Electrochemical Ruthenium-Catalyzed C-H Hydroxylation of Amine Derivatives in Aqueous Acid

Article abstract of DOI:10.1021/acs.orglett.0c01313

The development of an electrochemically driven, ruthenium-catalyzed C-H hydroxylation reaction of amine-derived substrates bearing tertiary C-H bonds is described. The reaction is performed under constant current electrolysis in a divided cell to afford alcohol products in yields comparable to those of our previously reported process, which requires the use of stoichiometric H5IO6 for catalytic turnover. With aqueous acid as solvent, the cathodic electrode reaction simply involves the reduction of protons to evolve hydrogen gas. The optimized protocol offers a convenient, efficient, and atom-economical method for sp3-C-H bond oxidation.

Full text of DOI:10.1021/acs.orglett.0c01313

This is an open access article published under an ACS AuthorChoice License, which permits
copying and redistribution of the article or any adaptations for non-commercial purposes.
pubs.acs.org/OrgLett
Letter
Electrochemical Ruthenium-Catalyzed C−H Hydroxylation of Amine
Derivatives in Aqueous Acid
Sophia G. Robinson, James B. C. Mack, Sara N. Alektiar, J. Du Bois,* and Matthew S. Sigman*
Cite This: https://dx.doi.org/10.1021/acs.orglett.0c01313
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: The development of an electrochemically driven, ruthenium-
catalyzed C−H hydroxylation reaction of amine-derived substrates bearing
tertiary C−H bonds is described. The reaction is performed under constant
current electrolysis in a divided cell to afford alcohol products in yields
comparable to those of our previously reported process, which requires the
use of stoichiometric H5IO6 for catalytic turnover. With aqueous acid as
solvent, the cathodic electrode reaction simply involves the reduction of
protons to evolve hydrogen gas. The optimized protocol offers a convenient,
efficient, and atom-economical method for sp3-C−H bond oxidation.
atalytic methods for selective C−H bond oxidation are
Cenabling technologies for total synthesis and medicinal
chemistry.1 The applicability of such processes has advanced
with the design of catalysts that oxidize specific C−H bonds in
the presence of common functional groups.2,3 To this end, we
recently reported a C−H hydroxylation method employing a
cis-bis(4,4′-di-tert-butylbipyridine)ruthenium complex (cis-Ru-
(dtbpy)2Cl2, 1) that operates in acidic aqueous media to achieve
selective oxidation of 3° and benzylic C−H bonds in the
presence of basic amines and heteroaromatic structural motifs.4
The acidic solvent conditions suppress amine and heterocyclic
amine N-oxidation.5 This process is compatible with structurally
disparate substrates, including select active pharmaceutical
ingredients and natural product derivatives. Nonetheless, a
limitation of the current method is the requirement for the use
of superstoichiometric amounts of a chemical oxidant (periodic
acid, H5IO6) to effect reasonable catalyst turnover numbers and
product yields. The requirement for excess terminal oxidant is a
general problem in C−H oxidation catalysis.6
Replacement of a bulk chemical oxidant with electrochemical
oxidation is well-established and offers an appealing alternative
for powering C−H functionalization reactions (Figure 1).7
Successful transition from chemical to electrochemical metal-
mediated oxidation is contingent on the efficient heterogeneous
Figure 1. Comparison between chemical and electrochemical
approaches for C−H hydroxylation.
oxidation of the catalyst.8 Cyclic voltammograms (CV) of
catalyst 1 reveal that five oxidation states (RuII−RuVI) are
electrochemically accessible over a span of 800 mV in aqueous
acid (Figure 2). As previously reported by Meyer and co-
workers, the RuIII/IV couple is kinetically slow to form at the
electrode and thus not observed on the time scale of the CV
recording.9
Received: April 15, 2020
Mechanistic studies of reactions with 1 demonstrated that
catalytic currents occur for both the RuIV/V and RuV/VI
couples.10 This finding suggested that the active catalyst species,
believed to be an oxo- or dioxo-Ru(V) or Ru(VI) intermediate,
https://dx.doi.org/10.1021/acs.orglett.0c01313
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

Organic Letters
pubs.acs.org/OrgLett
Letter
high solubility in aqueous acid. In CV studies of 1, the different
redox couples are more clearly distinguished in aqueous
perchloric acid than in aqueous triflic acid; thus, the reaction
was optimized using the former.10,12 Several parameters were
altered in an effort to find optimal electrochemical reaction
conditions, including the choice of electrode materials, cell
configuration, and electrochemical settings (i.e., controlled
potential vs constant current electrolysis).
Electrochemical oxidation of 2-amino-6-methylheptane by 1
does not proceed in an undivided cell. The inability to effect
hydroxylation of this substrate presumably arises from
unproductive reduction at the cathode of the Ru species, all
of which are more readily reduced than protons based on their
differing redox potentials.13 Thus, a H-cell with the anodic and
cathodic chambers separated by a fine glass frit was employed
for all subsequent screening. In this divided cell, the reaction
contents are loaded into the anodic chamber with 4 mL of 1:1
AcOH/0.75 M aqueous HClO4; an equivalent volume of 1:1
AcOH/0.75 M aqueous HClO4 is added to the cathodic
chamber.
Electrochemical oxidation was initially attempted by
controlled potential bulk electrolysis to generate a discrete
RuV-based oxidant. Our previous mechanistic studies showed
that one pathway for catalyst arrest involved ligand dissociation,
a reaction postulated to ensue from a RuVI dioxo species.9,10
Notably, oxo species of both RuVI and RuV were established as
active catalysts, but ligand dissociation is only believed to occur
from the former.9 Accordingly, we envisioned employing
controlled potential electrolysis to selectively generate a RuV
oxidant in order to suppress the putative catalyst decomposition
pathway. In practice, however, controlled potential electrolysis
required excessively long reaction times as a consequence of
sluggish electron transfer kinetics at the anode (Table 1, entries
3 and 4). This result is not particularly surprising given that
relatively slow CV scan rates (<50 mV/s) are necessary to
observe clear redox events with 1.
Figure 2. Cyclic voltammogram (CV) of 1 mM cis-[(dtbpy)2Ru-
(CO3)]11 in 1:1 AcOH/0.75 M aqueous HClO4 at a 10 mV/s scan rate
using a glassy carbon working electrode, platinum mesh counter
electrode, and SCE reference electrode.
can be readily accessed through outer-sphere oxidation, thus
motivating the development of an electrochemical protocol for
C−H hydroxylation. The operation of 1 in aqueous acid was
also considered advantageous for the development of an
electrochemical method, as the ionic medium would serve as
supporting electrolyte. Accordingly, no screening of supporting
electrolyte was necessary. Furthermore, the strongly acidic (pH
< 1) aqueous conditions enabled simple proton reduction (2H+
+ 2e− → H2) to function as the cathodic reaction (Figure 1), a
notable difference between electrocatalysis in aqueous versus
nonaqueous solvents. The latter requires addition of a
supporting electrolyte salt, and the precise reaction occurring
at the counter electrode is often unclear.
Initial proof-of-concept studies focused on establishing the
feasibility of the electrochemical hydroxylation by 1 with a
commercially available model substrate, 2-amino-6-methylhep-
tane (Table 1). This primary amine substrate was selected for its
Table 1. Analysis of Electrolysis Conditions for C−H
a
Hydroxylation
A marked improvement in reaction performance was noted
by switching from constant potential to constant current (CC)
bulk electrolysis. Performing the CC electrolysis reaction with
2-amino-6-methylheptane at 10 mA for 6 h afforded a > 2-fold
increase in product yield (Table 1, entry 6). Further
optimization of this process focused on examining a range of
fixed current values for electrolysis. Ultimately, it was
determined that performing the reaction at 25 mA for 6 h
afforded product in a yield comparable to the optimized
chemical oxidation with H5IO6 (Table 1, entry 1 vs 2).
Controlling the current, rather than performing electrolysis at
constant potential, forces the reaction to proceed by applying a
larger overpotential.14,15 Monitoring the potential through
inclusion of a SCE reference electrode in the anode compart-
ment reveals that the applied potential is 2.5 V when the
reaction is performed at 25 mA. This potential is substantially
higher than the redox potentials measured by CV for generating
the high valent Ru statesthe applied potential is over 1 V
higher than the onset potential for generation of RuVI. The need
for such a large overpotential reflects the slow electron transfer
kinetics for outer-sphere oxidation of the Ru catalyst.16
b
entry
deviation from standard conditions
none
chemical oxidant conditions
1.34 V vs SCE (RuVI), 24 h
1.27 V vs SCE (RuV), 24 h
4 h
10 mA
10 mA, 14 h
20 mA, 14 h
35 mA
yield (%)
1
2
3
4
5
6
7
8
63
65
15
<5
36
35
51
63
51
30
0
c
9
10
11
12
13
14
50 mA
no cis-Ru(dtbpy)2Cl2
2.5 mol % cis-Ru(dtbpy)2Cl2
no current
48
0
<5
undivided cell
Having identified optimal conditions for controlled current
electrolysis, we next examined the scope of this electrochemical
C−H hydroxylation protocol. A variety of structurally disparate
substrates tested in our earlier report were assessed under the
electrochemical protocol for direct comparison of the efficiency
of inner- versus outer-sphere oxidation.4 Overall, the electro-
a
b
Reactions conducted on a 0.24 mmol scale. Percent yield
1
determined by H NMR integration of unpurified reaction mixtures
versus 4-nitrotoluene as internal standard. Chemical oxidant
conditions: 5 mol % of cis-Ru(dtbpy)2Cl2, 2 equiv of H5IO6, 1:1
AcOH/H2O, 6 equiv of TfOH, 4 h. SCE = saturated calomel
electrode.
c
B
https://dx.doi.org/10.1021/acs.orglett.0c01313
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
chemical oxidation procedure provides the desired hydroxylated
products of basic amine substrates in comparable yields to the
protocol using H5IO6 (Table 2). A range of substrates
Table 3. Electrochemical C−H Oxidation Protocol
Nonamine Scope Compared with Chemical Oxidant
a
Protocol
Table 2. Substrate Scope of Optimized Electrochemical C−H
Oxidation Protocol Compared with Chemical Oxidant
a
Protocol
a
Reported yields for electrochemical protocol are in red and are of
isolated material on a 0.24 mmol scale. All reactions were performed
in duplicate. Yields in black are for chemical oxidant protocol;
conditions: 5 mol % of cis-Ru(dtbpy)2Cl2, 2 equiv of H5IO6, 1:1
AcOH/H2O, 4 h.
Despite the poor solubility of these substrates in the reaction
medium, the electrochemical protocol produces the desired 3°
alcohol products in comparable yields to the periodic acid
protocol. Amides, imides, benzoyl-protected alcohols, and
electron deficient arenes are all amenable to electrochemical
oxidation. Although not explicitly examined, the lower yields for
arene-based substrates may be related to issues similar to those
observed with pyridine derivatives.
In summary, this report describes the development of a
method for electrochemical, Ru-catalyzed C−H hydroxylation
of functionalized, 3° C−H bond-derived substrates. Using
electric current to drive catalyst turnover eliminates the need for
a superstoichiometric chemical oxidant without detriment to
catalyst performance. The stability of the cis-[Ru(dtbpy)2Cl2]
catalyst in aqueous acid and the use of a divided cell enables
proton reduction as the cathodic electrode reaction. Future
work is ongoing with second-generation Ru catalysts to further
advance this C−H functionalization technology.
a
Reported yields for electrochemical protocol are in red and are of
isolated material on a 0.24 mmol scale. All reactions were performed
in duplicate. Yields in black are for the chemical oxidant protocol.
Conditions: 5 mol % of cis-Ru(dtbpy)2Cl2, 2 equiv of H5IO6, 1:1
AcOH/H2O, 6 equiv of TfOH, 4 h. Reaction performed with
unprotected primary amine; benzoyl protection performed after
b
workup to facilitate product isolation.
containing oxidatively sensitive nitrogen functional groups are
amenable to the reaction conditions, yielding the desired C−H
hydroxylation products in moderate-to-high yields. Primary,
secondary, and tertiary amines are viable substrates (3a−d). A
cyclic imine, a memantine derivative, and an unprotected amino
acid derivative are also compatible with the reaction conditions,
forming the corresponding alcohol products in yields ≥60%
(3g−i).
A notable discrepancy between the chemical and electro-
chemical protocols is the functional group compatibility of
pyridine-derived substrates. Using the latter protocol, reactions
of pyridine-derived substrates afford lower product yields (e.g.,
3e, 3f). Furthermore, only 25% of starting material 2e is
recovered from this reaction. The incompatibility of the pyridyl
moiety to our conditions for CC electrolysis may be a
consequence of direct oxidation of this group at the anode,
adsorption of 2e to the anode, and/or poor aqueous solubility of
the substrate.16,17
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01313.
Experimental details (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
J. Du Bois − Department of Chemistry, Stanford University,
Stanford, California 94305, United States; orcid.org/0000-
0001-7847-1548; Email: jdubois@stanford.edu
Matthew S. Sigman − Department of Chemistry, University of
Utah, Salt Lake City, Utah 84112, United States; orcid.org/
0000-0002-5746-8830; Email: sigman@chem.utah.edu
Authors
Substrates lacking basic amine functional groups were also
examined under the electrochemical C−H oxidation protocol
(Table 3). Strong acid is not necessary in such cases; thus, these
reactions can be performed in a 1:1 AcOH/H2O mixture.
Sophia G. Robinson − Department of Chemistry, University of
Utah, Salt Lake City, Utah 84112, United States
James B. C. Mack − Department of Chemistry, Stanford
University, Stanford, California 94305, United States
C
https://dx.doi.org/10.1021/acs.orglett.0c01313
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
and Secondary Carbon−Hydrogen Bonds of Alkylamines by Methyl-
(trifuloromethyl)dioxirane in Acid Medium. J. Am. Chem. Soc. 1993,
115, 7250−7253.
Sara N. Alektiar − Department of Chemistry, University of Utah,
Salt Lake City, Utah 84112, United States
Complete contact information is available at:
(6) (a) Chen, J.; Lv, S.; Tian, S. Electrochemical Transition-Metal-
Catalyzed C−H Bond Functionalization: Electricity as Clean
Surrogates of Chemical Oxidants. ChemSusChem 2019, 12, 115−132.
(7) For examples of electrochemical C−H oxidations, see: (a) Sauer-
mann, N.; Meyer, T. H.; Qiu, Y.; Ackermann, L. Electrocatalytic C−H
Activation. ACS Catal. 2018, 8, 7086−7103. (b) Shrestha, A.; Lee, M.;
Dunn, A. L.; Sanford, M. S. Palladium-Catalyzed C−H Bond
Acetoxylation via Electrochemical Oxidation. Org. Lett. 2018, 20,
204−207. (c) Das, A.; Nutting, J. E.; Stahl, S. S. Electrochemical C−H
Oxygenation and Alcohol Dehydrogenation Involving Fe-oxo Species
Using Water as the Oxygen Source. Chem. Sci. 2019, 10, 7542−7548.
(d) Jiao, K.-J.; Xing, Y.-K.; Yang, Q.-L.; Qiu, H.; Mei, T.-S. Site-
Selective C−H Functionalization via Synergistic Use of Electro-
chemistry and Transition Metal Catalysis. Acc. Chem. Res. 2020, 53,
300−310. (e) Ma, C.; Fang, P.; Mei, T.-S. Recent Advances in C−H
Functionalization Using Electrochemical Transition Metal Catalysis.
ACS Catal. 2018, 8, 7179−7189. (f) Vannucci, A. K.; Chen, Z.;
Concepcion, J. J.; Meyer, T. J. Nonaqueous Electrocatalytic Oxidation
of the Alkylaromatic Ethylbenzene by a Surface Bound RuV(O)
Catalyst. ACS Catal. 2012, 2, 716−719.
(8) Meyer, T. H.; Finger, L. H.; Gandeepan, P.; Ackerman, L.
Resource Economy by Metallaelectrocatalysis: Merging Electro-
chemistry and C−H Activation. Trends in Chemistry 2019, 1, 63−76.
(9) Dobson, J. C.; Meyer, T. H. Redox Properties and Ligand Loss
Chemistry in Aqua/Hydroxo/Oxo Complexes Derived from cis- and
trans-[(bpy)2RuII(OH2)2]2+. Inorg. Chem. 1988, 27, 3283−3291.
(10) Mack, J. B. C.; Walker, K. L.; Robinson, S. G.; Zare, R. N.;
Sigman, M. S.; Waymouth, R. M.; Du Bois, J. Mechanisitc Study of
Ruthenium-Catalyzed C−H Hydroxylation Reveals an Unexpected
Pathway for Catalyst Arrest. J. Am. Chem. Soc. 2019, 141, 972−980.
(11) Cyclic voltammograms of Ru-carbonato complexes yield the
expected redox events, while dichloro adducts yield featureless CVs.
However, each complex performs comparably in the C−H oxidation
reaction.
https://pubs.acs.org/10.1021/acs.orglett.0c01313
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Science Foundation under the Center
for Chemical Innovation in Selective C−H Functionalization
(CHE-1700982) for financial support of this work. S.G.R.
acknowledges the NSF for a graduate research fellowship. We
acknowledge Prof. Shelley Minteer for helpful discussions.
NMR results included in this report were recorded at the David
M. Grant NMR Center, a University of Utah Core Facility.
Funds for construction of the Center and the helium recovery
system were obtained from the University of Utah and the
National Institutes of Health awards 1C06RR017539-01A1 and
3R01GM063540-17W1, respectively. NMR instruments were
purchased with support of the University of Utah and the
National Institutes of Health award 1S10OD25241-01.
REFERENCES
■
(1) For recent reviews on oxidative C−H functionalization, see:
(a) Cernak, T.; Dykstra, K. D.; Tyagarajan, S.; Vachal, P.; Krska, S. W.
The Medicinal Chemist’s Toolbox for Late Stage Functionalization of
Drug-Like Molecules. Chem. Soc. Rev. 2016, 45, 546−576. (b) White,
M. C.; Zhao, J. Aliphatic C−H Oxidations for Late-Stage
Functionalization. J. Am. Chem. Soc. 2018, 140, 13988−14009.
(c) Hartwig, J. F. Evolution of C−H Bond Functionalization from
Methane to Methodology. J. Am. Chem. Soc. 2016, 138, 2−24.
(d) Newhouse, T.; Baran, P. S. If C−H Bonds Could Talk: Selective
C−H Bond Oxidation. Angew. Chem., Int. Ed. 2011, 50, 3362−3374.
(12) Reactions performed with chemical oxidant in either aqueous
perchloric acid or aqueous triflic acid were found to yield equivalent
results.
̀
(e) Genovino, J.; Sames, D.; Hamann, L. G.; Toure, B. B. Accessing
Drug Metabolites via Transition-Metal Catalyzed C−H Oxidation:
The Liver as Synthetic Inspiration. Angew. Chem., Int. Ed. 2016, 55,
14218−14238.
(13) Proton reduction occurs at −0.242 V vs SCE, more negative than
the RuIII/II reduction peak by > 0.7 V and the RuVI/V couple by > 1.5 V.
(14) (a) Karkas, M. D. Electrochemical Strategies for C−H
Functionalization and C−N Bond Formation. Chem. Soc. Rev. 2018,
47, 5786−5865. (b) Kingston, C.; Palkowitz, M. D.; Takahira, Y.;
Vantourout, J. C.; Peters, B. K.; Kawamata, K.; Baran, P. S. A Survival
Guide for the “Electro-curious. Acc. Chem. Res. 2020, 53, 72−83.
(15) Bard, A. J.; Faulkner, L. R. Electrochemical Methods:
Fundamentals and Applications, 2nd ed.; John Wiley & Sons, Inc.:
Hoboken, NJ, 2001.
(2) For references on the incompatibility of high-valent transition
metals with basic amines, see: (a) Murahashi, S. L.; Naota, T.;
Yonemura, K. Ruthenium-Catalyzed Cytochrome P-450 Type
Oxidation of Tertiary Amines with Alkyl Hydroperoxides. J. Am.
Chem. Soc. 1988, 110, 8256−8258. (b) Bailey, A. J.; James, B. R.
Catalysed Aerobic Dehydrogenation of Amines and an X-ray Crystal
Structures of a Bis(benzylamine) Ruthenium(II) Porphyrin Species.
Chem. Commun. 1996, 2343−2344.
(3) For examples of chemoselective C−H oxidation in the presence of
basic amines, see: (a) Lee, M.; Sanford, M. S. Platinum-Catalyzed,
Terminal-Selective C(sp3)−H Oxidation of Aliphatic Amines. J. Am.
Chem. Soc. 2015, 137, 12796−12799. (b) Lee, M.; Sanford, M. S.
Remote C(sp3)−H Oxygenation of Protonated Aliphatic Amines with
Potassium Persulfate. Org. Lett. 2017, 19, 572−575. (c) Howell, J. M.;
Feng, K.; Clark, J. R.; Trzepkowski, L. J.; White, M. C. Remote
Oxidation of Aliphatic C−H Bonds in Nitrogen-Containing Molecules.
J. Am. Chem. Soc. 2015, 137, 14590−14593. (d) Dantignana, V.; Milan,
(16) Schmickler, W.; Santos, E. Interfacial Electrochemistry, 2nd ed.;
Springer: Berlin, 2010.
(17) A control reaction conducted with substrate 2e and no applied
current resulted in recovery of 75% of starting material, suggesting that
some pyridine substrate is adsorbed onto the RVC anode. However,
direct oxidation of the pyridine nucleus and aqueous solubility of the
substrate are also likely factors affecting results with these two
substrates.
́
M.; Cusso, O.; Company, A.; Bietti, M.; Costas, M. Chemoselective
Aliphatic C−H Bond Oxidation Enabled by Polarity Reversal. ACS
Cent. Sci. 2017, 3, 1350−1358. (e) Adams, A. M.; Du Bois, J.; Malik, H.
A. Comparative Study of the Limitations and Challenges in Atom-
Transfer C−H Oxidations. Org. Lett. 2015, 17, 6066−6069.
(4) Mack, J. B. C.; Gipson, J. D.; Du Bois, J.; Sigman, M. S.
Ruthenium-Catalyzed C−H Hydroxylation in Aqueous Acid Enables
Selective Functionalization of Amine Derivatives. J. Am. Chem. Soc.
2017, 139, 9503−9506.
(5) Asensio, G.; Gonzalez-Nunez, M. E.; Bernardini, C. B.; Mello, R.;
Adam, W. Regioselective Oxyfunctionalization of Unactivated Tertiary
D
https://dx.doi.org/10.1021/acs.orglett.0c01313
Org. Lett. XXXX, XXX, XXX−XXX