbonylnaphthalene; oxidation; palladium catalysis
Naphtholactone is an important moiety in chemistry, employed to create CÀ O bonds.[6] Although, first
commonly found in natural products of varying examples were developed with classical strongly
degrees of complexity (Figure 1).[1] Many studies have coordinating directing groups,[7] progress has recently
been carried out whether on their biosynthesis or on been made with weakly coordinating groups.[8] Con-
their biological activities.[2] For instance, norbadione A cerning ortho CÀ H hydroxylation of arenes with
is known as
a pigment displaying antioxidant carbonyl directing groups, different transition metals
properties.[3] Different synthetic studies have been were reported as efficient catalysts such as Pd,[9] Ru,[10]
Rh,[11] or Cu (Scheme 1a).[12] Regarding the
naphthalene core, several CÀ H functionalization meth-
ods have been reported over the last decade.[13] Nowa-
days, almost all naphthalene positions can be directly
functionalize even if the C2-position remains the most
studied. In regards to C8-functionalization with
carbonyl as weakly coordinating directing group, few
works have been reported.[14] Inspired by the work of
Xiao and Fu’s group on C8-triflation,[14a] we recently
disclosed
a
palladium-catalyzed C8-arylation of
naphthalene derivatives (Scheme 1b).[14d] However,
C8-functionalization of 1-carbonyl naphthalenes is still
under-studied. Another strategy, based on transient
directing groups, has been lately developed by Zhang’s
team.[15] With this in mind, we were keen to develop a
Figure 1. Natural products bearing a naphtholactone moiety.
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Table 1. Selected optimization results.[a]
Entry [Pd]
Oxidant (equiv.)
Temp
Yield
(%)[b]
°
( C)
1
2
3
Pd(OAc)2 PhI(OAc)2 (2)
Pd(OAc)2 Selectfluor (2)
Pd(OAc)2 Benzoyl peroxide
(2)
80
80
80
57
33
47
4
5
6
7
8
9
10
11
12
Pd(OAc)2 PhI(OAc)2 (2)
Pd(OAc)2 PhI(OAc)2 (2)
Pd(OAc)2 PhI(OAc)2 (2)
Pd(OAc)2 PhI(OAc)2 (1.5)
Pd(OAc)2 PhI(OAc)2 (2.5)
Pd(OAc)2 PhI(OAc)2 (3)
PdCl2(Ph3)2 PhI(OAc)2 (2)
20
40
60
40
40
40
20
40
20
47
75
57
52
64
58
30
60
0
Scheme 1. (a) Well-established CÀ H oxygenation of arenes. (b)
Previous naphthalene C8-functionalizations with carbonyl di-
recting groups. (c) This work on C8-oxygenation.
[c]
Pd(OAc)2 PhI(OAc)2 (2)
–
PhI(OAc)2 (2)
[a] Reactions were carried out using 1a (0.22 mmol), oxidant
and [Pd] (0.022 mmol) in TFA/TFAA (0.5 mL, 9:1) for 20 h.
[b] NMR yield determined using 1,3,5-trimethoxybenzene as
internal standard.
direct C8-oxygenation of naphthalene derivatives using
carbonyl moiety as directing group which would allow
a fast and easy access to naphtholactone (Scheme 1c).
Herein we present a palladium-catalyzed C8-oxy-
genation of 1-amidonaphthalene derivatives which
gives the first direct access to naphtholactone skeleton
via CÀ H activation.
[c] 5 mol% of Pd(OAc)2 was used.
groups for the C8-oxygenation. First, (8-hydroxynaph-
At the onset of our investigation, we focused our thalen-1-yl)(pyrrolidin-1-yl)methanone 2aa was iso-
attention on the C8-oxygenation of naphthalen-1-yl- lated in 73% yield, in line with the NMR yield
(pyrrolidin-1-yl)methanone 1aa. Pd(OAc)2 (10 mol%) previously observed (Table 2, entry 1). Similarly, pi-
was employed as catalyst and different oxidants were peridine and morpholine amides allowed the formation
tested in a mixture of trifluoroacetic acid (TFA)/ of corresponding naphthols in good yields (Table 2,
trifluoroacetic anhydride (TFAA) as solvant (Table 1, entries 2–3). Despite a lower yields, C8-oxygenation
entries 1–3). Since pioneering work of Sanford’s was also achieved with a non cyclic amide as well as
group,[16] several research groups have reported the use secondary amide (Table 2, entries 4–5). Other func-
of hypervalent iodine reagents in naphthalene tional groups, such as ester, aldehyde and carboxylic
functionalization.[17] For our reaction, (diacetoxyiodo) acid, were tried in the reaction without a lot of success
benzene was found to be the best oxidant, delivering (Table 2, entry 6–8). Ethyl 8-hydroxy-1-naphthoate
desired naphthol 2aa in 57% NMR yield. A full 2fa and 8-hydroxy-1-naphthaldehyde 2ga were iso-
optimization of the reaction was carried out,[18] and lated in low yields (24% and 29% respectively)
°
40 C was found to be the ideal temperature for the whereas no naphthol was observed with a carboxylic
reaction with a 75% NMR yield (Table 1, entries 4–6). acid as directing group. Finally, the reaction was
Finally, the amount of oxidant as well as other carried out with a Weinreb amide as directing group,
palladium sources were evaluated without any im- and very interestingly lactone 2ia was directly isolated
provement (Table 1, entries 7–10). It is important to as the only product in very good yield (85%) (Table 2,
note that a decrease in the amount of catalyst to entry 9).
5 mol% showed a small drop in yield (Table 1,
According to the results on the directing group
entry 11) while without palladium catalyst no product scope, several naphthalene derivatives with an amido-
was formed and only a slight degradation of the pyrrolidine group were engaged in the oxygenation
starting material was observed (Table 1, entry 12).
reaction (Table 3). 1-Amidonaphthalenes 1ab–1ae,
With the optimized conditions in hand, we inves- substituted by a halogen atom in position 4, were
tigated the scope of the reaction by studying first the compatible with the reaction conditions and delivered
influence of the nature of the directing group (Table 2). the corresponding naphthol in moderate to good yields
Cyclic amides were found to be efficient directing (33-59%). Unfortunately, a methoxy substituent was
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Table 2. Scope of the carbonyl directing group.[a,b]
Table 3. Scope of the pyrrolidine amide derivatives.[a,b]
[a] Reactions were carried out using 1a (0.5 mmol), PhI(OAc)2
(1 mmol) and Pd(OAc)2 (0.05 mmol) in trifluoroacetic acid/
°
trifluoroacetic anhydride (1.14 mL, 9:1) for 20 h at 40 C.
[b] Isolated yields were reported.
oxygenated product 2ai was isolated as the only
product.
Following our goal of naphtholactone synthesis for
synthetic applications, different Weinreb amide deriva-
tives were tested in the reaction (Table 4). Pleasingly,
as previously, naphthalenes bearing a halogen atom in
position 4 delivered corresponding lactones 2ib–2ie in
Table 4. Scope of the naphtholactone synthesis.[a,b]
[a] Reactions were carried out using 1 (0.5 mmol), PhI(OAc)2
(1 mmol) and Pd(OAc)2 (0.05 mmol) in trifluoroacetic acid/
°
trifluoroacetic anhydride (1.14 mL, 9:1) for 20 h at 40 C.
[b] Isolated yields were reported.
not tolerated in the reaction and only degradation was
observed, probably due to overoxidation products
which were unstable in acidic medium (yield of 2af=
0%). To extend the scope, naphthalene derivatives with
halogen atoms in position 5 1ag–1ah were success-
fully hydroxylated. Finally, 1,4-diamido naphthalene
1ai was tried under our reaction conditions and mono-
[a] Reactions were carried out using 1i (0.5 mmol), PhI(OAc)2
(1 mmol) and Pd(OAc)2 (0.05 mmol) in trifluoroacetic acid/
°
trifluoroacetic anhydride (1.14 mL, 9:1) for 20 h at 40 C.
[b] Isolated yields were reported.
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good yields (44–65%). Then, the effect of carbonyl coupling reactions, it would be possible to obtain
substituents was evaluated. When the reaction was easily complex naphtholactone derivatives. Finally,
realized with diamide 1if, monolactone 2if was naphthol 2ac was oxidized into quinone 6 in 71%
obtained in 46% yield. In addition, when naphthalene yield thanks to [bis(trifluoroacetoxy)iodo]benzene
derivative 1ig bearing a Weinreb amide and an ester (Scheme 2c).
group was engaged in the reaction, only the Weinreb
In conclusion, we developed a palladium-catalyzed
amide was an efficient directing group and lactone 2ig C8-oxygenation of naphthalenes based on a CÀ H
was synthesized. Other substituent positions were activation approach. Amides were found to be suitable
possible for the naphthalene derivative. Indeed, to our directing groups for this transformation. In particular,
delight, bromine or chlorine atoms in position 3 or 5 Weinreb amide directly delivered the corresponding
were compatible with the reaction conditions. The lactone opening up very interesting perspectives to
reaction was also carried out on gram scale and lactone apply our strategy for the synthesis of biologically
2ih was obtained in a similar yield of 53%. Finally active compounds. Further explorations of CÀ H
tetracyclic core of aristololide 2ik was obtained in a activation reactions with naphthalene derivatives are
very small number of steps. Indeed, amide 1ik was currently in progress in our laboratory.
obtained in one step based on the work of Li and Shi’s
group on phenanthrene derivative synthesis,[19] and
Experimental Section
therefore our methodology allowed the synthesis of
natural product skeleton in only two steps.
In order to demonstrate the synthetic utility of our
methodology, different transformations were realized
with our oxygenated products (Scheme 2). First,
although electron donating groups were not compatible
with our conditions, bromo-naphthol 2ab was coupled
with methyl 3-mercaptopropionate to obtain thioether
General procedure for the CÀ H oxygenation: Naphthalene 1
(0.5 mmol), Pd(OAc)2 (11 mg, 0.05 mmol, 0.1 eq.) and PhI
(OAc)2 (322 mg, 1 mmol, 2 eq.) were placed in a tube. TFA
(1.01 mL) and TFAA (113 μL) were added and the tube was
°
closed with a screw cap. The mixture was stirred at 40 C during
20 h. At r.t., the mixture was diluted with CH2Cl2 and a
saturated aqueous solution of NaHCO3 was slowly added. The
phases were separated and the aqueous phase was extracted
with CH2Cl2. The combined organic phases were dried over
MgSO4 and concentrated in vacuo. The residue was purified by
3 in 89% yield which, after acidic treatment, delivered
naphtholactone 4 (Scheme 2a). Next, lactone 2ih was
engaged in a Suzuki-Miyaura coupling reaction to
generate naphtholactone 5 in 79% yield bearing an
aromatic group in position 5 (Scheme 2b). Therefore,
these transformations show that, thanks to palladium
flash chromatography.
Acknowledgements
This work was supported by ANR JCJC grant NaFMeTS (ANR-
20-CE07-0017). The CNRS, ENSTA Paris and Ecole Poly-
technique are acknowledge for financial supports. We thank
Sophie Bourcier and Vincent Jactel for HRMS analyses.
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Palladium-Catalyzed C8-Oxygenation of Naphthalene Deriv-
atives: Direct Access to Naphtholactone Skeleton
Adv. Synth. Catal. 2021, 363, 1–6
C. Berrou, S. Prévost*