Regioselective Metal-Free Cross-Coupling of Quinoline N -Oxides with Boronic Acids

Article abstract of DOI:10.1021/acs.orglett.5b01456

A novel and operationally simple one-step C-H bond functionalization of quinoline N-oxides to 2-substituted quinolines was developed. This approach enables the regioselective functionalization under external oxidant- and metal-free conditions. The developed transformation represents the first application of the Petasis reaction in functionalization of heterocycles.

Full text of DOI:10.1021/acs.orglett.5b01456

Letter
pubs.acs.org/OrgLett
Regioselective Metal-Free Cross-Coupling of Quinoline N‑Oxides
with Boronic Acids
†
,‡
,†,‡
Luis Bering and Andrey P. Antonchick*
†
Abteilung Chemische Biologie, Max-Planck-Institut fu
̈
r molekulare Physiologie, Otto-Hahn-Straße 11, 44227 Dortmund, Germany
r Chemie und Chemische Biologie, Chemische Biologie, Technische Universitat Dortmund, Otto-Hahn-Straße 6, 44221
Dortmund, Germany
S Supporting Information
‡
Fakultat
̈
fu
̈
̈
*
ABSTRACT: A novel and operationally simple one-step C−H
bond functionalization of quinoline N-oxides to 2-substituted
quinolines was developed. This approach enables the regiose-
lective functionalization under external oxidant- and metal-free
conditions. The developed transformation represents the first
application of the Petasis reaction in functionalization of
heterocycles.
eterocycles are important scaffolds for organic synthesis1,
metal-catalyzed direct C−H bond functionalization in which
heteroaromatic N-oxides are employed as versatile templates
for C−H bond functionalization. Employed as substrates,
H
natural bioactive compounds, and advanced materials.
Functionalized quinolines are prevalent compounds with
medicinal benefits, especially with antimalarial and antimicro-
7
heteroaromatic N-oxides enable transformations including
deoxygenative ortho-functionalization, nondeoxygenative C−H
bond functionalization, or alternatively 1,3-dipolar cyclo-
2
bial activities. Consequently, the regioselective formation of
C−C bonds, especially at the C2-position of quinolines, is an
8
important strategy to functionalize nitrogenous heterocycles
addition. Utilizing boronic acids, Baran and co-workers
3
and represents a significant challenge. Transition-metal-
reported a silver catalyzed radical C−H bond arylation of
electron deficient heterocycles and Mai et al. proved the
catalyzed coupling is the most common strategy (Scheme
a), and widely employed among these reactions is the Pd-
1
arylation of pyridine N-oxides under comparable conditions
9
(
Scheme 1b). Although the utilization of N-oxides achieved an
Scheme 1. Cross-Coupling of N-Heterocycles with Boronic
improved regioselectivity and supersedes the use of a strong
Acids
acid, an additional reduction of the nitrogen−oxygen bond after
9b
the coupling step is required. The useful physical properties
of heteroaryl N-oxides result from the 1,2-dipolar nitrogen−
oxygen bond, whereby the reactivity toward nucleophiles is
10
enhanced on the C2- and C4-positions. Our group is involved
in developing novel methods for the synthesis and function-
11
alization of heterocycles. Therefore, heterocyclic N-oxides
aroused our attention toward metal-free C−H bond function-
alization of heterocycles. Complementary, boronic acids gained
increasing interest for the development of metal-free C−C
bond construction reactions since their employment in Petasis
12
reaction and its variants. Transition-metal-free reactions are of
great interest in terms of atom economy, environmental impact,
13
and cost reduction. Herein, we report the first oxidant- and
metal-free regioselective cross-coupling of quinoline N-oxides
with boronic acids (Scheme 1c).
Our studies toward the cross-coupling of quinoline N-oxides
and boronic acids were initiated by a hypothesized analogy
between an iminium-ion in a Petasis−Borono Mannich
multicomponent reaction and heteroaromatic N-oxides (Figure
catalyzed cross-coupling of aromatic halides and boronic acids
4
(
Suzuki−Miyaura reaction). Heteroaryl halides are accessible
5
by synthesis from N-oxides or using ortho-metalation reactions.
However, the synthesis of these halides is generally associated
6
with low yields and poor functional group compatibility. To
overcome the requirement of prefunctionalized starting
materials, more recent methods were developed based on
Received: May 19, 2015
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01456
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Organic Letters
Letter
1
4
a
1
). The Petasis reaction is a convenient method for the
Table 1. Screening of Reaction Conditions
preparation of α-amino acids, mostly simplified by means of a
b
entry
solvent
DMF
time (h)
yield (%)
1
2
3
41
NMP
3
58
c
3
toluene
8
traces
traces
25
c
4
chlorobenzene
EtOH
8
c
c
c
,
d
5
6
7
8
9
1
1
14
24
24
24
24
6
water
traces
e
ethylene glycol
diethylene glycol
diglyme
n.d.
traces
48
0
1,4-dioxane
DMSO
38
Figure 1. Reaction design.
1
3
73
1
5
12
sulfolane
acetic acid
pyridine
8
27
reaction among a glyoxylic acid, an amine, and a boronic acid.
1
1
1
1
3
4
5
6
24
24
12
3
n.d.
traces
33
According to density functional theory (DFT) studies by Gois
and co-workers, the Petasis reaction proceeds via formation of
an iminium-ion followed by the coordination of boronic acid to
the carboxylic acid, which finally undergoes an aryl migration
and leads to a C−C bond formation (Figure 1). Considering
that heterocyclic N-oxides simultaneously contain a formal
iminium-ion and a coordination site for boronic acids, a
heteroaryl Petasis reaction was expected. In this process
coordination of boronic acid would lead to an aryl migration,
which occurs via a nucleophilic attack on C2-position of
quinolines, followed by elimination of boric acid.
c
f
DMSO
g
DMSO
66
h
16
17
DMSO
2
56
a
Reaction conditions: 1a (0.2 mmol), 2a (0.6 mmol), solvent (0.6 M),
under argon atmosphere, 110 °C. Yields are given for isolated
products after column chromatography. Concentration = 0.4 M.
b
c
d
e
f
g
h
Reflux. n.d. = not detected. T = 90 °C. T = 100 °C. T = 120 °C.
Initially, the reaction between quinoline N-oxide (1a) and 2-
furanylboronic acid (2a) was examined in DMF under heating
conditions. According to our hypothesis the desired product 3a
was formed smoothly within 3 h in 41% yield (Table 1, entry
which yielded the desired products in moderate to good yield
(Scheme 2, products 3a−f). This observation was consistent
with the analogy to the Petasis reaction, which is known to be
17
most efficient for this type of boronic acids. The application
of cyclohexylboronic acid, thiophen-2-ylboronic acid, and alkyl
substituted vinylboronic acid did not yield the desired product.
Afterward, the scope of the cross-coupling reaction was
explored between various quinoline N-oxide derivatives (1) and
2-furanylboronic acid (2a). Starting from C3 functionalized
quinoline N-oxides, a great compatibility for cross-coupling was
found. Notably, substituents with an electron withdrawing
effect led to the desired products with high yields, whereas
electron-rich groups provided the products in good yields
(Scheme 2, products 3g,h). Substituents on C3 position
enhanced the reactivity toward nucleophiles by decreasing the
electron density in the tested quinolines. Phenanthridin 5-oxide
could be employed in the cross-coupling providing product 3k
with 88% yield. Further decorations with electron withdrawing
groups on the quinoline scaffold were well tolerated in every
tested position (Scheme 2, products 3m−o). Moreover, the
introduction of aliphatic groups was examined on position C4,
7, and 8 (Scheme 2, products 3l, 3p, 3q). Surprisingly, only
product 3q was formed in a short time and with good yields
among these compounds. In the next experiments, we tested
polysubstituted quinoline derivatives. The application of those
derivatives provided the cross-coupled products in good yields
(Scheme 2, products 3r−t). Finally, quinoxaline N-oxide
(Scheme 2, product 3u) was found to be an exception for
utilization of alternative nitrogenous heterocycles in the cross-
coupling reaction and provided the desired product with
moderate yield. Unfortunately, isoquinoline, pyridine, and
quinazoline N-oxides were not compatible with the developed
reaction.
1). To our delight the reaction proceeded in a deoxygenative
and regioselective manner, although first attempts of cross-
coupling suffered from an incomplete conversion and partial
nitrogen−oxygen bond cleavage of the starting material. To
improve the cross-coupling reaction, a broad range of solvents
was screened. By changing the solvent to NMP, an increase of
yield was observed (Table 1, entry 2). In contrast, the use of
nonpolar solvents yielded solely traces of 3a, due to low
solubility of reactants (Table 1, entries 3 and 4). In addition,
the reaction showed a high sensitivity toward the presence of
hydroxyl group bearing solvents (Table 1, entries 5−8). Acidic
and basic conditions inhibited the reaction as well (Table 1,
entries 13 and 14). Finally, the use of polar aprotic solvents
yielded product 3a in all cases (Table 1, entries 9−12), from
which DMSO led to the most significant increase of product
formation with 73% yield in a short reaction time. Highly polar
aprotic solvents turned out to be most advantageous for the
course of reaction, respectively. Furthermore, different temper-
atures and equivalents of boronic acid 2a were tested, but
provided no beneficial effect (Table 1, entries 15−17 and
Supporting Information for details). In an attempt to improve
the yield, selected additives were tested. Unfortunately, the use
of common additives led to a dramatic decrease of product
formation (see Supporting Information for details).
Having the optimized reaction conditions in hand, the scope
of this novel metal-free cross-coupling was examined by
investigating the reaction between quinoline N-oxides (1)
and boronic acids 2 (Scheme 2). The scope of boronic acids
was limited to electron-rich aromatic and alkenyl boronic acids,
B
DOI: 10.1021/acs.orglett.5b01456
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Organic Letters
Letter
Scheme 2. Substrate Scopea,b
Scheme 3. Sequence for Regioselective Stepwise C−H Bond
Functionalization of 3-Bromoquinoline
(
6) instead of the corresponding N-oxide clearly showed the
need of preactivated heterocyclic starting materials via oxidation
Scheme 4). Additionally, to exclude a radical mechanism
(
Scheme 4. Control Experiments
pathway, the cross-coupling of 1a and 2a was repeated in the
presence of radical trap 7. As expected, the desired product was
formed without any changes in the reaction behavior.
Taking the previously mentioned DFT calculation from Gois
17
and co-workers into account and reconciling them with the
results of our study, a reaction mechanism was proposed and
outlined in Scheme 5. Starting from quinoline N-oxide (1a),
Scheme 5. Proposed Reaction Mechanism
a
Reaction conditions: 1 (0.3 mmol), 2 (0.9 mmol), DMSO (0.6 M),
b
coordination of boronic acid 2 takes places and enhances the
proximity of both reactants. Similar to a Petasis reaction, aryl
migration of the boronic acid proceeds via a nucleophilic attack
at the C2 position (Scheme 5). This step is followed by a
concerted rearomatization and elimination of boric acid,
whereupon the functionalized quinoline is formed in a plausible
deoxygenative manner.
In summary, a novel and metal-free method for the
regioselective cross-coupling of quinoline N-oxides with
boronic acids has been developed under reagent-less reaction
conditions. A broad range of 2-substituted quinolines was
obtained in up to 95% yield. The regioselective cross-coupling
revealed a good functional group tolerance and proceeded
especially well when using electron demanding heterocyclic N-
oxides.
under argon atmosphere, 110 °C. Yields are given for isolated
products after column chromatography.
A highlight in our studies toward the selective substitution of
quinolines was found in the stepwise C−H bond functionaliza-
tion of 3-bromoquinoline (4) using the methods developed in
our group. Quinoline 3v was obtained by means of cross-
dehydrogenative coupling followed by N-oxidation and cross-
coupling with boronic acid 2a (Scheme 3). Functionalized
quinoline 3v was straightforwardly obtained without the
utilization of any metal containing reagent.
3
c
As proof of concept, we further examined the reaction
between quinoline N-oxide (1a) and furanylboronic acid (2a).
The absence of any product formation while using quinoline
C
DOI: 10.1021/acs.orglett.5b01456
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Lett. 2015, 17, 1445−1448. (d) Shen, Y.; Chen, J.; Liu, M.; Ding, J.;
Gao, W.; Huang, X.; Wu, H. Chem. Commun. 2014, 50, 4292−4295.
ASSOCIATED CONTENT
Supporting Information
■
*
S
(
e) Loska, R.; Szachowicz, K.; Szydlik, D. Org. Lett. 2013, 15, 5706−
General experimental procedure, characterization of quinoline
N-oxides, and products. The Supporting Information is
available free of charge on the ACS Publications website at
DOI: 10.1021/acs.orglett.5b01456.
5709. (f) Campeau, L.-C.; Rousseaux, S.; Fagnou, K. J. Am. Chem. Soc.
2005, 127, 18020−18021.
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Fujiwara, Y.; Sobel, A. L.; Baran, P. S. J. Am. Chem. Soc. 2010, 132,
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3194−13196. (b) Mai, W.; Yuan, J.; Li, Z.; Sun, G.; Qu, L. Synlett
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AUTHOR INFORMATION
Corresponding Author
■
*
(10) (a) Wang, Y.; Zhang, L. Synthesis 2015, 47, 289−305.
(b) Inamoto, K.; Araki, Y.; Kikkawa, S.; Yonemoto, M.; Tanaka, Y.;
Kondo, Y. Org. Biomol. Chem. 2013, 11, 4438−4441. (c) Lecointre, B.;
Azzouz, R.; Bischoff, L. Tetrahedron Lett. 2014, 55, 1913−1915.
E-mail: Andrey.Antonchick@mpi-dortmund.mpg.de.
Notes
(d) Kondo, Y. C−H Functionalization of Heteroaromatic N-Oxides.
The authors declare no competing financial interest.
In Metal Free C-H Functionalization of Aromatics; Charushin, V.,
Chupakhin, O., Eds.; Springer International Publishing: 2014; Vol. 37,
pp 155−177.
ACKNOWLEDGMENTS
We gratefully acknowledge Prof. Dr. H. Waldmann (Max-
■
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Sievers, S.; Antonchick, A. P. Chem. Commun. 2015, 51, 925−928.
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