Replacement of Stoichiometric DDQ with a Low Potential o-Quinone Catalyst Enabling Aerobic Dehydrogenation of Tertiary Indolines in Pharmaceutical Intermediates

Article abstract of DOI:10.1021/acs.orglett.9b00111

A transition-metal/quinone complex, [Ru(phd)₃]²⁺ (phd = 1,10-phenanthroline-5,6-dione), is shown to be effective for aerobic dehydrogenation of 3° indolines to the corresponding indoles. The results show how low potential quinones may be tailored to provide a catalytic alternative to stoichiometric DDQ, due to their ability to mediate efficient substrate dehydrogenation while also being compatible with facile reoxidation by O₂. The utility of the method is demonstrated in the synthesis of key intermediates to pharmaceutically important molecules.

Full text of DOI:10.1021/acs.orglett.9b00111

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Replacement of Stoichiometric DDQ with a Low Potential o‑Quinone
Catalyst Enabling Aerobic Dehydrogenation of Tertiary Indolines in
Pharmaceutical Intermediates
Bao Li, Alison E. Wendlandt,† and Shannon S. Stahl*
Department of Chemistry, University of WisconsinMadison, 1101 University Avenue, Madison, Wisconsin 53706, United States
S
* Supporting Information
ABSTRACT: A transition-metal/quinone complex, [Ru-
(phd)3]2+ (phd = 1,10-phenanthroline-5,6-dione), is shown to
be effective for aerobic dehydrogenation of 3° indolines to the
corresponding indoles. The results show how low potential
quinones may be tailored to provide a catalytic alternative to
stoichiometric DDQ, due to their ability to mediate efficient
substrate dehydrogenation while also being compatible with
facile reoxidation by O2. The utility of the method is
demonstrated in the synthesis of key intermediates to
pharmaceutically important molecules.
probe enzymatic mechanisms,3−12 while recent studies have
uinone cofactors present in copper amine oxidases
expanded on synthetic applications.13−31 These studies show
Q (CAOs) and other “quinoenzymes” (Scheme 1a) have
that o-quinones are effective catalysts for aerobic dehydrogen-
ation of primary and secondary amines (Scheme 1b). Primary
amines are the native substrates for CAO enzymes, and
mechanistic data support a pathway in which amine
condensation with the quinone affords an iminoquinone
intermediate that undergoes an internal redox reaction via
hydride transfer to generate the oxidized substrate (Scheme
1c).3−11 Consistent with this mechanism, biomimetic o-
quinones often support selective dehydrogenation of 1°
amines, without reacting with 2° and 3° amines.16,21,22,24 In
complementary efforts, we showed that 1,10-phenanthroline-
5,6-dione (phd, Scheme 1b), in the presence of ZnI2, can effect
catalytic dehydrogenation of 2° amines with O2 as the terminal
oxidant.17 This reactivity arises from a different mechanism
involving a hemiaminal intermediate (Scheme 1c).
inspired numerous efforts to mimic their reactivity with
synthetic catalysts.1,2 Early efforts used ortho-quinones to
Scheme 1. Quinone-Catalyzed Dehydrogenation of Amines
Quinone-catalyzed aerobic oxidation of 3° amines has not
yet been reported and remains a challenge. For example, the
phd/ZnI2 catalyst system showed poor reactivity in the
attempted dehydrogenation of a 3° indoline.17 The latter
reaction is a valuable target owing to the prevalence of N-
substituted indoles in bioactive natural products and
pharmaceuticals.32−34 Dehydrogenation of indolines provides
a strategic route to these compounds,35−38 often overcoming
limitations of other synthetic routes to indoles.39−44 Indoline
dehydrogenation is typically accomplished with (super)-
stoichiometric oxidants, such as DDQ (2,3-dichloro-5,6-
dicyano-1,4-benzoquinone), KMnO4, or MnO2.39,45−47 DDQ
has found especially broad use, including application in
Received: January 9, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00111
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Letter
process-scale pharmaceutical synthesis.38 The cost, toxicity,
and waste disposal associated with DDQ have motivated
efforts to identify catalytic alternatives.13,48−52 Herein, we
pursue this goal and report the first 3° amine dehydrogenation
reactions with CAO-inspired o-quinone catalysts, showing that
a phd-ligated Ru complex,18 [Ru(phd)3](PF6)2, enables
efficient conversion of 3° indolines to indoles (Scheme 1d).
This low-potential o-quinone catalyst system is shown to have
broader functional group compatibility than DDQ and
outperforms stoichiometric DDQ in the preparation of
important pharmaceutical intermediates.
The enthalpy of indoline dehydrogenation is ∼12 kcal/mol,
and assuming typical entropic contributions, the ΔG° for this
reaction is estimated to be ≤5 kcal/mol.53 DDQ is a high-
potential quinone that provides an unnecessarily strong driving
force for dehydrogenation (>40 kcal/mol).54 We postulated
that a lower-potential quinone for indoline dehydrogenation
could exhibit broader functional-group compatibility, while
also enabling efficient aerobic catalytic turnover (Scheme 2).
Figure 1. Substrate scope of aerobic dehydrogenation of N-
substituted indolines to indoles. Conditions (A): 1.0 mmol scale,
2.5 mol % [Ru(phd)3](PF6)2, 1 mol % Bu4NI, MeCN (0.1 M), O2,
room temperature. Conditions (B): 1.0 mmol scale, 2.5 mol %
[Ru(phd)3](PF6)2, 5 mol % Co(salophen), MeOH (0.1 M), O2, 65
°C. Isolated yields. aReactions were run at 65 °C. bReactions were run
at 40 °C.
Scheme 2. Quinone-Catalyzed Aerobic Dehydrogenation
Process Using Electron-Transfer Mediators (ETMs)56
derivatives 4a and 9a, good product yields were obtained with
both catalyst systems. Catalyst system B occasionally led to
substrate decomposition and poor yield (e.g., with 1a), but it
appears to be the more broadly effective of the two catalyst
systems.
Simple indoles such as those in Figure 1 are often accessible
by other methods, and therefore, the utility of dehydrogenation
methods is more evident in complex molecule synthesis. The
lower redox potential of the present quinone catalyst relative to
DDQ should enable broader functional group compatibility.
Substrate 6a, for example, features an oxidatively sensitive
pinacolboronate. This substrate underwent dehydrogenation in
80% yield with catalyst system B, while a significantly reduced
yield was obtained with stoichiometric DDQ (47% yield, with
complete substrate conversion). More extensive testing was
conducted by evaluating the dehydrogenation of 2a under
catalytic conditions B (cf. Figure 1) and with stoichiometric
DDQ in the presence of oxidatively sensitive molecules (Figure
2). Examples include those known to react with DDQ, such as
diphenylmethane,58 isochroman,59 and allylic alcohol.60 In
each case, 2b was generated in excellent yield under the
Several of the o-quinones in Scheme 1b were analyzed by cyclic
voltammetry.55 Q2, phd, and [Ru(phd)3]2+ exhibit reduction
potentials of −0.93, −0.88, and −0.59 V, respectively, vs Fc+/
Fc in MeCN. These potentials are 0.73−1.07 V lower than that
of DDQ (0.14 V vs Fc+/Fc) under the same conditions.
Tertiary amines are unlikely to be capable of generating stable
covalent adducts similar to those observed with 1° and 2°
amines (cf. Scheme 1c).3−11 Nevertheless, we reasoned that
transient adduct formation could lead to kinetically efficient
dehydrogenation, even in the absence of the strong
thermodynamic driving force available from DDQ.
To test our hypothesis, we assessed the reactivity of Q1, Q2,
and phd, in combination with various electron-transfer
mediators (ETMs), as catalysts for dehydrogenation of 1-
methylindoline 1a and the more electron-deficient derivative
2a. Two complementary catalyst systems/reaction conditions
were identified from these efforts: [Ru(phd)3]2+/Bu4NI/
CH3CN (A) and [Ru(phd)3]2+/Co(salophen)/MeOH57 (B),
respectively, for 1a and 1b (see Supporting Information for full
screening data). Catalytic conditions A and B were then
evaluated with a number of other indoline substrates (Figure
1). The [Ru(phd)3]2+/Bu4NI catalyst system A appears to fare
best with electronically neutral substrates. Good yields of
indole product were obtained with 1-methylindoline 1a, in
addition to derivatives 7a, 8a, 11a, 12a, and 13a bearing
modified N-substituents and/or small substituents on the
indoline core. More electron-rich substrates, such as 1-methyl-
5-methoxyindoline 3a and 1-methyl-7-benzyloxyindoline 10a,
and more electron-poor derivatives, such as 1-methyl-5-
bromoindoline 2a and 5-formylindoline 5a, afforded lower
yields with this catalyst system. In each of these cases, the
[Ru(phd)3]2+/Co(salophen) catalyst system B proved more
effective, enabling higher product yields and shorter reaction
time. In a few cases, such as the chloro- and cyano-substituted
Figure 2. Competition studies with oxidatively sensitive molecules.
B
DOI: 10.1021/acs.orglett.9b00111
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Letter
catalytic aerobic conditions (91−97% yield), with virtually no
decomposition of the additive (≥94% recovery). Meanwhile,
the reactions with DDQ led to moderate yields of 2b (40−78%
yield) and often resulted in significant decomposition of the
additive (up to 90%). The preferred reactivity of indoline 2a
over N-phenyl pyrrolidine and N-phenyl piperidine may be
rationalized by the conformational constraints of the indoline
ring, which enforce conjugation with the arene ring and should
enhance the hydride donor ability of the substrate.
formation of an adduct between the tertiary amine and the phd
o-quinone. As expected, however, the 3° amine substrate does
not form a resting state adduct with the quinone, as revealed
by variable-temperature NMR analysis of a solution of
[Ru(phd)3]2+ and 2a.62
To further probe the mechanism of the reaction, deuterium
kinetic isotope effects (KIEs) were obtained by independently
comparing the rate of dehydrogenation of 2a, 2a-C2-d2, 2a-C3-
d2, and 2a-d4 (Figure 3a). The data revealed a significant
The catalytic conditions obtained here were then evaluated
in the preparation of pharmaceutical intermediates (Scheme
3). Indole 16b is an intermediate en route to the natural
Scheme 3. Quinone-Catalyzed Dehydrogenation of
Pharmaceutical Intermediates
Figure 3. Kinetic isotope effect data from Ru(phd)3]2+/Co-
(salophen)-catalyzed dehydrogenation of 2a and its isotopologues.
(Note: The deuterium labels in the C3 position of 2a-d3 are a
byproduct of the synthetic protocol; NaBD3CN/DOAc-mediated
reduction of the indole leads to full H/D exchange at the C3 position.
Then, partial H incorporation from MeOH occurs at the C3 position
during the dehydrogenation reaction.)
product Enzastaurin (Scheme 3), which has been targeted as a
PET reagent for imaging of protein kinase C.61 Gram-scale
dehydrogenation of indoline 16a with the [Ru(phd)3]2+/
Co(salophen) catalyst system provided 17b in near-quantita-
tive NMR yield (97%; 88% isolated yield), reflecting the
excellent chemoselectivity for dehydrogenation of the indoline
rather than the tertiary piperidine and also demonstrating
compatibility with a pyridine substituent. This result may be
compared with a previously reported protocol, which
employed 1.1 equiv of DDQ and generated 16b in 68%
yield.43 Preparation of the asthma drug candidate LY290154
(Scheme 3) proceeds via the indole intermediate 17b.
Reported efforts to carry out N-alkylation of the substituted
indole with a secondary alkyl halide were complicated by
competing elimination reactions. Therefore, the synthesis of
17b was conducted by sequential alkylation and dehydrogen-
ation of the corresponding indoline with DDQ.38 Use of the
[Ru(phd)3]2+/Co(salophen) catalyst system in a gram-scale
aerobic dehydrogenation of 17a afforded 17b in 91% isolated
yield, again surpassing the reported outcome with stoichio-
metric DDQ (80% yield).
deuterium KIE at C2 (KIE = 1.9) but no KIE at the C3
position. An intramolecular competition deuterium KIE of 3.3
was observed at C2, obtained by probing the reaction of 2a-d3
(Figure 3b).63 The higher magnitude of the latter KIE relative
to the independent rate KIE suggests that the reaction does
not proceed by a single-step bimolecular hydride-transfer
pathway, and it is consistent with pre-equilibrium formation of
a transient covalent adduct prior to hydride transfer from the
C2 position of the indoline. This pathway is consistent with
the lack of reactivity exhibited by substrates bearing N-
carbonyl or -sulfonyl substituents (e.g., Ac, Ts; cf. last entry in
Figure 1). The latter results could also be rationalized by a
single-electron transfer pathway; however, such a pathway is
unlikely, considering the oxidative peak potentials of N-
methylindolines 1a and 2a are nearly 1 V higher than the
potential of [Ru(phd)3]2+ (approximately +0.40 V vs −0.59 V,
respectively).
The catalyst system described here should find application in
other tertiary amine dehydrogenation reactions. An important
example is cross-dehydrogenative coupling (CDC) for
functionalization adjacent to the nitrogen atom.64,65 As a
preliminary test of this application, we evaluated the
[Ru(phd)3]2+/Co(salophen) catalyst system in the reaction
of N-phenyltetrahydroisoquinoline with a series of different
The good reactivity of the low-potential quinone catalyst
may be rationalized by a mechanistic variant of the
“hemiaminal” mechanism in Scheme 1c, involving transient
C
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Letter
nucleophiles (Scheme 4). Excellent yields were obtained in C−
ACKNOWLEDGMENTS
■
C bond forming reactions with diethylmalonate, 4-hydroxy-
Financial support was provided by the NIH (R01 GM100143).
Spectroscopic instrumentation was partially supported by the
NIH (S10 OD020022-1) and the NSF (CHE-1048642).
Scheme 4. Quinone-Catalyzed Cross-Dehydrogenative
Coupling (CDC) Reactions of N-
a
Phenyltetrahydroisoquinoline
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00111.
Experimental procedures and characterization data for
all compounds (PDF)
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: stahl@chem.wisc.edu.
ORCID
Alison E. Wendlandt: 0000-0003-2970-9817
Shannon S. Stahl: 0000-0002-9000-7665
Present Address
†Department of Chemistry, Massachusetts Institute of
Technology, 77 Massachusetts Ave, Cambridge, MA 02139,
USA. E-mail: awendlan@mit.edu.
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
Notes
The authors declare no competing financial interest.
D
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Organic Letters
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