Pd-Catalyzed Ortho C-H Hydroxylation of Benzaldehydes Using a Transient Directing Group

Article abstract of DOI:10.1021/acs.orglett.7b02906

The direct Pd-catalyzed ortho C-H hydroxylation of benzaldehydes was achieved using 4-chloroanthranilic acid as the transient directing group, 1-fluoro-2,4,6-trimethylpyridnium triflate as the bystanding oxidant, and p-toluenesulfonic acid as the putative oxygen nucleophile. The unusual C-H chlorination and polyfluoroalkoxylation reactions signaled the importance of external nucleophiles to the outcome of Pd(IV) reductive eliminations.

Full text of DOI:10.1021/acs.orglett.7b02906

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Letter
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Cite This: Org. Lett. XXXX, XXX, XXX-XXX
Pd-Catalyzed Ortho C−H Hydroxylation of Benzaldehydes 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 direct Pd-catalyzed ortho C−H hydroxylation of
benzaldehydes was achieved using 4-chloroanthranilic acid as the
transient directing group, 1-fluoro-2,4,6-trimethylpyridnium triflate as
the bystanding oxidant, and p-toluenesulfonic acid as the putative
oxygen nucleophile. The unusual C−H chlorination and polyfluor-
oalkoxylation reactions signaled the importance of external nucleophiles to the outcome of Pd(IV) reductive eliminations.
atalytic C−H functionalization of arenes is a topic of
Central to this transformation was the use of anthranilic acid as a
transient directing group (TDG), which orchestrates two Pd-
catalyzed C−H functionalization events by reversibly binding to
the substrates. The TDG strategy is free from the stoichiometric
introduction and subsequent removal of directing elements and
becoming increasingly utilized to achieve site-selective function-
alizations of a wide range of aldehydes, ketones, and amines.11
Nevertheless, most of these methods have been limited to C−H
arylation only, and to date, no C−H oxygenation protocol has
been developed with any substrate using the TDG strategy. Our
continued focus on C−H functionalizations mediated by TDGs
prompted us to develop a new catalytic method for achieving
direct ortho C−H hydroxylations of benzaldehydes via Pd
catalysis (Scheme 1).
From the outset, we realized that a carefully chosen oxidant is
needed to (1) avoid the overoxidation of benzaldehydes; (2)
ensure its compatibility with the TDG; and (3) suppress other
undesired oxygenation reactions. With these considerations in
mind, a Pd-catalyzed ortho C−H hydroxylation reaction was
envisioned by combining electrophilic F+ reagents as the
bystanding oxidant for Pd with p-toluenesulfonic acid (p-
TsOH) as the oxygen nucleophile. Pioneered by the Sanford
and the Yu groups,12 this strategy was recently adopted by Dong
and co-workers in an oxime-derived alcohol β-C(sp3)−H
tosylation reaction.13 In our study, we reasoned that in situ
hydrolysis of the intermediate p-toluenesulfonate ester under
acidic conditions would reveal the phenolic hydroxyl of the
desired products.
C
increasing importance with a wide range of applications in
organic synthesis.1 In particular, Pd-,2 Ru-,3 Cu-,4 or Rh-
catalyzed5 C(sp2)−H oxygenation reactions provide direct
access to various substituted phenols from relatively simple
starting materials.6 Most of these reactions rely on the use of
strongly coordinating structural elements, such as pyridines,
oximes, or amides, to facilitate the C−H metalation process.
However, directed C(sp2)−H oxygenations mediated by the
moderate-to-weak coordinating power of the carbonyl of ketones
and aldehydes pose a steeper challenge.7 While site-selective
C(sp2)−H oxygenations can be achieved with aromatic ketones,8
directed oxidations of C(sp2)−H bonds with benzaldehyde
substrates are still largely undeveloped. The seminal examples of
these rare reactions, which were reported by Ackermann and co-
workers, featured the action of a ruthenium catalyst on
benzaldehydes with electron-rich arenes; electron-deficient
benzaldehydes displayed low reactivity in this method (Scheme
1).9 Aldehyde-directed ortho-hydroxylations of structurally
diverse benzaldehydes are attractive reactions, and yet their
continued development is hampered by the weak coordinating
ability of the CHO functional group and the tendency of this
group to undergo undesired oxidation, as well as competitive
metal insertions into formyl C−H bonds.
Our group recently described an efficient method to
synthesize fluorenones from benzaldehydes and aryl iodides.10
Scheme 1. Direct Ortho C−H Hydroxylation of
Benzaldehydes
Our study began by subjecting 3,4-dichlorobenzaldehyde to an
excess of F+ oxidants, p-TsOH in the presence of various Pd
catalysts, and a TDG in AcOH under an air atmosphere at 90 °C.
To our delight, the desired hydroxylation product was formed in
56% yield after a 24 h reaction that employed 10 mol % of
Pd(OAc)2 as the catalyst, 50 mol % of 2-amino-4-
(trifluoromethyl)benzoic acid (DG1) as the TDG, 1.5 equiv of
1-fluoro-2,4,6-trimethylpyridnium triflate as the bystanding F+
Received: September 16, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02906
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Letter
a
a
Table 1. Control Experiments
Scheme 2. Screening of Transient Directing Groups
b
entry
variation from the standard condition
yield of 1x (%)
1
none
no Pd(OAc)2
56
0
2
a
1
Yields are determined by H NMR using CH2Br2 as the internal
standard.
3
no DG1
0
4
30 mol % DG1
50
44
12
34
12
48
46
44
28
46
24
trace
40
40
34
42
26
44
5
70 mol % DG1
6
no p-TsOH
Using the standard conditions described in Table 1, we next
7
1.0 equiv p-TsOH
TFA instead of p-TsOH
TfOH instead of p-TsOH
Pd(TFA)2 instead of Pd(OAc)2
PdCl2 instead of Pd(OAc)2
O2 instead of O1
O3 instead of O1
O4 instead of O1
O5 instead of O1
in AcOH/HFIP (9:1)
0.15 M instead of 0.1 M
0.067 M instead of 0.1 M
with 5.0 equiv H2O
at 70 °C
investigated the substituent effect on the TDG (Scheme 2).
Although simple anthranilic acid (DG2) only gave a moderate
performance, electron-poor anthranilic acids delivered superior
results. Among the TDGs tested, 2-amino-4-chlorobenzoic acid
(DG4) was the most efficient TDG, affording the hydroxylated
product in 58% yield. In contrast, the electron-rich 2-amino-4-
methylbenzoic acid (DG7) was less effective. Interestingly, 2-
aminoisobutyric acid (DG8), which had been previously used for
the ortho C−H arylation of benzaldehydes,11h did not generate
any desired product in this process.
8
9
10
11
12
13
14
15
16
17
18
19
20
21
With an improved procedure in hand, we proceeded to probe
the scope of the method by varying the structure of benzaldehyde
reactant. To our delight, various electron-withdrawing groups
(EWG) and electron-donating groups (EDG) were all well
accommodated at the ortho position, affording the desired
products in good yields (Scheme 3, 1a−e). Comparable yields
were obtained when we changed the substituents’ location from
the ortho to the meta positions (Scheme 3, 1f−j), and even more
EWG became compatible, such as trifluoromethyl and methyl
ester groups (Scheme 3, 1h and 1i). This robust reactivity with
electron-deficient benzaldehydes complements Ackermann’s
Ru(II)-catalyzed benzaldehyde ortho hydroxylation method,9
which performs best with arenes bearing EDGs. Encouraged by
these results, we next evaluated the reactivities of disubstituted
benzaldehydes in this reaction. Gratifyingly, the reaction was
tolerant of various EWGs at the ortho and para positions, and it
was also possible to introduce both an EWG and an EDG to a
single substrate while still maintaining a high efficiency of the
reaction (Scheme 3, 1k−v). Importantly, the presence of an ortho
methoxy group in the substrates did not impede the reaction, and the
dioxygenated products were produced in decent yields (Scheme 3,
1u, 1v). We were also pleased to find that switching the
substituents’ location to the meta and para positions did not
cause a significant erosion in performance. Yields were generally
good for substrates containing two EWGs (Scheme 3, 1w−z) but
were very moderate for those bearing two EDGs (Scheme 3,
1aa−1cc). However, when both EWG and EDG were present on
a single substrate, the efficacy of the reaction was restored
(Scheme 3, 1dd−jj). This method was also amenable to a
number of ortho, meta-substituted benzaldehydes, as well as a
coumarin-containing aldehyde, in which case consistently good
yields were obtained (Scheme 3, 1kk−nn).
at 110 °C
a
The reaction was performed with 3,4-dichlorobenzaldehyde (0.1
mmol), Pd(OAc)2 (0.01 mmol), DG1 (0.05 mmol), O1 (0.15 mmol),
and p-TsOH (0.2 mmol) in AcOH (1.0 mL) under air at 90 °C for 24
h. Determined by H NMR using CH2Br2 as the internal standard.
b
1
oxidant, 2.0 equiv of p-TsOH as the oxygen nucleophile, and
AcOH (0.1 M) as the solvent (Table 1, entry 1). Several control
experiments were subsequently conducted to shed light on the
role of each additive. Not surprisingly, the reaction did not occur
in the absence of either Pd(OAc)2 or DG1 (Table 1, entries 2 and
3). Reaction efficiency was slightly affected upon reducing or
increasing the loading of DG1 (Table 1, entries 4 and 5), but
removing p-TsOH from the reaction resulted in a loss of catalyst
turnover (Table 1, entry 6). This suggested that p-TsOH might
be playing a pivotal role in the catalytic cycle as an oxygen
nucleophile. As depicted in entry 7 in Table 1, reaction
performance was reduced by using only 1 equiv of p-TsOH.
Attempts to replace p-TsOH with other strong acids, such as
trifluoroacetic or triflic acids, led to either no catalyst turnover or
a much lower yield (Table 1, entries 8 and 9). Inferior reaction
performance was also observed when other Pd catalysts such as
PdCl2 or Pd(TFA)2 or other F+ oxidants such as 1-fluoro-2,4,6-
trimethylpyridnium tetrafluoroborate (O2), 1-fluoropyridinium
triflate (O3), NFSI (O4), or Selectfluor (O5) were used (Table
1, entries 10−15). Reactions run in AcOH/hexafluoroisopropa-
nol (HFIP) (9:1), in other concentrations of AcOH or with an
additional 5 equiv of water (Table 1, entries 16−19) gave lower
yields. Lowering or raising the reaction temperature also reduced
the reaction efficiency (Table 1, entries 20 and 21).
In the course of our study, palladacycle 2 was isolated from the
reaction of 2,4-dichlorobenzaldehyde with stoichiometric
amounts of Pd(OAc)2, DG4, and 4-tert-butylpyridine.14 Upon
B
DOI: 10.1021/acs.orglett.7b02906
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a
Scheme 3. Scope of the Benzaldehydes
Scheme 4. Isolation and Subsequent Oxidation of
Palladacycle 2
Scheme 5. Ortho C−H Chlorination and
Polyfluoroalkoxylation
the reaction,15 which subsequently participates in the C−Cl
reductive elimination through a ligand-exchange reaction of the
putative Pd(IV) center.16 A similar C−H polyfluoroalkoxylation,
which presumably follows the same mechanistic process, was also
accomplished by employing DG8 as the TDG, O5 as the F+
oxidant, triflic acid as the acid additive, and HFIP as both the
solvent and the external nucleophile (Scheme 5). While it has
thus far proven difficult to intercept the Pd(IV) intermediate
with other anions, our results corroborate the importance of
external nucleophiles in promoting otherwise challenging
reductive eliminations from Pd(IV) intermediates generated
through bystanding F+ oxidants.12
On the basis of this study, a putative mechanism is outlined in
Scheme 6. We propose that the first step is the transient
formation of I-1 from benzaldehyde and DG4. Following
deprotonation and metal complexation, cyclopalladation of I-2
would give rise to the six-membered palladacycle I-3. Oxidative
addition with O1 would generate the putative Pd(IV)
intermediate I-4, with the fluoride and triflate anions of O1
being the X-type ligands on this Pd(IV) complex. Nucleophilic
displacement of the fluoride anion with a tosylate anion would
produce the tosylate-bound Pd(IV) intermediate I-5, which
could subsequently undergo C−O reductive elimination to forge
the p-toluenesulfonate-bearing I-6. Dissociation of the Pd
complex, followed by imine hydrolysis, would restore both the
free DG4 and the Pd catalyst with concomitant formation of the
ortho-tosylated benzaldehyde I-8. Finally, in situ hydrolysis of the
p-toluenesulfonate ester would furnish the desired salicylalde-
hyde.
a
b
All yields are reported as isolated yields. DG1 was used as the TDG.
treatment with O1 and p-TsOH, this intermediate was
transformed into salicylaldehyde 1l; the structure of 1l was
unambiguously confirmed by X-ray crystallography (Scheme 4).
Some unusual reactivity was also revealed when the reaction
conditions were changed. As shown in Scheme 5, ortho C−H
chlorination of 3,4-dichlorobenzaldehyde was achieved by using
DG4 as the TDG, O2 as the F+ oxidant, triflic acid as the acid
additive, and dichloroethane (DCE) as the solvent. We postulate
that the thermal decomposition of DCE into vinyl chloride and
HCl may be responsible for the generation of chloride anion in
In summary, an efficient method was developed for the direct
ortho C−H hydroxylation of benzaldehydes under an air
atmosphere. By merging O1 as a bystanding F+ oxidant with p-
TsOH as the putative oxygen nucleophile, the desired trans-
formation was achieved using a readily available TDG. The
combination of dynamic chemical processes with catalyst-
C
DOI: 10.1021/acs.orglett.7b02906
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ASSOCIATED CONTENT
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Experimental procedures, spectral data, and crystallo-
graphic data (PDF)
X-ray data for compound 1l (CIF)
AUTHOR INFORMATION
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Int. Ed. 2014, 53, 11285.
Corresponding Author
*E-mail: ejs@princeton.edu.
ORCID
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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, Princeton
University, for support of this work.
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