Gold-catalyzed cyclization of 1-(2′-Azidoaryl) propynols: Synthesis of polysubstituted 4-quinolones

Article abstract of DOI:10.1039/c9cc06652g

An unprecedented gold-catalyzed procedure for the synthesis of polysubstituted 4-quinolones from 1-(2′-Azidoaryl) propynols is described. The reaction undergoes an intramolecular nucleophilic attack of the azide group to the Au-Activated triple bonds in a 6-endo-dig manner and subsequent gold-Assisted expulsion of N₂ to furnish an α-imino gold carbene intermediate, which triggers a 1,2-carbon migration and finally is converted to 2,3-disubstituted 4-quinolone.

Full text of DOI:10.1039/c9cc06652g

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Gold-catalyzed cyclization of 1-(20-azidoaryl)
propynols: synthesis of polysubstituted
4-quinolones†
Cite this: Chem. Commun., 2019,
55, 14769
Received 27th August 2019,
Xiang Wu, * Lang-Lang Zheng, Li-Ping Zhao, Cheng-Feng Zhu and You-Gui Li*
Accepted 14th November 2019
DOI: 10.1039/c9cc06652g
rsc.li/chemcomm
An unprecedented gold-catalyzed procedure for the synthesis of poly-
4-Quinolones represent an important and abundant class of
substituted 4-quinolones from 1-(20-azidoaryl) propynols is described. nitrogen-containing heterocycles and have been found in a
The reaction undergoes an intramolecular nucleophilic attack of the broad range of natural products, commercially-available drugs
azide group to the Au-activated triple bonds in a 6-endo-dig manner and biological and medicinal fields.9 Because of their importance,
and subsequent gold-assisted expulsion of N2 to furnish an a-imino the efficient synthesis of 4-quinolones has attracted extensive
gold carbene intermediate, which triggers a 1,2-carbon migration and attention from chemists and pharmacologists. Classical approaches
finally is converted to 2,3-disubstituted 4-quinolone.
based on cyclocondensation are widely employed.10 Moreover,
recently, transition-metal catalyzed procedures,11 involving Pd12
Homogeneous gold catalysis has recently become a convenient and Cu catalysis,13 have been developed towards the synthesis of
tool in organic synthesis for the rapid generation of molecular quinolone derivatives providing an increased tolerance toward
complexity and diversity in a single step,1 due to the strong p functional groups and higher chemical yields.14 Gold complexes
Lewis acidic property of electrophilic gold species and their could also be used as a catalyst for the generation of 4-quinolones
ability to activate carbon–carbon unsaturated systems.2 In from alkyl- or aryl-substituted 1-(o-aminophenyl)-2-propyn-1-ones.15
particular, a gold catalyst is highly efficient for the electrophilic This is the only example reported to date by Helaja and co-workers
activation of alkyne followed by nucleophilic attack of the azide
group and subsequent gold-assisted expulsion of N2, giving an
a-imino gold carbene intermediate (Fig. 1A),3 which can be
subsequently employed in a wide range of transformations.4,5
Pioneering work in this context was reported by Toste in the
gold catalyzed intramolecular acetylenic Schmidt reaction,
which converts homopropargylazides 1 to pyrrole frameworks
3 with high regioselectivity (Fig. 1B).3a In this transformation,
the key intermediate a-imino gold carbene 2 undergoes
1,2-carbon (alkyl and aryl) migration from the adjacent carbon,
furnishing polysubstituted pyrroles. 1,2-Carbon migration triggered
by an a-imino gold carbene intermediate has only been reported by
Toste,3a Gagosz3f and Liu,6 however, which provides a beneficial tool
for rapid access of diverse nitrogen heterocycles.7,8 Inspired by the
special property of an a-imino gold carbene intermediate, herein, we
will describe a gold-catalyzed cyclization of 1-(20-azidoaryl)
propynols for the synthesis of polysubstituted 4-quinolones
through 1,2-carbon migration (Fig. 1C).
Anhui Province Key Laboratory of Advanced Catalytic Materials and Reaction
Engineering, School of Chemistry and Chemical Engineering, Hefei University of
Technology, 193 Tunxi Road, Hefei 230009, China. E-mail: wuxiang@hfut.edu.cn,
liyg@hfut.edu.cn
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
Fig. 1 Transformations based on a-imino gold carbenes.
c9cc06652g
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and only 2-substituted 4-quinolone products were obtained. There- substrate 4a, a slightly lower but still good yield of 8a was obtained
fore, the new method based on gold catalysis remains highly (vs. entry 8, Table 1). Then, a variety of 2-(2-azidophenyl)but-3-yn-
challenging and is in great demand.
2-ols 4b–n with different aryl or alkyl substituents adjacent to the
As shown in Fig. 1C, upon treatment with a gold catalyst, carbon–carbon triple bond were treated in the presence of 5 mol%
1-(20-azidoaryl) propynols 4 should undergo an intramolecular of JohnPhosAuNTf2 in DCE at 65 1C. Wherein R1 was an aryl
nucleophilic attack of the azide group to the Au-activated triple group, substrates 4b–l with electron-donating or -withdrawing
bonds in a 6-endo-dig manner to furnish intermediate 5. Loss of substitutions at various positions of the phenyl ring were
a molecule of N2 leads to the formation of a-imino gold carbene 6. amenable to this reaction, delivering the corresponding
The subsequent 1,2-carbon migration of the R1 group, resembling 4-quinolones 8b–l in good yields (up to 85%). Moreover,
a pinacol-type rearrangement, leads to the formation of a gold 2-thienyl substituted substrate 4m was well tolerated in this
intermediate 7 which finally converts to 2,3-disubstituted reaction, affording 8m in high yield. Alkyl such as cyclohexyl
4-quinolone 8.
substituted propynol could also react smoothly and afford the
The feasibility of the hypothesis was initially explored by screen- corresponding 4-quinolone 8n albeit in moderate yields. Addi-
ing the gold catalyst for the cyclization of 1-(20-azidophenyl) propynol tionally, the variation of the substituent on the azido-substituted
4a in 1,2-dichloroethane (DCE) at 65 1C under N2. To our delight, phenyl moiety (R2 group) was also tolerated to undergo the
both AuCl and AuCl3 could catalyse the reaction effectively albeit cascade reaction cleanly and furnished 4-quinolones in good
in moderate yield (Table 1, entries 1 and 2). Then, either the yields. Basically, either the electronic feature of the substituent
counterions or ligands of the gold complexes were found to
have a considerable impact on the catalytic activity. For
instance, gold chloride complexes with different ligands were
unable to promote the reaction (Table 1, entries 3–5). Both
ꢀ
ꢀ
NTf2 and SbF6 were good counterions for the gold complex
and afforded the desired product in appreciable yield (entries 6–9).
ꢀ
Importantly, the combination of the counterion NTf2 and the
ligand JohnPhos gave the corresponding product 8a in the best
yield (84%, entry 8). The final survey of solvents suggested that DCE
is the most suitable medium to enable the cascade reaction to give
the highest yield (entry 8 vs. entries 9–12).
After the optimal reaction conditions were established, we
next examined their applicability to other substrates (Scheme 1).
Firstly, when the reaction was performed on 1 mmol scale for the
Table 1 Optimization of the catalytic systema
Entry
[Au]
Sol.
Yieldb (%)
1
2
AuCl
AuCl3
DCE
DCE
42
50
3
4
5
6
7
8
9
10
11
12
PPh3AuCl
DCE
DCE
DCE
DCE
DCE
DCE
DCE
THF
Trace
Trace
Trace
43
38
84
44
Trace
31
tBuXPhosAuCl
JohnPhosAuCl
tBuXPhosAuNTf2
tBuXPhosAuSbF6
JohnPhosAuNTf2
JohnPhosAuSbF6
JohnPhosAuNTf2
JohnPhosAuNTf2
JohnPhosAuNTf2
CH3CN
Toluene
52
a
Scheme 1 Scope of 2-(2-azidophenyl)but-3-yn-2-ol substrates. The
reaction was carried out with 4 (0.1 mmol) in the presence of 5 mol% of
gold complexes in DCE (1.0 mL) under N2. The resulting solution was
stirred for 48 h at 65 1C. a Reactions were carried out on a 1 mmol scale.
The reaction was carried out with 4a (0.1 mmol) in the presence of
5 mol% of gold complexes in DCE (1.0 mL) under N2. The resulting
solution was stirred for 48 h at 65 1C. Yield of the isolated product.
DCE = 1,2-dichloroethene.
b
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In summary, we have established an unprecedented gold-
catalyzed procedure for the synthesis of polysubstituted
4-quinolones from 1-(20-azidoaryl) propynols. The reaction pro-
ceeds under mild experimental conditions and tolerates
the presence of various functional groups. The key a-imino
gold carbene intermediate is formed through 6-endo-dig cycli-
zation and triggers the 1,2-carbon migration to furnish the
N-heterocycle motifs that are frequently found in the structure
of biologically active compounds or natural products. This
protocol provides
4-quinolones.
a convenient route to polysubstituted
Scheme 2 Scope of 1-(2-azidophenyl)-3-phenylprop-2-yn-1-ol substrates.
The reaction was carried out with 4 (0.1 mmol) in the presence of 5 mol% of
gold complexes in DCE (1.0 mL) under N2. The resulting solution was stirred
for 48 h at 65 1C. a The reaction was carried out at 30 1C.
We are grateful for financial support from the National
Natural Science Foundation of China (grant no. 21672049)
and the Fundamental Research Funds for the Central Universities
of China (grant no. PA2019GDPK0056). We sincerely thank Dr Lei
Ren (Anhui Therapy Pharmaceutial Co., Ltd) for his advice and
support.
or the substitution pattern has little influence on the reaction
performance. Thus, the presence of electron-donating or electron-
withdrawing groups on the azido-substituted phenyl ring led to
the generation of the desired products in almost identical yields
except that the benzo[1,3]dioxolyl-substituted propynol (4r) gave a
relatively lower, but still moderate yield.
Conflicts of interest
There are no conflicts to declare.
Finally, and importantly, we explored the behavior of sub-
strates 4s–z possessing migrating groups of different nature at the
propargylic position (Scheme 2). For these 1,2-carbon shift
studies, both alkyl and aryl groups could shift smoothly and be
conveniently introduced at the 3-position of 4-quinolones. Open
chain alkyl such as ethyl, isopropyl and butyl groups could afford
the desired products 8s–u in good yields. Cyclic alkyl such as
cyclopentyl and cyclohexyl groups could also perform well and be
converted to the corresponding products 8v–w in moderate yields.
Moreover, a phenyl ring (4x) and 4-substituted phenyl ring with a
methyl (4y) or bromide (4z) group could also migrate smoothly
and furnish the products in moderate to good yield.
Interestingly, on replacement of the alkyl and aryl group, a
hydrogen atom in the 1-(2-azidophenyl)dec-2-yn-1-ol 9 could
undergo 1,2-shift smoothly under the standard conditions,
affording 2-heptyl-4-hydroxyquinoline (HHQ) 10 in 64% yield.
HHQ is an important signaling molecule involved in quorum
sensing and plays an important role in virulence regulation.9b,16
2-Phenyl-3-methyl-4-quinolone 8a could be methylated using the
MeI/NaH conditions to give polysubstituted quinolone 11 in 81%
yield, analogues of which are widely distributed in the plant
family Rutaceae.9a
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