Pd catalyzed couplings of “superactive esters” and terminal alkynes: Application to flavones and γ-benzopyranones construction

Article abstract of DOI:10.1016/j.molcata.2016.10.030

Lewis base, N-methylmorpholine (NMM) accelerated Pd-catalyzed Sonogashira coupling of steric hindered super active esters, 1a–1e, and terminal alkynes. This approach provided an efficient synthetic protocol for a broad array of acylated o-alkynoylphenols compounds, 3a–3e, under moderate conditions. The mechanistic study clearly demonstrated that NNM stabilized the catalytic palladium species, and accelerated the leaving of triazine moiety during the catalytic cycle of the cross-coupling reactions. In addition, piperazine was found to efficiently catalyze the 6-endo cyclization of acylated o-alkynoylphenols, which achieved the diversity oriented synthesis of γ-benzopyranones, 4aa–4eg, with 93–99% yields.

Full text of DOI:10.1016/j.molcata.2016.10.030

Journal of Molecular Catalysis A: Chemical 426 (2017) 24–29
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Editor’s choice paper
Pd catalyzed couplings of “superactive esters” and terminal alkynes:
Application to flavones and ꢀ-benzopyranones construction
Dandan Yang, Zhenhua Wang, Xiu Wang, Huaming Sun, Zunyuan Xie, Juan Fan,
Guofang Zhang, Weiqiang Zhang∗, Ziwei Gao∗
Key Laboratory of Applied Surface and Colloid Chemistry, Ministry of Education, School of Chemistry & Chemical Engineering, Shaanxi Normal University,
199 South Chang’an Road, Xi’an, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Lewis base, N-methylmorpholine (NMM) accelerated Pd-catalyzed Sonogashira coupling of steric hin-
dered super active esters, 1a–1e, and terminal alkynes. This approach provided an efficient synthetic
protocol for a broad array of acylated o-alkynoylphenols compounds, 3a–3e, under moderate condi-
tions. The mechanistic study clearly demonstrated that NNM stabilized the catalytic palladium species,
and accelerated the leaving of triazine moiety during the catalytic cycle of the cross-coupling reac-
tions. In addition, piperazine was found to efficiently catalyze the 6-endo cyclization of acylated
o-alkynoylphenols, which achieved the diversity oriented synthesis of ꢀ-benzopyranones, 4aa–4eg, with
93–99% yields.
Received 5 September 2016
Received in revised form 24 October 2016
Accepted 25 October 2016
Available online 3 November 2016
Keywords:
Palladium catalyzed alkynlation
1,3-Ynones
6-Endo cyclization
Flavones
© 2016 Elsevier B.V. All rights reserved.
␥-Benzopyranones
1. Introduction
products [7], they are often employed as key intermediates in
the rapid construction of sophisticated ꢀ-benzopyranones [8].
The ꢀ-benzopyranones represent one of the most prevalent
structural heterocycles in natural products, plant physiology and
pharmaceuticals [1]. The importance of ꢀ-benzopyranones deriva-
tives has led to the development of a variety of general approaches
for synthesizing their varied derivatives, such as Allan-Robinson
method [2], Baker-Venkataraman rearrangement [3], Algar-Flynn-
Oymanda method [4], the cyclization of chalcones [5]. Despite these
advances, the most of these methods are of limited use as they
suffer from low yields and often afford a mixture of products con-
taining flavones, flavanones and aurones [6]. These procedures,
generally require prolonged reaction times, multiple-step manipu-
lation and use of harsh reaction condition of high temperatures or
strong bases. Consequently, the efficient approaches towards the
diversity oriented synthesis of ꢀ-benzopyranones have received
considerable attention.
Yang et al. developed PdCl2(PPh3)2-Thiourea-dppp catalyst sys-
tem for the carbonylative annulation of o-acetoxyiodobenzenes
with arylacetylenes using DBU as base and diethylamine as sol-
vent (Scheme 1a) [9]. Wu et al. adopted a step by step approach
towards ꢀ-benzopyranones in which Pd/Cu catalyzed the cross-
coupling of o-acetylsalicyloyl chlorides and terminal alkynes whilst
KOtBu prompted the annulation of 1,3-ynones (Scheme 1b) [10].
The inevitable employment of dangerous toxic and odorless CO
as well as the requirement of strong bases limited these reactions
from development. At these points, developing a facile CO- free
synthesis of ꢀ-benzopyranones under mild condition is of vital
importance. Herein, we wish to report Lewis bases accelerated
Pd-catalyzed alkynylation of 2-acetoxybenzoic acid ester, and the
piperazine-mediated annulation for the diversity oriented synthe-
sis of ꢀ-benzopyranones (Scheme 1c). The new catalyst system of
Pd(OAc)2 and NMM were applied for the cross-coupling of steric
hindered 2-acetoxybenzoic acid esters and terminal alkynes of 24
examples with satisfactory yields. The mechanistic experiments
found that NMM stabilized the catalytic species, and promoted
the deprotonation of terminal alkynes. To best our knowledge, the
The palladium catalyzed cross-coupling offers one of the most
convergent approaches for the construction of complex molecu-
lar frameworks. Ynones are important structural motifs in natural
∗
Corresponding authors.
E-mail addresses: zwq@snnu.edu.cn (W. Zhang), zwgao@snnu.edu.cn (Z. Gao).
http://dx.doi.org/10.1016/j.molcata.2016.10.030
1381-1169/© 2016 Elsevier B.V. All rights reserved.

D. Yang et al. / Journal of Molecular Catalysis A: Chemical 426 (2017) 24–29
25
Scheme 1. Pd catalyzed diversity-oriented synthesis of ꢀ-benzopyranones.
ual solvent peak (CDCl3 at 7.26 ppm) unless otherwise noted. The
data are reported as follows: chemical shift, integration, multiplic-
ity (s = singlet, d = doublet, t = triplet, q = quartet and m = multiplet),
and coupling constant in Hz. For 13C NMR, CDCl3 was used as inter-
nal standard (␦ = 77.16) and spectra were obtained with complete
proton decoupling. LRMS (ESI) analysis was performed and (LRMS)
data were reported with sodium mass/charge (m/z) ratios as values
in atomic mass units.
2.2. General procedure for the synthesis of products 3aa-3eg
Under the protection of N2, 3 mL CH3CN was transferred into
Schlenk tubes containing Pd(OAc)2 (0.025 mmol) and triazine
esters 1a–1e (0.5 mmol). Alkynyl reagent 2a–2k (0.75 mmol) was
added by syringe. The reaction mixture was stirred at 50 ◦C for 10 h.
Then added 1.0eq NMM for 8 h. After the reaction cooled down to
room temperature, the crude products were extracted with ethyl
acetate and water, the water layer got white precipitate by using
rotary evaporator (C10H18N4O4 (258.11): calcd. C, 46.50; H, 7.02; N,
21.69; O, 24.78; found C 46.48, H 7.06, N 21.57 O 24.72). And then
organic layer were filtered off and purified by column chromatog-
raphy on silica gel using ethyl acetate/petroleum ether as eluent.
All products 3aa–3eg were identified by comparing their spectral
data with those of authentic samples.
Scheme 2. Amines accelerated Pd catalyzed cross-coupling of “Superactive Ester”
with phenylacetylene.
piperazine is the most active base, which efficiently mediated the
annulation at room temperature with 93%-99% yields.
2. Experimental
2.1. General materials and methods
Solvents for reactions were used without distillation (CH3CN,
Alfa, purity). All reagents were purchased from the suppliers
(TCI, Alfa, Acros, Aldrich) and used without further purification
unless specified otherwise. Triazine ester reagents were pre-
pared according to the general procedure. Unless otherwise stated,
all manipulations were performed in a sealed Schlenk tubes
under nitrogen atmosphere. Flash chromatography was performed
using 200–300 mesh silica gel with the indicated solvent sys-
tem according to standard techniques and analytical thin layer
chromatography was carried out using 250 ␮m commercial sil-
ica gel plates. 1H and 13C NMR spectra were recorded on a
Bruker EQUINX55 (400 MHz for 1H; 101 MHz for 13C) spectrom-
eter in CDCl3. For 1H NMR, tetramethylsilane (TMS) served as
internal standard (␦ = 0) and 1H NMR chemical shifts are reported
in ppm downfield of tetramethylsilane and referenced to resid-
2.3. General procedure for the synthesis of products 4aa–4eg:
Under atmospheric conditions, 3 mL CH3CN without water
was transferred into Schlenk tubes containing 1,3-yones 3aa–3eg
(0.5 mmol), then piperazine (0.25 mmol) was added. The reac-
tion mixture was stirred at 25 ◦C for 1.5 h–3 h. After the reaction
proceed completely, and the organic layer was purified by col-
umn chromatography on silica gel using dichloromethane or ethyl
acetate/petroleum ether as eluent. All products 4aa-4eg were iden-
tified by comparing their spectral data with those of authentic
samples.

26
D. Yang et al. / Journal of Molecular Catalysis A: Chemical 426 (2017) 24–29
Table 1
NMM mediated palladium catalyzed cross-couplings of triazine ester and terminal alkynes.a,b
a
Reaction conditions: triazine esters (0.5 mmol), Pd(OAc)2 (5 mol%), alkynyl reagent (0.75 mmol) and CH3CN (3 mL) was stirred at 50 ◦C for 10 h, then add the N-
methylmorpholine (0.5 mmol), response about 8 h.
b
Isolated yield.
3. Results and discussion
Under the optimized reaction conditions [1a:2a = 1:1.5, 5 mol%
Pd(OAc)2, 3 mL CH3CN, 50 ◦C, 18 h], we explored the scope of
“Super-Active Esters” [11] and terminal alkynes (Table 1). Acetyl-
salicylic acid ester 1a coupled to aromatic alkynes 2a–e with
80–97% yields. Arylacetylenes bearing 4-alkyl groups gave over 80%
yields (3aa, 3ac, 3ad, and 3ae). While 3ab with methoxy group
at the para site was isolated in 95% yield. The aliphatic terminal
alkynes were also active and gave the corresponding alkyl ynones
(3ag, 3ah, and 3ai) with 70–83% yields. Thiophene-yl heterocycles
were efficiently introduced to ynone compound (3af), with 83%
yields. The arylacetylenes bearing electron-withdrawing F group
gave 88% and 80% yields, respectively (3bg, 3bk). The scope of tri-
azine esters was examined in detail under the optimized reaction
conditions. The results showed that both electron-withdrawing
and electron-donating substituents on R1 were well-tolerated. Tri-
Initially, palladium catalyzed cross-coupling of 4, 6-dimethoxy-
1,3,5-triazinal-2-yl 2-acetoxybenzoate 1a was chosen to optimize
the reaction parameters (Scheme 2). Under N2 atmosphere, 5 mol%
Pd(OAc)2 gave 65% yield using Et2NH as base in CH3CN at 50 ◦C.
It was found that base was crucial to the cross-coupling reac-
tion. DIPEA and Et3N, afforded 71% and 82% yields respectively.
Pyridine, cyclohexylamine were less active, gave 67% and 70%,
respectively. 3aa was obtained with 62% yield in presence of mor-
pholine. Gratifyingly, N-methylmorpholine (NMM) afforded 97%,
whilst N-ethylmorpholine and 83% yields, which indicated the
coordination of NNM and palladium was beneficial to establish the
catalytic cycle. Inorganic base, such as K2CO3 failed to promote the
reaction (Table S1).

D. Yang et al. / Journal of Molecular Catalysis A: Chemical 426 (2017) 24–29
27
Scheme 3. Proposed reaction mechanism.
azine esters containing electron-donating groups, such as -Me (3ba,
3bd, 3bf and 3bg) and -OMe (3ca, 3cb, 3cc, 3cf, and 3cg), pro-
vided the corresponding 1, 3-ynones in good yields (65–95%). The
reactions of triazine esters with electron-withdrawing groups (-Cl
and −Br) also took place efficiently (50–86%, Table 1, 3df, 3dg, 3ef,
and 3eg). Gladly, the present method flourished 14 new acylated
o-alkynoylphenols.
to promote the cyclization. Secondary amine, Et2NH yielded 4aa
with 21% yield. Cyclohexyl amine and the N-methylpiperidine gave
40% and 36% yields, respectively. Notably, Piperazine was found
the most active base, and afforded 4aa with 95% yield. By adding
piperazine, the annulation successfully flourished 24 exmples of
flavones and ꢀ-benzopyranones with satisfactory yields. 8 flavones
compounds were synthesized for the first time (Table 2).
To elucidate the mechanism (Scheme 3), the cross-coupling
reaction of 4, 6-dimethoxy-1,3,5-triazinal-2-yl 2-acetoxybenzoate
1a and phenylacetylene 2a was investigated. ESI–MS analysis
unveiled two palladium triazine species during the reaction course.
The adduct of palladium acetate and triazine ester was detected as
cationic fragment I of m/z = 449.3609 ([M+Na]+). The cationic Pd
species with m/z = 681.3038 ([M+Na]+) was assigned as the oxida-
tive addition intermediate II. Therefore, a catalytic cycle is proposed
in Scheme 3. The catalytic active palladium oxidatively adds to the
4. Conclusions
In conclusion, palladium-catalyzed alkynylation reactions using
carboxylic triazine esters as electrophiles have been developed
[12]. The C O activation of triazine is so efficient that it enables
clean C C couplings showing a wide range of functional tolerance
and unprecedented selectivity. The acylated o-alkynoylphenols
derivatives were synthesized in excellent yields from aryl and
alkylterminal alkynes, respectively. An efficient protocol for the
synthesis of ꢀ-benzopyranones was developed through a facile and
selective 6-endo cyclization reaction mediated by piperazine. This
highly practical and modular synthesis represents an alternative
method to synthesize ꢀ-benzopyranones with a broad substrate
scope, high atom efficiency, and important synthetic potential of
the products.
C
O bond of 1a, and I form sequentially. Phenylacetylene enters
the inner sphere of II via coordination to Pd(II). NMM might accel-
erate the proton transfer from terminal alkynes to triazine moiety
and leaves the coordination sphere of II as triazine salt in the form
of IV. Finally, the reductive elimination releases 1,3-ynone product
3aa, and the catalytic active Pd(0) species regenerated.
In recent years, the synthesis of flavones through the cycliza-
tion of o-alkynoylphenol or its derivatives has become an attractive
topic [5c,10,13], partly because of the feasibility of this method
in the chemical and pharmaceutical industries. Hence, to continue
our program aiming at efficient construction of ꢀ-benzopyranones,
we studied the diverse oriented synthesis (DOS) of flavones and
ꢀ-benzopyranones derivatives via a Lewis base-catalyzed 6-endo
cyclization [10]. Et2NH and KOtBu were reported to efficient
catalyze the acylated o-alkynoylphenols derivatives. The initial
examination of cyclization step started by the treatment of o-
alkynoylphenyl acetate 3aa with 0.5 mol K2CO3 in dry acetonitrile
at 25 ◦C, we didn’t detect flavone product. (Table S2) Meanwhile,
the tetra-amines such as Et3N and 1,4-dimethyl Piperazine failed
Acknowledgements
This work was supported by the 111 Project (B14041), the grant
from National Natural Science Foundation of China (21271124,
21272186, 21371112), the Fundamental Funds Research for the
Central Universities (GK201501005, GK201302015, GK201503029)
the Project Supported by Natural Science Basic Research Plan in
Shaanxi Province of China (Program No. 2015JQ2056) and Shaanxi
Innovative Team of Key Science and Technology (2013KCT-17, the
Program for Changjiang Scholars and Innovative Research Team in
University (IRT 14R33).

28
D. Yang et al. / Journal of Molecular Catalysis A: Chemical 426 (2017) 24–29
Table 2
Piperazine-Catalyzed 6-endo Cyclization for ꢀ-Benzopyranones.
aReaction conditions: acylated o-alkynoylphenols (0.5 mmol), Piperazine (50 mmol%), and CH3CN (3 mL) without water.
bThe reaction was conducted under atmospheric conditions at 25 ◦C.
cIsolated yield.
Appendix A. Supplementary data
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