Solvent-Dependent Cyclization of 2-Alkynylanilines and ClCF2COONa for the Divergent Assembly of N-(Quinolin-2-yl)amides and Quinolin-2(1 H)-ones

Article abstract of DOI:10.1021/acs.orglett.1c01484

Herein, we present an expedient Cu-catalyzed [5 + 1] cyclization of 2-alkynylanilines and ClCF2COONa to divergent construction of N-(quinolin-2-yl)amides and quinolin-2(1H)-ones by regulating the reaction solvents. Notably, nitrile acts as a solvent and performs the Ritter reactions. ClCF2COONa is used as a C1 synthon in this transformation, which also represents the first example for utilization of ClCF2COONa as an efficient desiliconization reagent. The current protocol involves in situ generation of isocyanide, copper-activated alkyne, Ritter reaction and protonation.

Full text of DOI:10.1021/acs.orglett.1c01484

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Letter
Solvent-Dependent Cyclization of 2‑Alkynylanilines and
ClCF2COONa for the Divergent Assembly of N‑(Quinolin-2-yl)amides
and Quinolin-2(1H)‑ones
Ya Wang, Yao Zhou, Xingxing Ma, and Qiuling Song*
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ABSTRACT: Herein, we present an expedient Cu-catalyzed [5 + 1] cyclization of 2-alkynylanilines and ClCF2COONa to divergent
construction of N-(quinolin-2-yl)amides and quinolin-2(1H)-ones by regulating the reaction solvents. Notably, nitrile acts as a
solvent and performs the Ritter reactions. ClCF2COONa is used as a C1 synthon in this transformation, which also represents the
first example for utilization of ClCF2COONa as an efficient desiliconization reagent. The current protocol involves in situ generation
of isocyanide, copper-activated alkyne, Ritter reaction and protonation.
alofluorinated compounds have been witnessed as
Hversatile building blocks in organic synthesis over the
past years.1,2 Various deconstructive modes of XCF2R have
been devoted by our group1 and others.2 Among the
halofluorinated compounds, the elaboration of sodium
chlorodifluoroacetate (ClCF2COONa) has been flourishing.3
The well-informed applications of ClCF2COONa served as the
difluorocarbene precursors.3a,b Apart from the double cleavage
of ClCF2COONa, during the past few years, there is a
sequence of intriguing transformations of ClCF2COONa to be
harnessed as C1 synthon via quadruple cleavage of
ClCF2COONa.3c,d Despite this vigoroso advancement of
ClCF2COONa, the [5 + 1] cyclization of ClCF2COONa to
forge quinolines has yet to be addressed. Therefore, we
hypothesize that this [5 + 1] cycloaddition reaction of
ClCF2COONa can be realized by introducing some possible
reaction sites at the ortho position of the amino group. In
addition, the discarded F anion in the foregone quadruple
cleavage of ClCF2COONa is a waste. In fact, the F anion has
proven to be a good desiliconization reagent in organic
synthesis.4 In this regard, ClCF2COONa might be a potential
desiliconization reagent via cleavage of C−F bonds. However,
the utilization of ClCF2COONa as an efficient desiliconization
reagent has never been documented thus far.
nucleophilic acylation reagent and solvent could acylate the
product to streamline construction of N-(quinolin-2-yl)amides.
At the same time, quinolin-2(1H)-ones could be gained in
decent yields by regulating the reaction solvent to
dimethylformamide (DMF). The current method made use
of ClCF2COONa as a promising C1 synthon for producing the
isocyanide in situ, which was attacked by nucleophilic solvents
followed by intramolecular cyclization. When 2-
((trimethylsilyl)ethynyl)anilines were submitted to this re-
action, C3-unsubstituted N-(quinolin-2-yl)acetamides and
quinolin-2(1H)-ones were achieved in decent yields, in
which ClCF2COONa was first used as a novel desiliconization
reagent. Quinolines are one of the most important structural
motifs, which are extensively found in therapeutic agents and
natural products and pharmacologically active substances.10
Although a plethora of tactics have been developed for the
assembly of quinolines,11 there are scarce reports for direct
construction of N-(quinolin-2-yl)amides among the synthesis
of known quinolines (Scheme 1A). The current protocol
provides a facile and straightforward route for divergent
construction of N-(quinolin-2-yl)amides and quinolin-2(1H)-
Received: May 6, 2021
Published: July 14, 2021
The cyano group can be handily decorated to render diverse
valuable products via reduction,5 hydrolysis,6 cycloaddition,7
etc., which endows the multiple reactivities of nitriles. Apart
from the electrophilic property of the CN triple bond,8
nitriles also display weak nucleophilicity, owing to the lone-pair
electrons of the N atom.9 Herein, we envisage that nitrile as a
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Scheme 1. Synthesis of N-(Quinolin-2-yl)amides
Scheme 2. Scope for the Synthesis of N-(Quinolin-2-
c
yl)amides with Desiliconization
ones via [5 + 1] cyclization of 2-alkynylanilines and
ClCF2COONa (Scheme 1B).
To validate our hypothesis, we commenced our proof-of-
concept study with 2-((trimethylsilyl)ethynyl)aniline (1a) and
ClCF2COONa (2) in CH3CN. To our delight, when the
reaction was carried out in the presence of CuI with K3PO4 as
the base, desired N-(quinolin-2-yl)acetamide (3a) was
obtained in 40% yield (see the Supporting Information for
details). In this reaction, ClCF2COONa underwent the
quadruple cleavage to release the F ion, which is a good
desilylative reagent; thus, C3-unsubstituted N-(quinolin-2-
yl)acetamide (3a) was procured. Inspired by this result, we
evaluated a series of metal catalysts (see Table S1 of the
Supporting Information). However, frequently used transition
metal catalysts for activating alkynes, such as Ag2O, Ag2CO3,
and Pd(OAc)2, were proven to be invalid in this trans-
formation.12 Subsequently, a range of bases and halodifluor-
oalkylating reagents were screened to examine the effect on
this reaction, and it turned out that NaHCO3 and
ClCF2COONa were the best choice to deliver the desired
product 3a in 70% yield (see Tables S2 and S3 of the
Supporting Information). Of note, ligand screening indicated
that it was unserviceable for increasing the yield of compound
3a (see entries 9 and 10 in Table S2 of the Supporting
Information). Nevertheless, increasing the amount of base and
lowering the temperature are unfavorable for the reaction (see
entries 11−14 in Table S2 of the Supporting Information).
Control experiments indicated that Cu salt and base were all
indispensable for this transformation (see entries 15 and 16 in
Table S2 of the Supporting Information).
With the optimized conditions in hand, we next investigated
the substrate generality of this transformation (Scheme 2).
When the current protocol was scaled up to 10 times,
compound 3a could be readily obtained in 64%. Then, a wide
range of easily accessible 2-((trimethylsilyl)ethynyl)anilines
(1a−1q) could react smoothly with ClCF2COONa (2) to
provide the desired products N-(quinolin-2-yl)amides (3a−
3q) in good yields using CH3CN as the solvent and perform
the Ritter reactions. The structure of compound 3a was
unambiguously confirmed by X-ray single-crystal analysis. As
shown in Scheme 2, anilines bearing electron-donating groups
were amenable to this cyclization reaction, enabling the
formation of compounds 3b and 3c in modest yields.
Moreover, a variety of halo-substituted anilines were also
proven to be good candidates in this transformation, affording
the desired products 3d−3i in 50−82% yields. The steric
a
b
Reaction conditions: 120 °C and CH3CN (2 mL). Reaction
c
conditions: CH3(CH2)3CN (2 mL). Reaction conditions: 1a−1r
(0.2 mmol), 2 (0.3 mmol), CuCl2 (15 mol %), NaHCO3 (2 equiv),
CH3CN (2 mL), 100 °C, N2, and 16 h.
hindrance of anilines had no dramatic effect on this cyclization
reaction, because ortho-, meta-, and para-substituted anilines
(1d−1f) were well-compatible in this reaction. When the
current protocol was scaled up to 10 times, compound 3f could
be readily obtained in 60%. The submission of disubstituted 2-
((trimethylsilyl)ethynyl)anilines to this reaction was also
successful, in which expected compounds 3j and 3k were
achieved in 78 and 55% yields, respectively. In this reaction, a
series of 2-((trimethylsilyl)ethynyl)anilines containing elec-
tron-withdrawing groups were also detected, and the target
products 3l−3p were obtained in moderate to good yields.
Gladly, heterocyclic 2-((trimethylsilyl)ethynyl)aniline (1q)
was also engaged in the generation of quinolines via this
cyclization reaction, leading to the formation of the expected
product 3q in 30% yield. Of note, in comparison to CH3CN,
valeronitrile also performs the Ritter reactions, giving rise to
the production of compound 3r in 50% yield.
Encouraged by the success for the assembly of N-(quinolin-
2-yl)amides without substituents on the C3 position via this
cyclization of ClCF2COONa with 2-((trimethylsilyl)ethynyl)-
anilines, we were inquisitive whether the trimethylsilyl (TMS)
substituent on ethynyl could be replaced by an aryl or alkyl
group for this reaction. If so, the N-(quinolin-2-yl)amides with
various substituents on the C3 position would be achieved in a
single-vessel synthesis. To verify our hypothesis, the treatment
of 2-(phenylethynyl)aniline (1s) and ClCF2COONa (2) was
carried out under the identified conditions. To our delight, the
corresponding product N-(3-phenylquinolin-2-yl)acetamide
(3s) was obtained in 65% yield when we investigated a
range of bases and Cu salts (see Table S4 of the Supporting
Information). When the current protocol was scaled up to 10
times, compound 3s could be readily obtained in 56% yield.
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Having optimized the reaction conditions, the generality of
this cyclization reaction to forge 3-substituted N-(quinolin-2-
yl)amides was then evaluated, which was summarized in
Scheme 3. Electron-donating and electron-withdrawing group
we increased the amount of ClCF2COONa to 2 equiv and
replaced CuCl with CuTc in the absence of base, compound
4a could be isolated in 75% yield. Then, a series of
difluorocarbene reagents 2a−2h were also inspected (see
Table S7 of the Supporting Information). Among these,
ClCF2COONa demonstrated not only optimal efficiency but
was also the only one that facilitated the reaction work
smoothly without the necessity for an additional base. Next, we
tested various 2-((trimethylsilyl/aryl/alkyl)ethynyl)anilines
(1) in this cyclization reaction, finishing the targeted products
4a−4g in moderate to good yields (Scheme 4). The structure
of compound 4a was undoubtedly confirmed by X-ray single-
crystal analysis.13
Scheme 3. Scope for the Synthesis of N-(Quinolin-2-
c
yl)amides with Substituents on C3
a
Scheme 4. Scope for the Synthesis of Quinolin-2(1H)-ones
a
Reaction conditions: 1 (0.2 mmol), 2 (0.4 mmol), CuTc (15 mol
%), CH3CN (2 mL), 100 °C, N2, and 16 h.
As the follow-up investigation, the scalability of this
cyclization reaction to access N-(quinolin-2-yl)amides was
also inspected (see Table S9 of the Supporting Information).
Further transformations of 2-((trimethylsilyl)ethynyl)aniline
(1a) were executed as well (see Table S9 of the Supporting
Information). The hydrolysis of compounds 3a and 3f with
NH2NH2·H2O could expediently afford compounds 5 and 6 in
excellent yield via diacylation (see Table S9 of the Supporting
Information).14 In addition, compound 7 was readily obtained
via C−H/N−H oxidative cross-coupling/cyclization of com-
pound 5 and ethynylbenzene.15 Compound 5 could readily
react with isothiocyanate to finish compound 8 in 75% yield.16
The synthetic utility of this approach was also showcased by
the assembly of compounds 9 and 10 via metal-free annulation
of 2-aminoquinoline (5) and p-xylene.17
We then turned our attention to shed light on the
mechanism of this cyclization reaction. Radical trapping
experiments were investigated firstly (see Table S10 of the
Supporting Information). When 2,2,6,6-tetramethyl-1-piper-
idinyloxy (TEMPO), 2,6-di-tert-butyl-4-methylphenol (BHT)
and ethene-1,1-diyldibenzene served as radical scavengers
under the standard conditions, the target compound 3a is
still obtained with a good yield (see Table S10a of the
Supporting Information), indicating that a radical-type process
might not be involved in this cyclization of ClCF2COONa.
Subsequently, a suite of isotope-labeling experiments was
executed to gain insight into the H source in this reaction.
When compound 1a and ClCF2COONa (2) were exposed to
CD3CN, product 11 was obtained in 73% yield (see Table
S10b of the Supporting Information), which proved that
acetonitrile did not provide the H source. Next, we used
a
Reaction conditions: CuCl2 (15 mol %), Na2CO3 (2 equiv), and
b
CH3CN (2 mL). Reaction conditions: CH3(CH2)3CN (2 mL).
c
Reaction conditions: 1s−1al (0.2 mmol), 2 (0.3 mmol), CuCl (15
mol %), NaHCO3 (2 equiv), CH3CN (2 mL), 100 °C, N2, and 16 h.
substitutive aromatic rings were all amenable to this cyclization
reaction, providing compounds 3s−3z in modest yields.
Heterocycle and fused ring-containing 2-alkynylanilines could
work smoothly in this transformation as well, delivering the
expected compounds 3aa−3ae in 30−62% yields. Trisub-
stituted anilines 1af and 1ag were also good candidates in this
reaction, in which the targeted products 3af and 3ag were
achieved in 56 and 65% yields, respectively. When the current
protocol can be extended to valeronitrile, compound 3ah could
be acquired in 54% yield.
After that, we attempt to prepare 3-alkyl N-(quinolin-2-
yl)amides to further enlarge the substrate scope of this
cyclization reaction. Delightfully, a battery of functionalizated
3-alkyl N-(quinolin-2-yl)amides was achieved in 25−74%
yields with CH3CN as the solvent and performs the Ritter
reactions, which was summarized in the bottom of Scheme 3.
Of note, the current method could be applied for late-stage
functionalization of geraniol, albeit with a low yield of
compound 3al.
When we use mixed solvent (CH3CN/DMF = 1:3),
quinolin-2(1H)-one (4a) was obtained in 45% yield (see
Table S6 of the Supporting Information). Gratifyingly, when
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CD3CN as the solvent and added 10 equiv of D2O to obtain
N-(quinolin-2-yl)acetamide compound 12 with deuterium
incorporated on C3 and C4 positions (see Table S10c of the
Supporting Information). This result indicates that H2O in the
solvent may be the H source of this cycloaddition reaction.
When isocyanide 13 was submitted to the reaction, the desired
product 3a was obtained in 20% yield (see Table S10d of the
Supporting Information), which might require desiliconization
with ClCF2COONa. Subsequently, we conducted a control
experiment, which proved that ClCF2COONa could desilicon-
ize because it underwent quadruple cleavage to release the F
ion (see parts e and f of Table S10 of the Supporting
Information). Next, on the basis of Table S10d of the
Supporting Information, with the addition of ClCF2COONa,
compound 3a can be obtained with a yield of 75% (see Table
S10g of the Supporting Information), which manifested that
isocyanide might be the key intermediate for this cyclization
reaction. To clarify the origination of the carbonyl oxygen
atom of the desired product 4a, an isotope-labeling experiment
was carried out. When the reaction was conducted with 40
equiv of H218O underlying the identified conditions, 45% of
18O-labeled product 4a was detected by gas chromatography−
mass spectrometry (GC−MS) (see Table S10f of the
Supporting Information), which indicated that oxygen of the
carbonyl group should come from the water.
streamline assembly of N-(quinolin-2-yl)amides and quinolin-
2(1H)-ones. When DMF was employed as the reaction
medium, a sequence of quinolin-2(1H)-ones was achieved in
decent yields. When the reaction proceeded in nitriles, a vast
array of N-(quinolin-2-yl)amides was gained with good
functional group compatibility using nitrile as the solvent
and performs the Ritter reactions in this reaction. The current
protocol took advantage of ClCF2COONa as a promising C1
synthon, which also represents the first example for utilization
of ClCF2COONa as a novel desiliconization reagent. In
analogy of the reaction, the current protocol proceeded via
transformation of in situ generated isocyanide, which was
attacked by nucleophilic solvents, followed by intramolecular
cyclization. Further applications of this unique tandem reaction
are underway in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01484.
General experimental procedures and spectroscopic data
for the corresponding products (PDF)
Accession Codes
CCDC 1962438 and 2035896 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
On the basis of the above experimental results and previous
literature,12c,18 a possible reaction mechanism for the
cyclization reaction of 2-alkynylanilines and ClCF2COONa is
depicted in Scheme 5. First, difluorocarbene is formed via
Scheme 5. Proposed Reaction Mechanism for This
Cyclization Reaction
AUTHOR INFORMATION
Corresponding Author
■
Qiuling Song − Institute of Next Generation Matter
Transformation, College of Materials Science & Engineering,
Huaqiao University, Xiamen, Fujian 361021, People’s
Republic of China; Key Laboratory of Molecule Synthesis and
Function Discovery (Fujian Province University), College of
Chemistry, Fuzhou University, Fuzhou, Fujian 350108,
People’s Republic of China; State Key Laboratory of
Organometallic Chemistry and Key Laboratory of
Organofluorine Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, Shanghai 200032,
People’s Republic of China; orcid.org/0000-0002-9836-
8860; Email: qsong@hqu.edu.cn
Authors
Ya Wang − Institute of Next Generation Matter
Transformation, College of Materials Science & Engineering,
Huaqiao University, Xiamen, Fujian 361021, People’s
Republic of China
Yao Zhou − Hubei Key Laboratory of Pollutant Analysis &
Reuse Technology, College of Chemistry and Chemical
Engineering, Hubei Normal University, Huangshi, Hubei
435002, People’s Republic of China; orcid.org/0000-
0002-3500-7355
Xingxing Ma − Key Laboratory of Molecule Synthesis and
Function Discovery (Fujian Province University), College of
Chemistry, Fuzhou University, Fuzhou, Fujian 350108,
People’s Republic of China
dechlorination and decarboxylation of ClCF2COONa. In situ
generated difluorocarbene is immediately captured by 2-
alkynylanilines (1) with the assistance of a base to afford
isocyanide A. Simultaneously, isocyanide A reacts with Cu(II)
species to give the formation of Cu species B, which further
goes through intramolecular cyclization to render Cu complex
C. Next, Cu complex C was attacked by nucleophiles (such as
CH3CN and H2O) to obtain intermediates D and E,
respectively, which subsequently undergo protonation to
furnish the desired product 3 or 4, regenerating the Cu
species for the next catalytic cycle (Scheme 5).
In conclusion, we have disclosed a novel solvent-dependent
divergent cyclization of 2-alkynylanilines and ClCF2COONa to
Complete contact information is available at:
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phosphine-free copper-catalyzed isothiocyanation of amines with
sodium bromodifluoroacetate and sulfur. Chem. Commun. 2019, 55,
1144−1147.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
Financial support from the National Natural Science
Foundation (21772046 and 2193103) is gratefully acknowl-
edged. The authors also thank the Instrumental Analysis
Center of Huaqiao University for analysis support. Ya Wang
thanks the Subsidized Project for Cultivating Postgraduates’
Innovative Ability in Scientific Research of Huaqiao University.
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