A Direct C2-Selective Phenoxylation and Alkoxylation of Quinoline N-Oxides with Various Phenols and Alcohols in the Presence of H-Phosphonate

Article abstract of DOI:10.1002/ejoc.201701080

A practical and efficient method for the synthesis of 2-aroxy(alkoxy)quinolines has been developed by direct cross-dehydrogenative coupling reaction between quinoline N-oxides and readily available phenols and alcohols in the presence of H-phosphonate and

Full text of DOI:10.1002/ejoc.201701080

A Journal of
Accepted Article
Title: A direct C2-selective phenoxylation and alkoxylation of quinoline
N-oxides with various phenols and alcohols in the presence of H-
phosphonate
Authors: Wenzhu Bi, Chen Qu, Xiaolan Chen, Lingbo Qu, Zhidong Liu,
Kai Sun, Xu Li, and Yufen Zhao
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201701080
Link to VoR: http://dx.doi.org/10.1002/ejoc.201701080
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10.1002/ejoc.201701080
European Journal of Organic Chemistry
COMMUNICATION
A direct C2-selective phenoxylation and alkoxylation of quinoline
N-oxides with various phenols and alcohols in the presence of H-
phosphonate
Wen-Zhu Bi,[a,e] Chen Qu,[b] Xiao-Lan Chen,*[a] Ling-Bo Qu,*[a,c] Zhi-Dong Liu,[a] Kai Sun,[a] Xu Li,[d] and
Yu-Fen Zhao*[a,e]
Dedication ((optional))
Abstract: A practical and efficient method for the synthesis of 2-
aroxy(alkoxy)quinolines has been developed, via direct cross-
dehydrogenative coupling reaction between quinoline N-oxides and
readily available phenols and alcohols in the presence of H-
phosphonate and CCl4 under mild conditions.
at 115 °C for 20 h.13c Even though a low amount of palladium
were used, this reaction, like other transition-metal-catalyzed
reactions, requires well-designed complex ligands, inert reaction
atmosphere as well as long reaction time. Moreover, the starting
compound, 2-chloroquinoline, is usually obtained by chlorination
of quinoline N-oxide with low yield and poor 2,4-
regioselectivity.14
Through
cyclization
of
o-alkynylaryl
isocyanides with phenols or alcohols as nucleophiles, Zhu et al.
reported the synthesis of 2-aroxy(alkoxy)-3-substituted
quinolines in the presence of 1,4-diazabicyclo[2.2.2]octane
(DABCO) (Scheme 1b).15 However, this DABCO-promoted
cyclization reaction employed an unstable starting compound, o-
alkynylaryl isocyanides, which was synthesized through the
dehydration of N-formylamide by the use of a harsh reagent
POCl3 and a much excess of (iPr)2EtN (8 eq.). Recently,
quinoline N-oxides have been well studied in the field of
selective C2-C,16 C2-N17 and C2-S18 bonds construction.
Comparatively, there are only few reports in literature
concerning the selective construction of C2-O bond.19 In 2016,
Introduction
2-Aroxy(alkoxy)quinoline derivatives are a kind of medicinally
interesting compounds with wide variety of biological activities,
such as antitumor agents, antibacterial, HIV integrase inhibitors,
antithrombin etc.1-8 Due to this prevalence of 2-
aroxy(alkoxy)quinolines in medicinal chemistry, numerous
synthetic strategies for the preparation of this kind of heteroaryl
ethers have been frequently reported. The traditional synthetic
approach in literature may be the Williamson-type reaction of
previously activated 2-haloquinolines with phenols or alcohols in
the presence of strong bases, such as solid sodium,9 NaOH,10
tBuOK,11 or NaH,5 under high reaction temperatures. Obviously,
the required harsh reaction conditions greatly limited their
applications. Alternatively, this nucleophilic substitution of 2-
haloquinoline with phenols or alcohols could also be promoted
by the use of transition-metal-catalyzed reactions, such as
copper-catalyzed
reactions,12
and
palladium-catalyzed
reactions.13 As shown in Scheme 1a, Saeys’s group reported a
palladium-catalyzed etherification of 2-chloroquinoline with
functionalized phenols in the presence of a triphosphane ligand
[a]
[b]
W. Z. Bi, X. L. Chen, L. B. Qu, Z. D. Liu, K. Sun, Y. F. Zhao
College of Chemistry and Molecular Engineering
Zhengzhou University
Henan Province, Zhengzhou, 450052, (P. R. China)
E-mail: chenxl@zzu.edu.cn
C. Qu
Department of Chemical and Biomolecular Engineering
University of Notre Dame
Notre Dame, Indiana 46556, United States
L. B. Qu
Luoyang Institute of Science and Technology
Luoyang, 471023, China
[c]
[d]
X. Li
Institute of Chemistry Co. Ltd
Henan Academy of Sciences
Zhengzhou, 450002, China
[e]
Y. F. Zhao
The Key Laboratory for Chemical Biology of Fujian Province
Xiamen University
Xiamen, 361005, China
Scheme 1. Comparison of previous works with this work.
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/ejoc.201701080
European Journal of Organic Chemistry
COMMUNICATION
Londregan et al. developed an efficient and direct procedure for
the synthesis of 2-alkoxyquinolines from quinoline N-oxides and
alcohols in the presence of a substrate activator PyBroP at
25 °C for 18-24 h (Scheme 1c).20 However, it is especially worth
mentioning that the phosphonium salt PyBroP is relatively
expensive and a much longer reaction time is required. Very
recently, Itami’s group reported a de novo synthesis of 2-
we continuously committed our efforts to explore our practical
methodology for the selective construction of the challenging
C2-O bond. Herein, we would like to disclose the highly efficient
one-pot synthetic method for the synthesis of 2-
aroxy(alkoxy)quinolines in the presence of H-phosphonate and
CCl4 under mild conditions (Scheme 1e).
aroxyquinolines
decarbonylation of aromatic esters in the presence of dcypt [3,4-
bis(dicyclohexylphosphino)thiophene] or dcppt [3,4-
bis(dicyclopentylphosphino)thiophene] at 150 °C for 18
(Scheme 1d).21 In spite of the significant efficiency, examples for
the synthesis of 2-alkoxyquinolines could not be achieved by this
decarbonylation method. In our previously reported works, we
described the H-phosphonate mediated C2-selective amination,
alkylation and sulfonation of quinoline N-oxides towards 2-
substituted quinolines and found that H-phosphonate played a
key role in the C2-H covalent bond activation.17a-b,18b Therefore,
through
nickel
or
palladium-catalyzed
Results and Discussion
h
Initially, the model reaction of quinoline N-oxide (1a) with
phenol (2a) was carried out under the optimal reaction
conditions previously reported for the C2-selective amination
and alkylation of quinoline N-oxides as shown in Table 1, entries
1-2.17a-b It was found that the required product 3a was obtained
in relatively low yields, 23% and 35%, respectively. Thus, the
reaction conditions for the phenoxylation and alkoxylation of
Table 1. Optimization of reaction conditions [a]
H-phosphonate
(HP(O)(OR)2, R=) (eq.)
Entry
Solvent
Base (eq.)
CCl4 (mL)
Temp. (°C)
Time (h)
Yield (%)[b]
1
CH2CH3 (2)
CH(CH3)2 (2)
CH(CH3)2 (2)
CH(CH3)2 (2)
CH(CH3)2 (2)
CH(CH3)2 (2)
CH(CH3)2 (2)
CH(CH3)2 (2)
CH(CH3)2 (2)
CH(CH3)2 (2)
CH(CH3)2 (2)
--
DMF
THF
K2CO3 (2)
Et3N (2)
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.3
0.7
0.5
0.5
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
30
40
50
40
40
40
40
40
40
40
40
40
40
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
1
2
3
4
2
2
2
2
2
2
23
35
25
17
27
58
13
21
65
71
67
n.r.[c]
65
63
42
32
73
83
82
77
85
84
83
45
81
31
80
48
79
2
3
THF
K2CO3 (2)
KOH (2)
4
THF
5
THF
Et2NH (2)
iPr2EtN (2)
iPr2EtN (2)
iPr2EtN (2)
iPr2EtN (2)
iPr2EtN (2)
iPr2EtN (2)
iPr2EtN (2)
iPr2EtN (2)
iPr2EtN (2)
iPr2EtN (2)
iPr2EtN (2)
iPr2EtN (2)
iPr2EtN (2)
iPr2EtN (2)
iPr2EtN (2)
iPr2EtN (2)
iPr2EtN (2)
iPr2EtN (2)
iPr2EtN (2)
iPr2EtN (2)
iPr2EtN (2)
iPr2EtN (2)
iPr2EtN (1)
iPr2EtN (3)
6
THF
7
DMSO
DMF
8
9
CH2Cl2
CH3CN
toluene
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
CH3 (2)
CH2CH3 (2)
Ph (2)
CH2Ph (2)
CH(CH3)2 (2)
CH(CH3)2 (2)
CH(CH3)2 (2)
CH(CH3)2 (2)
CH(CH3)2 (2)
CH(CH3)2 (2)
CH(CH3)2 (2)
CH(CH3)2 (2)
CH(CH3)2 (2)
CH(CH3)2 (2)
CH(CH3)2 (2)
CH(CH3)2 (2)
CH(CH3)2 (2)
[a] Optimal conditions: 1a (0.4 mmol), 2a (0.4 mmol), H-phosphonate (0.4-1.2 mmol), base (0.4-1.2 mmol), CCl4 (0.3-0.7 mL), solvent
(2 mL) for 1-5 h. [b] Isolated yields. [c] Detected by TLC. n.r. = no reaction.
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10.1002/ejoc.201701080
European Journal of Organic Chemistry
COMMUNICATION
quinoline N-oxides would must be re-established. As it can be
seen, adding different bases, Et3N, K2CO3, KOH, Et2NH or
iPr2EtN, to the reaction mixture, product 3a was obtained in
very significantly different yields, respectively (35%, 25%, 17%,
27% and 58%) (entries 2-6). Among those tested bases,
iPr2EtN gave the best yield (58%, entry 6). Following that, the
effect of solvents on the model reaction was investigated
(entries 6-11). The results showed that the yields sharply
decreased in both DMSO and DMF (13% and 21%), while,
increased markedly in CH2Cl2 (65%), CH3CN (71%), toluene
(67%). The influence of various H-phosphonates on the model
reaction was further evaluated in the presence of iPr2EtN in
CH3CN (entries 10, 12-16). It can be seen that, no any 3a was
found in the absence of H-phosphonate (entry 12), and
diisopropyl H-phosphonate still brought us the most satisfied
yield (71%, entry 10), in contrast with the decreases resulted
by dimethyl H-phosphonate (65%, entry 13), diethyl H-
phosphonate (63% entry 14), diphenylH-phosphonate (42%,
entry 15) and dibenzyl H-phosphonate (32%, entry 16). The
investigations of the influence of reaction temperature and
reaction time (entries 10, 17-23) on the model reaction showed
that the most satisfied yield of 3a (85%) was obtained at a
slightly elevated reaction temperature (40 °C) for a relatively
short reaction time (2 h) (entry 21). Furthermore, the influence
of the amount of diisopropyl H-phosphonate (entries 21, 24-25)
and the amount of CCl4 (entries 21, 26-27) as well as the
amount of iPr2EtN (entries 21, 28-29) on the model reaction
were investigated. As it can be seen, the amounts employed in
entry 21 still brought about the best result. Therefore, the
newly established optimal reaction conditions are 0.4 mmol
quinoline N-oxide and 0.4 mmol phenol in the presence of 2.0
eq. diisopropyl H-phosphonate, 2 eq. iPr2EtN and 0.5 mL CCl4
in 2 mL CH3CN at 40 °C for 2 h as shown in entry 21.
Scheme 2. Scope of the phenoxylation and alkoxylation of quinoline N-
oxides: Reaction conditions: 1 (0.4 mmol), 2 (0.4 mmol), diisopropyl H-
phosphonate (0.8 mmol), CCl4 (0.5 mL), iPr2EtN (0.8 mmol) in CH3CN (2
mL), at 40 °C for 2 h. Isolated yields were provided.
With the optimized reaction conditions in hand, the substrate
scopes were then examined as shown in Scheme 2. A series
of phenols bearing electron donating groups (-CH3, -C2H5,
-CH(CH3)2, -C(CH3)3) or electron withdrawing groups (-F, -Cl,
-Br) reacted well with quinoline N-oxide, giving a group of 2-
phenoxyquinolines in good to excellent yields (3a-j). No
obvious electronic effects were observed in the reactions of
substituted phenols with quinoline N-oxide. Meanwhile, phenol
was employed to react with various substituted quinoline N-
oxides bearing electron donating groups (-CH3, -OCH3) or
electron withdrawing groups (-Cl, -Br, -NO2), affording us the
corresponding 2-phenoxyquinolines in good to excellent yields
(3k-r). The electronic effects of the substituent were not
obviously observed except the relatively low isolated yield of
3q, which should be attributed to the steric hindrance of the o-
bromo-group. It is especially worth mentioning here that there
are many methods published concerning synthesizing bis-aryl
ethers, however, there are comparably few ways available for
synthesizing alkyl-aryl ethers. Thus, in this research work,
focusing more on aliphatic alcohols as nucleophile would be a
better way to showcase the advantages of this methodology
over others. As it can be seen in Scheme 2 (3s-ab), this newly
developed methodology were totally suitable for synthesizing
various heteroaryl alkyl ethers, for which so far very few
synthetic methodologies have been reported. Various aliphatic
alcohols, including ethanol, n-propanol, propan-2-ol, n-butanol,
phenylmethanol, as well as but-3-yn-2-ol, could successfully be
employed to react with quinoline N-oxide, affording the
corresponding 2-alkoxyquinolines in moderate to good yields
(3s-x). It can be seen that the ethynyl group in the compound
3w could survive the mild reaction conditions. Moreover,
various substituted quinoline N-oxides bearing electron
donating groups or electron withdrawing groups were used to
react with n-propanol, giving the corresponding 2-
alkoxyquinolines in moderate to good yields (3y-ab), in which
the electron donating groups (-CH3, -OCH3) resulted in
relatively low yields (3y-z), while the electron withdrawing
groups (-Br, -NO2) resulted in relatively high yields (3aa-ab).
To our delight, isoquinoline N-oxide also could react smoothly
with phenol as well as n-propanol, producing the
corresponding
1-phenoxyisoquinoline
(3ac)
and
1-
propoxyisoquinoline (3ad) in yield of 76% and 69%,
respectively.
A plausible reaction mechanism was presented as shown in
Scheme 3. Initially, diisopropyl H-phosphonate (1) react with
CCl4 to produce diisopropyl chlorophosphate (2) in the
presence of iPr2EtN (Scheme 3-1).22 Then, the negative
charged oxygen atom of quinoline N-oxide (3) attacks the
phosphorus atom of 2, resulting in the leaving of a chloride
anion and the formation of a quinolinium cation 4 or 4’ (4 is in
resonance with 4’). Owing to the formation of an intramolecular
hydrogen bond between phosphoryl-oxygen and 2C-hydogen
and the consequently formed six-membered ring, the
intermediate 4’ should be relatively stable. Thus, the 2C-H
bond in 4’ is strongly activated. After that, phenols 5, working
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COMMUNICATION
The newly established synthetic methodology can successfully
be used not only for the synthesis of the related heteroaryl arly
ethers but also for the synthesis of the comparably fewer
reported heteroaryl alkyl ethers. The newly established
synthetic methodology owns multiple remarkable merits,
including metal-free mild reaction conditions, one-pot
procedure, short reaction time, and most importantly, readily
available starting materials and the wide scope of products.
The methodology will undoubtedly be a far more superior
alternative for the synthesis of the biologically and chemically
significant 2-aroxy(alkoxy)quinolines. Further research on the
applications of this strategy is still in process.
Experimental Section
Scheme 3. Proposed reaction mechanism.
Quinoline N-oxide (0.4 mmol), phenols or alcohols (0.4 mmol),
diisopropyl H-phosphonates (0.8 mmol), CCl4 (0.5 mL), iPr2EtN (0.8
mmol) in CH3CN (2 mL) was stirred at 40 °C for 2 h. The mixture was
quenched with water (5 mL), extracted with CH2Cl2 (3 × 5 mL). The
combined organic layers were washed with brine (15 mL) and dried
over anhydrous Na2SO4. After filtration, the solvent was evaporated in
vacuo. The crude product was purified by silica gel chromatography
(petroleum ether : ethyl acetate = 10 : 1, v : v) to give the desired
products.
as a nucleophile, attacks the positively charged C2 in 4’ to give
6, which initiates a multi-electron rearrangement process to
afford the phosphate 7 and protonated 8. Then, deprotanation
of 8 by chloride ion gives the final product 9. iPr2EtN
neutralizes HCl, and the whole reaction is thus driven to
completion (Scheme 3-2). By the way, the newly formed
phosphate 7 reacted with 2, forming tetraisopropyl pyrophos-
phate 10 (Scheme 3-3). Two additional experiments were
performed to support the related reaction mechanism (Scheme
4). When the initially formed intermediate diisopropyl
chlorophosphate (2) were directly used in the reaction, a
relatively good yield of 3a was obtained (Scheme 4a). When
diisopropyl phenyl phosphate, which could be formed under
this Atherton-Todd reaction conditions,23 was employed to
react with quinoline N-oxide under standard reaction conditions,
the corresponding product 3a was not obtained (Scheme 4b).
This two additional experiments strongly backed the above
proposed mechanism.
Acknowledgements
Financial support from the Chinese National Natural Science
Foundation (No. 21072178 and No. 20472076), and the 2017
Science and Technology Innovation Team in Henan Province.
Keywords: Cross-dehydrogenative Coupling • Quinoline N-
oxides • Phenoxylation and alkoxylation • H-phosphonate •
Metal-free
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COMMUNICATION
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This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701080
European Journal of Organic Chemistry
COMMUNICATION
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COMMUNICATION
Synthetic method *
Wen-Zhu Bi, Chen Qu, Xiao-Lan Chen,*
Ling-Bo Qu,* Zhi-Dong Liu, Kai Sun, Xu
Li, Yu-Fen Zhao*
Page No. – Page No.
A direct C2-selective phenoxylation
and alkoxylation of quinoline N-
oxides with various phenols and
alcohols in the presence of H-
phosphonate
Various of 2-aroxy(alkoxy)quinolines were synthesized via direct cross-
dehydrogenative coupling reaction of quinoline N-oxides and phenols and alcohols
in the presence of H-phosphonate and CCl4.
* Cross-dehydrogenative coupling reaction
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