Hypervalent Iodine(III)-Mediated Regioselective Cyanation of Quinoline N-Oxides with Trimethylsilyl Cyanide

Article abstract of DOI:10.1002/adsc.201801185

A regioselective cyanation of quinoline N-oxides with trimethylsilyl cyanide was developed by using (Diacetoxyiodo) benzene (PIDA) as mediated hypervalent iodine(III) reagent under metal-free and base-free reaction conditions to obtain 2-cyanoquinolines. The efficient PIDA reagent could play the role of an activator of the substrates and an accelerator of N?O bond cleavage. The reaction system featured a wide range of substrate suitability and high yields. The procedure was enlarged gram-scale to synthesize the tuberculosis (TB) inhibitor. Finally, according to some experimental results, a plausible mechanism for the cyanation reaction is proposed. (Figure presented.).

Full text of DOI:10.1002/adsc.201801185

Title: Hypervalent Iodine(III)-Mediated Regioselective Cyanation of
Quinoline N-Oxides with Trimethylsilyl Cyanide
Authors: Feng Xu, Yuqin Li, Xin Huang, Xinjie Fang, Zhuofei Li,
Hongshuo Jiang, Jingyi Qiao, wenyi chu, and zhizhong sun
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201801185
Link to VoR: http://dx.doi.org/10.1002/adsc.201801185

10.1002/adsc.201801185
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Hypervalent Iodine(III)-Mediated Regioselective Cyanation of
Quinoline N-Oxides with Trimethylsilyl Cyanide
Feng Xuab, Yuqin Liab, Xin Huangab, Xinjie Fangab, Zhuofei Liab, Hongshuo Jiangab,
Jingyi Qiaoab, Wenyi Chuab* and Zhizhong Sunab*
a
School of Chemistry and Materials Science, Heilongjiang University, Harbin 150080, P. R. China
Corresponding author. Tel.: +86-451-86609135; fax: +86-451-86609135 and E-mail: wenyichu@hlju.edu.cn or
sunzz@hlju.edu.cn
Key Laboratory of Chemical Engineering Process & Technology for High-efficiency Conversion, College of
b
Heilongjiang Province, Harbin 150080, P. R. China
Corresponding author. Tel.: +86-451-86609135; fax: +86-451-86609135 and E-mail: wenyichu@hlju.edu.cn or
sunzz@hlju.edu.cn
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))
Abstract. A regioselective cyanation of quinoline N-oxides the tuberculosis (TB) inhibitor. Finally, according to some
with trimethylsilyl cyanide was developed by using experimental results, a plausible mechanism for the
(Diacetoxyiodo) benzene (PIDA) as mediated hypervalent cyanation reaction is proposed.
iodine(III) reagent under metal-free and base-free reaction
conditions to obtain 2-cyanoquinolines. The efficient PIDA
reagent could play the role of an activator of the substrates
and an accelerator of N-O bond cleavage. The reaction
system featured a wide range of substrate suitability and high
yields. The procedure was enlarged gram-scale to synthesize
Keywords: Cyanation; Metal-free; PIDA; Quinoline N-
oxides; Trimethylsilyl cyanide
have a few limitations, such as the requirement of
higher reaction temperature and the use of
stoichiometric amounts of toxic CuCN. Another
common method involves the transition-metal-catalyzed
C-H bond cyanation of quinoline.[8] In 2004, Tagawa
and co-workers reported the Pd-catalyzed direct C-H
activation and cyanation of quinoline N-oxides by
using trimethylsilyl cyanide as cyanation reagent and
DDQ as oxidant (Scheme 1b).[9] However, the author
only investigated the reaction of 4-substituted
quinoline N-oxides, and the reaction of quinoline N-
oxides with electron-withdrawing groups at the 4-
position did not proceed at all.
Introduction
N-containing heterocycle compounds are widely used
in pharmaceuticals, agricultures and material
sciences.[1] Functionalized quinoline derivatives as
important N-containing heterocycle compounds are
increasingly utilized in pharmaceutical chemistry,
particularly in the fields of antimalarial and
anticancer activities.[2] Meanwhile, cyanide as a
common functional group that plays an important role
in chemistry, biology and medicine.[3] The nitrile
group also possess multifunctional applications as
intermediates in organic synthesis because it can be
easily converted into various functional groups, such
as amines, amides, carboxylic acids and heterocyclic
compounds, etc.[4] Some derivatives of 2-cyano
quinoline/pyridine are important structural units in
pharmaceutical, natural products and preclinical drug
candidates. (Figure 1).[5] Therefore, synthesis of
derivatives of 2-cyano quinoline/pyridine has
attracted more attention.
Regioselective cyanation is an important synthetic
strategy to get 2-cyano quinolines. Over the past
years, the synthesis of 2-cyano quinolines were
commonly to use cyanation of 2-haloquinolines or
quinoline diazonium salt with CuCN, namely the
Sandmeyer and the Rosenmund-von Braun reactions
(Scheme 1a).[6-7] Traditional synthetic approaches
Figure 1. Representative bioactive derivatives of 2-cyano
quinoline/pyridine. (1) Topiroxostat (anti-gout); (2) MIV-
150 (anti-HIV); (3) Regorafenib (anti-cancer); (4) TB inhibitor;
(5) PBT2 (anti-AD); (6) perspicamides A.
1
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10.1002/adsc.201801185
Advanced Synthesis & Catalysis
Sandmeyer reaction and Rosenmund-von Braun reaction
reagent as an eco-friendly and inexpensive reagent
could induce functional groups to the 2-position of
quinoline N-oxides derivatives.[15] In 2017, Yu and
colleagues reported that quinoline N-oxides and
sulfonamides were induced by PhI(OAc)2 (PIDA) and
PPh3 to synthesize 2-sulfonamideyl quinoline.
Nevertheless, a stoichiometric amount of phosphorus
Transition-metal-catalyzed cyanation reaction
Transition-metal-free catalyzed cyanation reaction
reagent was necessary for the successful
[15c]
intermolecular sulfamidation.
In addition,
PhI(OAc)2 has become one of the most popular
research topics in organic synthesis. Herein, we
developed a highly regioselective synthesis of 2-
cyanoquinoline derivatives by the PhI(OAc)2-
mediated N-O bond disruption and direct cyanation
of quinoline N-oxide substrates by using TMSCN as
cyano source (Scheme 1g). The method avoided
using the transition-metal, phosphorus reagent and
base additives.
Results and Discussion
Table 1. Screening of the reaction conditionsa)
This work
Ent Iodine (equiv)
ry
“CN”
source
Solvent
T
(°C)
Yield
(%)b)
Scheme 1. Strategies for C2-cyanation of quinolines.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
PhI(OAc)2 (1)
PhI(OTf)2 (1)
IBX (1)
TMSCN
TMSCN
TMSCN
TMSCN
TMSCN
TMSCN
TMSCN
TMSCN
TMSCN
TMSCN
TMSCN
TMSCN
TMSCN
TMSCN
TMSCN
DME
DME
DME
DME
DME
DME
DME
DMF
DMSO
MeOH
Toluene
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
80
80
80
80
80
80
80
80
80
80
80
80
30
50
100
80
80
80
80
45
35
traces
n,d.c)
50
60
57
28
23
n,d.
65
73
25
46
58
n,d
12
n,d
traces
In most of the cases, expensive transition metals
may pollute the product, thereby limiting their
applications, especially in the pharmaceutical
industry and advanced functional material. Thus, it is
necessary to develop the method of transition-metal-
free catalyzed cyanation reaction.[10] A metal-free
approach for regioselective C-2 functionalization of
quinolines or pyridines involves initial oxidation to
quinoline/pyridine N-oxides, followed by O-
activation and nucleophilic substitution (Scheme
1c).[11] In 2017, Paton et al. reported the cyanation of
6-ring N-containing heterocycles by using a triflic
anhydride (Tf2O) / N-methylmorpholine (NMM)
system with trimethylsilyl cyanide as the cyano-
group source. Moreover, triflic anhydride (Tf2O) was
found to be predominant as an activator. Nonetheless,
the reaction had other isomers with poor
regioselectivity (Scheme 1d).[12] In 2017, P. S. Fier
reported that cyanation of pyridine used NaCN as an
cyanation reagent with α-chloro O-methanesulfonyl
aldoximes as an activator under mild conditions
(Scheme 1e).[13] However, NaCN as a toxic cyanation
reagent was required. In 1983, Fife reported N,N-
dimethylcarbamoyl chloride could be used as an
activation reagent for the cyanation of the pyridine N-
oxides with TMSCN in dichloromethane. In addition,
Miyashita et al. reported that DBU was an effective
base for the cyanation of the quinoxaline/ quinazoline
N-oxides with TMSCN in 1992 (Scheme 1f).[14]
Reaction A requested harsh acylating reagent N,N-
dimethylcarbamoyl chloride and long reaction time.
Reaction B requires that its substrates are mainly
suitable for quinoxaline/ quinazoline N-oxides. Iodine
I2 (1)
PhI(OAc)2 (2)
PhI(OAc)2 (3)
PhI(OAc)2 (4)
PhI(OAc)2 (3)
PhI(OAc)2 (3)
PhI(OAc)2 (3)
PhI(OAc)2 (3)
PhI(OAc)2 (3)
PhI(OAc)2 (3)
PhI(OAc)2 (3)
PhI(OAc)2 (3)
PhI(OAc)2 (3) K4Fe(CN)6
PhI(OAc)2 (3)
--
PhCOCN
TMSCN
TMSCN
PIFA(3)
a) Reaction conditions: 1a (0.1 mmol), TMSCN (3.0 equiv)
and iodine (3 equiv) in solvent (5 ml) for 6 hours.
b)
Isolated yield after purification by column chromatography.
c) n.d. = not detected.
Quinoline N-oxide (1a) and TMSCN were selected as
an initial model reaction to screen various reaction
conditions. The experimental results were summarized
in Table 1. Quinoline N-oxide (1 equiv) was initially
chosen as the model substrate to react with TMSCN
(3 equiv) in the presence of PhI(OAc)2 (1 equiv) in
1,2-dimethoxyethane at 80 °C under an air atmosphere.
Much to our delight, the reaction proceeded to give
2
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10.1002/adsc.201801185
Advanced Synthesis & Catalysis
Table 2. Substrate scope of quinoline N-oxides with
access to the desired cyanation product 2a with a low
yield (45%, Table 1, entry 1). Encouraged by this
result, we planned to employ different iodine reagents,
cyanide sources, tempretures and solvents to search
for the optimal reaction conditions. The use of
PhI(OTf)2 or 2-iodoxybenzoic acid (IBX) as
hypervalent iodine compounds to instead of
PhI(OAc)2 result in significant decline in yield or
traces (35% and traces, respectively; Table 1, entries
2-3). Even when I2 was used, no reaction was
observed (Table 1, entry 4). Therefore, PhI(OAc)2
should be a good catalyst. When loading of
PhI(OAc)2 was increased, yields of 2a was increased
significantly to 50% and 60% (Table 1, entries 5-6).
While loading of 4 equivalents PhI(OAc)2, yield of
2a only gave 57% (Table 1, entry 7). Next, other
different solvents were examined towards the same
reaction. The use of polar aprotic solvents DMF (28%)
and DMSO (23%) gave relatively low yields of 2a
(Table 1, entries 8-9). While the use of protic solvent
MeOH did not produce anything (Table 1, entry 10).
Finally, the use of nonpolar solvents toluene and
DCE gave relatively good yields of 2a (Table 1,
entries 11-12), wherein, DCE gave the most
significant increase of product in 73% yields. Upon a
comparison of different reaction temperatures, we
found that 80 °C is to be optimal (Table 1, entries 13-
14). However, a continued increase in temperature to
100°C failed to improve the reaction, which was
probably due to fast decomposition of PhI(OAc)2.
(Table 1, entry 15). Other inorganic and organic
cyanide source like K4Fe(CN)6 and PhCOCN did not
become effective cyanide sources (not detected and
12%, respectively; Table 1, entries 16-17) under
optimized condition. No product was obtained in the
absence of PhI(OAc)2 (Table 1, entry 18). The result
emphasized the importance of PhI(OAc)2 in this
transformation. PIFA was used in the optimization of
reaction conditions to afford the trace amount of
product (Table 1, entry 19). Under the optimal
reaction conditions, the PIFA is apt to decompose
because of the high reaction temperature. Thus, the
optimized conditions for the cyanation of the
quinoline N-oxide involved 3.0 equiv of PhI(OAc)2
as the catalyst and 3.0 equiv of TMSCN as the
cyanating reagent in DCE at 80°C for 6 h.
TMSCNa)
a) Reaction conditions: Compound 1 (0.1 mmol), TMSCN
(3.0 equiv) and PhI(OAc)2 (3.0 equiv) in DCE (5 ml) for 6
hours. Isolated yield after purification by column
chromatography. No reaction is denoted by “--”.
contained electron-withdrawing groups (-Cl, -Br and
-NO2) at the C-5 and C-6 position afforded the
corresponding products (2g-2i and 2m-2n) in 55-72%
yield. However, Quinoline N-oxides attached
electron-donating substitutents at the C-5 and C-6
positions, including -NHAc, -Me and -OMe, the
yields of the target products 2j-2l increased with
improvement of electron-donating ability of these
groups. These outcomes indicated that changing the
electron density in the substituents on the quinoline
N-oxides had a remarkable influence on the
efficiency of the reaction. Medium yields could be
obtained for halogen substituents at 7-position of
quinoline ring (-Cl, 2q, 67% and -Br, 2p, 63%).
Furthermore, the survival of a halogen substituent
offered a great opportunity to further functionalize
the products. Notably, the relatively low yield of 2r
and 2s were attributed to the steric effect of the 8-
methoxy and hydroxy groups in quinoline N-oxide
substrate. Unfortunately, 2t and 2u were not
converted into their target products. 2t outcome
indicated that the strong electron-withdrawing effect
and large steric hindrance at the 8-nitro group of
quinoline ring restrained the process of reaction
seriously. 2u outcome was attributed to the steric
effect and intramolecular hydrogen bonding
interaction of the 8-acetyl amino group in quinoline
N-oxide substrate. In the next experiment,
polysubstituted quinoline N-oxides (1v) provided the
desired product in 41% (2v) yield, suggesting that the
methyl at the 3-position of quinoline N-oxide did not
display an obvious steric hindrance effect in this
course. To our excitement, pyridine N-oxide (1w) and
isoquinoline N-oxide (1x) could proceed efficiently
With an optimized general procedure in hand, the
substrate scope of the cyanation was investigated
(Table 2), the current catalytic system was suitable
for a wide range of substituted quinoline N-oxides
(1a-1x). First, compound 1a without substituent
group gave desired product 2a with 73% yield. Then,
starting from C-4 functionalized quinoline N-oxides
(2b-2f), a remarkable compatibility for produce was
found. Particularly, the electron-donating substituents
(-Me, 2e, 82%) were more favorable to the reaction
compared with electron-poor substituents (-NO2, 2d,
42%). Quinoline N-oxides bearing electron-donating
and electron-withdrawing substituents (such as, -Me,
-OMe, -Ph, -NHAc, -Cl, -Br and -NO2) at the C-5,
6 positions of quinoline ring (2g-2o) all underwent
cyanation smoothly at the 2-position. Substrates that
3
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10.1002/adsc.201801185
Advanced Synthesis & Catalysis
and afford the corresponding products in 32% and 76%
yields respectively. Compared with the optimized
protocol, pyridine N-oxide (1w) were generally less
reactive for nucleophilic attack.[16]
More control experiments were designed to gain an
insight into the reaction mechanism. When the radical
scavenger TEMPO was employed in the reaction
mixture, product 2a was produced in 67% yield
(Scheme 3, eq-1), indicating that the reaction
possibly involved a non-radical pathway. Without the
TMSCN, 2-acetoxyquinoline (2y) and PhIO were
obtained under the standard conditions (Scheme 3,
eq-2) (The compound data of NMR and IR were in
the Supporting Information). This result indicated
that PhI(OAc)2 was decomposed into acetoxyl anion
under the reaction conditions, and PhIOAc+ might
react with the oxygen atom in the quinoline N-oxide
(1a). When quinoline was used to take the place of
quinoline N-oxide as the reactant under the standard
reaction conditions (Scheme 3, eq-3), the reaction did
not proceed, which suggested that the N-O group
played a crucial role in this reaction system.
Furthermore, to compare the reactivity of the
electronically different quinoline N-oxides, a ratio of
equimolar N-oxides with electron-withdrawing
groups (1d) and electron-donating groups (1e) were
processed by TMSCN under standard conditions
(Scheme 3, eq-4). The intermolecular competition
reaction provided 2d:2e in 1:4 ratio. This implied that
the reaction might favour for an electrophilic reagent
to attack the quinoline N-oxide.
Scheme 2. Synthesis of the TB inhibitor in gram-scale.
In order to further demonstrate the synthetic utility
of this cyanation reaction, a gram-scale reaction was
carried out to the synthesis of the TB inhibitor.[5c, 17]
As illustrated in Scheme 2, 1s and TMSCN were
chosen to the optimized reaction conditions and
subjected to hydrolysis to obtain the TB inhibitor
with 52% yield. Compared with other protocols,[18]
this scheme had the features of mild reaction
conditions, simple operation and easy availability of
raw materials.
On the basis of these experimental results and
literatures,[19] a plausible mechanism for this metal-
free induced cyanation of quinoline N-oxide is
proposed in Scheme 4. Initially, PhI(OAc)2 attacks
the oxygen atom in the quinoline N-oxide (1a) to
form intermediate A. Next, the intermediate A can
transform into dearomatized intermediate B (or B’)
through regioselective nucleophilic attacks of cyanide
ion (or acetate ion) at α-carbon of quinoline. Finally,
the resulting intermediate B (or B’) underwent
deprotonation/ aromatization to give the 2-cyano
product (or 2-acetoxy product) and deliver the HOAc
and PhIO.
Scheme 3. Control experiments in the search for a reaction
mechanism.
Conclusion
In summary, we have developed a mild, efficient and
metal-free system for the highly regioselective
cyanation of the quinoline N-oxides and other N-
containing heterocycle N-oxides system. This
cyanation method was induced by the efficient and
economical PhI(OAc)2 reagent, and it proceeded the N-
O bond disruption to form 2-cyano quinoline
derivatives. Moreover, this reaction used an organic
and less toxic TMSCN as a cyanation reagent.
Furthermore, the procedure was extended to
synthesize the TB inhibitor in gram-scale. Finally, a
plausible mechanism for this PIDA induced
cyanation of quinoline N-oxides is proposed on the
basis of some experimental results and literatures.
Further exploration of the other functionalization
with quinoline N-oxides is underway in our
laboratory.
Scheme 4. Proposed reaction mechanisms.
4
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10.1002/adsc.201801185
Advanced Synthesis & Catalysis
Experimental Section
[3] a) F. F. Fleming, L. Yao, P. C. Ravikumar, L. Funk, B.
C. Shook, J. Med. Chem. 2010, 53, 7902-7917; b) J. P.
Ferris, in: The Chemistry of the Cyano Group, (Eds.: Z.
Rappoport), John Wiley & Sons Ltd, New York, 1970,
pp. 718-739.
1. General Procedure for Synthesis of quinoline N-
oxides
Representative Procedure: To a mixture of quinoline (1.3
g, 10.0 mmol) in AcOH (20 mL) was added H2O2 (30 wt%,
1.40 mL) at room temperature. The reaction mixture was
stirred at 70 °C for 36 h, and then was cooled to room
temperature. The product was extracted with dichloromethane
(3 × 20 mL), and the combined organic layers were dried
over Na2SO4. The solvent was removed under reduced
pressure, and the residue obtained was purified via silica
gel chromatography (eluent: ethyl acetate/methanol = 8/1)
to afford quinoline N-oxide (1a) as a yellowish solid (1.3 g,
90%).
[4] a) R. C. Larock, T. Yao, in: Comprehensive Organic
Transformations: A Guide to Functional Group
Preparations, (Eds.: R. C. Larock), John Wiley& Sons,
New York, 1989. pp 819-995; b) A. J. Fatiadi, in:
Triple-Bonded Functional Groups, 1st ed., Vol. 2 (Eds.:
S. Patai, Z, Rapporoport), John Wiley & Sons Ltd,
Chichester, 1983, pp. 1057-1303.
[5] a) T. Horino, Y. Hatakeyama, O. Ichii, T. Matsumoto,
Y. Shimamura, K. Inoue, Y. Terada, Y. Okuhara, Clin.
Exp. Nephrol. 2018, 22, 337-345; b) O. Mizenina, M.
Hsu, N. Jean-Pierre, M. Aravantinou, K. Levendosky,
G. Paglini, T. M. Zydowsky, M. Robbiani, J. A.
Fernandez-Romero, Drug. Deliv. Transl. Re. 2017, 7,
859-866; c) Y. N. Song, H. Xu, W. Chen, P. Zhan, X.
Liu, Medchemcomm. 2015, 6, 61-74; d) J. Bruix, S. K.
Qin, P. Merle, A. Granito, Y. H. Huang, G. Bodoky, M.
Pracht, O. Yokosuka, O. Rosmorduc, V. Breder, R.
Gerolami, G. Masi, P. J. Ross, T. Q. Song, J. P.
Bronowicki, I. Ollivier-Hourmand, M. Kudo, A. L.
Cheng, J. M. Llovet, R. S. Finn, M. A. LeBerre, A.
Baumhauer, G. Meinhardt, G. H. Han, I. Resorce,
Lancet. 2017, 389, 56-66; e) L. Lannfelt, K. Blennow,
H. Zetterberg, S. Batsman, D. Ames, J. Hrrison, C. L.
Masters, S. Targum, A. I. Bush, R. Murdoch, J. Wilson,
C. W. Ritchie, P. E. S. Grp, Lancet. Neurol. 2008, 7,
779-786; f) M. J. McKay, A. R. Carroll, R. J. Quinn, J.
Nat. Prod. 2005, 68, 1776-1778.
2. General procedure for the synthesis of 2-
cyanoquinolines
Representative Procedure: A 10 mL screw-cap vial
charged with quinoline N-oxides (58.1 mg, 0.4 mmol),
TMSCN (119.1 mg, 1.2 mmol), PIDA (386.5 mg, 1.2
mmol) and anhydrous DCE (6 ml), the mixture was stirred
o
at 80 C temperature for 6-7 h. After completion of the
reaction, the solution was extracted with dichloromethane
(3×20 mL). Organic layers were combined and dried over
Na2SO4, filtered and concentrated under reduced pressure.
The crude material was separated on a silica gel column
with petroleum ether/ethyl acetate (1/5) as the eluent to get
product quinoline-2-carbonitrile (2a) as a white solid (45.0
mg, 73%).
Acknowledgements
We are grateful for financial support from the Research Project
of the Natural Science Foundation of Heilongjiang Province of
China (No. B2018012).
[6] a) T. Sandmeyer, Ber. Dtsch. Chem. Ges. 1884, 17,
1633-1635; b) T. Sandmeyer, Chem. Ber. 1884, 17,
2650-2653.
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FULL PAPER
Hypervalent Iodine(III)-Mediated Regioselective
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Adv. Synth. Catal. Year, Volume, Page – Page
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Chuab* and Zhizhong Sunab*
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