Chelation-assisted Pd-catalysed ortho-selective oxidative C-H/C-H cross-coupling of aromatic carboxylic acids with arenes and intramolecular Friedel-Crafts acylation: One-pot formation of fluorenones

Article abstract of DOI:10.1039/c6cc00103c

Pd-Catalysed ortho-selective oxidative C-H/C-H cross-coupling of aromatic carboxylic acids with arenes and subsequent intramolecular Friedel-Crafts acylation has been accomplished for the first time through a chelation-assisted C-H activation strategy. Starting from the readily available substrates, a variety of fluorenone derivatives are obtained in one pot. The direct use of naturally occurring carboxylic acid functionalities as directing groups avoids unnecessary steps for installation and removal of an extra directing group.

Full text of DOI:10.1039/c6cc00103c

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Chelation-assisted Pd-catalysed ortho-selective oxidative C–H/C–
H cross-coupling of aromatic carboxylic acids with arenes and
intramolecular Friedel-Crafts acylation: one-pot formation of
fluorenones
rReceived 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Denan Sun, Bijin Li, Jingbo Lan,* Quan Huang and Jingsong You*
www.rsc.org/
9
Pd-catalysed ortho-selective oxidative C–H/C–H cross-coupling of and synthetic products. From the perspective of synthetic
aromatic carboxylic acids with arenes and subsequent simplicity and availability of starting materials, the direct use of
intramolecular Friedel-Crafts acylation has been accomplished for naturally occurring carboxylic acid functionalities as directing
the first time through chelation-assisted C–H activation strategy. groups to activate ortho-C–H bonds of aromatic carboxylic acids is
Starting from readily available substrates, a variety of fluorenone doubtless one of the most ideal strategies to achieve the ortho-
derivatives are obtained in one pot. The direct use of naturally selective arylation of arenes, which avoid unnecessary steps for
occurring carboxylic acid functionalities as directing groups avoids installation and removal of an extra directing group.
unnecessary steps for installation and removal of an extra
OH
OMe
directing group.
Et
2
N
NEt
2
OH
O
O
n
Fluorenone derivatives have attracted widespread interest because
of their important applications in the fields of biomedical and
O
O
O
Dengibsin
PF
Tilorone
Interferon inducer
1
Natural product
Electron-injection material
photoelectric materials (Scheme 1). Traditional methods towards
R
the synthesis of fluorenones include Friedel-Crafts cyclization of
S
2
2
CO H
biaryl carboxylic acids, Pschorr cyclization of 2-amino diaryl
N
1
NC
3
4
99
17
ketones, and oxidation of fluorenol. However, these methods
suffer from some limitations such as multistep procedures,
C
8
H
17
C
8
H
O
O
PFO-F (1%)
White electrophorescent material
HIQF1 (R = C
8
H17O)
R
Sensitized dye for solar cell
inaccessible
synthetic
precursors
and/or
tedious
Scheme 1. Natural products, pharmaceutical drugs and photoelectric materials
prefunctionalization. During recent decades, transition metal-
catalysed C–H bond functionalization has emerged as a powerful
containing the fluorenone framework.
5
method to construct C–C bonds, many of which have thus been
a. Intramolecular cyclizations
6
-7
developed to access fluorenone frameworks. For instance, the
transition metal-catalysed intramolecular cyclizations of 2-aryl-
benzaldehydes, 2-aryl-benzonitrile, biaryl-2-carboxylic acids, o-
halobiaryls and CO, as well as various diaryl ketone derivatives are
X
O
Y
Ar
or
Ar
Ar
Ar
X = CHO, CN, COOH, Br
Y = I, H
efficient methodologies for the synthesis of fluorenones (Scheme
6
2
a). In addition, the directing group assisted ortho-arylations of
b. Directing group assisted ortho-arylation and cyclizations
aryl nitriles, benzamides, aryl aldoxime ethers, or benzylamines
with iodo arenes, aryl boronic acids, or simple arenes (as solvent),
and subsequent intramolecular cyclizations have also been
O
DG
Ar
+
X
Ar
Ar
Ar
DG = CN, CONHR, C=NOMe, CH
X = I, B(OH) , H
2 2
NH
6
b,7
extensively studied to provide fluorenones (Scheme 2b).
2
The carboxylic acid group is one of the most common organic
This work: carboxylic acid directed ortho-arylation and cyclization
COOH
8
functionalities. Aromatic carboxylic acids are widespread in natural
COOH
Ar
one-potreaction
H
H
Ar
Ar
+
Ar
4
.0 equiv
•
•
Dual C-H activation strategy
•
•
•
Easily available starting materials
Mild reaction condition
Avoidance of installation and removal
of an external directing group
One-pot synthesis of fluorenones
Scheme 2. Synthesis of fluorenone derivatives.
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Recently, the Rh(III)-catalysed carboxylic acid directed ortho-C–H with both electron-donating groups, such as m-xylene, p-xylene and
heteroarylation of aromatic carboxylic acids have been toluene, and electron-withdrawing groups, such as o-
implemented through the oxidative C–H/C–H cross-coupling with difluorobenzene and p-difluorobenzene, to deliver fluorenones in
thiophenes, furans, indoles, azoles, etc. by Su and our group, satisfactory yields (Table 2). The cross-coupling of 1b with o-
1
0,11
respectively.
However, the carboxylic acid directed oxidative C– difluorobenzene occurred highly regioselectively at the 4-position
H/C–H cross-coupling of aromatic carboxylic acids with simple and then intramolecular Friedel-Crafts acylation at the 5-position of
arenes still remains unsettled. One of the greatest challenges in this benzene ring (4c). The coupling of 1b with m-xylene also occurred
transformation is that aromatic carboxylic acids are peculiarly prone at the 4-position and then acylation at 5-position (4d). However,
1
2
to undergo decarboxylation in the presence of transition metals.
the coupling reaction of 1b with 2-chloro-m-xylene occurred
In addition, due to the generally low reactivity of C−H bonds, arenes regioselectively at the 5-position and then acylation at 4-position
are usually used as solvent or cosolvent, which impose a limitation (4e). The reaction of toluene with 1b gave fluorenone 4f in a lower
1
3
on synthetic applications. As part of our program for the C−H yield due to the generation of a small amount of regioisomer. The
11,14
bond activation of (hetero)arenes,
we present the solution to structures of 4c, 4d, 4e and 4f were verified by single-crystal X-ray
these problems and disclose the direct oxidative ortho-C−H analysis (Table 2), HMBC (see ESI†) or NOESY (see ESI†).
arylation of aromatic carboxylic acids through dual C−H acꢀvaꢀon
a
and subsequent intramolecular Friedel-Crafts acylation to construct Table 1. Scope of benzoic acids
O
diverse substituted fluorenone derivatives (Scheme 2).
COOH
Pd(OAc)2 (10 mol%), Ac-Ile-OH (20 mol%)
Na S O (3.0 equiv), DMSO (2.0 equiv)
To test the feasibility of the dual C−H acꢀvaꢀon strategy, we
explored the oxidative C–H/C–H cross-coupling of benzoic acid (1a)
and benzene (2a). Surprisingly, the coupling reaction of 1a with 2a
directly provided the fluorenone 3a in 45% yield with concomitant
H
+
H
2
2
8
R1
R1
TfOH (5.0 equiv), 80 C, 24 h
1a-p
2a
3a-p
O
O
O
O
MeO
Cl
intramolecular Friedel-Crafts acylation in the presence of Pd(OAc)
and trifluoromethanesulfonic acid (TfOH) by using Na as the
2
2 2 8
S O
oxidant (Table S1, entry 5). Considering the importance of the
Fluorenone derivatives, the reaction conditions were further
optimized. Several key parameters including different acids,
oxidants, reaction temperature, ligands and the amount of benzene
were screened, and rewardingly, this protocol produced a high yield
of fluorenone in model systems at a relatively low temperature
3a
3d
(81%)
(
82%)
3c (76%)
3
b (80%)
O
O
O
O
F
MeO
Br
3e (81%)
3
f (75%)
3g
(73%)
3h (79%)
O
O
O
O
(
Table S1-S6). Finally, the optimal reaction condition was obtained
when 1a (0.40 mmol), 2a (1.60 mmol), Pd(OAc) (10 mol%) and
Na (3.0 equiv) in TfOH (5.0 equiv), DMSO (2.0 equiv), and Ac-
Cl
2
2 2 8
S O
t-Bu
Ph
Ile-OH (20 mol%) at 80 °C for 24 h under an air atmosphere (Table
S6, entry 5). We supposed that DMSO might play important roles in
activating catalyst and preventing the formation of palladium
3i (75%)
3j (73%)
3k (58%)b
3l (53%)b
O
O
O
O
O
1
5
Cl
black. It is worthwhile to note that this coupling reaction could
deliver fluorenone in 82% yield with only 4.0 equiv of arene
Cl
1
6
3m (55%)b
coupling partner.
3n (55%)
3o (60%)
3p (70%)
Using the optimal conditions, the scope of aromatic carboxylic
acids was examined with benzene (2a) as an arylating reagent.
Aromatic carboxylic acids with ortho-, meta-, and para-substituents
a
Reaction conditions: aromatic carboxylic acid (0.4 mmol), arene (4.0 equiv),
Pd(OAc) (10 mol%), Na (3.0 equiv), TfOH (5.0 equiv), DMSO (2.0 equiv), Ac-
Ile-OH (20 mol%) at 80 C under an air atmosphere for 24 h. 2a (10.0 equiv)
2
2 2 8
S O
o
b
reacted with benzene in good yields (3b-3k). 2-Naphthoic acid could DMSO = dimethyl sulfoxide. Ac-Ile-OH = 2-acetamido-3-methylpentanoic acid.
undergo the cross-coupling at C3-position to afford 11H-
benzo[b]fluoren-11-one in acceptable yield (3l). 1-Naphthoic acid
reacts at C8-position to produce 7H-benzo[de]anthracen-7-one in coupling of aromatic carboxylic acids with arenes and
5% yields (3m). The cross-coupling of both 2,4- and 2,3- intramolecular Friedel-Crafts acylation, the kinetic H/D isotope
To gather further insight into the oxidative C–H/C–H cross-
5
disubstituted benzoic acids with benzene gave the disfunctionalized effect (KIE) studies were performed for both benzoic acid and
fluorenone derivatives in synthetically useful yields (3n-3p). benzene. The intermolecular competition reaction between benzoic
Notably, this oxidative cross-coupling reaction could tolerate acid and benzoic-d
reactive chloride and bromide, which would provide a benefit for (S1)], indicating that the C−H bond cleavage of benzoic acid would
the further synthetic transformations. Unfortunately, benzoic acids not be the rate-determining step. However, a significant KIE (k /k
with strong electron-withdrawing substituents, such as nitro and 2.0) was observed in the competition experiment of benzene and
cyano could not react with benzene to afford corresponding benzene-d [see Eq. (S2)], suggesting that the C−H bond breaking of
fluorenones.
benzene might be the rate-limiting step. Based on these findings, a
5 H D
acid gave a small KIE value (k /k = 1.0) [see Eq.
H
D
=
6
Furthermore, the scope of arenes was next examined using 2- plausible catalytic cycle could involve: the coordination of 1a to
methoxy benzoic acid (1b) as the coupling partner. It was found Pd(II) and subsequent ortho-C−H acꢀvaꢀon form the five
1
7
that this reaction could tolerate a wide range of arene substrates membered palladacycle IM-1; The oxidation of IM-1 generates the
2
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Pd(IV) intermediate IM-2, which reacted with the substrate 2a to (diphenylamino)phenyl)-1-methoxy-9H-fluoren-9-one
(6)
was
afford the critical aryl–palladacycle intermediate IM-3; Reductive synthesized via the Suzuki coupling of 3n and (4-
1
4a
elimination leads to the ortho-arylated product 5 and Pd(II) for the (diphenylamino)phenyl)boronic acid (Scheme 4). Gratifyingly, 6
next catalytic cycle; The Friedel-Crafts acylation of 5 gives exhibits strong yellow-green emissions and high fluorescence
fluorenone 3a (Scheme 3).
quantum yields in both toluene solution (45%) and PS film (35%)
Scheme 4, and see Figure S2).
(
a
Table 2. Scope of arenes
a
Reaction conditions: aromatic carboxylic acid (0.4 mmol), arene (4.0 equiv),
Pd(OAc)
2 2 2 8
(10 mol%), Na S O (3.0 equiv), TfOH (5.0 equiv), DMSO (2.0 equiv), Ac-
o
b
Ile-OH (20 mol%) at 80 C under an air atmosphere for 24 h. MeCN (2.0 equiv).
c
d
Structure was verified by NOESY. Structure was verified by HMBC.
Scheme 4 Synthesis of 3-(4-(diphenylamino)phenyl)-1-methoxy-9H-fluoren-9-one
(
6). Absolute quantum yields, absorption and emission maxima were measured
-5
[
a] in toluene (5.0 × 10 M) and [b] in PS films (5.0 wt%), respectively. Insert:
-5
fluorescence images of 6 in toluene (5.0 × 10 M), and in PS films (5.0 wt%) under
UV light (365 nm).
In conclusion, we have developed an efficient method for the
Scheme 3. Proposed mechanism for the catalytic reaction of benzoic acid (1a) synthesis of fluorenone derivatives through chelation-assisted Pd-
with benzene (2a)
catalysed ortho-selective oxidative C–H/C–H cross-coupling of
aromatic carboxylic acids with arenes and subsequent
To support this catalytic cycle, the biphenyl-2-carboxylic acid (5) intramolecular Friedel-Crafts acylation. A variety of fluorenones are
was prepared and its reactivity was examined. Under optimal obtained in good yield with only 4.0 equiv of arene coupling
conditions, the intramolecular Friedel-Crafts reaction of 5 occurred partner. Furthermore, the direct use of naturally occurring
readily to afford the cyclization product 9-fluorenone in 89% yield carboxylic acid functionalities as directing groups avoids
[Eq. (1)]. However, when benzophenone was treated in the same unnecessary steps for installation and removal of an extra directing
condition, the cyclization product was not obtained [Eq. (2)]. group. As an example to illuminate the synthetic utility of our
Moreover, when the same reaction was carried out in the absence protocol, we furthermore demonstrated that the TPA-modified
2 2 2 8
of Pd(OAc) and Na S O , 3a was obtained in 90% yield [Eq. (3)]. The fluorenone derivative 6 is a potential organic luminescent material.
observations indicate that fluorenone could be formed by the
intramolecular Friedel-Crafts reaction of biphenyl-2-carboxylic acid
in the presence of TfOH.
This work was supported by grants from the National NSF of
China (Nos 21432005, 21372164, 21321061 and 21272160), and
The triphenylamine (TPA) group is widespread in various Sichuan Provincial Foundation (2012JQ0002).
photoelectric materials due to their good electron-donating
property,
hole-transporting
capability
and
nonplanar
1
8
Notes and references
characteristic. To illuminate the synthetic utility of our
methodology and highlight the importance of fluorenone skeletons
in the construction of organic luminescent materials, 3-(4-
‡ CCDC 1444004 (4c) and 1443932 (4d) contain the
supplementary crystallographic data for this paper. These data
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