Palladium-catalyzed C–H alkenylation of quinoxaline N-oxide enabled by a mono-N-protected amino acid

Article abstract of DOI:10.1016/j.tetlet.2018.05.054

The efficient alkenylation of quinoxaline N-oxide was achieved via Pd-catalyzed C–H activation, using the assistance of a mono-N-protected amino acid. Further deoxygenation of the 2-styrylquinoxaline-N-oxides yielded the corresponding styrylquinoxaline de

Full text of DOI:10.1016/j.tetlet.2018.05.054

Tetrahedron Letters xxx (2018) xxx–xxx
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Palladium-catalyzed C–H alkenylation of quinoxaline N-oxide enabled
by a mono-N-protected amino acid
Márcia Silvana Freire Franco, Murilo Helder de Paula, Paulina Cecylia Glowacka, Fernando Fumagalli,
⇑
Giuliano Cesar Clososki, Flavio da Silva Emery
School of Pharmaceutical Sciences of Ribeirão Preto (FCFRP), University of São Paulo (USP), Ribeirão Preto, SP, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
The efficient alkenylation of quinoxaline N-oxide was achieved via Pd-catalyzed C–H activation, using the
assistance of a mono-N-protected amino acid. Further deoxygenation of the 2-styrylquinoxaline-N-oxides
yielded the corresponding styrylquinoxaline derivatives.
Received 11 April 2018
Revised 4 May 2018
Accepted 18 May 2018
Available online xxxx
Ó 2018 Elsevier Ltd. All rights reserved.
Keywords:
C–H activation
Quinoxaline
Palladium
Alkenylation
Introduction
Considering the importance of the quinoxaline scaffold in
medicinal chemistry, the functionalization of quinoxaline is an
Quinoxaline is a privileged benzodiazine heterocycle, present as
a key structural element in several biologically active com-
important strategy for expanding the chemical space and produc-
ing innovative compounds for drug discovery programs. C–H acti-
vation is a promising approach for functionalization of the
1
,2
pounds.
It exhibits a wide spectrum of biological activities,
2
2
including antibacterial, antiprotozoal, anticancer, and antidepres-
quinoxaline core. Among the various methods for direct func-
tionalization via C–H bond activation, the Fujiwara-Moritani reac-
tion is an important strategy for the olefination of aromatic
3
–7
sant effects.
Although quinoxaline rarely occurs in Nature, it is
widely distributed in biologically important synthetic molecules
that include many known drugs such as Quinacilin, Brimonidine,
and Varenicline (Fig. 1).8 Besides neutral quinoxalines, mono-
and di-N-oxide derivatives have also been described in the litera-
2
3–25
compounds.
Importantly, this reaction has also been recently
26,27
used for the olefination of diazines.
Azine N-oxides possess increased a-hydrogen acidity and nucle-
9
–12
ture as exhibiting bioactivity against a diverse range of targets.
ophilicity, conferring good reactivity and selectivity to this hetero-
cyclic class. This strategy has been used by several groups, who
have developed important methodologies for the direct C–H func-
Quinoxaline ring substituents, found in biologically active com-
pounds, are normally introduced before the heterocyclization step.
However, in recent years, new strategies for ring functionalization
have received increasing attention from the synthetic commu-
2
8–37
tionalization of pyridine rings.
Among them, Cho and co-
workers performed a palladium-catalyzed alkenylation using azine
1
3
26
nity. trans-Styrylquinoxalines can be considered as isosteres of
stilbenes, which are widely present in natural compounds exhibit-
ing a wide range of biological activities,14–18 and chemical modifi-
cations strategies for this core could be useful for medicinal
chemistry applications. Styrylquinoxalines are generally prepared
N-oxides and acrylates (Scheme 2). Inspired by this methodology
and in an attempt to expand the quinoxaline chemical space for
medicinal chemistry purposes, we herein describe the C–H alkeny-
lation of quinoxaline N-oxide (Scheme 2). The present study high-
lights the importance of ligands in the catalytic activity of Pd(II) in
the Fujiwara-Moritani reactions.
by the aldol-type condensation of methyl quinoxaline derivatives
with aromatic aldehydes (Scheme 1).1
9,20
Recently Zhang and co-
workers reported the synthesis of 2-styrylquinoxaline from
quinoxaline N-oxide by direct C–H activation using iodine
Results and discussion
2
1
(Scheme 1).
We began our study by investigating the synthesis of (E)-2-
styrylquinoxaline 1-oxide 3a using the best conditions reported
by Cho and co-workers (Table 1, entry 1).
⇑
Corresponding author.
E-mail address: flavioemery@usp.br (F. da Silva Emery).
2
6
https://doi.org/10.1016/j.tetlet.2018.05.054
040-4039/Ó 2018 Elsevier Ltd. All rights reserved.
0
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M.S. Freire Franco et al. / Tetrahedron Letters xxx (2018) xxx–xxx
Fig. 1. Commercially available drugs and other biologically active compounds containing the quinoxaline core.
Scheme 1. Synthetic strategies to obtain 2-styryl quinoxalines.
Scheme 2. Palladium-catalyzed Fujiwara-Moritani reaction using quinoxaline N-oxide and styrenes and acrylates.
When other solvents were used, such as 2-propanol, acetoni-
ever, silver carbonate was found to be a better oxidant than silver
acetate for synthesizing compounds 3c and 3f (Scheme 3).
trile, DMSO, DMF, and toluene (Table S1, entries 2–6; ESI), no
improvement in yield was observed. Moderate yields were also
obtained when 1,4-dioxane was used with different sources of
Pd(II) (Table 1, entries 2–4). The use of bidentate ligands such
as 1,10-phenanthroline (Phen) and 4,4-di-tert-butyl-2,2-bipyridyl
BBBPY) were found to decrease the yields of the olefination pro-
duct (Table 1, entries 5 and 6) compared to the pyridine ligand
Table 1, entry 1). Subsequently, different amino acids were used
Quinoxaline N-oxide proved to be an ideal substrate for the
Fujiwara-Moritani coupling and presented specific reactivity of
the N-oxide functionality at the ortho position. The remarkable
ability of the mono-N-protected amino acid (Fmoc-Val-OH) to
accelerate Pd(II)-catalyzed oxidative C–H cross-coupling reactions,
first discovered by Yu and co-workers, was also observed in this
(
3
8,39
(
study.
as ligands (Table 1, entries 7–10). Among these, Fmoc-Val-OH
gave the best result (Table 1, entry 10). Several oxidants were
also screened in order to improve the yield (Table 1, entries
A probable reaction mechanism has been proposed (Scheme 4)
based on the experimental results obtained from this work and the
extensive experimental and computational studies described in the
3
8,40,41
1
0–14). Use of silver acetate led to the highest yield of (E)-2-
literature.
It is proposed that palladium(II) acetate initially
styrylquinoxaline N-oxide (Table 1, entry 14,). Upon investigating
the different ratios of quinoxaline N-oxide/styrene (Table 1,
entries 15–18), the 4:1 ratio was found to be optimal. Reduction
in the amount of the additive led to a considerable decrease in
the yield (Table 1, entries 19–21); in the absence of an additive,
a poor yield was obtained (Table 1, entry 22). Furthermore, no
reaction was possible without an oxidant or a palladium source
forms a complex with the N-protected amino acid, with both the
–NH and carboxylate groups coordinating with the Pd center in a
bidentate manner. Subsequently, this Pd-complex coordinates
with the oxygen at the N-oxide and reversible ligand exchange
takes place by concerted metalation/deprotonation (CMD), forming
complex C (Scheme 4), which is relatively stable due to the forma-
tion of a hydrogen-bond between the acetic acid ligand and the
anionic oxygen. That the coordination occurs with the N-oxide
moiety and not with nitrogen was verified by the experimental
observation that the neutral quinoxaline did not yield the alkeny-
lated product (result not showed). Finally, coordination of Pd to the
(Table 1, entries 23 and 24).
After establishing the optimal reaction conditions (Table 1,
entry 14,), the scope and limitations of the protocol were investi-
gated (Scheme 3). Typically, when silver acetate was used as the
oxidant, it was possible to obtain the desired product in good to
excellent yield, even with bromine-substituted styrene 3e. How-
styrene followed by carbopalladation leads to complex
E
(Scheme 4), which forms the quinoxaline 3, substituted at the
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M.S. Freire Franco et al. / Tetrahedron Letters xxx (2018) xxx–xxx
3
Table 1
a
Optimization of reaction conditions.
Entry
Catalyst
Pd(OAc)
Additive
Oxidant
Yield 3a (%)b
1
2
3
4
5
6
7
2
Pyridine
Pyridine
Pyridine
Pyridine
BBBPY
Ag
Ag
Ag
Ag
Ag
Ag
Ag
2
CO
2
CO
2
CO
2
CO
2
CO
2
CO
2
CO
3
3
3
3
3
3
3
64
23
38
29
30
11
–
Pd(acac)
PdCl (PPh
PdI
2
2
3 2
)
2
Pd(OAc)
Pd(OAc)
Pd(OAc)
2
2
2
Phen
L
-proline
8
9
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
2
2
2
2
2
2
Fmoc-Ala-OH
Fmoc-Gly-OH
Fmoc-Val-OH
Fmoc-Val-OH
Fmoc-Val-OH
Fmoc-Val-OH
Fmoc-Val-OH
Fmoc-Val-OH
Fmoc-Val-OH
Fmoc-Val-OH
Fmoc-Val-OH
Fmoc-Val-OH
Fmoc-Val-OH
Fmoc-Val-OH
–
Ag
Ag
Ag
K O S
2 8 2
2
Ag O
Cu(OAc)
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
–
2
2
2
CO
CO
CO
3
3
3
53
54
75
18
74
75
85
85
61
42
28
70
67
50
45
–
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
2
Pd(OAc)
2
c
d
e
f
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
–
2
2
2
2
2
2
2
2
g
h
i
Fmoc-Val-OH
Fmoc-Val-OH
Pd(OAc)
2
Traces
a
b
c
d
e
f
Reagents and conditions: 1 (4.0 equiv.), solvent (0.5 mL), palladium catalyst (10 mol%), additive (1.0 equiv.), oxidant (1.5 equiv.), 2a (1.0 equiv.), 120 °C, 12 h.
Isolated Yield.
1:2a = 5:1.
1:2a = 3:1.
1:2a = 2:1.
1:2a = 1:1.
g
h
i
Additive 50 mol%.
Additive 30 mol%.
Additive 15 mol%.
Scheme 3. Scope for the reaction between quinoxaline N-oxide and styrenes.
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M.S. Freire Franco et al. / Tetrahedron Letters xxx (2018) xxx–xxx
Scheme 4. Proposed mechanism for quinoxaline N-oxide alkenylation by the Fujiwara-Moritani reaction.38,40,41
Scheme 5. Deoxidation of quinoxaline N-oxide derivatives.
a
-position to the N-atom, after b-elimination (Scheme 4), and the
Conclusion
A practical and useful Fmoc-Val-OH ligand/palladium-catalyzed
system was described for the C–H alkenylation of quinoxaline N-
oxide to obtain six novel 2-styrylquinoxaline N-oxides in moderate
to good yields. Considering the results presented herein, along with
data available in the literature, a rational pathway for this reaction
was fully described. Furthermore, efficient reduction of the 2-
styrylquinoxaline N-oxides to styrylquinoxaline was also success-
fully accomplished.
Pd returns to the catalytic cycle.
In order to evaluate the reactivity of these compounds
under reductive conditions, the respective styrylquinoxaline-N-
oxides were reduced using Zn in the presence of NH
obtain the corresponding styrylquinoxalines 4a–e (Scheme 5).
Although moderate yields were observed, the generation of the
deoxygenated quinoxaline products highlighted the suitability
of the present route to obtain functionalized quinoxalines
4
Cl to
4
2
(Scheme 5).
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M.S. Freire Franco et al. / Tetrahedron Letters xxx (2018) xxx–xxx
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