Palladium-Catalyzed C(sp3)-H Oxygenation via Electrochemical Oxidation

Article abstract of DOI:10.1021/jacs.7b01232

Palladium-catalyzed C-H activation/C-O bond-forming reactions have emerged as attractive tools for organic synthesis. Typically, these reactions require strong chemical oxidants, which convert organopalladium(II) intermediates into the Pd^III or Pd^IV oxidation state to promote otherwise challenging C-O reductive elimination. However, previously reported oxidants possess significant disadvantages, including poor atom economy, high cost, and the formation of undesired byproducts. To overcome these issues, we report an electrochemical strategy that takes advantage of anodic oxidation of Pd^II to induce selective C-O reductive elimination with a variety of oxyanion coupling partners.

Full text of DOI:10.1021/jacs.7b01232

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Article
Palladium-Catalyzed C(sp3)-H Oxygenation via Electrochemical Oxidation
Qi-Liang Yang, Yi-Qian Li, Cong Ma, Ping Fang, Xiu-Jie Zhang, and Tian-Sheng Mei
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b01232 • Publication Date (Web): 08 Feb 2017
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Palladium-Catalyzed C(sp3)−H Oxygenation via Electrochemical Ox-
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idation
,
†,‡
†
†
†
†
†
Qi-Liang Yang, Yi-Qian Li, Cong Ma, Ping Fang, Xiu-Jie Zhang, and Tian-Sheng Mei*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 345 Lingling Lu, Shanghai 200032, China
‡Key Laboratory for Advanced Materials and Institute of Fine Chemicals, School of Chemistry & Molecular Engi-
neering, East China University of Science and Technology, Meilong Road No. 130, Shanghai, 200237, China
Electrochemical Oxidation, Oxygenation, C–H Functionalization, Palladium, Oximes
ABSTRACT: Palladium-catalyzed C–H activation/C–O bond-forming reactions have emerged as attractive tools for organ-
ic synthesis. Typically, these reactions require strong chemical oxidants, which convert organopalladium(II) intermediates
into the PdIII or PdIV oxidation state to promote otherwise challenging C–O reductive elimination. However, previously
reported oxidants possess significant disadvantages, including poor atom economy, high cost, and the formation of unde-
sired byproducts. To overcome these issues, we report an electrochemical strategy that takes advantage of anodic oxida-
tion of PdII to induce selective C–O reductive elimination with a variety of oxyanion coupling partners.
tional chemical oxidants because it obviates the use of dan-
1. Introduction
gerous and toxic reagents.13–14
The development of site-selective catalytic methods for the
conversion of aliphatic carbonhydrogen (CH) bonds to
carbonoxygen (CO) bonds remains a significant challenge
in synthetic chemistry.1 During the past decade, transition-
metal-catalyzed site-selective CH functionalization has
emerged as a promising tool to construct carbon–carbon (C–

3
C) and carbonheteroatom (C–Y) bonds.2 Pd(II)-catalyzed
C–H oxygenation reactions, in particular, have received sig-
nificant attention.4–7 Previous studies have revealed that C–O
reductive elimination, which is typically sluggish from Pd(II)
centers, takes place under comparatively mild conditions
from PdIII or PdIV centers (Figure 1).8–9 While these transfor-
mations hold great promise in offering new disconnections
in retrosynthetic analysis, the need for an external chemical
oxidant constitutes a practical disadvantage in these systems
(Figure 1).10 The most typical oxidants in Pd-catalyzed C–H
oxygenation include PhI(OAc)2, t-BuOOAc, and K2S2O8.5–7
These oxidants have drawbacks in that they produce unde-
sired byproducts, have poor atom economy, or are expensive.
Recently, Sanford and co-workers elegantly developed aero-
bic oxygenation of C(sp3)–H bonds using catalytic amount of
NaNO3.11 However, oxygen-mediated reactions on a large
scale have been explicitly avoided by industry, owing to safe-
ty issues.12 Thus, the development of novel oxidation systems
represents a central challenge in the field of oxidative Pd(II)-
catalyzed C–H functionalization.
Figure 1. PdII/PdIV or PdII/PdIII catalytic cycles.
The utilization of electric current as a potentially ideal ox-
idant for Pd(II)-catalyzed C–H functionalization is an attrac-
tive approach.15–17 In this context, two major strategic ap-
proaches for aryl C(sp2)–H functionalization reactions have
recently been investigated (Figure 2a and 2b). In mediated
electron transfer, the anion (for example, a halide) is oxi-
dized by the anode to produce the corresponding cation,
which in turn oxidizes Pd(II) to high-valent PdIII or PdIV spe-
cies, triggering product formation via reductive elimina-
tion.18–19 In contrast, in direct electron transfer, the Pd(II)
species is oxidized by the anode directly to yield high-valent
PdIII or PdIV species in the presence of the spectator coun-
teranion, which is then incorporated into the product
Electrochemical oxidation has a rich history in synthetic
chemistry and has become a promising alternative to tradi-
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through reductive elimination.20–21 Following a seminal re-
found to be optimal (entries 46). Increase of electric current
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8
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port by Kakiuchi and co-workers in 2009,18 a number of ex-
amples of Pd-catalyzed aryl C(sp2)–H functionalization reac-
tions using electrochemical oxidation have been reported.19–21
To date, however, no examples of electrochemical Pd(II)-
catalyzed oxidation of unactivated C(sp3)–H bonds, arguably
the most challenging class of substrates, have been reported.
from 1.5 mA to 3 mA or 5 mA gave lower yields (entries 7 and
8). A control experiment revealed that no reaction was ob-
served in the absence of electric current or Pd(OAc)2 (entries
9 and 10). It is worth noting that the common chemical oxi-
23
dants such as PhI(OAc)2, t-BuOOAc, or NaNO3/O2 used as
oxidants in lieu of electric current resulted in low yields due
to the formation of corresponding di or tri-acetoxylated
product (entries 11–13).
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Table 1. Reaction Optimization with Substrate 1aa
Figure 2. Approaches to Pd(II)-catalyzed C–H functionaliza-
tion via electrochemical oxidation.
We reasoned that following C(sp3)–H cleavage, the anode
could oxidize the resulting alkyl palladium(II) intermediate
to a high-valent PdIII or PdIV species.22 In the presence of
oxygen counteranions, we envisioned that ligand exchange
would occur to set up a C–O reductive elimination step, giv-
ing the corresponding C(sp3)–H oxygenated product. We
rationalized that this sequence of events would be viable if
the oxidation potential of the counteranions was higher than
that of Pd(II) (Figure 2b). Herein, we report the first example
of Pd(II)-catalyzed oxygenation of C(sp3)–H bonds with vari-
ous oxyanions under electrochemical conditions (Figure 2c).
2. Results
2.1 Initial Studies and Reaction Optimization. Our ini-
tial studies of electrochemical alkane oxidation focused on
Pd-catalyzed -oxygenation of pinacolone O-3-phenylpropyl
oxime (1a). We were motivated to use this substrate because
oxime moiety has previously been identified as a powerful
directing group for C(sp3)–H functionalization reactions, and
the resultant products can be subsequently transformed into
useful products through standard functional group intercon-
version (Table 1).5,11 Gratifyingly, the reaction of 1a with 10
mol% Pd(OAc)2 in the presence of sodium acetate (4 equiv.)
under constant-current electrolysis conditions at 1.5 mA (J =
0.75 mA•cm-2) gave 82% mono-acetoxylated product 2a (en-
try 1). Decreasing the amount of palladium catalyst resulted
in slightly lower yield (entry 2). Interestingly, approximately
10% chlorination product was formed when palladium chlo-
ride was used instead of palladium acetate (entry 3). Among
the acetate sources that were tested, sodium acetate was
aReaction conditions: 1a (0.3 mmol), Pd(OAc)2 (10 mol%),
NaOAc (4 equiv.), acetic acid (2 mL) [anode], and NaOAc (2
equiv.), acetic acid (1 mL) [cathode] in an H-type divided cell
with two platinum electrodes and a Nafion 117 membrane,
70 °C. bThe yield was determined by GC with tridecane as the
c
d
internal standard. Isolated yield is in the parentheses. Ap-
proximately 10% chlorination product was formed.
2.2 Substrate Scope for C(sp3)–H Oxygenation via Elec-
trochemical Oxidation. Having optimized the reaction
conditions, we next examined the scope of the Pd(II)-
catalyzed C–H acetoxylation reaction by testing a series of
oxime substrates containing differrent substitution patterns
and various functional groups (Scheme 1). Several different
oxime directing groups were found to be effective in this
acetoxylation reaction (2b–d). To our satisfaction, a variety
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of functional groups, including ester, acetoxy, OTBS, chloro,
tion temperature is 100 °C. eThe reaction temperature is
50 °C. 1.04 g (4.0 mmol) 1h is used under electrochemical
oxidation.
f
amino, and cyano substituents, were well tolerated in the
reaction system (2k–q). However, the substrate containing
the acetoxy group in the hindered side of the oxime sub-
strates (2s) resulted in low yield. In addition, substrates con-
taining an -hydrogen atom reacted more slowly, giving low-
er yields (2t). Encouragingly, our standard conditions also
proved to be effective for C–H acetoxylation of oxazoline,6b
although a slightly lower yield was obtained (2u). Further-
more, electrolysis of 1.04 g (4.0 mmol) 1h produced 2h in 84%
yield, which demonstrated the synthetic potential of this
protocol. Among the chemical oxidants that we tried, the
NaNO3/O2 oxidation system (entry 13, Table 1) developed by
Sanford and co-workers produced the best results.11 Thus, we
have also included the yields of every substrate where a
chemical oxidant (NaNO3/O2) was used for a direct compari-
son. This clearly demonstrates the advantage of anodic oxi-
dation over chemical oxidation to achieve mono-
acetoxylation products, although chemical oxidation resulted
in better yields with the substrates containing the -H (2t)
and other (2r).
Based on the proposed reaction pathway (Figure 2b), we
reasoned that it should be possible to incorporate other func-
tional groups under anodic oxidation conditions through the
utilization of different oxyanion nucleophiles in solution. To
test this idea, we employed several different oxygen anions in
the reaction system and were pleased to find that they also
competently participated in the reaction (Scheme 2). The
lower yields in these examples (3e–h) mainly stem from the
formation of acetoxylation product in the reaction conditions.
Nevertheless, the success of these transformations clearly
demonstrates the potential generality of this electrochemical
oxidation approach for enabling C(sp3)–H functionalization
with different reaction partners. Similarly, compared to
chemical oxidation (NaNO3/O2), anodic oxidation gave supe-
rior yields in all substrates except 3b (Scheme 2).
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Scheme 2. Scope of Oxygen Nucleophilesa,b
Scheme 1. Substrate Scope of Oximesa
aIsolated yield. bThe corresponding carboxylic acids or sodi-
um salts were used in lieu of HOAc and NaOAc in the anode.
cThe yields in the parentheses use NaNO3/O2 as an oxidant.
2.3 Mechanistic Considerations and Catalytic Cycle. To
gain insight into the reaction mechanism, kinetic isotope
effect (KIE) experiments were carried out, and a large KIE
was measured in both a parallel single-component experi-
ment (kH/kD = 3.7) and a competition experiment (kH/kD =5.0)
(Scheme 3).24 This indicates that the C–H bond cleavage step
is the turnover-limiting step in the catalytic cycle.
Scheme 3. Kinetic Isotope Effect Studies
b
aIsolated yield. The yields in the parentheses use NaNO3/O2
as an oxidant. cThe reaction temperature is 90 °C. dThe reac-
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C–H activation/C–O bond formation sequence to occur, re-
sulting in a di or tri-acetoxylation product.
160
140
120
100
80
3. Summary
E
= 1.57 v
= 1.54 v
We have demonstrated the first example of Pd(II)-
catalyzed C(sp3)–H oxygenation via anodic oxidation. This
process offers an alternative to conventional methods that
require harsh chemical oxidants and represents an environ-
mentally benign tool for coupling various oxygen anions,
including acetate, toslyate, and alkoxides, with C(sp3)–H
bonds. Investigations aimed at understanding the reaction
mechanism and further increasing the scope of these reac-
tions are currently underway in our laboratory.
p
E
p
E
= 1.07 v
60
p
(d)
(c)
E
= 1.05 v
(a)
p
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(b)
0
-20
0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.
E vs (Ag/AgCl)/V
4. Experimental Section
Figure 3. Cyclic voltammograms recorded on a glassy carbon
electrode (area = 7.1 cm2) at 100 mVs-1 in: (a) Ac2O containing
0.1 M of n-Bu4NOAc; (b) solution (a) with 10 mM of 1u; (c)
solution (a) with 7 mM of complex 4; (d) as (c) in the pres-
ence of 10 mM of 1u.
4.1 General Information. All the electrochemical
oxidations were performed in an H-type divided cell equipped
with two platinum electrodes (1.0×1.0 cm2) unless otherwise
noted. The two compartments were separated by a DuPont
Nafion PFSA membrane N-117. Solvents and commercially
available reagents were used without purification. All
commercial reagents were purchased from TCI, Sigma-Aldrich,
Adamas-beta, 9-Ding chemistry and Energy Chemical of the
highest purity grade. They were used without further
Furthermore, a cyclic voltammogram of cyclometallated
Pd(II) complex 4,6b,25 a plausible intermediate in the catalytic
cycle, in Ac2O reveals two oxidation waves: one at 1.05 V, and
one at 1.54 V Vs Ag/AgCl (c, Figure 3). Since the oxazoline
ligand is not redox active within this potential range (a, b,
Figure 3). This provides evidence that the anode could oxi-
dize the alkyl palladium(II) intermediate to a high-valent
PdIII or PdIV species, which induces selective C–O reductive
elimination.21–22
1
purification unless specified. H NMR and 13C NMR spectra were
recorded on Agilent AV 400, Varian Inova 400 (400 MHz and 100
MHz, respectively). 19F NMR spectra were recorded on Agilent
AV 400, Varian Inova 400 (376 MHz) instrument and are
reported relative to the CFCl3 as the internal standard. The peaks
were internally referenced to TMS (0.00 ppm) or residual
undeuterated solvent signal. Infrared spectra were obtained on a
Bio-Rad FTS-185 instrument. High resolution mass spectra were
recorded at the Center for Mass Spectrometry, Shanghai
Institute of Organic Chemistry.
Scheme 4. Proposed Reaction Mechanism.
4.2 General Procedure for the Preparation of Oxime
Substrates. Substrates 1a, 1c–1j, 1l, 1n–1t were prepared ac-
cording to a literature procedure.27 To a 250 mL RB flask
equipped with
a stirring bar were added hydroxylamine
hydrochloride (15 mmol, 1.5 equiv.), NaOAc (25 mmol, 2.5 equiv.),
solvent (100 mL, H2O:EtOH = 2:3), and ketone (10 mmol, 1.0
equiv.). The reaction was allowed to heat to 100 °C and refluxed
for overnight. After cooled to room temperature, the reaction
was diluted with H2O (20 mL) and extracted with ethyl acetate
(100 mL, ×3). The combined organic layer was dried by MgSO4
and evaporated. The crude oxime was used directly for next step
without further purification. To a 100 mL RB flask equipped with
a stirring bar were added resulting oxime (5.0 mmol, 1.0 equiv.),
alkyl bromide (7.5 mmol, 1.5 equiv.), tetrabutylammonium
iodide (0.25 mmol, 0.05 equiv.), NaI (0.75 mmol. 0.15 equiv.),
KOH (6.0 mmol, 1.2 equiv.), and THF (30 mL).The reaction was
stirred at room temperature for 16 h. The reaction mixture was
concentrated under reduced pressure and the residue was made
alkaline with saturated NaHCO3, and extracted with ethyl
acetate. The organic layer was washed with brine, dried and
evaporated. Further purification was carried out by flash
chromatography.
A plausible mechanism for this Pd(II)-catalyzed C–H oxy-
genation via electrochemical oxidation is proposed in
Scheme 4. Initially, the palladium catalyst coordinates with a
nitrogen atom in the substrate 1a, which brings it in close
proximity to the -C–H bond. Next, C–H activation takes
place to give palladacycle B,26 which constitutes the rate-
limiting step in the catalytic cycle. The resulting complex B is
directly oxidized at the anode to form a Pd(III) or Pd(IV)
species C.9 Finally, reductive elimination from the high-
valent palladium center gives the palladium(II)−product
complex D, which can undergo ligand exchange with a new
substrate molecule, releasing the product and closing the
catalytic cycle. Alternatively, complex D can cause another
Substrates 1b, 1k, 1m were prepared according to a litera-
ture procedure.28 To a 50 mL RB flask equipped with a stirring
bar were added methoxyammonium chloride (7.5 mmol, 1.5
equiv.), NaOAc (12.5 mmol, 2.5 equiv.), solvent (15 mL,
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H2O:MeOH = 2:1), and ketone (5.0 mmol, 1.0 equiv.). The
S. Chem. Rev. 2010, 110, 1147. (e) Daugulis, O.; Do, H.-Q.;
Shabashov, D. Acc. Chem. Res. 2009, 42, 1074.
5. (a) Neufeldt, S. R.; Sanford, M. S. Org. Lett. 2010, 12, 532.
(b) Dick, A. R.; Hull, K. L.; Sanford, M. S. J. Am. Chem.
Soc. 2004, 126, 2300.
6. (a) Wang, D.-H.; Wu, D.-F.; Yu, J.-Q. Org. Lett. 2006, 8,
3387. (b) Giri, R.; Liang, J.; Lei, J.-G.; Li, J.-J.; Wang, D.-H.;
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reaction was allowed to heat to 100 °C and refluxed for 5 h. After
cooled to room temperature, the reaction was diluted with H2O
(10mL) and extracted with dichloromethane (50 mL, ×3). The
combined organic layer was dried by MgSO4, filtered, and
concentrated under reduced pressure. Further purification was
carried out by flash chromatography.
4.3 General Procedure for C(sp3)–H Oxygenation via
Electrochemical Oxidation. The electrochemical oxidation
was carried out in an H-type divided cell equipped with two
platinum electrodes (1.0×1.0 cm2). The two compartments were
separated by a DuPont Nafion PFSA membrane N-117. The
anodic chamber was charged with a solution of NaOAc (2 mL,
0.6 M in HOAc), an oxime compound (0.3 mmol) and Pd(OAc)2
(0.03 mmol ). The cathodic chamber was charged with a solution
of NaOAc (1 mL, 0.6 M in HOAc) and a certain amount of silica
sand. Then the mixture in the anodic chamber was stirred at a
7. For other selected examples on Pd-catalyzed C(sp3)–H
oxygenation, see: (a) Huang, Z.; Wang, C.; Dong, G.
Angew. Chem., Int. Ed. 2016, 55, 5299. (b) Thompson, S. J.;
Thach, D. Q.; Dong, G. J. Am. Chem. Soc. 2015, 137, 11586.
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829. (d) Wang, M.; Yang, Y.; Fan, Z.; Cheng, Z.; Zhu, W.;
Zhang, A. Chem. Comm. 2015, 51, 3219. (e) Liu, P.; Han, J.;
Chen, C. P.; Shi, D. Q.; Zhao, Y. S. RSC Adv. 2015, 5, 28430.
(f) Liu, B.; Shi, B.-F. Tetrahedron Lett. 2015, 56, 15. (g)
Chen, K.; Zhang, S.-Q.; Jiang, H.-Z.; Xu, J.-W.; Shi, B.-F.
Chem. Eur. J. 2015, 21, 3264. (h) Li, Q.; Zhang, S.-Y.; He, G.;
Nack, W. A.; Chen, G. Adv. Syn. Catal. 2014, 356, 1544. (i)
Zhou, L.; Lu, W. Org. Lett. 2013, 16, 508. (j) Chen, F.-J.;
Zhao, S.; Hu, F.; Chen, K.; Zhang, Q.; Zhang, S.-Q.; Shi,
B.-F. Chem. Sci. 2013, 4, 4187. (k) Ye, X.; He, Z.; Ahmed, T.;
Weise, K.; Akhmedov, N. G.; Petersen, J. L.; Shi, X. Chem.
Sci. 2013, 4, 3712. (l) Shan, G.; Yang, X.; Zong, Y.; Rao, Y.
Angew. Chem., Int. Ed. 2013, 52, 13606. (m) Ren, Z.; Mo, F.;
Dong, G. J. Am. Chem. Soc. 2012, 134, 16991. (n) Zhang, S.-
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Am. Chem. Soc. 2012, 134, 7313. (o) Rit, R. K.; Yadav, M. R.;
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Correa, A.; Donaire, R.; Martin, R. Angew. Chem., Int. Ed.
2011, 50, 12236. (q) Hou, X.-F.; Wang, Y.-N.; Göttker-
Schnetmann, I. Organometallics 2011, 30, 6053. (r) Reddy,
B. V. S.; Reddy, L. R.; Corey, E. J. Org. Lett. 2006, 8, 3391.
8. For selected reviews on PdIV chemistry, see: (a) Hickman,
A. J.; Sanford, M. S. Nature 2012, 484, 177. (b) Byers, P. K.;
Canty, A. J.; Skelton, B. W.; White, A. H. J. Chem. Soc.,
Chem. Commun. 1986, 1722. For the selected examples on
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o
constant current of 1.5 mA at 70 C for 12 h. At the end of the
reaction, the reaction mixture from both chambers was
transferred to a flask through a funnel. The electrodes and silica
sand were washed with EtOAc (20 mL). Then the solvent was
evaporated under the reduced pressure and further purification
was carried out by flash chromatography.
Acknowledgment. This work was financially supported by
the Strategic Priority Research Program of the Chinese Acad-
emy of Sciences (Grant XDB20000000), “1000-Youth Talents
Plan”, NSF of China (Grant 21421091, 21572245), and S&TCSM
of Shanghai (Grant 15PJ1410200).
Supporting Information Available: Detailed experimental
procedures and characterization of new compounds. This ma-
terial is available free of charge via the Internet at
http://pubs.acs.org.
Reference
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