Direct Carbamoylation of Quinoline N-oxides with Hydrazinecarboxamides via C?H Bond Activation Catalyzed by Copper Catalyst

Article abstract of DOI:10.1002/adsc.201801430

An efficient method for the carbamoylation of quinoline N-oxides catalyzed by copper was developed. A variety of quinoline N-oxides and hydrazinecarboxamides with different groups was well tolerated in this system. (Figure presented.).

Full text of DOI:10.1002/adsc.201801430

Title: Direct Carbamoylation of Quinoline N-oxides with
Hydrazinecarboxamides via C-H Bond Activation Catalyzed by
Copper Catalyst
Authors: Zu-Li Wang, guanghui li, Dao-Qing Dong, yun yang, and
xianyong yu
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201801430
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10.1002/adsc.201801430
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Direct Carbamoylation of Quinoline N-oxides with
Hydrazinecarboxamides via C-H Bond Activation Catalyzed by
Copper Catalyst
Guang-Hui Li,a# Dao-Qing Dong,a# Yun Yang,b Xian-Yong Yub and Zu-Li Wanga*
a
College of Chemistry and Pharmaceutical Sciences, Qingdao Agricultural University, Qingdao 266109, PR China
[wangzulichem@163.com; wangzuli09@tsinghua.org.cn]
School of Chemistry and Chemical Engineering, Hunan University of Science and Technology, Xiangtan 411201,
b
China
#
These authors contributed equally to this article.
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######.((Please
delete if not appropriate))
dehydrogenative cross-coupling reaction was also
Abstract. An efficient method for the carbamoylation of
quinoline N-oxides catalyzed by copper was developed. A realized by the same group, providing quinoline-
variety of quinoline N-oxides and hydrazinecarboxamides
with different groups was well tolerated in this system.
containing heterocyclic molecules in moderate to
excellent yields (Scheme 1b).[10] In 2011, a Pd(II)-
catalyzed oxidative coupling between quinoline N-
oxides and N-substituted indoles via 2-fold C-H bond
activation was presented by Li group (Scheme 1c).[11]
In 2013, Wu et al. found that aryl sulfonyl chlorides
was good reagent for the synthesis of sulfonylated
quinoline N-oxides. (Scheme 1d).[12] Additionally,
lactams/cyclamines were also good pater to react with
quinolone N-oxides. The Cu(OAc)2-catalyzed
dehydrogenative coupling of quinoline N-oxides with
lactams/cyclamines was achieved by Li’s group for
the construction of 2-aminoquinoline skeleton
(Scheme 1e).[13] Although various reactions for the
synthesis of quinoline derivatives have been realized,
trying to develop new versatile and practical methods
are still desirable. Recently, Tian’s group realized
carbamoylation of N-arylacrylamides[16a] and
nitrogen heteroarenes using hydrazinecarboxamides
as substrates.[16b] Encouraged by Tian’s work and on
the basis of our continued pursuit of C-H bond
activation,[14] herein we disclose a new strategy to
access carbamoylated quinolone N-oxides via CuBr-
catalyzed carbamoylation of quinolone N-oxides with
hydrazinecarboxamides.
Keywords: quinolone N-oxides; hydrazinecarboxamides;
C-H activation; copper
Quinoline derivatives are one of the most valuable
compounds and have been found widespread
application in diverse areas, such as bioactive natural
products,[1] pharmaceuticals,[2] and functional
materials.[3] Although the direct functionalization of
pyridine ring still remains a significant challenge
because of its low reactivity and poor selectivity,
there has been much effort devoted to the
functionalization of quinolone skeleton in the past
few decades.[4] For example, series of quinoline
derivatives have been efficiently synthesized from
quinolone N-oxides in recent years.[5] Without using
any base and organic solvent, various functionalized
quinolin-2(1H)-ones were synthesized from the
reaction of quinolone N-oxides with water by He’s
group.[6] This group also realized the reaction
between quinolone N-oxides and nitriles, obtaining
various N-acylated 2-aminoquinolines.[7] Zhao’s
group developed an efficient one-pot methodology
for C2-selective amination and alkylation of
quinoline N-oxides. A large variety of primary and
secondary amines, as well as active methylene
compounds were well tolerated in this system.[8] In
2013, an efficient and direct 2-acetoxylation of
quinoline N-oxides via copper(I) catalyzed C–H bond
activation was presented by Wu and coworkers.
However, this reaction was limited to the electron-
withdrawing aldehydes and heterocyclic aldehydes
(Scheme 1a).[9] Direct C-2 alkylation of quinoline N-
oxides with ethers via Palladium-catalyzed
1
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10.1002/adsc.201801430
Advanced Synthesis & Catalysis
4
5
Cu(OAc)2
CuO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
CH3CN
DMF
10
5
6
Cu(OTf)2
CuBr
17
7
92
8
Pd(OAc)2
PdCl2
CuBr
Trace
Trace
16
9
10
11
12
13
14b
15c
16d
CuBr
38
CuBr
PhCI
57
CuBr
Toluene
DMSO
DMSO
DMSO
36
CuBr
19
CuBr
43
CuBr
23
aReaction conditions: 1a (0.2 mmol), 2a (0.4 mmol),
catalyst (5 mol%), TBHP (5−6 M in decane, 3.0 equiv),
Scheme 1. Functionalization of quinoline N-oxides.
b
At the start of our investigation, the reaction between
DMSO(2 mL), under air, 100 °C, 12 h. 3.0 equiv of H2O2
c
d
quinoline
1-oxide
(A1)
and
N-
was used. 3.0 equiv of TBPB was used. 3.0 equiv DTBP
was used.
phenylhydrazinecarboxamide (B1) was selected as a
model reaction. As show in Table 1, when the
reaction of A1 and B1 was carried out in the presence
of CuSO4, product P1 was obtained in 21% yield
(table 1, entry 1). When other copper catalysts such
as CuOTf, CuI, Cu(OAc)2, CuO, Cu(OTf)2 and CuBr
were subjected to the reaction, CuBr was found to be
the best catalyst (table 1, entries 2-7). Palladium
catalyst Pd(OAc)2 and PdCl2 were also tested in this
reaction, but the result was disappointing (table 1,
entries 8-9). The effect of solvents on the model
reaction was also examined. Among these solvents
examined in the model reaction, DMSO was optimal.
Only 16-57% yields of the product was isolated when
other solvents (CH3CN, DMF, PhCl, Toluene) were
used (table 1, entries 10-13). Encouraged by this
result, various oxidants were further investigated and
performed with lower yields in this reaction (table 1,
entries 14-16). Finally, the best yield of P1(92%) was
obtained by employing CuBr as catalyst and TBHP as
oxidant in DMSO under air. To put the structure
beyond any ambiguity, a single crystal of P1[15]
cultivated by slow evaporation of solvent from its
solution in a mixture of ethyl acetate and chloroform
and its X-ray molecular structure was determined
(Fig 1).
Fig 1. X-Ray molecular structure of P1.
Using the developed optimized reaction conditions,
the substrates scope of this reaction was examined
with respect to both hydrazinecarboxamides and
quinoline N-oxides and the results were summarized
in Table 2. Under the optimal reaction conditions, the
reaction of hydrazinecarboxamides containing both
electron-withdrawing and electron-donating groups,
such as CH3, Br, Cl and F, on the benzene ring with
quinoline 1-oxide took place smoothly and generated
the corresponding products in moderate to high yields
(table 2, P1-P6). Different quinolone N-oxides were
tested for this transformation. 6-chloroquinoline 1-
oxide afforded the desired products in 82-90% yields
(table 2, P7-P10). 65-85% yields of the products were
obtained when 6-fluoroquinoline 1-oxide was tested
as substrates (table 2, P11-P14). To our delight, N-
cyclohexylhydrazinecarboxamide and N-(naphthalen-
1-yl)hydrazinecarboxamide were also well tolerated
in this system. They were all reacted smoothly with
quinolone N-oxides and give the corresponding
products with moderate to high yields (table 2, P15-
P20). To our disappointment, no reaction occurred
Table 1 Optimization of the reaction conditionsa
Entry
Catalyst
CuSO4
CuOTf
CuI
Solvent
DMSO
DMSO
DMSO
Yield(%)
1
2
3
21
54
34
when
6-methoxyquinoline
N-oxide,
6-
2
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10.1002/adsc.201801430
Advanced Synthesis & Catalysis
methylquinoline N-oxide, 3-bromoquinoline N-oxide
and 6-(methoxycarbonyl)quinoline N-oxide were
subjected to this reaction (Table 2).
P22 NR
P24 NR
P23 NR
Table 2. Reaction scopea
aReaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), CuBr
(5 mol%), TBHP (5−6 M in decane, 3.0 equiv), DMSO(2
mL), under air, 100 °C, 12 h.
P1 (92%)
P3 (75%)
P6 (81%)
P9 (82%)
P12 (80%)
P2 (80%)
To gain insight into the reaction mechanism, some
control experiments were conducted (Scheme 3).
When the reaction was conducted in the presence of
di-tert-butylhydroxytoluene (BHT) and 2,2,6,6-
tetramethylpiperidine-1-oxyl (TEMPO) as a radical
trapping reagent, the oxidation was seriously
suppressed and only a trace amount of P1 was
observed. The radical adducts between the active
intermediate and BHT or TEMPO have been
identified by HRMS (Scheme 2). These results
indicated that a free radical intermediate was
involved in this oxidation.
P4 (70%)
P5 (78%)
P7 (84%)
P8 (90%)
P11 (65%)
P10 (82%)
Scheme 2. Mechanism Research.
P13 (85%)
P15 (65%)
P14 (84%)
P18 (82%)
P17 (66%)
P16 (63%)
Scheme 3. Possible reaction pathway.
Based on the above experimental results and previous
reports,[16] a possible reaction pathway was proposed
as shown in Scheme 3. Firstly，carbamoyl radical 2
generated from the reaction of hydrazinecarboxamide
with TBHP.[17] Subsequently, the reaction of
carbamoyl radical 2 and intermediate1, which was
generated from the reaction of quinolone N-oxides
P21 NR
P19(90%)
P20 (70%)
3
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10.1002/adsc.201801430
Advanced Synthesis & Catalysis
and CuBr, give the corresponding intermediate 3.
Finally, the desired product was produced with the
concomitant formation of copper catalyst.
5646. h) L.-Y. Xie, J. Qu, S. Peng, K.-J. Liu, Z. Wang,
M.-H. Ding, Y. Wang, Z. Cao, W.-M. He, Green Chem.
2018, 20, 760-764. i) L.-Y. Xie, S. Peng, F. Liu, G.-R.
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In summary, a facile and highly efficient method has
been successfully developed for the synthesis of
carbamoylated quinoline N-oxides. A series of
structurally diverse products could be effectively
obtained using TBHP as oxidant in the presence of
CuBr. Further studies on the scope, mechanism, and
synthetic application of this reaction are under
investigation
Experimental Section
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A sealable reaction tube equipped with a magnetic stirrer
bar was charged with quinoline N-oxide (0.2 mmol), N-
phenylhydrazinecarboxamide (2.0 equiv.), CuBr (5mol%),
TBHP(5.0-6.0 mol/L in decane, 3.0 equiv.), DMSO (2.0
ml). The reaction vessel was carried out 100 ℃. After
completion, it was diluted with ethyl acetate. After the
solvent was removed under reduced pressure, the residue
was purified by column chromatography on silica gel to
afford the corresponding product.
[6] L.-Y. Xie, Y. Duan, L.-H. Lu, Y.-J. Li, S. Peng, C. Wu,
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Acknowledgements
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We gratefully acknowledge the financial support from National
Natural Science Foundation of China (21402103, 21772107), the
China Postdoctoral Science Foundation (150030), and the
Research Fund of Qingdao Agricultural University’s Highlevel
Person (631303).
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5
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10.1002/adsc.201801430
Advanced Synthesis & Catalysis
COMMUNICATION
Direct Carbamoylation of Quinoline N-oxides with
Hydrazinecarboxamides via C-H Bond Activation
Catalyzed by Copper Catalyst
Adv. Synth. Catal. Year, Volume, Page – Page
Guang-Hui Li,a# Dao-Qing Dong,a# Yun Yang,b
Xian-Yong Yub and Zu-Li Wanga*
6
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