Access to Densely Functionalized Chalcone Derivatives with a 2-Pyridone Subunit via Pd/Cu-Catalyzed Oxidative Furan-Yne Cyclization of N -(2-Furanylmethyl) Alkynamides under Air

Article abstract of DOI:10.1021/acs.orglett.8b00618

A protocol for synthesis of chalcone derivatives with a 2-pyridone subunit from N-(2-furanylmethyl) alkynamides is reported. This synthesis involves Pd/Cu-catalyzed oxidative furan-yne cyclization at room temperature in air and may proceed via nucleopalladation of the alkyne to form a vinylpalladium intermediate, with a furan ring acting as the nucleophile.

Full text of DOI:10.1021/acs.orglett.8b00618

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Access to Densely Functionalized Chalcone Derivatives with a
2‑Pyridone Subunit via Pd/Cu-Catalyzed Oxidative Furan−Yne
Cyclization of N‑(2-Furanylmethyl) Alkynamides under Air
Yongjie Yang,† ChengCheng Fei,‡ Kai Wang,§ Bo Liu,§ Dingxin Jiang,*,‡ and Biaolin Yin*,†
†Key Laboratory of Functional Molecular Engineering of Guangdong Province, School of Chemistry and Chemical Engineering,
South China University of Technology, Guangzhou 510640, P. R. China
‡Key Laboratory of Natural Pesticide and Chemical Biology, Ministry of Education, Laboratory of Insect Toxicology, South China
Agricultural University, Guangzhou 510642, P. R. China
§Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou 510006, P. R. China
S
* Supporting Information
ABSTRACT: A protocol for synthesis of chalcone derivatives with a 2-
pyridone subunit from N-(2-furanylmethyl) alkynamides is reported. This
synthesis involves Pd/Cu-catalyzed oxidative furan−yne cyclization at
room temperature in air and may proceed via nucleopalladation of the
alkyne to form a vinylpalladium intermediate, with a furan ring acting as
the nucleophile.
furans with terminal alkynes to furnish phenols through a
he development of efficient methods for carbo- and
Theterocycle synthesis is an important area of research in cyclopropyl metal-carbene intermediate formed by exo-
organic chemistry.1 One method that has proven to be versatile
for this purpose is the intramolecular cyclization of furan−ynes.
Four main strategies for furan−yne cyclization have been
reported. One strategy is Friedel−Crafts-type reaction of 4-, 5-,
and 6-aryl-1-ynes with catalysis by electrophilic metal halides to
afford furan-fused bicyclic compounds (Scheme 1, eq 1).2 A
second strategy is the intramolecular [4 + 2] cycloaddition of
furans with alkynes to afford oxabicyclic compounds, which can
be cleaved to form phenols. In such reactions, the alkyne that
acts as a dienophile is usually activated by η2-coordination to a
metal halide or by the influence of an electron-withdrawing
substituent (Scheme 1, eq 2).3 A third strategy is the reaction of
cyclization of the alkyne with the C2−C3 double bond of the
furan ring (Scheme 1, eq 3).4 Finally, gold-catalyzed furan−yne
endo-cyclization accompanied by furan ring opening has been
shown to give enal or enones (Scheme 1, eq 4).5 Owing to the
varied and useful chemistry of furans6 and alkynes, particularly
chemistry mediated by transition-metal catalysts and/or Lewis
acids, the development of novel furan−yne cyclization methods
continues to be an active area of research.
Pd-catalyzed transformation of functionalized alkynes7 is a
powerful method for the efficient formation of carbon−carbon
and carbon−heteroatom bonds. Various nucleophiles, including
acetic acid, amides and amines, halides and pseudohalides, and
boronic acids, have been used for nucleopalladation of alkynes
to generate the corresponding vinylpalladium species, which
can then react with carbon monoxide,8 boronates,9 halides and
pseudohalides,10 unactivated olefins,11 allylic alcohols,12 acrylic
aldehydes,13 allyl acid,14 allyl esters,15 cyanides,16 and
isocyanides17 to afford difunctionalized alkynes.18 The develop-
ment of new coupling partners for difunctionalization of
alkynes can be expected to expand the synthetic applications of
this method.
Scheme 1. Intramolecular Cyclizations of Furan−Ynes
Given that the aromatic furan ring is electron-rich and often
acts as a nucleophile, we hypothesized that nucleopalladation of
alkynes 1 bearing a pendant furan ring would generate
vinylpalladium intermediate A, which could then couple with
various partners to provide access to chalcone derivatives 2,
some of which show bioactivities19 and interesting photo-
electronic properties20 (Scheme 1, eq 5). Chalcones are
Received: February 21, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00618
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
generally synthesized via aldol reactions between aldehyde and
ketone substrates, but the preparation of the substrates tends to
be difficult, requiring multiple steps if they are structurally
complex and/or densely functionalized. As part of our ongoing
work on the synthetic applications of furans,21 we herein report
a protocol for the synthesis of densely functionalized chalcone
derivatives 2 with a 2-pyridone subunit22 via a Pd/Cu-catalyzed
furan−yne oxidative cyclization reaction of N-(2-furanylmeth-
yl) alkynamides, in which both the furan ring and an external
halide act as nucleophiles and air serves as the terminal oxidant
at room temperature.
The success of the protocol relied on the development of
reaction conditions to suppress side reactions such as [4 + 2]
cycloaddition to form a fused phenol and Friedel−Crafts-type
reactions to form a fused furan. To optimize the reaction
conditions, we used alkynamides 1a as the substrate (Table 1).
revealed that CuBr2 was optimal (Table 1, entries 11−15).
Replacing DCE with DCM, THF, MeCN, toluene, acetone,
MeOH, or DMF did not improve the yield (Table 1, entries
16−22). Both PdBr2 and CuBr2 were essential: in the absence
of either catalyst, no 2a was detected (Table 1, entries 23 and
24). Thus, we concluded that the optimal conditions involved
the use of PdBr2 (10 mol %) and CuBr2 (20 mol %) as the
catalysts, LiBr (2 equiv) as the bromide source, and DCE as the
solvent at room temperature under an air atmosphere (Table 1,
entry 2).
With the optimized conditions in hand, we explored the
substrate scope with respect to the R1 substituent on the furan
ring (Table 2). For this purpose, we used substrates 1 with a
a
Table 2. Substrate Scope with Respect to R1
a
Table 1. Optimization of Reaction Conditions
b
entry
R1
2 (yield %)
1
2
3
4
5
6
7
Ph
2a (76)
2b (79)
2c (79)
2d (76)
2e (72)
2f (77)
2g (71)
2h (55)
2i (48)
2j (57)
2k (50)
2l (60)
2m (60)
4-Me-C6H4
4-MeO-C6H4
3-Me-C6H4
2-Me-C6H4
3,5-di-Me-C6H3
3-F-C6H4
b
entry
[Pd]
[Cu]
CuBr2
solvent
yield (%)
1
2
3
4
5
6
7
8
Pd(OAc)2
PdBr2
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCM
THF
76
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuSO4
Cu(OAc)2
Cu(OTf)2
Cu(TFA)2
CuCl2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
−
80
Pd(TFA)2
PdCl2
70
76
c
8
4-F-C6H4
Pd(PPh3)2Cl2
Pd(CH3CN)2Cl2
Pd(PPh3)4
Pd2(dba)3
PdBr2
ND
41
c
9
4-Cl-C6H4
4-Br-C6H4
4-CF3-C6H4
3-Me-4-F-C6H4
Me
c
10
ND
29
c
11
c
c
12
9
10
d
13
14
10
PdBr2
37
H
2n (68)
b
11
12
13
14
15
16
17
18
19
20
21
22
23
24
PdBr2
41
a
PdBr2
70
All the reactions were carried out on 0.4 mmol scale. Isolated yields
are reported. This reaction was carried out for 12 h under otherwise
standard conditions.
c
PdBr2
63
PdBr2
trace
63
PdBr2
PdBr2
51
phenyl substituent on the alkyne and an n-Pr group on the
amide nitrogen. The reaction was sensitive to the electron
density of the furan ring. When R1 was a phenyl group with an
electron-donating substituent group (Me or OMe), the
corresponding products were obtained in good yields (72−
79%, Table 2, entries 2−6). However, when the R1 phenyl
group bore a 4-F, 4-Cl, 4-Br, or 4-CF3 substituent, the yields
were relatively low (48−60%, Table 2, entries 7−12). Notably,
even when R1 was H or Me, the reaction smoothly gave 2a in
60% and 69% yields, respectively (Table 2, entries 13 and 14).
To explore the scope of the protocol with respect to the R2
substituent on the alkyne, we used a series of substrates with a
phenyl group on the furan ring and an n-Pr group on the
nitrogen (Table 3). From substrates with a phenyl group
bearing one or more electron-donating substituents (Me, OMe,
or t-Bu), the corresponding products were obtained in
moderate to good yields (Table 3, entries 1−6). When R2
was a phenyl group with a halogen atom (F or Cl), the reaction
also proceeded smoothly in good yields (Table 3, entries 7−9).
However, when R2 was 4-CN-C6H4, no reaction took place
(Table 3, entry 10). The exact reason for this failure is not clear
at present. When R2 was 4-CF3-C6H4 or Me, complicated
product mixtures were obtained, and the yields of 2y and 2z
were low (Table 3, entries 11 and 12).
PdBr2
ND
ND
trace
ND
trace
ND
ND
ND
PdBr2
MeCN
toluene
acetone
CH3OH
DMF
DCE
DCE
PdBr2
PdBr2
PdBr2
PdBr2
PdBr2
−
CuBr2
a
b
All the reactions were carried out on a 0.2 mmol scale. Determined
c
by 1H NMR (internal standard: 1,3,5-trimethylbenzene). N2 was used
d
instead of air. O2 was used instead of air.
At room temperature in the presence of Pd(OAc)2 (0.1 equiv)
and CuBr2 (0.2 equiv) as the catalysts, LiBr (2 equiv) as the
added nucleophile, and air as the oxidant, 1a could be
transformed into brominated chalcone 2a in 76% yield
(Table 1, entry 1). The structure of 2a was assigned on the
basis of single-crystal X-ray data obtained for 2ak (see the
Supporting Information (SI)). Screening of various other Pd
catalysts (Table 1, entries 2−8) indicated that PdBr2 was
optimal (Table 1, entry 2). Notably, the yields were lower when
the reaction was carried out under nitrogen or oxygen (Table 1,
entries 9 and 10). Evaluation of various other Cu catalysts
B
DOI: 10.1021/acs.orglett.8b00618
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Table 3. Substrate Scope with Respect to R2
Table 5. Synthesis of Chlorinated Chalcone Derivatives
b
R2
2 (yield %)
b
entry
R1
R2
2 (yield %)
entry
1
4-Me-C6H4
4-MeO-C6H4
4-t-Bu-C6H4
3-Me-C6H4
2-Me-C6H4
3,4-di-Me-C6H3
4-F-C6H4
2o (70)
2p (66)
2q (75)
2r (63)
2s (63)
2t (70)
2u (76)
2v (75)
2w (75)
2x (ND)
2y (44)
2z (46)
1
2
3
4
5
6
Ph
Ph
Ph
Ph
Ph
2ae (70)
2af (77)
2ag (69)
2ah (74)
2ai (82)
2
4-MeO-C6H4
4-F-C6H4
3-Me-4-F-C6H4
Ph
3
4
5
4-t-Bu-C6H4
6
Ph
4-F-C6H4
2aj (79)
7
a
b
All the reactions were carried out on a 0.4 mmol scale. Isolated
yields are reported.
8
4-Cl-C6H4
3-F-C6H4
9
10
11
12
4-CN-C6H4
4-CF3-C6H4
Me
Scheme 2. Control Experiments
a
All the reactions were carried out on a 0.4 mmol scale. ND = not
b
detected. Isolated yields are reported.
Finally, substrates with various R3 groups on the amide
nitrogen were screened (R1 = R2 = Ph, Table 4). When R3 was
a
Table 4. Substrate Scope with Respect to R3
Scheme 3. Proposed Reaction Mechanism
b
entry
R3
2 (yield %)
1
2
3
4
iPr
t-Bu
Bn
H
2aa (51)
2ab (trace)
2ac (74)
2ad (ND)
a
All the reactions were carried out on a 0.4 mmol scale. ND = not
b
detected. Isolated yields are reported.
a sterically bulky iPr group, the yield dropped dramatically (to
51%), and when R3 was t-Bu, only a trace of 2ab was detected.
However, a substrate with a removable Bn group afforded
corresponding product 2ac in 74% yield. When R3 was H, no
2ad was detected.
To our delight, a range of chlorinated chalcone derivatives
could also be synthesized in good yields from 1 with PdCl2 and
CuCl2 as catalysts and LiCl as the chloride source (Table 5).
Notably, however, a longer reaction time (24 h) was required,
possibly because Cl is a weaker nucleophile than Br.
To gain insight into the mechanism of this oxidative coupling
reaction, we conducted two control experiments (Scheme 2).
First, treatment of 1a with AlCl3 (1 equiv) and NBS (1 equiv)
in DCE did not give 2a indicating that the transition-metal
catalysts of palladium and copper were essential to the
transformation. Second, compound 3aa, which was detected
in the reaction mixture, could not be transformed into 2aa
under the standard conditions, suggesting that 2aa did not form
via electrophilic bromination of 3aa.
opening gives intermediate 5, which undergoes deprotonation
and reductive elimination to furnish 2 and generate Pd(0).23 In
the presence of Cu(II) and air, oxidation of Pd(0) to PdX2
completes the catalytic cycle.
In summary, we have developed a simple, practical protocol
for access to densely functionalized chalcone derivatives with a
2-pyridone subunit from N-(2-furanylmethyl) alkynamides.
This protocol, which proceeds at room temperature, involves
a novel Pd-catalyzed oxidative difunctionalization reaction of
alkynes using furan rings as a nucleophile and air as the
terminal oxidant. The protocol opens a new route to
vinylpalladium compounds and a new method for trans-
formation of furans into other useful compounds. Further
exploration of this reactionincluding variation of the aryl
rings of the substrate, trapping of the vinylpalladium with
carbon nucleophiles, and evaluation of the bioactivities of the
productsis underway in our laboratory.
On the basis of the above-described results and the results of
previous studies of Pd-catalyzed difunctionalization of
alkynes,7,19 a plausible mechanism is proposed in Scheme 3.
Reaction of 1 with PdX2 provides complex 3, which undergoes
nucleopalladation to afford vinylpalladium 4. Subsequent ring
C
DOI: 10.1021/acs.orglett.8b00618
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b00618.
■
S
Details about experimental conditions, characterization
1
data, copies of H and 13C NMR spectra of all new
́
reactions of functionalized alkynes, see: (a) Chinchilla, R.; Najera, C.
compounds (PDF)
Chem. Rev. 2014, 114, 1783. (b) Liu, X.; Mao, R.; Ma, C. Org. Lett.
2017, 19, 6704. (c) Cai, Z.; Li, F.; Wang, S.; Ji, S. Org. Lett. 2016, 18,
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A. J. Am. Chem. Soc. 2014, 136, 6255. (g) Zheng, Y.; Bao, M.; Yao, R.;
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Accession Codes
CCDC 1822466 contains 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.
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AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: blyin@scut.edu.cn.
*E-mail: dxj2005@scau.edu.cn.
ORCID
Biaolin Yin: 0000-0002-2547-0231
Notes
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77, 2029. (b) Zheng, M.; Huang, L.; Tong, Q.; Wu, W.; Jiang, H. Eur.
J. Org. Chem. 2016, 2016, 663.
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
This work was supported by grants from the National Program
on Key Research Project (No. 2016YFA0602900), the National
Natural Science Foundation of China (No. 21572068), the
Science and Technology Program of Guangzhou, China (No.
201707010057), Guangdong Natural Science Foundation (No.
2017A030312005), and the Science and Technology Planning
Project of Guangdong Province, China (Nos. 2017A020216021
and 2014A020221035).
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DOI: 10.1021/acs.orglett.8b00618
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