Transition-Metal-Free Aminoacylation of Ynones with Amides: Synthesis of 3-Carbonyl-4-quinolinones or Functionalized Enaminones

Article abstract of DOI:10.1021/acs.orglett.8b01492

A transition-metal-free tandem process for the synthesis of substituted quinolin-4(1H)-ones or enaminones is presented. A base-promoted insertion of ynones into the C-N σ-bond of amides is the key step in this process, which provides the corresponding aminoacylation products in good to high yields. Quinolin-4(1H)-ones are selectively formed via the subsequent N-cyclization pathway in the cases of ynones bearing an ortho-bromo-substituted aryl ring. Easily accessible starting materials and high atom economy make this procedure attractive.

Full text of DOI:10.1021/acs.orglett.8b01492

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Transition-Metal-Free Aminoacylation of Ynones with Amides:
Synthesis of 3‑Carbonyl-4-quinolinones or Functionalized
Enaminones
Zhong Zheng, Qihai Tao, Yujuan Ao, Murong Xu, and Yanzhong Li*
Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of Chemistry and Molecular Engineering, East China
Normal University, 500 Dongchuan Road, Shanghai 200241, China
S
* Supporting Information
ABSTRACT: A transition-metal-free tandem process for the synthesis of substituted quinolin-4(1H)-ones or enaminones is
presented. A base-promoted insertion of ynones into the C−N σ-bond of amides is the key step in this process, which provides
the corresponding aminoacylation products in good to high yields. Quinolin-4(1H)-ones are selectively formed via the
subsequent N-cyclization pathway in the cases of ynones bearing an ortho-bromo-substituted aryl ring. Easily accessible starting
materials and high atom economy make this procedure attractive.
Scheme 1. Recent Progress on Aminoacylation of Alkynes
with Amides
he direct addition of a C−N bond to alkynes is one of the
T
most atom-economical transformations toward difunc-
tionalized alkenes, with both C−C and C−N bonds being
constructed simultaneously. In the last two decades, there were
few procedures concerning transition-metal-catalyzed or -medi-
ated aminoacylation of alkynes with amides for the functional-
ization of C−C triple bonds.1,2 However, these reports are very
rare due to lack of reactivity, and most of the reactions took place
in an intramolecular fashion.1,2a−c The pioneering work
reported by Yamamoto realized the Pt-catalyzed intramolecular
aminoacylation of alkynes (Scheme 1a).2a Li developed the Ru-
catalyzed annulation of alkynes with amides.2b Liu disclosed Pd-
catalyzed difunctionalization of alkynes via C−N bond
cleavage.2c Only one example of Rh/Cu-catalyzed intermolec-
ular aminoacylation of alkynes with amides was reported by Shi’s
group (Scheme 1b).2d Despite this remarkable progress, most
protocols are still confined to noble metals or in situ generated
arynes.3 Therefore, the development of novel procedures
providing general access to aminoacylation from readily
available starting materials, especially in a transition-metal-free
manner, is highly desirable.
The 4-quinolinone ring is a common crucial structure in
numerous naturally occurring products,4 and it also serves as a
vital substructure in hundreds of drugs, including antibiotics,5
antivirals,6 and anticancer agents.7 Particularly, carbonyl
substituents at the 3-position in 4-quinolinone derivatives are
essential for biochemical functions such as gyrase binding and
bacterial transport.6 A recent report showed that 2-substituted 3-
aroylquinolin-4(1H)-ones could inhibit the hedgehog signaling
pathway, in which two carbonyls in the quinolinone compound
provided the crucial H-bond interactions.8 Classic methods for
the syntheses of 4-quinolinones such as Lappin cyclization9 and
Grohe−Heitzer synthesis10 usually require a multistep proce-
dure to build enaminone precursors11 and high temper-
ature6a,b,11a−d for cyclization. Other methods for the synthesis
of 4-quinolinones used transition metal catalysts for cyclizatio-
Received: May 11, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01492
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
n,8,11e,f,12 and high pressure or toxic carbon monoxide were
sometimes involved. These limitations make it an intriguing goal
to synthesize highly functionalized quinolinones in one pot with
easily accessible substrates. During the course of our continuing
work of activating inert C−X bonds (X= C, N, etc.),13 we found
that the aminoacylation of alkynes with amides was efficiently
achieved in the presence of Cs2CO3, and 4-quinolinones could
be obtained in high yields via sequential cyclization. To the best
of our knowledge, this is the first example of transition-metal-
free intermolecular aminoacylation of isolated alkynes with
amides.
We started the investigation using N-phenylbenzamide 2a as a
model substrate. When the reaction of ynone 1a with amide 2a
was carried out in the presence of Cs2CO3 (3.0 equiv) in toluene
at room temperature, no reaction occurred. By increasing the
reaction temperature to 100 °C, the desired quinolinone 3a
could be detected only in a trace amount. At 130 °C, to our
delight, 3a was obtained with a yield of 44% (Table 1, entry 1).
substituted phenanthrolines and bipyridines were tested as well;
however, no better results were achieved (entries 8−11).
Organic bases such as 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU) and 1,4-diazabicyclo[2.2.2]octane (DABCO) were
also examined, which did not generate satisfactory results
(entries 12 and 13). Based on the experimental results above, we
presumed that 1,10-phenanthroline hydrate could act as a metal
ion chelator,14 and thus increased the basicity of cesium
carbonate and increased the reaction speed. Other bases such as
NaOBut and NaOH were subsequently screened, and no better
results were observed (entries 14 and 15). A decrease of Cs2CO3
to 2.0 equiv led to a lower yield of 3a (entry 16). Increase of
Cs2CO3 to 4.0 equiv did not significantly affect the yield (entry
17). The reaction could not occur in the absence of the Cs2CO3
(entry 18), indicating a base condition is mandated.
With the optimal reaction conditions in hand (Table 1, entry
3), the scope of this reaction was subsequently investigated
(Figure 1). First, substituent effects of R1 on the aryl ring were
a b
,
Table 1. Optimization of Reaction Conditions
temp
(°C)
time
(h)
yield
b
a
entry
base (equiv) additive (mol %)
(%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Cs2CO3 (3.0)
Cs2CO3 (3.0)
/
/
130
150
150
150
150
150
150
150
150
150
150
150
150
150
150
150
150
150
72
15.5
12
8
12
6
6
14
6
21
20
12
30
20
20
12
12
24
44
64
72
78
76
64
70
66
53
58
61
/
66
/
n.r.
55
76
trace
Cs2CO3 (3.0) Phen·H2O (20)
Cs2CO3 (3.0) Phen·H2O (50)
Cs2CO3 (3.0) Phen·H2O (50)
Cs2CO3 (3.0) Phen·H2O (100)
Cs2CO3 (3.0) Phen·H2O (200)
Cs2CO3 (3.0) 2,2′-biPy (50)
Cs2CO3 (3.0) L1 (50)
Cs2CO3 (3.0) L2 (50)
Cs2CO3 (3.0) L3 (50)
Cs2CO3 (3.0) DBU (50)
Cs2CO3 (3.0) DABCO (50)
tBuONa (3.0) Phen·H2O (50)
NaOH (3.0)
Cs2CO3 (2.0) Phen·H2O (50)
Cs2CO3 (4.0) Phen·H2O (50)
Phen·H2O (50)
/
Phen·H2O (50)
a
b
Reactions were conducted on 0.2 mmol scale under air. Isolated
yields.
Figure 1. Scope of the synthesis of substituted quinolinone 3. The
reactions were all carried out under air on a 0.2 mmol scale with the
ratio of 1:2 = 1:1.
Further increasing the reaction temperature to 150 °C
accelerated this reaction with a better yield of 64% (entry 2).
The structure of 3a was confirmed by X-ray crystallography. In
order to achieve a better reaction outcome, several additives
were screened, and it was interesting to find that 1,10-
phenanthroline hydrate afforded higher yields with shorter
reaction time (entries 3−7). 50 mol % of 1,10-phenanthroline
hydrate gave the best yield of 78% within 8 h. A longer reaction
time of 12 h did not improve the yield (entry 5). Other
studied (Figure 1, 3a−3e). Substrates with electron-with-
drawing groups (4-F, 5-F) and electron-donating groups (4,5-
dimethoxy) were suitable for this reaction, giving the
corresponding products 3a−3c and 3e with yields ranging
between 70% and 80%. A heterocycle was also compatible,
affording pyridine-fused product 3d in 72% yield. Next, R2
substituents on the triple bond were screened. A naphthyl-
B
DOI: 10.1021/acs.orglett.8b01492
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
substituted ynone afforded 3f in 63% yield. R2 with electron-
donating aryl groups (4-Me, 4-OMe, and 3,4,5-(OMe)3) gave
the corresponding products 3g−3i with 66%, 73%, and 62%
yields, respectively. The electron-withdrawing aryl group (4-Cl)
also afforded the desired 3j with 58% yield. However, alkyl-
substituted (C5H11) ynone failed to give the desired product.
The substituent effects of amides were subsequently
investigated. For the R3 groups attached to the carbonyl, it
was clear that both electron-donating (R3 = 4-MeC6H4, 4-
OMeC6H4) and electron-withdrawing groups (R3 = 4-ClC6H4,
4-FC6H4) on the aryl ring were suitable for this reaction, offering
the desired quinolinones 3k−3n with moderate to high yields. It
should be noted that electron-withdrawing amides provided the
desired quinolinones (3m, 3n) with higher yields in shorter
reaction times. tert-Butyl-substituted R3 also resulted in the
formation of quinolinone 3o, albeit in a low yield, possibly due to
steric hindrance. A methyl substituent did not give the desired
product, presumably due to the existence of acidic α-H.
Substituent effects of R4 on the amides were subsequently
explored (Figure 1, 3p−3r). Substrates with electron-donating
groups (R4 = 4-MeC6H4, 4-OMeC6H4) required longer reaction
times than those of electron-withdrawing groups (R4 = 4-
ClC6H4) to furnish the desired products (3p−3r). However, the
alkyl substituent (C4H9) of R4 was unable to give the desired
product.
our delight, 6aa could be converted to enaminone 7a under the
optimized conditions (Scheme 2, d). This implied that an
insertion of C−N σ-bond of amide occurred after the Michael
addition step.
These results offered an atom-economy protocol involving
direct C−N bond activation for the synthesis of highly
functionalized enaminones, which are useful building blocks
toward heterocycles in organic chemistry.15 Thus, we further
explored this protocol for the synthesis of functionalized
enaminones in a one-pot manner. A variety of ynones and
amides containing electron-withdrawing or election-donating
groups on the aryl ring were employed, resulting in good to high
yields of the desired products (Figure 2). It should be noted that
To clarify the reaction mechanism, several control experi-
ments were performed (Scheme 2). When ynone 1a reacted
Scheme 2. Control Experiments
Figure 2. Synthesis of enaminone 7. The reactions were all carried out
under air on a 0.2 mmol scale with the ratio of 5:2 = 1:1.
enaminone 7a was obtained with 58% yield as a pair of 1:1 E/Z
isomers of a CC double bond of the enamine, the isomerism
possibly due to the imine−enamine tautomerization under basic
conditions.
Based on our experimental results, and the previously
reported works,13 a plausible reaction mechanism has been
proposed (Scheme 3). First, an amide undergoes a Michael-type
addition with ynone under basic conditions to give an allenol
intermediate A. An intramolecular nucleophilic addition
subsequently occurred to form a highly reactive cyclobutenol
Scheme 3. Possible Mechanism
with amide 2a under the standard reaction conditions in 50 min,
a Michael addition product 4aa was obtained in 61% yield
(Scheme 2, a). Product 4aa could be converted to quinolinone
3a in 13 h under the optimized conditions (Scheme 2, b).
However, no C−N bond cleavage intermediate could be
detected, even under a lower temperature or shorter reaction
time. It indicated that the ring closure reaction might be much
faster than the C−N bond cleavage reaction. In order to observe
the C−N bond cleavage intermediate, we envisioned that
ynones without an ortho-bromo substituent would be suitable
candidates to react with amides. When ynone 5a reacted with 2a
under the optimal reaction conditions, 6aa and 6aa′ were
obtained in 67% and 2% yields, respectively (Scheme 2, c). The
structure of 6aa was confirmed by X-ray diffraction analysis. To
C
DOI: 10.1021/acs.orglett.8b01492
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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insertion intermediate C. Imine−enamine tautomerization of C,
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In summary, we have developed an efficient base-promoted
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With advantages such as readily available materials and simple
operations, it has the potential to be widely used in synthetic and
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b01492.
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Accession Codes
CCDC 1562831 and 1835528 contain the supplementary
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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.
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: yzli@chem.ecnu.edu.cn.
ORCID
Zhong Zheng: 0000-0002-3868-006X
Murong Xu: 0000-0001-7363-8222
Yanzhong Li: 0000-0002-2898-3075
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(grant no. 21272074) and the Program for Changjiang Scholars
and Innovative Research Team in University (PCSIRT) for
financial support.
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DOI: 10.1021/acs.orglett.8b01492
Org. Lett. XXXX, XXX, XXX−XXX