Synthesis of Fluorenones from Benzaldehydes and Aryl Iodides: Dual C-H Functionalizations Using a Transient Directing Group

Article abstract of DOI:10.1021/acs.orglett.7b00161

The first synthesis of substituted fluorenones directly from benzaldehydes and aryl iodides via a Pd(II)-catalyzed C(sp²)-H functionalization cascade is reported. Featuring anthranilic acid as an inexpensive transient directing group, the process is compatible with a variety of benzaldehydes and aryl iodides. A three-step synthesis of the antiviral drug Tilorone was completed in an excellent overall yield (40%), demonstrating the utility of this method.

Full text of DOI:10.1021/acs.orglett.7b00161

Letter
pubs.acs.org/OrgLett
Synthesis of Fluorenones from Benzaldehydes and Aryl Iodides: Dual
C−H Functionalizations Using a Transient Directing Group
Xiao-Yang Chen,† Seyma Ozturk,† and Erik J. Sorensen*,†
†Department of Chemistry, Princeton University, Princeton, New Jersey 08544, United States
S
* Supporting Information
ABSTRACT: The first synthesis of substituted fluorenones
directly from benzaldehydes and aryl iodides via a Pd(II)-
catalyzed C(sp2)−H functionalization cascade is reported.
Featuring anthranilic acid as an inexpensive transient directing
group, the process is compatible with a variety of
benzaldehydes and aryl iodides. A three-step synthesis of the
antiviral drug Tilorone was completed in an excellent overall yield (40%), demonstrating the utility of this method.
he prevalence of fluorenone-containing natural products,
Tbiologically active molecules, and pharmaceutically im-
portant agents has underscored the importance of general
synthetic methods for their efficient construction.1 Traditional
strategies, such as the Friedel−Crafts cyclization of biarylcarbox-
ylic acids2 and the oxidation of fluorenes,3 usually require
multistep syntheses of the substrates and are limited to electron-
rich arenes. Recent C−H functionalization4 approaches involve
intramolecular cyclization of biarylaldehydes, imines, carboxylic
acids, or diaryl ketone derivatives,5 as well as directed ortho C−H
arylation of benzonitriles, benzyl amines, benzamides, or benzoic
acids with subsequent cyclization.6 However, the possibility of
utilizing abundant, synthetically versatile but weakly coordinating
benzaldehydes as the substrates remains enigmatic, due to their
susceptibilitytowardoxidationandthecompetingmetalinsertion
into formyl C−H bonds. To address this issue, the laboratories of
Cheng and Shi used benzaldehyde oxime ethers with aryl iodides,
aryl boronic acids, or arenes as the coupling reagent to obtain
fluorenones via a Pd-catalyzed C−H functionalization cascade
(Scheme 1).7 Nevertheless, the practicability of these methods
was undermined by the additional steps required for the
stochiometric installation and removal of the oxime directing
group (DG).
As part of our efforts to expand our repertoire for synthesizing
fluorenone-containing natural products, we were intrigued by the
possibility of using benzaldehydes and aryl iodides as simple
starting materials to directly access substituted fluorenones via a
C−H functionalization cascade. For such an approach to work
without initial substrate modifications, we realized that an
appropriate, transient directing group (TDG) could enable the
process by reversibly binding and directing the C−H function-
alizations. This strategy has been exploited in several Rh catalyzed
C−H functionalization reactions;9 however, successful utilization
of Pd is a more recent advent, with the first example of Pd(II)-
catalyzed C(sp3)−H arylation of 2-methyl benzaldehydes and
aliphatic ketones featuring amino acids as the TDG reported by
Yuandco-workers.10 Subsequently, thelaboratoriesofHuandGe
reported similar reactions with 2-methyl benzaldehydes and
aliphatic aldehydes as the substrates using acetylhydrazide and β-
alanineastheTDG, respectively.11 In2016, Dongandco-workers
also described a Pd(II)-catalyzed γ-C(sp3)−H arylation of free
primary amines with a DG generated in situ from 8-formylquino-
line.12 The substrate scope of the reaction was expanded very
recently by the laboratories of Yu, Ge, and Murakami using 2-
hydroxynicotinaldehyde, glyoxylic acid, and 3,5-di-tert-butyl-
salicylaldehyde as the catalytic TDG, respectively.13
Inspired by these contributions, we reasoned that a similar
strategy could be employed to arylate the ortho C−H bond of
benzaldehydes14 and that fluorenone frameworks could arise in
the wake of a second C−H functionalization and a terminal,
oxidative Heck reaction15 (Scheme 1). With this idea in mind, we
commenced our studies by treating benzaldehyde with an excess
of iodoanisole in the presence of Pd catalysts, TDGs, and silver
saltsinvarious solventsystemsunderanairatmosphere at120°C.
After an extensive screening effort, the desired fluorenone was
formed in 45% yield after a 36 h reaction that employed 10 mol %
of Pd(OAc)2 as the catalyst, 2 equiv of AgTFA as the oxidant, 40
mol % of anthranilic acid (DG1) as the TDG, and 9:1 AcOH/
Our laboratory recently constructed the key hydrofluorenone
skeleton in Hirsutellone B through a double cyclization cascade.8
Scheme 1. Synthesis of Fluorenones via a Transient-Directing-
Group-Enabled C−H Functionalization Cascade
Received: January 17, 2017
© XXXX American Chemical Society
A
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Letter
HIFP (0.15 M) as the solvent (Table 1, entry 1). A series of
control experiments were subsequently conducted to elucidate
Scheme 2. Scope of the Benzaldehydes
a
Table 1. Control Experiments for Fluorenone Syntheses
b
entry
variation from the standard condition
yield of 1a (%)
c
1
none
45 (36%)
2
no Pd(OAc)2
0
3
no DG1
0
4
DG2 instead of DG1
DG3 instead of DG1
20 mol % DG1
trace
9
5
6
30
37
15
35
29
24
20
38
27
39
30
39
43
45
7
60 mol % DG1
8
at 100 °C
9
Pd(TFA)2 instead of Pd(OAc)2
PdCl2 instead of Pd(OAc)2
AgOAc instead of AgTFA
AgF instead of AgTFA
in AcOH
10
11
12
13
14
15
16
17
18
19
in AcOH/H2O (9:1)
in AcOH/HFIP (3:1)
in AcOH/HFIP (1:3)
with 5 equiv of H2O
0.1 M instead of 0.15 M
under argon
a
The reaction was performed with benzaldehyde (0.1 mmol),
iodoanisole (0.14 mmol), Pd(OAc)2 (0.01 mmol), DG1 (0.04
mmol), and AgTFA (0.2 mmol) in 9:1 AcOH/HFIP (0.667 mL)
b
under air at 120 °C for 36 h. Determined by 1H NMR using CH2Br2
c
as the internal standard. Isolated yield (based on a 0.3 mmol-scale
reaction).
the role of each additive. Not surprisingly, no reaction was
observed in the absence of either Pd(OAc)2 or DG1 (Table 1,
entries 2 and 3). Attempts to replace the TDG with either DG2 or
DG3 resulted in a significant loss of reactivity (Table 1, entries 4
and 5). The reaction was only slightly affected upon reducing or
increasing the loading of TDG (Table 1, entries 6 and 7);
however, lowering the reaction temperature to 100 °C had a
detrimental effect (Table 1, entry 8). Inferior reaction perform-
ance was also observed when other Pd catalysts or silver salts were
used (Table 1, entries 9−12). Attempts to use AcOH or AcOH/
H2O (9:1) as the solvent, or changes in the ratio of AcOH to
HFIP, were all accompanied by poorer reaction performance
(Table 1, entries 13−16). Addition of 5 equiv of H2O or a lower
concentration of benzaldehyde did not further increase the yield
(Table1,entries17and18). Thereactionwasnotimprovedwhen
performed under argon, suggesting that it is not sensitive to
moisture or air (Table 1, entry 19).
With the optimized conditions in hand, the scope of the
benzaldehydes was next investigated to examine the utility of this
method. To our delight, various para electron-withdrawing
groups (EWGs) and electron-donating groups (EDGs) (e.g.,
halides, ester, trifluoromethyl, andmethylgroups)inthealdehyde
component were all tolerated, affording the desired products in
moderate yields (Scheme 2, 1a−1g). When we changed the
placement of the substituent groups from the para to the meta
position, we observed a significant improvement in the efficiency
of the reaction (Scheme 2, 1h−1j). m-Anisaldehyde reacted with
p-iodoanisole to give the desired fluorenone 1l in 64% yield, and
interestingly, it was also possible to produce an unsymmetrical,
disubstituted fluorenone 1k by pairing m-nitrobenzaldehyde with
p-iodoanisole (Scheme 2). The reaction is also tolerant of various
ortho functional groups in the aldehyde component (Scheme 2,
1m−1q), as well as substrates possessing two EWGs or EDGs
(Scheme 2, 1s, 1r). 2-Naphthaldehyde can also be transformed to
1t, although the yield is modest with this substrate (Scheme 2). It
is noteworthy that the fluorenones 1r and 1t are formed in a
regioselective fashion; directed functionalizations of ortho-C−H
bonds can thus be selective in substrates containing two ortho-C−
H bonds (Scheme 2).
Havingshownthatdirectsynthesesoffluorenonesfromdiverse
aldehydes are possible, we evaluated the couplings of structurally
diverse aryl iodides with the particular aldehyde, 2-bromoben-
zaldehyde, due to its excellent performance in our initial studies.
As shown in Scheme 3, a variety of substituted aryl iodides are
transformed to fluorenone products, although the substrates
bearing donor alkyl groups in the para position display
significantly higher efficiencies in relation to the less electron-
rich aryl iodides (e.g., Scheme 3, 2g−2i vs 2b−2f). Comparable
yields were obtained when meta-substituted aryl iodides were
employed; however, mixtures of regioisomeric fluorenones were
formed (Scheme 3, 2k−2m).
B
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Scheme 3. Scope of the Aryl Iodides
Scheme 5. Mechanistic Rationalization
In our efforts togain insight into the mechanism of this process,
we isolated the cyclopalladated complex 3 from the reaction of m-
anisaldehyde with stoichiometric amounts of Pd(OAc)2, DG1,
and pyridine.16 Upon treatment with iodoanisole and AgTFA,
this intermediate was successfully transformed into fluorenone 1l
in a satisfactory overall yield; the structure of 1l was
unambiguously confirmed by X-ray crystallography (Scheme 4).
Scheme 4. Isolation of Palladacycle 3 and Its Oxidation
resulting intermediate I-6 entersthe second catalytic cycle. After a
second C−H palladation to give the transient seven-membered
palladacycle I-7, a ring-contracting, intramolecular migratory
insertion into the coordinated imine function would generate the
second C−C bond and intermediate I-8.19 Finally, a β-hydride
elimination would produce imine I-9 and extrude the Pd catalyst
fromtheanthranilateligand,whichcanbereturnedtothereaction
after a simple hydrolysis of the imine function; this final imine
hydrolysis step would also generate the fluorenone product 1a.
The hydride-bound Pd species would also be converted into the
active Pd(II) catalyst after reductive elimination and reoxidation
by Ag(I).20
To highlight the utility of this new method, we executed a short
synthesis of Tilorone, an orally active, broad-spectrum antiviral
drug.21 As depicted in Scheme 6, 1l was first prepared under the
standard conditions in 64% yield. A high-yielding cleavage of the
two methyl ethers with HBr in AcOH afforded compound 4 and
set the stage for a final, twofold substitution reaction with the free
base derived from 2-chloro-N,N-diethylethylamine hydrochlor-
ide, which produced Tilorone in 72% yield. In relation to the
previously reported approaches,22 this synthesis uses cheaper
starting materials and requires only three steps.
A putative mechanism for this fluorenone synthesis method is
outlined in Scheme 5. We propose that the reaction begins with
the transient formation of I-1 from benzaldehyde and anthranilic
acid (DG1). After deprotonation and metal complexation, an
intramolecular C−H palladation occurs with the loss of one
molecule of AcOH, possibly via a concerted metalation−
deprotonation process.17 Oxidative addition of palladacycle I-3
with iodoanisole subsequently produces the putative Pd(IV)
intermediate I-4,18 which undergoes reductive elimination to
generate the arylated species I-5. A ligand exchange promoted by
AgTFA restores the TFA (or acetate) bound Pd species, and the
C
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Corresponding Author
*E-mail: ejs@princeton.edu.
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Xiao-Yang Chen: 0000-0003-3449-4136
Erik J. Sorensen: 0000-0002-9967-6347
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank John Eng and Phil Jeffery at Princeton University for
their technical assistance with our mass spectrometric and X-ray
crystallographic analyses. We gratefully acknowledge the NSF-
CCI Center for Selective C−H Functionalization (CHE-
1205646), Princeton University, and a Taylor Fellowship (to
X.-Y.C.) from the Department of Chemistry at Princeton
University for supporting this work.
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