Potassium Hydroxide-Catalyzed Alkynylation of Heteroaromatic N-Oxides with Terminal Alkynes

Article abstract of DOI:10.1002/adsc.201700931

An efficient potassium hydroxide-catalyzed alkynylation of heteroaromatic N-oxides under transition-metal-free conditions with the assistance of visible-light has been developed. Various C2-alkynylheterocycles were obtained in up to 92% yield with good functional group tolerance. This new method is operational simple, highly efficient, atom economic, and environmental friendly. (Figure presented.).

Full text of DOI:10.1002/adsc.201700931

Title: Potassium Hydroxide-Catalyzed Alkynylation of Heteroaromatic
N-Oxides with Terminal Alkynes
Authors: Xiaopei Chen, Fangfang Yang, Xiuling Cui, and Yangjie Wu
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201700931
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10.1002/adsc.201700931
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Potassium
Hydroxide-Catalyzed
Alkynylation
of
Heteroaromatic N-Oxides with Terminal Alkynes
Xiaopei Chen,a,§ Fangfang Yang, a,§ Xiuling Cui a,b,* and Yangjie Wu a,*
a
Department of Chemistry, Henan Key Laboratory of Chemical Biology and Organic Chemistry, Key Laboratory of
Applied Chemistry of Henan Universities, Zhengzhou University, Zhengzhou 450052, Peoples Republic of China. Fax:
(+86)-371-6776-7753; e-mail: cuixl@zzu.edu.cn or wyj@zzu.edu.cn
School of Biomedical Sciences, Engineering Research Center of Molecular Medicine of Chinese Education Ministry,
Xiamen Key Laboratory of Ocean and Gene Drugs, Institute of Molecular Medicine of Huaqiao University, Xiamen,
Fujian, 361021, Peoples Republic of China
b
§
X.-P. Chen and F.-F. Yang contributed equally.
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######
Abstract ： An efficient potassium hydroxide-catalyzed
alkynylation of heteroaromatic N-oxides under transition-
metal-free conditions with the assistance of visible-light
has been developed. Various C2-alkynylheterocycles were
obtained in up to 92% yield with good functional group
tolerance. This new method is operational simple, highly
efficient, atom economic, and environmental friendly.
Keywords: quinoline N-oxides, alkynylation, visible-light,
transition-metal-free, potassium hydroxide-catalyzed.
Figure 1. Examples illustrating the importance of 2-
alkynylquinolines.
Alkynylated arenes have been proven to be
ubiquitous structural motifs in organic synthesis,
pharmaceuticals
and
organic
materials.[1]
contributions in this regard. Recently, Yu[10] and
Shi[11] groups demonstrated Cu(II)-mediated and
Ni(II)-catalyzed alkynylation of unactivated C(sp2)-H
with terminal alkynes using amide-oxazoline and PIP
(2-pyridinyl isopropyl) as directing groups. Another
representative example was developed by Su and co-
workers[12] involving Pd-catalyzed direct alkynylation
of thiophenes and furans using terminal alkynes.
However, there are still some drawbacks with these
procedures, including the undesired homocoupling of
alkynes, requirement of transition metal catalysts and
stoichiometric oxidants.
Owing to the wide application of 2-
alkynylquinolines in advanced functional materials
and pharmaceuticals,[13] as exemplified in Figure 1, a
general method for direct dehydrogenative cross-
coupling of quinolines with terminal alkynes under
green and efficient conditions is highly desirable. In
our continued efforts for the development of direct C-
H functionalization of quinoline N-oxides,[14] we have
Consequently the development of efficient methods
to construct this privileged motif is of particular
interest. The conventional procedures involve Pd/Cu-
cocatalyzed Sonogashira coupling reaction of aryl
halides or its analogs with terminal alkynes.[2] Direct
alkynylation of (hetero)aromatic compounds has also
been developed with various alkynylating reagents,
such as alkynyl halides/analogs,[3] hypervalent iodine
reagents,[4] arylsulfonylacetylene,[5] and Grignard
reagents.[6] From the viewpoint of atom- and step-
economy, the direct dehydrogenative cross-coupling
reaction of (hetero)arenes with terminal alkynes has
appeared as a straightforward and efficient strategy.
Following the pioneer work of Nevado and co-
workers on the gold-catalyzed ethynylation of
electron-rich
arenes
using
electron-deficient
alkynes,[7] Su and co-workers reported a Cu-catalyzed
direct
alkynylation
of
electron-deficient
polyfluoroarenes using terminal alkynes.[8] The
heteroarenes with highly acidic (low pKa) C-H bonds,
such as indoles and azoles, were also easily subject to
dehydrogenative coupling with terminal alkynes.[9]
The groups of Li,[9a] Bobade,[9b] Chang,[9c] Miura,[9d,
9e] and Murai[9f, 9g] had made outstanding
successfully
realized
the
base-promoted
heteroarylation of quinoline N-oxides,[14g,14h] in which
N-oxide served as a directing group resulting in easy
cleavage of the ortho C-H bonds of heteroaryls. We
1
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10.1002/adsc.201700931
Advanced Synthesis & Catalysis
Table 1. Optimization of the coupling of quinoline N-
oxide 1a with phenylacetylene 2a[a]
entry 1). Other bases, such as potassium carbonate
(K2CO3), cesium carbonate (Cs2CO3), and lithium
tert-butoxide (tBuOLi), did not lead to the formation
of 3aa (entries 3-5). We then examined both nonpolar
and polar solvents. Toluene gave the highest yield,
while only trace amount of 3aa was observed in DCE,
CH3CN, THF, DMF, and DMSO (entries 9-11, 13,
14). The reaction did not proceed in 1,4-dioxane
(entry 12). It is worth noting that the slightly lower
yield was obtained when the loadings of KOH were
reduced to 0.5 or 0.3 equiv (entries 15-16 vs entry 1).
Interestingly, we found that the light could promote
the reaction. The desired product 3aa was isolated in
85% yield under irradiation of a 40 W energy saving
lamp (entry 20). Further screening of light source
demonstrated that blue LED could also promote this
alkynylation (entries 22-26). After surveying the
reaction parameters, the optimal reaction conditions
were determined as follows: KOH (0.3 equiv),
toluene 2.0 mL, 40 W energy saving lamp, refluxing
for 12 h.
With the optimal conditions in hand, we turned our
attention to explore the scope of the substrates. The
results are shown in Table 2 and Table 3. A series of
representative alkynes were tested with quinoline N-
oxide 1a in Table 2. It was found that both electron-
rich and electron-deficient aryl substituted alkynes
were tolerated and afforded the corresponding
products in good yields. Generally, arylacetylenes
with electron-donating groups on their phenyl rings
gave higher yields than that with electron
withdrawing groups (3ab, 3ag, and 3ak vs 3af).
Meta-substituted phenylac etylenes also worked well
and gave the desired products 3ag-3aj in good to
excellent yields (68-82%). Steric hindrance on the
Entry
Bases(equiv)
KOH(1.0)
NaOH(1.0)
K2CO3(1.0)
Cs2CO3(1.0)
tBuOLi(1.0)
tBuONa(1.0)
tBuOK(1.0)
KOH(1.0)
KOH(1.0)
KOH(1.0)
KOH(1.0)
KOH(1.0)
KOH(1.0)
KOH(1.0)
KOH(0.5)
KOH(0.3)
KOH(0.2)
KOH(0.3)
KOH(0.3)
KOH(0.3)
KOH(0.3)
KOH(0.3)
KOH(0.3)
KOH(0.3)
KOH(0.3)
KOH(0.3)
Solvents
toluene
toluene
toluene
toluene
toluene
toluene
toluene
xylene
DCE
Yield [%][b]
66
1
2
3
4
5
6
7
8
17
ND[l]
ND[l]
ND[l]
52
Trace
41
Trace
Trace
Trace
ND[l]
Trace
Trace
61
60
45
66
74
85
85
59
58
68
85
85
9
CH3CN
THF
1,4-dioxane
DMF
10
11
12
13
14
15
16
17
18[c]
19[d]
20[e]
21[f]
22[g]
23[h]
24[i]
25[j]
DMSO
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
Table 2. KOH-catalyzed alkynylation of quinoline N-
26[k]
oxides with terminal alkynes[a],[c]
[a]
Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol),
solvent (2.0 mL), dark, reflux, 12 h. [b] Isolated yields. [c]
[d]
15 W energy saving lamp. 26 W energy saving lamp.
[e] 40 W energy saving lamp. [f] two 40 W energy saving
[g]
[h]
[i]
lamps. 3 W green LED. 3 W purple LED. 3 W
blue LED. [j] 9 W blue LED. [k] 12 W blue LED. [l] ND =
not detected. DCE = 1,2-dichloroethane, CH3CN =
acetonitrile, THF = tetrahydrofuran, DMF = N,N-
dimethylformamide, DMSO = dimethylsulfoxide.
herein report a highly efficient and transition-metal-
free direct dehydrogenative cross-coupling reaction
of quinoline N-oxides and terminal alkynes.
With quinoline N-oxide (1a) and phenylacetylene
(2a) as model substrates, various reaction parameters
were investigated (Table 1). We were pleased to find
that the reaction worked smoothly to produce the
desired alkynylated product 3aa in 66% yield using
potassium hydroxide (KOH) as the base and toluene
as the solvent under reflux (entry 1, Table 1).
Although sodium hydroxide (NaOH), sodium tert-
butoxide (tBuONa) and potassium tert-butoxide
(tBuOK) could also promote the reaction, they gave
lower yields comparing to KOH (entries 2, 6 and 7 vs
[a]
Reaction conditions:1a (0.2 mmol), 2 (0.4 mmol), KOH
(0.3 equiv), toluene (2.0 mL), reflux, 12 h, 40 W energy
saving lamp, 12 h. [b] KOH (0.5 equiv). [c] Isolated yields.
2
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10.1002/adsc.201700931
Advanced Synthesis & Catalysis
Table 3. KOH-catalyzed alkynylation of quinoline N-
oxides with terminal alkynes [a],[b]
[a] Reaction conditions: 1 (0.2 mmol), 2a (0.4 mmol), KOH
(0.8 equiv), toluene (2.0 mL), reflux, 12 h, 40 W energy
saving lamp. [b] Isolated yields.
Scheme 1. Controlled experiments
carried out (Scheme 1). The desired product 3aa was
not obtained when the condensation of quinoline with
2a was processed under standard reaction conditions,
which indicated that N-oxide moiety was necessary
for this transformation (eq 1). A 1:1 mixture of 6-
methoxyquinoline N-oxide (1i) and quinoline had
been added to the reaction system under standard
reaction conditions, and compound 3ia was obtained
in 56% yield, while 3aa was not observed. This result
demonstrated that quinoline was not a reaction
intermediate (eq 2). Dimerization of 1a was found in
the absence of 2a (eq 3). However, no homo-coupling
product of either the terminal alkynes or the N-oxides
was observed in the model reaction, which suggested
that quinoline N-oxide could react as both
electrophile and nucleophile. To clarify the role of
light, two parallel reactions were conducted under the
standard conditions. In dark, 3aa was obtained in
60% yield (eq 4), and quinoline N-oxide was not
detected. Furthermore, the yield of 3aa was not
improved after prolonging the reation time to 24 h.
aryl group of phenylacetylene had no significant
influence on this transformation, e.g. the coupling
reaction of o-methoxy-phenylacetylene (2k) with
quinoline N-oxide (1a) gave the desired product in an
excellent
yield
of
92%.
In
addition,
heteroarylacetylene, for example 2-ethynylthiophene
was also tested, affording the corresponding product
3an in 60% yield. While, this catalytic system was
not
applied
to
alkylacetylenes.
When
cyclohexylacetylene and trimethylsilylacetylene were
used as the substrates, the corresponding products
were not obtained.
Encouraged by the results obtained with alkynes,
this catalytic system was applied to other N-oxides
under optimized reaction conditions. The desired
products was provided in lower yields. N-oxides
could be employed as suitable substrates using 0.8
equivalent of KOH, giving the corresponding
products 3ba-3qa in good yields for most cases
(Table 3). When the pyridine ring of quinoline N-
oxide was substituted by methyl and halogen groups,
the products were isolated in 29-76% yields (3ba-
3ea). The reactions also provided the desired
products in moderate to good yields when the
substituents were on the benzene ring of quinoline N-
oxides (3fa-3oa). This method could also be applied
to alkynylation of isoquinoline N-oxide and
quinoxaline N-oxide, giving the products 3pa and
3qa in 52% and 40% yields. When pyridine N-oxide
was used as the substrate, the corresponding product
was not obtained. The molecular structure of 3na was
confirmed by single crystal X-ray diffraction
analysis,[15] and is shown in Figure S1 in the
Supporting Information.
To gain insights into the mechanism of this
transformation, some control experiments were
Scheme 2. Proposed reaction mechanism.
3
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10.1002/adsc.201700931
Advanced Synthesis & Catalysis
Another reaction proceed in dark for 12 h, and then
proceed in 40 W energy saving lamp, 3aa was
obtained in 83% yield (eq 5). These results indicated
that quinoline N-oxide could be first afforded as an
electrophilic reagent which was further converted
into the corresponding alkynylation quinoline via the
assistance of visible light, but the reason why light
promotes the reaction is still unknown in this case.
On the bases of the results obtained above and
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addition-elimination process was proposed (Scheme
2). First, phenylacetylene 2a was deprotonated
byKOH to generate a phenylacetylene carbanion A,
which further attacked the ortho-position of quinoline
N-oxide 1a and gave intermediate B. Finally, product
3aa was produced through [1,3]-hydrogen migration
assisted by visible light, and the catalyst KOH re-
entered the next catalytic cycle.
In conclusion, we have developed a KOH-
catalyzed alkynylation of heteroaromatic N-oxides
under transition-metal-free conditions with the
assistance of visible-light. A series of ortho-
alkynylated heterocycles were synthesized in up to
92% yield. This reaction features atom economy,
environmental friendliness, high efficiency, additive-
free, and good functional group tolerance. The
present protocol provides an important approach to
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synthesize
ortho-alkynylated
heteroaromatic
compounds, which would be useful to build
multitudinous biologically active molecules and
functionalized materials.
Experimental Section
Typical Procedure
The mixture of quinoline N-oxides (29.0 mg, 0.2 mmol),
phenylacetylenes (44 uL, 0.4 mmol) and KOH (3.4 mg,
0.06 mmol, 30% mol) in anhydrous toluene (2.0 mL) was
stirred and refluxed conditions under 40 W energy saving
lamp for 12 hours. When the reaction was completed, the
crude mixture was cooled to room temperature. The
mixture was purified by column chromatography on silica
gel. (Elute: petroleum ether-EtOAc) to give the desired
product 3aa as a yellow oil; yield: 38.6 mg (85%).
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Acknowledgements
We greatly acknowledge partial financial support from the
Ministry of Science and Technology of China (2016YFE0132600),
the Science and Technology Innovation Program of Universities
in Henan Province (16HASTIT007), and Zhengzhou University.
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10.1002/adsc.201700931
Advanced Synthesis & Catalysis
COMMUNICATION
Potassium Hydroxide-Catalyzed Alkynylation of
Heteroaromatic N-Oxides with Terminal Alkynes
Adv. Synth. Catal. Year, Volume, Page – Page
Xiaopei Chen, Fangfang Yang, Xiuling Cui* and
Yangjie Wu *
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