Regioselective remote C5 cyanoalkoxylation and cyanoalkylation of 8-aminoquinolines with azobisisobutyronitrile

Article abstract of DOI:10.1039/d0cc00014k

The efficient regioselective C-H cyanoalkoxylation and cyanoalkylation of 8-aminoquinoline derivatives at the C5 position have been achieved under O2 and N2 atmospheres, respectively. Using 2,2′-azobisisobutyronitrile (AIBN) as a radical precursor, the pr

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Regioselective remote C5 cyanoalkoxylation and cyanoalkylation
of 8-aminoquinolines with azobisisobutyronitrile
Chunxia Wen,a Ronglin Zhong,b Zengxin Qin,a Mengfei Zhaoa and Jizhen Li*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
AIBN was extensively used as radical initiators and radical
precursors in organic synthesis. In general, AIBN could generate
three different kinds of free radicals as illustrated in Scheme 1.12
Among them, the cyanopropyl radical (.C(CH3)2CN) could be
easily produced along with the release of one molecule of N2
once AIBN was heated (eq 1). Whereas, the cyanopropyloxyl
radical (.OC(CH3)2CN) generation required two steps including
the oxygen atom capture by cyanopropyl radical in the presence
of oxygen and one molecule of O2 release spontaneously from
the two peroxy radicals (eq 2 and eq 3). In addition, the cyano
radical (.CN) was available from the cyanopropyloxyl radical as
well as the acetone production (eq 4). Due to the steric
hindrance of isobutyronitrile group, AIBN usually serves as
cyano radical source for direct aryl C-H or SP3 C-H cyanation via
radical pathway.12b, 13 In very recent years, the cyanopropyl
radical derived from AIBN was explored successfully in the
copper-catalized direct cyanation of terminal alkynes.14 Copper-
catalyzed oxidative coupling of cyanopropyl radical and ketone-
derived enoxysilanes to r-ketonitriles was also achieved.15
Furthermore, the direct cyanoisopropylation of alkenes in N-
arylacrylamides or benzamides for the synthesis of cyano-
containing heterocycles was developed extensively via
oxidative cyclization.16 During the research of copper-catalyzed
8-amido chelation-induced remote C-H amination of quinolines,
Baidya group firstly mentioned the cyanoalkylation of 8-
aminoquinoline with the very low yield 24%, which proved the
introduction of steric hindered quaternary carbon to C5
position of quinolines was still difficult.5b But, considering the
cyanopropyloxyl radical, which contains one oxygen atom, to
the best of our knowledge, there’s no any report for the direct
C-H functionalization to construct C-O ether bond.
The efficient regioselective C-H cyanoalkoxylation and
cyanoalkylation of 8-aminoquinoline derivatives at the C5
position have been achieved under O2 and N2 atmosphere
respectively. Using 2,2’-azobisisobutyronitrile (AIBN) as
radical precursor, the protocols afforded the corresponding
products in moderate to good yields with broad substrate
generality through Cu(OAc)2 or NiSO4 catalysis. Furthermore,
the single electron transfer (SET) mechanism was proposed via
radical coupling pathway.
The quinoline scaffolds are of great importance frequently
existed in natural products, materials and bioactive molecules.1
For example, aryloxyquinolines, as vital chemical entities, show
good biological activities such as antiviral, anti-inflammatory
and anticancer (Figure 1).2 Consequently, the straightforward
regioselective functionalization of quinolines has been evolved
as an attractive research topic.3 Especially, in recent years, the
difficult remote C5 site selectivity was controlled successfully by
SET radical mechanism. Then, many methodologies to construct
C-C, C-N, C-S, C-Hal, C-P and C-Se bonds etc at the C5 position
have been developed under transition metals (TM) catalysis
conditions.4-9 In our previous work, the C5 fluorination of 8-
aminoquinolines was explored for the first time catalyzed by
NiSO4 or under metal-free conditions.10 However, for the direct
C-O bond formation of quinolines, only few examples such as C5
tosyloxylation and oxygenation to form esters were achieved.11
Figure 1 Selected biologically active pharmaceuticals.
Scheme 1 Cyanopropyl, cyanopropyloxyl and cyano radicals
produced by AIBN.
On the other hand, cyano-containing compounds have been
widely applied in many fields, such as materials, pharmaceutic-
als and organic synthesis.17 Moreover, cyano group can be easily
converted into diverse functional groups such as carboxyl,
a. Department of Organic Chemistry, College of Chemistry, Jilin University, Jiefang
Road 2519, Changchun, 130023, China, E-mail: ljz@jlu.edu.cn.
b. Laboratory of Theoretical and Computational Chemistry, Institute of Theoretical
Chemistry, College of Chemistry, Jilin University, Changchun, 130023, China.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
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Table 1 Optimization of the reaction conditionsa
aldehyde and amide etc.18 Given the importance of quinoline
derivatives and nitriles, it is meaning for the introduction of
cyano-containing group to quinoline scaffold to acquire
molecules with diversity and complexity. During our continuing
research work about cyanation reaction and remote selective
C-H functionalization,19 under O2 and N2 atmosphere
View Article Online
DOI: 10.1039/D0CC00014K
Entry
Catalyst
Oxidant
Te
Solvent
Yieldb
(%)2a
or 3a
mp
(°C)
respectively (Scheme 2), we envisioned that it might be feasible
to achieve cyanoalkoxylation and cyanoalkylation of 8-
aminoquinolines with AIBN as cyanopropyloxyl and
cyanopropyl radicals source through different catalysis systems.
Herein, we report our research results.
1
2
3
4
5
6c
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
PhI(OAc)2 90
CH3CN
CH3CN
CH3CN
DCE
CH3OH
CH3CN
2a, 20
2a, 60
2a, 70
2a, 10
2a, 20
2a, n.r
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
90
70
70
70
70
7
NiSO4
NiSO4
NiSO4
K2S2O8
K2S2O8
K2S2O8
CH3CN
THF
CH3CN/
DMSO
3a, 24
3a, 28
3a, 35
90
90
90
8
9d
Scheme 2 Direct C-H cyanoalkoxylation and cyanoalkylation of 8-
aminoquinolines at the C5 position.
10d, e
11d, f
12d
NiSO4
K2S2O8
K2S2O8
K2S2O8
K2S2O8
150 CH3CN/
DMSO
150 CH3CN/
DMSO
150 CH3CN/
DMSO
150 CH3CN/
DMSO
3a, 67
3a, 50
3a, 42
Undoubtedly, considering the reaction of AIBN and
quinolines, the product selectivity depends on the different
radicals controlling procedures, in which, O2, N2, TM and
temperature were important factors. In fact, at 50 °C-70 °C, the
cyanopropyl radical indeed was produced from AIBN, and
following the subsequent low steric cyanopropyloxyl radical
under O2.12a The cheap metal copper has achieved great results
in the C5-H functionalizations of 8-aminoquinolines. [5d, 7b] Thus,
we initiated our studies by investing the reaction of 2-methyl-
N-(quinolin-8-yl)benzamide (1a) as model in the presence of
Cu(OAc)2, PhI(OAc)2 and PivOH. To our delight, the desired
product 2a was obtained in 20 yield (Table 1, entry 1). K2S2O8
was the best oxidant, providing the single product 2a in 60%
yield (entry 2). The optimal temperature was 70 °C (entry 3).
Other solvents were examined (entries 4-5), and it was found
that CH3CN was still significantly superior. Without O2, the
reaction could not run (entry 6). With a set of optimized
conditions for the product 2a, next we were intrigued by the
possibility of product 3a under N2. However, copper catalyst
failed to get the desired product 3a. Recently, nickel catalyst
was reported showing good performance in C5-H
functionalizations of 8-aminoquinolines.[10a, 20] Therefore, we
further attempted to accomplish cyanoalkylation using NiSO4 as
catalyst with the same model substrate 1a. Fortunately,
compound 3a was obtained as the exclusive product in 24%
yield (entry 7). Changing several commonly used solvents, it
turned out that mixed CH3CN/DMSO (3/1) resulted in excellent
yield (entries 8-9). In addition, in the presence of additives e.g.
Cu(OAc)2 or Fe(acac)3, the product 3a represented a significant
rise at 150 °C (entries 10-11). Either nickel or copper was absent,
the yield showed a negative effect (entries 12-13), (details see
the ESI, Table S1 and S2). Thus, the optimal conditions were
showed in entry 3 and entry 10 respectively. In addition, the
molecular structure of 2a was unambiguously confirmed by
single-crystal X-ray diffraction (Figure 2).
NiSO4
NiSO4
13d
Cu(OAc)2
3a,tra
ce
a Reaction conditions for 2a [Method A]: 1a (0.2 mmol), AIBN (4.0 equiv),
catalyst (0.1 equiv), oxidant (1.0 equiv), PivOH (0.2 equiv), solvent (2.0 mL),
under O2 for 12 h. 3a [Method B]: 1a (0.2 mmol), AIBN (4.0 equiv), catalyst
(0.1 equiv), oxidant (2.0 equiv), solvent (2.0 mL), PivOH (2.0 equiv), under N2
for 24 h. b Isolated yield. c Under N2. d CH3CN/DMSO (3/1). e Added 10 mol%
Cu(OAc)2. f Added 10 mol% Fe(acac)3.
Figure 2 Single-crystal X-ray structure of 2a.
methoxyl) had good activity without significant electronic effect.
Notably, the ortho-substitution of benzene ring did not hardly
influence the yield of the products (2a vs 2f, 2k and 2d vs 2g).
Additionally, heterocyclic amide also gave slightly low yield (2n),
which revealed good functional groups tolerance. Sterically bulky
groups did not hinder the reaction obviously (2o-2s). Then, the
substrates containing a substituent on the quinoline such as 2-Me,
4-Cl (2t-2u) were also examined with appropriate yields. Analogue of
AIBN was also detected. The reaction of 1a with 1,1′-azobis
(cyclohexane-1-carbonitrile) showed relatively lower yield (2v).
After successfully describing the substrate scope of C5
cyanoalkoxylation, the reaction of aminoquinoline derivatives with
AIBN for providing C5 cyanoalkylation products has been examined
in Table 3. Pleasingly, a series of electron-donating groups such as
methyl, ethyl, tert-butyl, methoxyl on the aromatic ring were
observed to be well compatible with corresponding cyanoalkylation
products (3a, 3c-3d, 3f-3g, 3j-3l), and electron-withdrawing groups
(fluoro, chloro, iodine) also had excellent products (3e, 3h-3i, 3m).
Firstly, under the optimized conditions, the substrate scope was
explored for the C5 cyanoalkoxylation in Table 2. Both arylcarboxa-
mides and alkylcarboxamides were good reaction substrates (2a-2n,
2o-2s). Arenes bearing electron-withdrawing groups (chloro, bromo,
iodine) and electron-donating groups (methyl, ethyl, tert-butyl,
2 | J. Name., 2012, 00, 1-3
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Table 2 Cyanoalkoxylation substrates scope of 8-aminoquinolinesa
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DOI: 10.1039/D0CC00014K
aStandard reaction conditions: 1 (0.2 mmol), AIBN (0.8 mmol), NiSO4 (0.02
mmol), K2S2O8 (0.4 mmol), PivOH (0.4 mmol), Cu(OAc)2 (0.02 mmol) were
mixed in CH3CN/DMSO (1.5 mL/0.5 mL) and stirred for 24 h at 150 °C under
N2. Isolated yield.
aStandard reaction conditions: 1 (0.2 mmol), AIBN (0.8 mmol), Cu(OAc)2 (0.02
mmol), K2S2O8 (0.2 mmol), PivOH (0.04 mmol) were mixed in CH3CN (2.0 mL)
and stirred for 12 h at 70 °C under O2. Isolated yield.
Obviously, the reaction was little influenced by the electronic nature
of the substrates. Heterocyclic amide was also detected to obtain the
related product with inferior yield (3n). Moreover, various alkyl
amides were applicable in the cyanoalkylation reaction (3o-3t).
Besides, a substitution at the C4 position of quinoline was also
examined with suitable yield (3u). Further experiments
demonstrated analogues of AIBN were also suitable for this reaction
to provide the desired products (3v, 3w, 3x, 3y, 3z, 3aa), except the
one with a carboxylic acid group (3bb).
Scheme 4 Isotopic labeling experiments.
To gain insight into the reaction mechanisms, some control
experiments were carried out (Scheme 3). Only a trace of the desired
products 2a and 3a were obtained in the presence of radical
scavenger TEMPO (3.0 equiv), which implied the involvement of free
radical in the reaction pathway (eq 1 and eq 2). Furthermore, we
tried to capture cyanopropyloxyl radical and cyanopropyl radical by
using 3.0 equiv 1, 1-diphenylethylene, and radical coupling products
9 and 10 were detected by LC-MS (eq 3 and eq 4).
proving oxygen atom in the ether bond completely originated from
O2.
On the basis of the above experimental results and previous
literature reports,4a, d, 6c a plausible mechanism for cyanoalkoxylation
reaction was depicted (Scheme 5, (1)). The coordination of substrate
1 with Cu(OAc)2 provided the complex A. Then, complex A turned
into complex B by losing a molecule of acetic acid and intermediate
C was formed through single electron transfer (SET) process. Addition
of cyanopropyloxyl radical to intermediate C proceeded at the C5
position, affording the complex D. Next, complex E was generated via
oxidation. Intermediate F was formed by a proton transfer (PT)
process automatically. In the end, product 2 was achieved and
Cu(OAc)2 was regenerated to accomplish the catalytic cycle. Similarly,
a plausible reaction pathway for cyanoalkylation reaction was
proposed (Scheme 5, (2)). The catalytic cycle of cyanoalkylation
underwent the processes of complexation, the loss of proton from
NH, SET, cyanopropyl radical addition, oxidation by K2S2O8 and PT
transfer to form F. Then the nickel was dissociated to afford product
3. Among them, the metal nickel, like copper, took place a conversion
between divalent and monovalent. Here, it was noteworthy that the
presence of copper acetate was conducive to promoting the addition
of sterically hindered cyanopropyl radicals by coordinating with N
and O atoms together, which could reduce the energy of transition
state D ( details see the ESI ).
Scheme 3 Investigation of the radical pathway.
In order to verify that the oxygen atom of product 2 comes from
O2, we further performed isotopic labeling experiment under 18O2 (97
atom% 18O) (Scheme 4). The 18O-labeled product 2a’ and 2g’ (yields
64% and 59%) could be detected by LC-MS, undoubtedly
Table 3 Cyanoalkylation substrates scope of 8-aminoquinolinesa
To demonstrate the potential application, the transformations of
the products were also investigated (Scheme 6). The treatment of 2a
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DOI: 10.1039/D0CC00014K
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Scheme 6 Functional groups transformation.
In summary, we have developed
a novel regioselective
cyanoalkoxylation and cyanoalkylation of 8-aminoquinoline
derivations at the C5 position with AIBN as radical source. The
protocols provide useful methodologies for the efficient construction
of C-O and C-C bond on quinoline scaffold with functional group
tolerance. In addition, cyanopropyloxyl radical was explored to form
site selective C-O ether bond directly for the first time. The plausible
radical mechanism was also demonstrated. Further efforts to extend
the applications of these new protocols are underway in our lab.
This work was mainly supported by Department of Science &
Technology of Jilin Province (Grant No. 20170414052GH) and
National Natural Science Foundation of China (NSFC No. 51573069).
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Graphic
Regioselective remote C5 cyanoalkoxylation and cyanoalkylation of
8-aminoquinolines with azobisisobutyronitrile
Chunxia Wen, Ronglin Zhong, Zengxin Qin, Mengfei Zhao and Jizhen Li
The C5-H cyanoalkoxylation and cyanoalkylation of 8-aminoquinoline derivatives were achieved
with azobisisobutyronitrile under different catalysis system.
O
O
CN
Cu(OAc)2
R1
N
H
H
R2
CN
PivOH, CH3CN
N
O
70 oC,12 h, O2
AIBN
+
R1
N
H
O
R2
N
NiSO4, PivOH
R1
N
CH3CN/DMSO
150 oC, 24 h, N2
H
R2
N