Experimental and mechanistic analysis of the palladium-catalyzed oxidative C8-selective C-H homocoupling of quinoline N-oxides

Article abstract of DOI:10.1039/c5cc02227d

A novel site-selective palladium-catalyzed oxidative C8-H homocoupling reaction of quinoline N-oxides has been developed. The reaction affords substituted 8,8′-biquinolyl N,N′-dioxides that can be readily converted to a variety of functionalized 8,8′-biquinolyls. Mechanistic studies point to the crucial role of the oxidant and a non-innocent behavior of acetic acid as a solvent.

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Communication
Experimental and Mechanistic Analysis of the Palladium-Catalyzed
Oxidative C8-Selective C–H Homocoupling of Quinoline N-Oxides
David E. Stephens,a Johant Lakey-Beitia,a,b,c Gabriel Chavez,a Carla Ilie,a Hadi D. Arman,a and Oleg V.
Larionov*a
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
certain conditions favor formation of homodimer 1 as a minor by-
35 product (<10% yield), that was hypothesized to be formed by the
oxidative C–H homocoupling (Scheme 1). From the synthetic
perspective, 8,8'-biquinolyl is a structurally important framework
that has been successfully employed in the design of chiral
ligands, as shown by Blackmore and co-workers,13 and is a key
40 structural element of dimeric aporphinoid alkaloids.14
Mechanistically, Pd-catalyzed oxidative C–H homocoupling
reactions remain poorly understood: while a PdII/Pd0 catalytic
cycle has generally been postulated,5 mechanistic evidence
suggests that in some cases higher oxidation state Pd species (e.g.
45 a PdIV/PdII cycle)15 can be operative. This paper reports the
development and a preliminary mechanistic study of the oxidative
C8–H homocoupling of quinoline N-oxides.
A novel site-selective palladium-catalyzed oxidative C8–H
homocoupling reaction of quinoline N-oxides has been
developed. The reaction affords substituted 8,8'-biquinolyl
10 N,N'-dioxides that can be readily converted to a variety of
functionalized 8,8'-biquinolyls. Mechanistic studies point to
the crucial role of the oxidant and a non-innocent behavior of
acetic acid as a solvent.
Heteroaryl-heteroaryl bond formation is an important synthetic
15 strategy en route to homo- and heterodimeric structural motifs
with applications in catalysis,1 drug discovery2 and materials
science.3 Catalytic oxidative C–H homocoupling of heteroarenes
is an attractive method of direct biheteroaryl synthesis, as it by-
passes prefunctionalization of the heteroarene precursors (e.g. as
20 halides, stannanes or boronic acids). Recent examples of
regioselective catalytic oxidative C–H homocoupling of
heteroarenes include thiophenes (C24/C35), indoles (C2,5,6
C2/C37), indolizines (C3),8 azoles (C2),9 and furans (C2).4c In
addition, pyridine and 1,2,3-triazole N-oxides undergo oxidative
25 C2–H and C5–H homocoupling reactions, respectively.10
Table 1. Oxidative C–H homocoupling of quinoline N-oxide (2).a
O-
N+
N+
O-
Conditions
N+
O-
2
1
50
Entry
1
2
3
4
5
6
7
8
Catalyst
Pd(OAc)2
Pd(O2CCF3)2
PdCl2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Solvent (equiv.)
AcOH (30)
AcOH (30)
Oxidant (equiv.) Yield (%)b
AgOAc (3)
Ag3PO4 (0.5)
Ag3PO4 (0.5)
Oxone (2)
Cu(OAc)2 (2)
Ag3PO4 (2)
AgOAc (3)
AgOAc (2)
AgOAc (4)
AgOAc (4)
44
32
3
12
0
AcOH (30)
AcOH (30)/H2O (5)
AcOH (30)/H2O (5)
AcOH (15)/H2O (5)
AcOH (30)/H2O (15)
AcOH (15)/H2O (5)
AcOH (15)/H2O (5)
AcOH (5)/H2O (1.5)
64
66
61
57
82
9
10c
a Reaction conditions: 2 (0.2 mmol), catalyst (10 mol %), oxidant for 12 h
b
at 120 C. Yields were determined by 1H NMR analysis with 1,4-
c
dimethoxybenzene as an internal standard added prior to work-up. The
reaction was carried out on 3.45 mmol scale.
55 Initial experiments showed that Pd(OAc)2 was superior to other
Pd catalysts (Table 1, entries 1–3), and that silver acetate and
silver phosphate can both serve as efficient oxidants for the
formation of biquinolyl 1. Other oxidants, e.g. Cu(II) salts,
Oxone, PhI(OAc)2, led to low conversions (0–15%). The
60 homocoupling was not observed in other solvents (e.g. N,N-
dimethylformamide, tert-butanol, 1,2-dichloroethane, dioxane)
confirming the crucial role of acetic acid in the cyclopalladation.
Based on our earlier observation of the accelerating effect of
water on C8–H arylation of substrate 2,11 reactions were carried
65 out in the acetic acid/water system, and a 57–66% conversion
Scheme 1. Plausible mechanistic pathways for the oxidative C8–H
homocoupling of quinoline N-oxides.
We have recently developed a regioselective Pd-catalyzed C8–H
30 arylation of quinoline N-oxides.11,12 Kinetic and DFT
computational studies point to the important role of acetic acid as
a non-innocent solvent/ligand that directs the turnover-limiting
cyclopalladation to the C8 position. It was later observed that
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DOI: 10.1039/C5CC02227D
was achieved with a 2–3 : 1 molar ratio of AcOH/H2O (entries 6–
9, Table 1).
substrate for the homocoupling is quinoline N-oxide. The facile
30 Ag-catalyzed decarboxylation may be due to the stabilization of
the transition state by the electron-withdrawing N–O moiety, as it
has been recently rationalized for ortho-substituted benzoic
acids.16 The tandem C2-decarboxylation/C8–H homocoupling
process was successfully expanded to the readily available
Table 2. Scope of the oxidative C8–H homocoupling reaction.a,b
R
Pd(OAc)2 (10 mol %)
R
AgOAc (4 equiv)
AcOH (5 equiv)
O-
N+
N+
O-
N+
O-
H2O (1.5 equiv)
120 oC
35 substituted N-oxide 14.
R2
R1
R
Pd(OAc)2 (10 mol %)
R2
Ag3PO4 (2 equiv)
H3CO
O-
N+
N+
O-
R1
AcOH (15 equiv)
O-
N+
N+
O-
O-
N+
N+
O-
H2O (5 equiv)
120 oC, 71 h
N+
O-
CO2H
R1
R2
(X-ray)
13 (R1=H, R2=H)
1 (R1=H, R2=H), 71%
OCH3
14 (R1=Ph, R2=OCH3)
16 (R1=Ph, R2=OCH3), 44%
(1 g scale, 83 %)
(63 %)
1
3
F
H3C
H3CO2C
Pd(OAc)2 (5 mol %)
Ag3PO4 (50 mol %)
O-
N+
N+
O-
O-
N+
N+
O-
O-
N+
N+
O-
N+
O-
CO2H
N+
O-
ArI (3 equiv), AcOH (30 equiv)
H2O (40 equiv),
Ar
180 oC (MW), 50 min
15
13
(Ar=4-CF3C6H4), 87%
F
CH3
CO2CH3
CH3
(69 %)c
(70 %)
(61 %)d
6
4
5
Scheme 2. Tandem C2-decarboxylation/C8–H homocoupling reaction of
substituted 2-carboxyquinoline N-oxides.
Br
As a corollary, the C8–H arylation of substrate 13 was carried
40 out, and the corresponding cross-coupling product 15 was
obtained in an 87% yield. This result compliments Hoarau’s Ag-
and Cu-mediated, Pd/phosphine-catalyzed C2-selective arylation
of 2-carboxyquinoline N-oxides.17
O-
N+
N+
O-
O-
N+
N+
O-
CH3
O-
N+
N+
O-
H3C
Br
(78 %)e
(56%)
(74 %)c
7
8
9
CH3
The N-oxide moiety in the homocoupling products can be
45 transformed into a number of functional groups in the C2-
position (Table 3). For example, methoxy18 and N-tert-
butylamino groups19 were installed in the 2 and 2'-positions in
74% (17) and 67% (18) yields, respectively.
Cl
CH3
N+
O-
O-
N+
O-
N+
N+
O-
O-
N+
N+
O-
Table 3. Synthesis of 2,2'-susbtitited 8,8'-biquinolyls from N-oxide 1.
Cl H3C
(42 %)c
(72 %)
(90%)
10
11
12
a
5
Reaction conditions: N-oxide (0.50 mmol), Pd(OAc)2 (10 mol %),
o b
AgOAc (4 equiv), AcOH (5 equiv), H2O (1.5 equiv), 120 C, 12–24 h.
c
The yields are reported for isolated 8,8'-biquinolyl N,N'-dioxides. 15
equiv AcOH and 5 equiv H2O was used. d 20 mol % Pd(OAc)2 was used. e
The reaction was carried out with Ag3PO4 (2 equiv.), AcOH (15 equiv),
10 and H2O (5 equiv).
The conversion was further improved by reducing the amounts of
acetic acid and water to 5 and 1.5 equiv, respectively, as a
consequence of the increased effective concentrations of the
reactants (entry 10). The C–H homocoupling was successfully
15 carried out on a 1 g scale and afforded product 1 in an 83% yield.
The reaction can be carried out in the atmosphere of air that has
no effect on the conversion. The C8/C2 selectivity is estimated to
be >30:1, as no formation of C2-C2 or C2-C8 regioisomers was
observed by 1H NMR spectroscopy. The reaction exhibits a broad
20 scope and tolerates a variety of substituents in the quinoline core
(Table 2). Halogens, including Br, are well tolerated, and
benzylic C–H bonds remain unaffected. 4,7-Dichloroquinoline N-
oxide did not undergo the C8-dimerization, indicating that C7-
substituents may be detrimental to the reaction.
50
Similarly, a deoxygenation with hypophosphorous acid furnished
55 8,8'-biquinolyl (19), whereas a reaction with thionyl chloride20
afforded 2,2'-dichloro-8,8'-biquinolyl (20) in an 84% yield. In
addition, 2,2'-dialkyl-8,8'-biquinolyl 21 was readily obtained by a
copper-catalyzed reaction with a Grignard reagent,21 and 8,8'-
biquinolone 22 was formed by a trifluoroacetic anhydride-
25 2-Carboxyquinoline N-oxide (13) underwent
a
smooth
decarboxylation and C8–H homocoupling (Scheme 2).
Monitoring of the reaction progress proved that the rapid
decarboxylation precedes the dimerization, and the actual
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DOI: 10.1039/C5CC02227D
mediated rearrangement.22 A reaction of 2 with CF3Si(CH3)3 in
the presence of potassium tert-butoxide23 unexpectedly led to a
In conclusion, we have developed a new C8-selective C–H
homocoupling of quinoline N-oxides. The reaction proceeds with
nearly quantitative conversion to 8,8'-biquinolyl (19) presumably 45 a high degree of site-selectivity to give 8,8'-biquinolyl N,N'-
due to the increased steric encumbrance in the dimeric N-oxide.
The mechanism of the homocoupling reaction was briefly
examined by means of kinetic isotope effect and Hammett plot
studies. We previously determined by means of H/D-exchange
experiments that a highly C8-selective (>30:1) cyclopalladation
of 1 occurs in the Pd(OAc)2/AcOH system.
dioxides that can serve as precursors to a number of 2,2'-
substituted 8,8'-biquinolyls. Preliminary mechanistic analysis
points to involvement of the higher oxidation state Pd and the
crucial role of acetic acid for the C8-regioselectivity.
Financial support by the Welch Foundation (AX-1788),
NIGMS (SC3GM105579), the Voelcker Fund and UTSA is
gratefully acknowledged. JLB is supported by the Institute for
Training and Development of Human Resources (IFARHU),
National Secretariat for Science, Technology and Innovation
5
50
55 (SENACYT), and Ministry of Economic and Finance
(DIPRENA-DPIP-10866-2013) of Panama. Mass spectroscopic
analysis was supported by
(G12MD007591).
a
grant from NIMHD
10
Notes and references
60 a Department of Chemistry, University of Texas at San Antonio, San
Antonio, TX 78249, United States. E-mail: oleg.larionov@utsa.edu
b Centre for Biodiversity and Drug Discovery, Institute for Scientific
Research and High Technology Services (INDICASAT-AIP), City of
Knowledge, Panama City, Republic of Panama.
65 c Department of Biotechnology, Acharya Nagarjuna University,
Nagarjuna Nagar, India.
† Electronic Supplementary Information (ESI) available: Experimental
procedures and characterization data. See DOI: 10.1039/b000000x/
1
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Figure 1. Hammett plot for the oxidative C8–H homocoupling of
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35 experiments with varied amounts of Pd(OAc)2 in the absence of
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