Synthesis of Quinoline N-Oxides by Cobalt-Catalyzed Annulation of Arylnitrones and Alkynes

Article abstract of DOI:10.1002/adsc.201600834

A new and straightforward protocol for the synthesis of quinoline N-oxides from the annulation of arylnitrones and alkynes is described. For the first time, a [4+2] cyclization of nitrone and alkynes has been achieved by cobalt catalysis via a nitrone-assisted dual C–H cleavage under relatively mild conditions. (Figure presented.).

Full text of DOI:10.1002/adsc.201600834

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DOI: 10.1002/adsc.201600834
Synthesis of Quinoline N-Oxides by Cobalt-Catalyzed Annulation
of Arylnitrones and Alkynes
Yue Liu,a Chen Wang,b Ningning Lv,a Zhanxiang Liu,a and Yuhong Zhanga,c,*
a
Department of Chemistry, Zhejiang University, Hangzhou 310027, Peopleꢀs Republic of China
Fax : (+86)-571-8795-3244; e-mail: yhzhang@zju.edu.cn
Zhejiang Key Laboratory of Alternative Technologies for Fine Chemicals Process, Shaoxing University, Shaoxing 312000,
b
Peopleꢀs Republic of China
c
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, Peopleꢀs Republic of China
Received: July 28, 2016; Revised: January 5, 2017; Published online: && &&, 0000
Supporting information for this article is available under http://dx.doi.org/10.1002/adsc.201600834.
Abstract: A new and straightforward protocol for assisted dual C–H cleavage under relatively mild
the synthesis of quinoline N-oxides from the annula- conditions.
tion of arylnitrones and alkynes is described. For the
first time, a [4+2] cyclization of nitrone and alkynes Keywords: C–H activation; cobalt; heterocycles; ni-
has been achieved by cobalt catalysis via a nitrone- trones; quinoline N-oxides
Introduction
Nitrones are important building blocks that are
easily accessible, and their chelation properties in rho-
Heterocycles are important motifs of natural prod- dium-catalyzed C–H activation reactions have been
ucts, pharmaceuticals, and functional materials. As explored.[13] The elegant work by the groups of Chang
a consequence, a great deal of effort has focused on and Li have demonstrated the dual role of nitrones as
developing new and efficient synthetic approaches to both directing group and oxygen source in the rhodi-
heterocycles.[1] In particular, there has been much in- um-catalyzed synthesis of indolines (Scheme 1a).[14]
terest in the discovery of transition metal-catalyzed The rhodium(III)-catalyzed C–H annulation of nitro-
C–H functionalizations for the synthesis of heterocy- nes with internal alkynes to furnish multi-substituted
cles that are less reliant on preactivation.[2] Many im- indoles was reported by Wan and Lu (Scheme 1b and
portant nitrogen-containing heterocycles, including c).[15a,b] The catalytic properties of low-cost cobalt for
pyrroles,[3] pyridines,[4] indoles,[3a,5] and quinolines,[6,7] this annulation were explored by Ackermann and co-
have been prepared through the direct functionaliza- workers (Scheme 1c).[15c] In these transformations, the
À
tion of otherwise unreactive C H bonds. Quinoline five-membered indole derivative is always formed
N-oxides constitute an important class of compounds through the nitrone-assisted C–H activation.
that possess a range of physiological activities[8] and
valuable coordination properties.[9] More importantly,
quinoline N-oxides have been proven to be common Results and Discussion
precursors to prepare derivatives of quinolines due to
the poor regioselectivity and reactivity of quinoline.[10] We recently reported an annulation of anilides and al-
More recently, the N-oxide group of quinoline N- kynes for the synthesis of quinolones[6c] by using the
oxides was found to be able to function as a directing unique nucleophilic reactivity of a cobalt catalyst.[16]
group as well as the source of oxygen for the synthesis In our initial experiment, none of the expected cycli-
of derivatives of quinolines.[11] However, a straightfor- zation product quinoline N-oxide was formed in the
ward approach to quinoline N-oxides remains chal- reaction of (Z)-N-benzylideneaniline oxide 1b and di-
lenging, and the installation of the N-oxide group gen- phenylacetylene 2a, yet the indole product could be
erally requires an additional oxidation step.[12] Due to obtained the same as in Ackermannꢀs report in low
its important application as a precursor of quinoline yield (Figure 1) (for more details see the Supporting
derivatives and the prevalence of this heterocycle in Information) However, we did not focus on the
many molecules of interest, the direct formation of indole product because it had been reported from
quinoline N-oxides is highly desirable.
a similar rhodium catalysis. We wondered whether we
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heterocycles. To probe this poor reactivity, we envi-
sioned that introducing different substituents in the
ortho position of aryl structure on the carbon center
could enhance its reactivity. It was observed that the
use of 2,6-dichlorophenyl (DCP) substrate afforded
the six-membered annulation product of quinoline N-
oxide (Figure 1).
Relying on the efficiency of phenylnitrone 1a, we
performed some studies on the reaction conditions as
summarized in Table 1. Silver salts for activation of
the cobalt catalyst were first tested by reacting of phe-
nylnitrone 1a with alkyne 2a in DCE at 708C for 15 h
in air. It was found that AgOTf and AgNTf2 delivered
the product 3a in low yields (entries 1 and 2), but
AgPF6 was inactive (entry 3). The use of AgSbF6 im-
proved the yield to 65% (entry 4), and AgBF4 afford-
ed the best result (entry 5). Among the oxidants
tested (entries 6–9), AgOAc showed the optimal effi-
ciency to give the quinoline N-oxide in 75% yield.
The solvent also influenced the reaction. Lower yields
were obtained when the reaction was performed in
DCM, TFE and PhCF3 (entries 10–12), and DCE was
Table 1. Optimization of the reaction conditions.[a]
Scheme 1. Annulation of nitrones with alkynes.
Entry Catalyst
Additive Oxidant
Yield of 3a
[%][b]
1
2
3
Cp*Co(CO)I2 AgOTf AgOAc
Cp*Co(CO)I2 AgNTf2 AgOAc
42
48
0
Cp*Co(CO)I2 AgPF6
AgOAc
4
5
6
7
8
9
10
11
12
13
14
15
16
Cp*Co(CO)I2 AgSbF6 AgOAc
65
75
Cp*Co(CO)I2 AgBF4
Cp*Co(CO)I2 AgBF4
Cp*Co(CO)I2 AgBF4
Cp*Co(CO)I2 AgBF4
Cp*Co(CO)I2 AgBF4
Cp*Co(CO)I2 AgBF4
Cp*Co(CO)I2 AgBF4
Cp*Co(CO)I2 AgBF4
AgOAc
Cu(OAc)2 30
Ag2CO3
CuO
Ag2O
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
trace
trace
trace
40[c]
28[d]
30[e]
NR
NR
NR
NR
Cp*Co(CO)I2
–
–
AgBF4
AgBF4
AgBF4
{Cp*RhCl2}2
RuCl2(p-
cymene)
Pd(OAc)2
17
–
AgOAc
NR
[a]
Reaction conditions: 1a (0.3 mmol), 2a (0.2 mmol), cata-
lyst (10 mol%), AgBF4 (20 mol%), oxidant (0.4 mmol) in
solvent (1.0 mL) in air at 708C for 15 h.
Yield of isolated product.
DCM was used as solvent.
TFE was used as solvent.
Figure 1. Screen of various nitrone substrates for the annula-
tion.
[b]
[c]
[d]
[e]
could use the unique nucleophilic activity of the orga-
nocobalt species to realize the synthesis of different
PhCF3 was used as solvent. DCP=2,6-dichlorophenyl.
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the best reaction medium. No reaction was observed smoothly (3s and 3t). However, the reactivity of sub-
in the absence of the cobalt catalyst or AgBF4 (en- strates with steric hindrance decreased drastically. For
tries 13 and 14). Furthermore, the cobalt catalyst ex- example, when 2-methylphenylnitrone was used, the
hibits unique reactivity in this annulation reaction. corresponding product was not observed. Electron-de-
Other catalysts, including {Cp*RhCl2}2, RuCl2(p- ficient arylnitrones showed less reactivity but worked
cymene), and Pd(OAc)2, were inactive (entries 15– to produce the expected quinoline N-oxide products
17).
in lower yields (Scheme 2, 3u–3w). The structure of
With the optimized conditions in hand, we next in- quinoline N-oxide 3a[17] was further confirmed by X-
vestigated the scope of arylnitrones and alkynes in ray crystallographic analysis (Scheme 2).
this annulation reaction and the results are summar-
This annulation reaction proceeded smoothly using
ized in Scheme 2. Substrates with electron-donating a variety of internal alkynes. A range of substituents
groups in the aryl ring were reactive toward dipheny- is tolerated on the aryl moiety of alkynes such as
lethyne 2a and gave the quinoline N-oxide products methyl, ethyl, methoxy, fluoro, chloro and bromo
in good yields (Scheme 2, 3a–3h). Synthetically versa- groups (Scheme 2, 4a–4h). After we had demonstrat-
tile halogen substituents can be positioned at various ed the success of the annulation of arylalkynes, we
points on the aryl motif to afford the corresponding were prompted to investigate the reactivity of alkyl-
quinoline N-oxides smoothly (Scheme 2, 3i–3q). The arylalkynes under similar reaction conditions since
methylthio group was tolerated to give the corre- they may give two possible products from two possi-
sponding quinoline N-oxide in 54% yield (3r). Multi- ble annulation directions.[3a,18] To our surprise, a single
À
substituted substrates participated in the reaction regioisomeric product is observed with C C bond for-
Scheme 2. Substrate scope of arylnitrones and alkynes.
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mation between the ortho-position of phenylnitrone value of kH/kD =2.6 (Scheme 4). These results indicat-
and the carbon of the alkynyl triple bond adjacent to ed that C–H activation is likely involved in the rate-
the alkyl group (Scheme 2, 4i–4l). This regioselectivity limiting step. After the reaction was performed for
is consistent with the insertion of unsymmetrical al- 1 h, two products were observed that were assigned as
[19]
À
kynes into the Rh C bond. The examined dialkyl- quinoline N-oxide product 3a and alkenylated inter-
alkynes only gave products in relatively lower yields mediate 9. Treatment of the alkenylated intermediate
(4m–4o).
9 under the standard reaction conditions afforded the
Some derivatizations to demonstrate the synthetic quinoline N-oxide product 3a [Scheme 4, Eq. (1)].
utility of using an as-prepared quinoline N-oxide as The structure of alkenylated intermediate 9[21] was
precursors are presented in Scheme 3. For example, confirmed by X-ray crystallographic analysis. Either
by using the N–O moiety as directing group, the rho- cobalt catalyst or silver oxidant is needed for the an-
dium-catalyzed C-8 alkylation was successfully ach- nulation of alkenylated intermediate 9 [Scheme 4, Eq.
ieved to give the quinoline 6 in high yield. Selective (2)]. Air may be involved as oxidant to promote the
C-8 amination and iodination were performed from reaction. For instance, more quinoline N-oxide 3a was
quinoline N-oxide 3a under iridium catalysis and rho- generated when the reaction was performed under
dium catalysis under mild reaction conditions to give air, and in contrast, more quinoline 3a’ was observed
compounds 7 and 8. Quinoline N-oxide 3a could be under nitrogen [Scheme 4, Eq. (3)]. The by-product
readily reduced to deliver the corresponding quino- quinoline 3a’ failed to form the quinoline N-oxide
line 3a’ using the PhCH2OH/NaOEt system.[20]
product 3a under the standard reaction conditions,
In order to explore the possible reaction mecha- suggesting that quinoline N-oxide product 3a is gener-
nism, a series of control experiments was carried out. ated from the catalytic cycle rather than from the oxi-
The kinetic isotope effect was studied by two side-by- dation of quinoline 3a’ [Scheme 4, Eq. (4)].
side reactions using 1a and 1a-d5 under the standard
To gain insights into the origin of the observed ac-
conditions, from which a kH/kD value of 3.7 was ob- tivity of arylnitrone 1, theoretical calculations were
1
tained on the basis of H NMR analysis. In addition, conduct.[23] Since the concerted metalation–deproto-
the competitive coupling of an equimolar mixture of nation of carboxylate-assisted transition metal-cata-
1a and 1a-d5 with diphenylacetylene gave a consistent lyzed C–H activation by Co catalysts[16] or other tran-
sition metals[24] has been well studied, here we focus
on the alkyne insertion and nucleophlic attack steps
(Figure 2). It should be note that in the transition
state corresponding to the nucleophlic attack, the
phenyl on the carbon atom of the imine might be syn-
or anti- to the Cp*Co (Figure 3). Interestingly, it is
found that the relative stabilities of the syn- and anti-
transition states are related to the substituents on the
phenyl. For the di-ortho-chloride-substituted phenyl,
the anti-transition state is more favorable than the
syn-one (anti-2Cl-TS-NA 27.4 vs. syn-2Cl-TS-NA
32.2 kcalmolÀ1). In contrast, for the non-substituted
phenyl, the syn-transition state is more stable than
the anti-one (syn-2H-TS-NA 31.7 vs anti-2H-TS-NA
33.1 kcalmolÀ1). As shown in Figure 2, the alkyne in-
sertion step always has a lower energy barrier than
the nucleophilic attack step and should not account
for the observed activity. Comparing the nucleophilic
attack steps for 2Cl-INT1 and 2H-INT1, it can be
seen that the energy demand of anti-2Cl-TS-NA is
significantly lower than that of syn-2H-TS-NA (27.4
vs. 31.7 kcalmolÀ1), meaning that the nucleophlic
attack for the former is much faster than that for the
latter. Therefore, these calculation results provide the-
oretical support that the nucleophlic attack step is re-
sponsible for the distinct activity between 2Cl-INT1
and 2H-INT1.
On the basis of previous studies of cobalt chemis-
try[15c] and our experimental findings, a plausible reac-
Scheme 3. Syntheic utility of quinoline N-oxide 3a.
tion mechanism is proposed as shown in Scheme 5.
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Scheme 4. Control experiments.
The first step is the formation of active cobalt catalyst bond of the nitrone forms the intermediate IV, which
I by the abstraction of iodide from the pre-catalyst undergoes protonation to give the intermediate V.
Cp*Co(CO)I2 by AgBF4. The following cobalt-cata- Oxidation of intermediate V gives the quinoline N-
lyzed C–H cleavage assisted by the nitrone group af- oxide product 3a, and dehydration of V generates the
fords the cyclic cobalt intermediate II, which under- by-product quinoline 3a’.[22] In the process of forma-
goes insertion with the alkyne to give the intermedi- tion of IV from III, the DCP group has a great influ-
ate III. The protonation of intermediate III produces ence on the intramolecular nucleophilic attack. The
the alkenylated product 9. The intramolecular nucleo- DCP group not only breaks the planarity between the
philic attack of intermediate III into the C=N double aryl group and carbon-nitrogen double bonds but also
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Figure 2. Energy profiles for the alkyne insertion and nucleophlic attack steps starting from Cp*Co(III)(k2-OAc)-1a/1b and
1,2-diphenylethyne.
Figure 3. Optimized structures of the syn- or anti-transition states for the nucleophlic attack step. Energies are in kcalmolÀ1.
Bond distances are in ꢂngstrom units.
enhances the electrophilicity of the carbon-nitrogen valuable quinoline derivatives. Further research on
double. Then the process of intramolecular nucleo- the development of novel nitrone-directed C–H acti-
philic attack could be carried out smoothly.
vations is currently ongoing in our laboratory.
Conclusions
Experimental Section
In summary, we have developed a straightforward
cobalt-catalyzed method involving dual C–H activa-
tion for the synthesis of quinoline N-oxides from
easily accessible substrates. The new reaction is highly
selective and shows good functional group tolerance.
The derivatizations by using as-prepared quinoline N-
General Procedure
To a test-tube with a stir bar were added diphenylacetylene
(2a, 0.20 mmol), nitrone (1a, 0.30 mmol), Cp*Co(CO)I2
(0.02 mmol), AgBF4 (0.04 mmol) and AgOAc (0.4 mmol) in
DCE (1.0 mL) under atmospheric conditions. The reaction
mixture was stirred at 708C for 15 h, cooled to room tem-
oxide as precursors are achieved for the synthesis of perature and the organic solvents were removed under re-
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Acknowledgements
We gratefully acknowledge the Natural Science Foundation
of China (21272205, 21472165), Natural Science Foundation
of Zhejiang Province (LY16B020005) and the Program for
the Zhejiang Leading Team of Science and Technology Inno-
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FULL PAPERS
Synthesis of Quinoline N-Oxides by Cobalt-Catalyzed
9
Annulation of Arylnitrones and Alkynes
Adv. Synth. Catal. 2017, 359, 1 – 9
Yue Liu, Chen Wang, Ningning Lv, Zhanxiang Liu,
Yuhong Zhang*
Adv. Synth. Catal. 0000, 000, 0 – 0
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ꢁ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers!