Zinc-catalyzed C-H alkenylation of quinoline: N -oxides with ynones: A new strategy towards quinoline-enol scaffolds

Article abstract of DOI:10.1039/d1cc00245g

A zinc-catalyzed C-H alkenylation of quinoline N-oxides with ynones has been developed to rapidly assemble a broad collection of valuable quinoline-enol organic architectures. Uncommonly, this novel reaction involves C-H functionalization, and N-O, C-C and CC bond cleavage in one operation, and leads exclusively to the formation of an enol rather than a keto product. Application of the enols generated was highlighted by further derivative transformation and preparation of a series of BODIPY analogues with high quantum yields (up to 86%). This journal is

Full text of DOI:10.1039/d1cc00245g

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Zinc-catalyzed C–H alkenylation of quinoline
N-oxides with ynones: a new strategy towards
quinoline-enol scaffolds†
Cite this: DOI: 10.1039/d1cc00245g
Received 16th January 2021,
Accepted 6th April 2021
Yan Hu,a Jiang Nan, *a Xue Gong,b Jiawen Zhang,a Jiacheng Yina and
Yangmin Ma*a
DOI: 10.1039/d1cc00245g
rsc.li/chemcomm
A zinc-catalyzed C–H alkenylation of quinoline N-oxides with of synthetic methods that allow simple and common building
ynones has been developed to rapidly assemble a broad collection blocks under mild reaction conditions is remarkably alluring.
of valuable quinoline-enol organic architectures. Uncommonly, this
In terms of simple starting materials and greater reaction
novel reaction involves C–H functionalization, and N–O, C–C and efficiency, exploiting direct C–H functionalization provides the most
R
C
C bond cleavage in one operation, and leads exclusively to the powerful and succinct platform for synthesizing pyridine-enol units
formation of an enol rather than a keto product. Application of the because additional operations for preparing complicated substrates
enols generated was highlighted by further derivative transforma- are avoided.7 Conversely, in recent years, ynone compounds have
tion and preparation of a series of ‘‘BODIPY’’ analogues with high been widely utilized as multipurpose synthetic intermediates to
quantum yields (up to 86%).
reconstruct new C–C bonds, especially via C(O)–C dissociation.8
The appealing and challenging synergistic merger of C–H functio-
Pyridine-enol scaffolds, featuring N,O-chelated fragments, have nalization with C(O)–C dissociation (and the even more challenging
always drawn considerable attention as an appealing class of cleavage of the CRC bond of ynones) is in its infancy.9 In our
bidentate ligands and have been extensively employed in ongoing efforts in quinoline chemistry,10 we herein report a Lewis
various chemical disciplines.1 Pyridine-enol scaffolds can coordi- acid-catalyzed C–H functionalization of quinoline N-oxides with
nate with a wide variety of metals to generate adducts with ynones through a simple reaction system. In this protocol, exclusive
prominent photophysical characteristics, and even as potential enol formation was observed instead of keto formation. Most
catalysts for use in catalytic synthesis (Scheme 1a, left).2 Alterna-
tively, they can react with boron compounds to form chelated
boron dipyrromethenes (BODIPYs). The latter are fluorescence-
emitting molecules with sharp absorption and emission spectra,
large Stokes shifts, and high quantum yields (Scheme 1a, right).3
To date, however, only two efficient and applicable approaches for
the syntheses of the organic skeleton are available:4 (i) CNꢀ salts-
promoted dimerization of 2-formylpyridines (Scheme 1b)5 and (ii)
condensation of 2-methylpyridines with esters or nitriles towards
pyridine-enols (Scheme 1c).6 Despite their practicality, typically
these two approaches encounter unamiable reaction systems, such
as toxic or strongly basic reagents (e.g. nBuLi), and are restricted to
substrates that are not easily accessible and architecturally finite
pyridine-enol molecules. Accordingly, enhancement of the efficiency
a Key Laboratory of Chemical Additives for China National Light Industry,
College of Chemistry and Chemical Engineering, Shaanxi University of Science and
Technology, Xi’an 710021, China. E-mail: nanjiang@sust.edu.cn
b College of Bioresources Chemical and Materials Engineering, Shaanxi University of
Science and Technology, Xi’an 710021, China
† Electronic supplementary information (ESI) available. CCDC 2049499. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
d1cc00245g
Scheme 1 Applications and synthetic approaches for pyridine-enol
scaffolds.
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importantly, this newly established methodology involves breaking
multiple chemical bonds in a single operation, including CRC,
C–C, C–H, and N–O bonds (Scheme 1d).
We commenced our studies with isoquinoline N-oxide 1a
and ynone 2a as model substrates to explore the optimal
reaction conditions. Gratifyingly, the highly selective C1–H
functionalization of N-oxide was realized upon exposure to
the common Cu(OTf)2 catalyst, which afforded the enol mole-
cule 3a as an exclusive isomer in 42% yield (Table 1, entry 1).
Other Lewis acids, such as Zn(OTf)2, Zn(OAc)2ꢁ2H2O, ZnCl2, and
Mg(NTf)2, also proved to be viable (Table 1, entries 2–5).
Zn(OAc)2ꢁ2H2O appeared preferential and provided 52% yield
(Table 1, entry 3). The absence of a catalyst hampered this
protocol, and delivered only 8% yield of 3a (Table 1, entry 6).
Further attempts with a series of solvents revealed that acetone
was the optimum choice (Table 1, entries 7–11), which led to
the isolated target product in 65% yield. Changing the reaction
temperature did not promote this conversion further. However,
an increased temperature was relatively beneficial (Table 1,
entries 12 and 13), which also implied that this class of enol
structure was could tolerate heat. Unfortunately, reducing the
catalyst load resulted in an obviously diminished output
(Table 1, entry 14). More detailed information on reaction
optimization is shown in ESI.†
The substrate scope of this developed C–H alkenylation
reaction was investigated according to the reaction conditions
stated above (Scheme 2). A wide range of symmetrical ynones
with various substituents, including methyl (2a), methoxyl (2c),
chloro (2d), fluoro (2e), cyano (2f), trifluoromethyl (2g) and
bromo (2h) groups at the meta or para sites of the phenyl ring,
were employed to react with 1a. They smoothly generating the
Scheme 2 Substrate scope of ynones.
anticipated isoquinoline-enol derivatives in moderate-to-good unambiguously by X-ray diffractometry (CCDC 2049499†).
yields. The absolute molecular structure of 3c was elucidated
A widely applicable heterocyclic fragment, such as the
2-thiophene precursor 2i, was also involved in this procedure.
Furthermore, this conversion could be extended to the alkyl
substrate (2j, 2k, and 2l) and gave rise to 3j, 3k, and 3l. In
addition, unsymmetrical ynones also underwent this transfor-
mation appropriately. Among them, all the biaryl-substituted
reagents (2n–p) afforded almost equal amounts of two regiose-
lective enol compounds and the phenyl–methyl ynone (2m), but
with relatively high selectivity (5 : 1), which is consistent with
the latter reaction mechanism proposed.
Table 1 Optimization of the reaction conditionsa
Entry
Catalyst
Solvent
Temp. (1C)
Yieldb (%)
Given the outstanding potential for use of this pyridine-enol
bidentate organic framework, we next looked into the reaction
scope with respect to N-oxides to obtain more diverse molecules. As
shown in Scheme 3, an array of substituents, including electron-
withdrawing and electron-donating groups, were attached at the
isoquinoline and reacted with diphenyl ynone 2b to furnish the
envisioned products 3a0–f0 suitably. Importantly, the bromo sub-
stitution was well tolerated (3a0–b0), which could permit rapid
syntheses of diverse and complicated molecules. Likewise, switching
the coupling partner to quinoline N-oxide enabled release of the
respective adduct 3g0, and several common functional groups,
such as methyl (3h0, 3o0), halogen (3i0, 3j0, and 3n0), ester (3k0),
dimethylamino (3l0), and methoxyl (3m0), moieties embedded at
the vacant C3–C7 positions of quinoline were accommodated.
1
2
3
4
5
6
7
8
Cu(OTf)2
Zn(OTf)2
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
DCE
MeCN
DMF
Acetone
THF
Acetone
Acetone
Acetone
100
100
100
100
100
100
100
100
100
100
100
80
42
45
52
41
29
8
45
47
39
65
58
44
63
48
Zn(OAc)2ꢁ2H2O
ZnCl2
Mg(NTf)2
—
Zn(OAc)2ꢁ2H2O
Zn(OAc)2ꢁ2H2O
Zn(OAc)2ꢁ2H2O
Zn(OAc)2ꢁ2H2O
Zn(OAc)2ꢁ2H2O
Zn(OAc)2ꢁ2H2O
Zn(OAc)2ꢁ2H2O
Zn(OAc)2ꢁ2H2O
9
10
11
12
13
14c
120
100
a
Reaction conditions: 1a (0.2 mmol), 2a (0.24 mmol), catalyst
b
(20 mol%) in solvent (2.0 mL) were stirred for 12 h in air. Isolated
yields. 10 mol% Zn(OAc)2ꢁ2H2O.
c
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the five-numbered amide 6 accompanied with 49% yield of the
six-numbered amide 7.
(3) Identification of boron compounds (especially those
without fluorescence) is desirable. We attempted to introduce
product 3b for direct treatment with several common boron
agents, such as C6H13BO2(BHpin), PhB(OH)2, B(OCH3)3,
PhBF3K, and HBF4, using thin-layer chromatography. Delight-
edly, experimental outcomes illustrated that this type of
quinoline-enol structure could detect boron-containing rea-
gents and represented a promising chromogenic agent.
Scheme 3 Substrate scope of the (iso)quinoline N-oxides.
More strikingly, the p-extended precursor 1q continued to display
an appreciable reaction performance for producing the phenan-
thridine-derived enol 3p0. However, at the current stage, the
pyridine N-oxide was not compatible, probably due to its more
stable aromatic system.11
To showcase the utility of this new transformation, addi-
tional experiments on products were conducted on synthetic
derivatives and fluorescence properties, as follows:
(1) Upon treatment with BF3 reagent, the enols easily led to
the assembly of boron-containing coordination complexes 4a–h
which, to an extent, enriched the scope of the family of BODIPY
derivatives (Scheme 4a). This technology was appropriate for
diverse substituents on both product components, including
bromo (4b), trifluoromethyl (4c), methyl (4d, 4g), ester (4f), and
methoxyl (4h) groups, and delivered the corresponding boron
adducts in good yields. Fluorescence imaging demonstrated
that all of these created compounds were bright green and,
more remarkably, most had acceptable-to-excellent quantum
yields (even up to 86%).
(2) The scale-up catalytic process was found to be viable in
terms of productivity with a loading amount of 4.0 mmol, and
delivered 3b in 60% yield (Scheme 4b). Furthermore, several
molecules with architecturally more intriguing features were
forged via further converting products. Relying on the KOtBu
system, product 3b was treated with 1-ethynyl-2-fluorobenzene,
wherein the seven-numbered ether 5 was accessed with exclu-
sive regioselectivity. When adapting methyl 3-phenylpropiolate
as a coupling partner, compound 3b resulted in 33% yield of
Scheme 4 Large-scale transformation and further derivatization.
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Scheme 5 Proposed mechanism.
During implementation of this newly developed metho-
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diphenyl ynone 2b without the ZnII catalyst led to the fully
substituted enol 8 in 75% yield, which could be effectively
converted into the final product 3g0 under standard reaction
conditions (Scheme 5a). According to this finding and in
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could be postulated (Scheme 5b). This conversion originated
from the [3+2] cyclization of N-oxide with ynone to result in the
five-numbered intermediate A, followed by 1,4-H transfer to
yield the ring-opening C2–H alkenyl adduct 8 or its tautomer 80.
Subsequently, based on the Lewis-acid trait of Zn(OAc)2, a retro-
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acid was also observed. Similarly, the tautomer 80 accounted for
the formation of product 3g0 involving O-atom transfer based
on the same route.
In summary, a potent and versatile method towards rapidly
construction of a pyridine-enol skeleton was disclosed through
Zn-catalyzed C–H functionalization of (iso)quinoline N-oxides
with ynones. In this way, a wide collection of prevalent pyridine-
enols bearing bi-coordination function were obtained with
good functional-group tolerance. In stark comparison with
existing synthetic strategies, this new protocol features a simple
substrate-and-reaction system. Notably, this process to the best
of our knowledge, represents an extraordinarily infrequent
example of merging C–H functionalization with cleavage of
C–C bonds and CRC bonds in a single manipulation.
This work was financially supported by the NSFC (2180
1159), the China Postdoctoral Science Foundation (2018M
640944), and the Natural Science Foundation of Shaanxi Pro-
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Conflicts of interest
There are no conflicts to declare.
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