Preparation of 3-acyl-4-arylcoumarins via metal-free tandem oxidative acylation/cyclization between alkynoates with aldehydes

Article abstract of DOI:10.1021/jo502220b

A new and efficient metal-free tandem acylation/cyclization of alkynoates with aldehydes was developed for the synthesis of 3-acyl-4-arylcoumarins. The reaction was achieved by the addition of acyl radical to alkynes and a C-H bond functionalization to form two new C-C bonds simultaneously.

Full text of DOI:10.1021/jo502220b

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Article
Preparation of 3-Acyl-4-aryl-coumarins via Metal-free Tandem
Oxidative Acylation/Cyclization between Alkynoates with Aldehydes
Xia Mi, Chenyang Wang, Mengmeng Huang, Yusheng Wu, and Yangjie Wu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo502220b • Publication Date (Web): 03 Dec 2014
Downloaded from http://pubs.acs.org on December 9, 2014
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Preparation of 3-Acyl-4-aryl-coumarins via Metal-free Tandem Oxidative
Acylation/Cyclization between Alkynoates with Aldehydes
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Xia Mi,† Chenyang Wang,† Mengmeng Huang,*,† Yusheng Wu,*,ǂ and Yangjie Wu*,†
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†College of Chemistry and Molecular Engineering, Henan Key Laboratory of
Chemical Biology and Organic Chemistry, Key Laboratory of Applied Chemistry of
Henan Universities, Zhengzhou University, Zhengzhou 450052, P. R. China,
wyj@zzu.edu.cn, hmm@zzu.edu.cn
ǂTetranov Biopharm, LLC. 75 Daxue Road, Zhengzhou 450052, P.R. China,
yusheng.wu@tetranovglobal.com
ABSTRACT
A new and efficient metal-free tandem acylation/cyclization of alkynoates
with aldehydes was developed for the synthesis of 3-acyl-4-aryl-coumarins.
The reaction was achieved by the addition of acyl radical to alkynes and a
C-H bond functionalization to form two new C-C bonds simultaneously.
INTRODUCTION
Coumarins, an important class of heterocycles, are commonly found in natural
compounds1, pharmaceuticals2, dyes3, and as versatile synthetic blocks4 in
organic synthesis. Among these compounds, 3-acyl derivatives
(coumarin-chalcone hybrid compounds) have received considerable attention
since they display important biological activities5 such as antioxidant activity,
monoamine oxidase (MAO) inhibitor, antimalarial, antitumor, and
antiinflammatory. Because of these important applications, various methods for
their synthesis have been reported (Fig. 1, eqn (1), (2), (3), (4)).6, 7, 8, 9 However,
these protocols can suffer from several drawbacks, such as inaccessible
substrates and catalysts, tedious performances, hazardous reagents, low atom
economy, and limited substrate scope. Therefore, the development of general,
highly efficient and direct strategies to access 3-acylcoumarins is still desirable
in synthetic chemistry.
Recently, oxidative coupling involving a C-H functionalization process has
begun to emerge as an alternative route for C-C bond formation.10 The current
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protocol enables the direct construction of target molecules by avoiding the
prefunctionalization of the coupling partners, and serves as an elegant example
of an atom economy approach. A lot of efforts have been devoted to the
oxidative coupling with an aldehyde C(sp2)-H bond to introduce a carbonyl
group, and significant improvements have been made in recent years. Many
groups successfully developed the transition-metal-catalyzed direct arylation of
aldehydes.11 The direct oxidative coupling of aldehyde C(sp2)-H bonds with
alkenes has been employed to furnish saturated ketones12, β-peroxy ketones13 or
unsaturated ketones14. In addition, alkynes have been widely used in oxidative
transformations catalyzed by the transition-metal complexes (especially RhI
catalysts) to obtain the α-alkenyl ketones via hydroacylation.15Recently,
transition-metal-free cross-coupling has been employed as an environmentally
friendly and alternative approach to the metal catalyzed/mediated
transformations.16 In this context, Liang and Li respectively demonstrated the
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tandem oxidative coupling of alkynes with aldehydes via
a
single-electron-transfer (SET) process to produce fluorine and
3-acylspiro[4,5]trienone derivatives.17 Inspired by these works and based on
our previous study,18 herein, we describe a metal-free TBAB-mediated
oxidative tandem coupling of alkynoates with aldehydes for selective synthesis
of biologically attractive 3-acylcoumarins (Fig. 1, eqn (5)). This method was
achieved by sequential acylation and carbocyclization to form two new C-C
bonds simultaneously, providing a new, efficient and atom-economic route to
3-acyl-4-aryl-coumarins.
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Figure1 Synthesis of 3-acylcoumarins
RESULTS AND DISCUSSION
At the outset of our investigation, the reaction conditions were optimized by
using phenyl 3-phenylpropiolate (1a) and diethyl p-tolualdehyde (2a).
According to the protocol by Liang et al. on fluorine derivatives formation from
TBHP/PivOH system,17a the desired product 3a was only obtained in 37% yield
(Table 1, entry 1). Fortunately, the first breakthrough was achieved when we
replaced PivOH with TBAB as an additive (Table 1, entry 2). Next, various
oxidants were examined in the presence of TBAB, and K2S2O8 was found to be
the most efficient oxidant for this reaction (Table 1, entries 3-5). Other
quaternary ammonium salts (Bu4NF, Bu4NCl, and Et4NBr) led to a slight
decrease in product yield of 3a (Table 1, entries 6-8). Notably, n-Bu4NI as an
efficient catalyst19 in radical chemistry showed negligible activity (Table 1,
entry 9), and no product 3a was formed without TBAB (Table 1, entry 10).
Various solvents were also surveyed, revealing that DCE is the best suited
solvent as compared to other solvents such as CH3CN, dioxane, toluene,
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chlorobenzene and H2O (Table 1, entries 11-15). The yield was increased to
73% by using 4 equiv of 2a (Table 1, entry 16). Lowering the reaction
o
o
temperature to 90 C was feasible, however, reducing further to 80 C led to a
lower yield (Table 1, entries 17, 18). The yields were markedly decreased when
the amount of TBAB was reduced to 0.5 equiv (Table 1, entry 19). In addition,
the structure of 3a was confirmed by X-ray analysis (see supporting
information).20
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Table 1. Optimization of Conditionsa
entry
1c
additive
PivOH
TBAB
TBAB
TBAB
TBAB
TBAC
TBAF
TEAB
TBAI
-
oxidant
TBHP
yieldb (%)
37
2c
TBHP
51
3
K2S2O8
Na2S2O8
(NH4)2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
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4
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5
55
6
57
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34
8
52
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trace
nr
10
11d
12e
13f
14g
TBAB
TBAB
TBAB
TBAB
nr
nr
17
25
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15h
16i
TBAB
TBAB
TBAB
TBAB
TBAB
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
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75
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17i, j
18i, k
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a Reaction conditions: 1a (0.25 mmol), 2a (0.5 mmol), additive (0.25 mmol), oxidant
o
(0.5 mmol), 1,2-dichloroethane (DCE, 1.5 mL) in a sealed tube under N2 at 100 C
(oil bath) for 24 h, PivOH: pivalic acid; TBAF: n-Bu4NF; TBAC: n-Bu4NCl; TBAB:
b
n-Bu4NBr; TBAI: n-Bu4NI; TEAB: Et4NBr. Isolated yields. 70 % aq. CH3CN as
solvent. Dioxane as solvent. f Toluene as solvent. Chlorobenzene as solvent. h H2O
as solvent. i 4 equiv of 2a (2.0 mmol). j 90 oC (oil bath). k 80 oC (oil bath). l 0.5 equiv
TBAB.
c
d
e
g
Under the optimal conditions, various aldehydes were firstly evaluated with phenyl
3-phenylpropiolate (1a). As demonstrated in Scheme 1, the metal-free
acylation/cyclization reaction could proceed well to give corresponding products in
moderate to good yields. The substrates bearing electron-donating groups at the
para-position of the aromatic rings work more efficiently than those bearing
electron-withdrawing groups (3a-3g) except product 3d. Although meta-substituted
benzaldehydes were also suitable for this transformation, generally, a slight decrease
in product yields was found (3h-3k). Due to the steric effect, ortho-substituted
benzaldehydes gave target products only in moderate yields (3l-3n). Alkyl and cyclic
aldehydes could also be used as the coupling partners to provide the corresponding
products in moderate yields (3o-3q).
Encouraged by above results, we next focused our attention on the scope of aryl
alkynoates (Scheme 2). Generally, the reactions with either electron-rich or
electron-poor groups at the 4-positions of phenoxy ring proceeded well, and the
corresponding products were furnished in good yields except 4c (4a-4g). With a
strong electron-withdrawing group (CF3) on the phenoxy ring, the product 4g was
only obtained in 38% yield. It was found that the steric effect on the phenoxy ring was
distinct. A moderate yield (57%) was obtained with the reaction of 3,5-dimethyl
substituted aryl phenylpropiolate (4i). Furthermore, no product was formed for
ortho-substituted system (4j). Upon using substrates with methyl group at the
meta-position of the phenoxy ring, a mixture of two regioisomers 4k and 4k’ were
formed in a ratio of 1.6:1, however, aryl alkynoates bearing meta-methoxyl
substituted phenoxy ring gave the product 4l in 76% yield with complete regiocontrol.
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In addition, different substituted aryl groups linked with the alkynyl could also be
used to construct the 3-acyl-4-arylcoumarin derivatives in moderate to good yields
(4m-p). Disappointingly, no desired product was observed when phenyl 2-octynoate
was employed in the reaction.
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Scheme 1. Cyclization of Phenyl Alkynoate 1a with Various Aldehydes 2a,b
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Ph
TBAB (1 equiv)
K2S2O8 (2 equiv)
Ph
O
O
R
RCHO
+
DCE
90 °C, 24h
O
O
O
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Ph
O
O
Ph
O
Ph
O
O
R1
Me
Me
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O
O
O
R1
3k (55%)
3h, R1 = Me (75%)
3i, R1 = OMe (72%)
3j, R1 = Cl (49%)
3a, R1 = Me (75%)
3b, R1 = H (77%)
3c, R1 = OMe (86%)
3d, R1 = F (85%)
3e, R1 = Cl (70%)
3f, R1 = Br (69%)
3g, R1 = CF3 (38%)
R1
Ph
O
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O
Cl
Ph
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O
O
Cl
3n (52%)
3l, R1 = Me (67%)
3m, R1 = OH (55%)
Ph
O
O
Ph
O
O
O
Ph
O
nPr
O
O
O
3q (37%)
3o (57%)
3p (61%)
a
Reaction conditions: 1a (0.25 mmol), 2 (1.0 mmol), TBAB (0.25 mmol),
K2S2O8 (0.5 mmol), DCE (1.5 mL) in a sealed tube under N2 at 90 oC (oil bath)
for 24 h. b Isolated yields.
Scheme 2. Cyclization of Various Alkynoates
b
1 with 4-Methoxybenzaldehyde
2ca
,
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a Reaction conditions:
1 (0.25 mmol), 2c (4-methoxybenzaldehyde, 1.0 mmol),
TBAB (0.25 mmol), K2S2O8 (0.5 mmol), DCE (1.5 mL) in a sealed tube under
N2 at 90 oC (oil bath) for 24 h. b Isolated yields.
Scheme 3. Control Experiments.
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To obtain a detailed mechanism for this transformation, some control
experiments were performed. The intramolecular and intermolecular kinetic
isotope effects (kH/kD = 0.9 and 1.3) were measured by using the deuterium
labeled substrates [D1]-1a and [D5]-1a in competing experiments (Scheme 3).
The observed low kH/kD values imply that the C-H bond cleavage is not the
rate-limiting step in this process. Subsequently, a radical scavenger TEMPO or
BHT (2,2,6,6-tetramethylpiperidinooxy or 2,6-di-tert-butyl-4-methylphenol)
was added to the reaction mixture. The formation of 3a was suppressed, and an
adduct of p-tolualdehyde (2a) with TEMPO or BHT was detected from ESI-MS
analysis (see supporting information). Thus, we inferred that the
acylation/cyclization reaction may involve a radical mechanism.
Scheme 4. Possible Mechanism
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Based on the results above and previous reports13, 17, a plausible reaction
mechanism via free-radical-type process is depicted in Scheme 4. Initially, the
peroxydisulfate
was
reacted
with
TBAB
to
generate
the
bis(tetrabutylammonium) peroxydisulfate which could be readily converted
into the tetrabutylammonium sulfate radical anions at high temperature.11k, 21
The tetrabutylammonium sulfate radical reacted with 2a to form an acyl radical
A
. Selective addition of the radical
alkynoate 1a generated the vinyl radical
the arene to form the radical intermediate
transfer from intermediate to another sulfate radical could give cation
A
to the α-position of the C=O bond in
. The intermediate then cyclized to
. Subsequently, a single electron
B
B
C
C
D
which was deprotonated by formed sulfate dianion to give the product 3a and
another bisulfate anion.
In summary, we have demonstrated a novel approach to the synthesis of
biologically attractive 3-acyl-4-aryl-coumarins starting with readily prepared
alkynoates and the commercially available aldehydes. Various
3-acyl-4-aryl-coumarins were selectively prepared in moderate to high yields.
This method comprises an acylation with concomitant arene formation,
providing a new, efficient and atom-economic route to the coumarin core
structure. We anticipate further development of the presented method and its
application towards systhesis of bioactive compounds.
EXPERIMENTAL SECTION
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General Information. All reactions were performed under a N2 atmosphere.
Solvents were dried and degassed by standard methods before use. All alkynoates
were synthesized according to reported procedures.22 Purification of the reaction
products was carried out by column chromatography using silica gel. Analytical TLC
was performed on a silica gel GF 254 Plate. NMR spectra were recorded on a
400MHz NMR spectrometer (400MHz for 1H and 100MHz for 13C) using CDCl3 and
DMSO-d6 as solution. Chemical shifts δ are reported in ppm relative to Me4Si or
residual CHCl3. The multiplicity of signals is designated by the following
abbreviations: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet). High
resolution mass spectra (HRMS) were obtained on an MSD-Trap spectrometer with
micromass MS software using electrospray ionisation (ESI). X-ray analysis were
obtained with a X-ray single crystal diffractometer. Melting points were measured on
microscopic apparatus and are uncorrected.
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General Procedure for Carbon-cyclization of Alkynoates and Aldehydes.
Compound 1 (0.25 mmol), TBAB (0.25 mmol), K2S2O8 (0.5 mmol) were added to a
25mL dried Schlenk tube with a magnetic bar and degassed with N2 three times.
Degassed 1,2-dichloroethane (1.5 mL) was added followed by the addition of
aldehyde 2 (1.0 mmol). The tube was sealed and was stirred at 90 oC for the indicated
time. The reaction mixture was diluted with EtOAc and filtered. The filtrate was
concentrated under reduced pressure and then was purified by chromatography on
silica gel (elute: EtOAc/ Petroleum ether (bp 60-90 °C) 1/1 - 1/10, v/v) to give the
desired product.
3-(4-Methylbenzoyl)-4-phenyl-2H-chromen-2-one (3a): 63.8 mg, 75%; yellow solid;
mp 146-147 °C. 1H NMR (400 MHz, CDCl3): δ 7.72 (d, J = 8.1 Hz, 2H), 7.65-7.60
(m, 1H), 7.48 (d, J = 8.2 Hz, 1H), 7.37-7.35 (m, 3H), 7.32-7.26 (m, 4H), 7.18 (d, J =
8.0 Hz, 2H), 2.38 (s, 3H). 13C NMR (100 MHz, CDCl3+DMSO-d6): δ 191.0, 158.2,
152.9, 152.1, 144.4, 133.1, 132.1, 131.7, 128.9, 128.8, 128.7, 128.0, 127.9, 127.3,
+
125.3, 124.2, 118.8, 116.4, 21.2. HRMS (ESI): calcd for C23H17O3 [M+H]+ m/z
341.1172, found 341.1173.
3-Benzoyl-4-phenyl-2H-chromen-2-one (3b): 62.8 mg, 77%; yellow solid; mp
146-147 °C. 1H NMR (400 MHz, CDCl3): δ 7.79 (d, J = 7.3 Hz, 2H), 7.63-7.58 (m,
1H), 7.51-7.44 (m, 2H), 7.37-7.29 (m, 5H), 7.28-7.22 (m, 4H), 7.18 (d, J = 8.0 Hz,
2H), 2.38 (s, 3H). 13C NMR (100 MHz, CDCl3+ DMSO-d6): δ 192.1, 158.7, 153.7,
152.9, 136.1, 133.8, 132.6, 132.2, 129.4, 129.2, 128.6, 128.5, 128.5, 127.9, 125.9,
+
124.6, 119.4, 117.1. HRMS (ESI): calcd for C22H15O3 [M+H]+ m/z 327.1016, found
327.1018.
3-(4-Methoxybenzoyl)-4-phenyl-2H-chromen-2-one (3c): 81.3 mg, 86%; yellow
solid; mp 121-123 °C. 1H NMR (400 MHz, CDCl3): δ 7.77 (d, J = 8.8 Hz, 2H),
7.62-7.58 (m, 1H), 7.45 (d, J = 8.3 Hz, 1H), 7.34-7.32 (m, 3H), 7.29-7.22 (m, 4H),
6.83 (d, J = 8.8 Hz, 2H), 3.82 (s, 3H). 13C NMR (100 MHz, CDCl3+ -DMSO-d6): δ
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190.1, 163.8, 158.5, 153.2, 152.1, 132.2, 131.9, 131.3, 129.1, 128.9, 128.2, 128.1,
+
127.5, 125.7, 124.3, 119.0, 116.6, 113.5, 55.1. HRMS (ESI): calcd for C23H16O4
[M+Na]+ m/z 379.0941, found 379.0937.
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3-(4-Flurobenzoyl)-4-phenyl-2H-chromen-2-one (3d): 73.1 mg, 85%; yellow solid;
mp 179-181 °C. 1H NMR (400 MHz, CDCl3): δ 7.84-7.80 (m, 2H), 7.65-7.60 (m, 1H),
7.47 (d, J = 8.3 Hz, 3H), 7.36-7.34 (m, 3H), 7.31-7.24 (m, 4H), 7.03 (d, J = 8.3 Hz,
3H), 2.32 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 190.5, 166.1 (d, JC-F = 254.9 Hz),
158.7, 153.7, 153.1, 132.8, 132.7 (d, JC-F = 3.1 Hz), 132.2, 131.9 (d, JC-F = 9.6 Hz),
129.6, 128.6, 128.6, 127.9, 125.6, 124.7, 119.3, 117.2, 115.8 (d, JC-F = 22.0 Hz).
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HRMS (ESI): calcd for C22H14FO3 [M+H]+ m/z 345.0921, found 345.0922.
+
3-(4-Chlorobenzoyl)-4-phenyl-2H-chromen-2-one (3e): 63.0 mg, 70%; yellow solid;
mp 180-182 °C. 1H NMR (400 MHz, CDCl3): δ 7.73 (d, J = 8.6 Hz, 2H), 7.64-7.59
(m, 1H), 7.46 (d, J = 8.2 Hz, 1H), 7.36-7.31 (m, 5H), 7.29-7.23 (m, 4H). 13C NMR
(100 MHz, CDCl3): δ 190.9, 158.6, 153.7, 153.3, 140.3, 134.5, 132.9, 132.1, 130.5,
129.6, 128.9, 128.6, 128.6, 127.9, 125.4, 124.7, 119.3, 117.2. HRMS (ESI): calcd for
+
C22H14ClO3 [M+H]+ m/z 361.0626, found 361.0627.
3-(4-Bromobenzoyl)-4-phenyl-2H-chromen-2-one (3f): 69.7 mg, 69%; yellow solid;
mp 182-183 °C. 1H NMR (400 MHz, CDCl3): δ 7.66-7.60 (m, 3H), 7.51-7.45 (m, 3H),
7.36-7.34 (m, 3H), 7.32-7.23 (m, 4H). 13C NMR (100 MHz, CDCl3): δ 191.1, 158.7,
153.7, 153.4, 134.9, 132.9, 132.1, 131.9, 130.6, 129.7, 129.2, 128.7, 128.6, 128.0,
+
125.4, 124.7, 119.3, 117.2. HRMS (ESI): calcd for C22H14BrO3 [M+H]+ m/z
405.0121, found 405.0120.
4-Phenyl-3-(4-trifluromethylbenzoyl)-2H-chromen-2-one (3g): 37.4 mg, 38%;
yellow solid; mp 169-171 °C. 1H NMR (400 MHz, CDCl3): δ 7.89 (d, J = 8.0 Hz, 2H),
7.66-7.61 (m, 3H), 7.36-7.32 (m, 3H), 7.30-7.25 (m, 4H). 13C NMR (100 MHz,
CDCl3): δ 191.2, 158.6, 153.9, 153.8, 138.9, 134.8 (q, JC-F = 32.5 Hz), 133.1, 132.1,
129.7, 129.4, 128.7, 128.6, 128.1, 125.7 (q, JC-F = 3.7 Hz), 125.2, 124.8, 123.4 (q, JC-F
+
= 271.6 Hz), 119.3, 117.3. HRMS (ESI): calcd for C23H14F3O3 [M+H]+ m/z
395.0890, found 395.0893.
3-(3-Methylbenzoyl)-4-phenyl-2H-chromen-2-one (3h): 63.8 mg, 75%; yellow solid;
mp 99-100 °C. 1H NMR (400 MHz, CDCl3): δ 7.63-7.57 (m, 3H), 7.47 (d, J = 8.2 Hz,
1H), 7.34-7.33 (m, 3H), 7.30 (s, 1H), 7.28-7.22 (m, 5H), 2.32 (s, 3H). 13C NMR (100
MHz, CDCl3): δ 192.2, 158.7, 153.6, 152.7, 138.3, 136.1, 134.6, 132.6, 132.3, 129.5,
129.4, 128.6, 128.5, 128.4, 127.9, 126.6, 126.1, 124.6, 119.4, 117.1, 21.1. HRMS
+
(ESI): C23H17O3 [M+H]+ m/z 341.1172, found 341.1174.
3-(3-Methoxybenzoyl)-4-phenyl-2H-chromen-2-one (3i): 64.0 mg, 72%; yellow
1
solid; mp 100-101 °C. H NMR (400 MHz, CDCl3): δ 7.63-7.59 (m, 1H), 7.47-7.44
(m, 1H), 7.37-7.33 (m, 5H), 7.30-7.24 (m, 5H), 7.06-7.03 (m, 1H), 3.78 (s, 3H). 13C
NMR (100 MHz, CDCl3): δ 191.9, 159.7, 158.7, 153.6, 152.8, 137.4, 132.6, 132.2,
129.5, 129.4, 128.6, 128.5, 127.9, 125.9, 124.6, 122.4, 120.5, 119.3, 117.1, 112.7,
+
55.3. HRMS (ESI): calcd for C23H17O4 [M+H]+ m/z 357.1121, found 357.1122.
3-(3-Chlorobenzoyl)-4-phenyl-2H-chromen-2-one (3j): 44.1 mg, 49%; yellow solid;
mp 110-113 °C. 1H NMR (400 MHz, CDCl3): δ 7.74 (s, 1H), 7.67-7.61 (m, 2H),
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7.48-7.44 (m, 2H), 7.36-7.34 (m, 3H), 7.31 (d, J = 8.0 Hz, 2H), 7.26-7.24 (m, 2H).
13C NMR (100 MHz, CDCl3): δ 190.9, 158.6, 153.7, 153.5, 127.7, 134.8, 133.6, 132.9,
132.1, 129.9, 129.6, 128.9, 128.6, 128.6, 128.0, 127.3, 125.2, 124.7, 119.2, 117.2.
HRMS (ESI): calcd for C22H14ClO3 [M+H]+ m/z 361.0626, found 361.0628.
+
7
8
9
3-(3,4-Dimethylbenzoyl)-4-phenyl-2H-chromen-2-one (3k): 48.7 mg, 55%; yellow
solid; mp 180-182 °C. 1H NMR (400 MHz, CDCl3): δ 7.63-7.58 (m, 2H), 7.53 (d, J =
7.8 Hz, 1H), 7.46 (d, J = 8.3 Hz, 1H), 7.35-7.33 (m, 3H), 7.30-7.25 (m, 3H), 7.23 (d, J
= 7.8 Hz, 1H), 7.12 (d, J = 7.8 Hz, 1H), 2.26 (s, 3H), 2.23 (s, 3H). 13C NMR (100
MHz, CDCl3): δ 191.8, 158.8, 153.6, 152.5, 143.7, 136.9, 134.1, 132.5, 132.4, 130.1,
129.8, 129.3, 128.6, 128.5, 127.9, 127.2, 126.2, 124.5, 119.5, 117.1, 20.1, 19.6.
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HRMS (ESI): calcd for C24H19O3 [M+H]+ m/z 355.1329, found 355.1330.
+
3-(2-Methylbenzoyl)-4-phenyl-2H-chromen-2-one (3l): 57.0 mg, 67%; yellow solid;
mp 160-162 °C. 1H NMR (400 MHz, CDCl3): δ 7.62-7.55 (m, 2H), 7.45 (d, J = 8.3
Hz, 1H), 7.33-7.29 (m, 4H), 7.23-7.19 (m, 4H), 7.14 (d, J = 7.6 Hz, 1H), 7.10 (d, J =
7.3 Hz, 1H), 2.38 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 193.7, 158.8, 153.7, 152.2,
140.1, 135.9, 132.6, 132.4, 132.4, 131.9, 131.0, 129.3, 128.5, 128.4, 127.5, 125.5,
+
125.4, 124.6, 119.6, 117.1, 21.2. HRMS (ESI): calcd for C23H17O3 [M+H]+ m/z
341.1172, found 341.1172.
3-(2-Hydroxylbenzoyl)-4-phenyl-2H-chromen-2-one (3m): 47.0 mg, 55%; yellow
solid; mp 179-181 °C. 1H NMR (400 MHz, CDCl3): δ 11.51 (s, 1H), 7.65-7.61 (m,
1H), 7.51-7.45 (m, 2H), 7.42-7.24 (m, 8H), 6.89 (d, J = 8.4 Hz, 1H), 6.79 (d, J = 7.6
Hz, 1H). 13C NMR (100 MHz, CDCl3+DMSO-d6): δ 197.0, 162.1, 158.1, 153.1, 152.8,
136.9, 132.7, 131.7, 131.6, 129.4, 128.3, 128.1, 127.7, 124.5, 123.9, 119.3, 118.9.,
+
118.7, 117.8, 116.8. HRMS (ESI): calcd for C22H15O4 [M+H]+ m/z 343.0965, found
343.0972.
3-(2,4-Dichlorobenzoyl)-4-phenyl-2H-chromen-2-one (3n): 51.2 mg, 52%; yellow
solid; mp 119-121 °C. 1H NMR (400 MHz, CDCl3): δ 7.64-7.58 (m, 1H), 7.46-7.43
(m, 2H), 7.29 (d, J = 1.8 Hz, 1H), 7.24-7.22 (m, 4H), 7.15 (dd, J1 = 8.4 Hz, J2 = 1.9
Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 189.7, 158.3, 153.7, 138.8, 134.9, 133.5,
133.0, 132.4, 130.3, 129.5, 128.6, 128.3 (2C), 128.2, 127.3, 126.6, 124.6, 119.5, 117.1.
+
HRMS (ESI): calcd for C22H13Cl2O3 [M+H]+ m/z 395.0236, found 395.0235.
3-Butyryl-4-phenyl-2H-chromen-2-one (3o): 41.6 mg, 57%; yellow solid; mp
72-73 °C. 1H NMR (400 MHz, CDCl3): δ 7.59-7.55 (m, 1H), 7.50-7.49 (m, 3H), 7.40
(d, J = 8.0 Hz, 1H), 7.32-7.31 (m, 2H), 7.25-7.22 (m, 2H), 2.45 (t, J = 7.2 Hz, 2H),
1.52-1.42 (m, 2H), 0.70 (t, J = 7.3 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 201.7,
158.5, 153.4, 151.3, 132.5, 132.4, 129.6, 128.8, 128.7, 128.4, 127.9, 124.5, 119.4,
+
117.0, 45.5, 16.5, 13.3. HRMS (ESI): calcd for C19H17O3 [M+H]+ m/z 293.1172,
found 293.1178.
3-(3-Methylbutanoyl)-4-phenyl-2H-chromen-2-one (3p): 46.7 mg, 61%; yellow
solid; mp 107-109 °C. 1H NMR (400 MHz, CDCl3): δ 7.59-7.55 (m, 1H), 7.51-7.49
(m, 3H), 7.40 (d, J = 8.0 Hz, 1H), 7.33-7.31 (m, 2H), 7.21 (d, J = 4.2 Hz, 2H), 2.36 (d,
J = 6.8 Hz, 2H), 2.09-2.01 (m, 1H), 0.70 (d, J = 6.4 Hz, 6H). 13C NMR (100 MHz,
CDCl3): δ 201.1, 158.5, 153.3, 151.2, 132.5, 132.3, 129.6, 128.8, 128.7, 128.0, 127.9,
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124.5, 119.4, 116.9, 52.4, 23.4, 22.2. HRMS (ESI): calcd for C20H19O3+ [M+H]+ m/z
307.1329, found 307.1337.
6
7
8
9
3-(Cyclopropanecarbonyl)-4-phenyl-2H-chromen-2-one (3q): 26.8 mg, 37%;
yellow solid; mp 127-128 °C. 1H NMR (400 MHz, CDCl3): δ 7.60-7.56 (m, 1H),
7.50-7.48 (m, 3H), 7.29 (d, J = 8.0 Hz, 1H), 7.35-7.32 (m, 2H), 7.29-7.20 (m, 2H),
2.08-2.02 (m, 1H), 0.99-0.94 (m, 1H), 0.83-0.78 (m, 1H). 13C NMR (100 MHz,
CDCl3): δ 201.5, 158.4, 153.5, 151.9, 132.9, 132.6, 129.5, 128.8, 128.1 (2C), 124.5,
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119.4, 117.0, 23.1, 12.7. HRMS (ESI): calcd for C19H15O3 [M+H]+ m/z 291.1016,
+
found 291.1016.
3-(4-Methoxybenzoyl)-6-methyl-4-phenyl-2H-chromen-2-one (4a): 74.0 mg, 80%;
yellow solid; mp 80 °C. 1H NMR (400 MHz, CDCl3): δ 7.76 (d, J = 8.8 Hz, 2H),
7.33-7.31 (m, 3H), 7.26-7.24 (m, 3H), 7.15 (d, J = 8.0 Hz, 1H), 7.04 (d, J = 8.0 Hz,
1H), 6.81 (d, J = 8.8 Hz, 2H), 3.80 (s, 3H), 2.47 (s, 3H). 13C NMR (100 MHz,
CDCl3): δ 190.6, 163.9, 159.1, 153.7, 152.5, 143.9, 132.6, 131.6, 129.4, 129.3, 128.6,
128.4, 127.5, 125.7, 124.9, 117.2, 116.9, 113.8, 55.4, 21.6. HRMS (ESI): calcd for
+
C24H19O4 [M+H]+ m/z 371.1278, found 371.1284.
6-t-Butyl-3-(4-methoxybenzoyl)-4-phenyl-2H-chromen-2-one (4b): 79.3 mg, 77%;
yellow solid; mp 106-107 °C. 1H NMR (400 MHz, CDCl3): δ 7.77 (d, J = 8.8 Hz, 2H),
7.46 (s, 1H), 7.33-7.26 (m, 6H), 7.21 (d, J = 8.4 Hz, 1H), 6.81 (d, J = 8.8 Hz, 2H),
3.81 (s, 3H), 1.37 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 190.6, 163.9, 159.2, 157.2,
153.7, 152.4, 132.6, 131.6, 129.5, 129.3, 128.6, 128.4, 127.4, 125.2, 122.1, 116.9,
+
113.8, 113.8, 55.4, 35.2, 30.9. HRMS (ESI): calcd for C27H25O4 [M+H]+ m/z
413.1747, found 413.1751.
3-(4-Methoxybenzoyl)-6-methoxyl-4-phenyl-2H-chromen-2-one (4c): 39.6 mg, 41%;
yellow solid; mp 155-156 °C. 1H NMR (400 MHz, CDCl3): δ 7.77 (d, J = 8.8 Hz, 2H),
7.33-7.31 (m, 3H), 7.26-7.22 (m, 2H), 7.17 (d, J = 8.9 Hz, 1H), 6.93 (d, J = 2.4 Hz,
1H), 6.83-6.78 (m, 3H), 3.90 (s, 3H), 3.81 (s, 3H). 13C NMR (100 MHz, CDCl3): δ
190.8, 163.9, 163.3, 159.2, 155.5, 152.9, 132.8, 131.7, 129.7, 129.3, 128.9, 128.6,
128.4, 122.9, 113.8, 112.9, 112.8, 100.9, 55.9, 55.4. HRMS (ESI): calcd for
+
C24H19O5 [M+H]+ m/z 387.1227, found 387.1230.
3-(4-Methoxybenzoyl)-6-phenoxyl-4-phenyl-2H-chromen-2-one (4d): 88.4 mg, 79%;
yellow solid; mp 145-146 °C. 1H NMR (400 MHz, CDCl3): δ 7.77 (d, J = 8.8 Hz, 2H),
7.43 (t, J = 7.7 Hz, 2H), 7.34-7.32 (m, 3H), 7.26-7.25 (m, 3H), 7.21 (d, J = 8.9 Hz,
1H), 7.11 (d, J = 8.0 Hz, 2H), 6.95 (d, J = 2.3 Hz, 1H), 6.87 (dd, J1 = 8.8 Hz, J2 = 2.3
Hz, 1H), 6.83 (d, J = 8.8 Hz, 2H), 3.82 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 190.6,
164.1, 161.9, 158.9, 155.2, 154.9, 152.6, 132.7, 131.7, 130.2, 129.6, 129.4, 129.3,
128.6, 128.5, 128.3, 125.3, 123.9, 120.4, 119.2, 114.5, 114.4, 113.8, 105.1, 55.5.
+
HRMS (ESI): calcd for C29H21O5 [M+H]+ m/z 449.1384, found 449.1386.
6-Fluoro-3-(4-methoxybenzoyl)-4-phenyl-2H-chromen-2-one (4e): 73.8 mg, 79%;
yellow solid; mp 143-144 °C. 1H NMR (400 MHz, CDCl3): δ 7.76 (d, J = 8.8 Hz, 2H),
7.35-7.33 (m, 3H), 7.29-7.26 (m, 3H), 7.17 (dd, J1 = 8.8 Hz, J2 = 2.3 Hz, 1H), 6.87
(td, J1 = 8.4 Hz, J2 = 2.2 Hz, 1H), 6.83 (d, J = 8.8 Hz, 2H), 3.82 (s, 3H). 13C NMR
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(100 MHz, CDCl3): δ 190.1, 164.8 (d, J = 254.1 Hz), 164.2, 158.5, 154.8 (d, J = 15.8
Hz), 152.1, 132.3, 131.7, 129.7 (d, J = 10.2 Hz), 129.6, 129.3, 128.6, 128.5, 125.1 (d,
J = 2.9 Hz), 116.3 (d, J = 2.8 Hz), 113.9, 112.7 (d, J = 22.3 Hz), 104.6 (d, J = 25.5
Hz), 55.4. HRMS (ESI): calcd for C23H16FO4 [M+H]+ m/z 375.1027, found
+
7
8
9
375.1027.
6-Chloro-3-(4-methoxybenzoyl)-4-phenyl-2H-chromen-2-one (4f): 68.3 mg, 70%;
yellow solid; mp 171 °C. 1H NMR (400 MHz, CDCl3): δ 7.75 (d, J = 8.7 Hz, 2H),
7.45 (s, 3H), 7.34-7.29 (m, 3H), 7.25-7.20 (m, 4H), 6.82 (d, J = 8.8 Hz, 2H), 3.80 (s,
3H). 13C NMR (100 MHz, CDCl3): δ 190.0, 164.2, 158.2, 153.8, 151.8, 138.5, 132.0,
131.7, 129.6, 129.1, 128.8, 128.6, 128.5, 126.0, 125.1, 118.1, 117.3, 113.9, 55.4.
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HRMS (ESI): calcd for C23H16ClO4 [M+H]+ m/z 391.0732, found 391.0734.
+
6-Bromo-3-(4-methoxybenzoyl)-4-phenyl-2H-chromen-2-one (4g): 80.3 mg, 74%;
yellow solid; mp 147-148 °C. 1H NMR (400 MHz, CDCl3): δ 7.75 (d, J = 8.8 Hz, 2H),
7.62 (d, J = 1.4 Hz, 1H), 7.37-7.33 (m, 4H), 7.25 (t, J = 4.1 Hz, 2H), 7.13 (d, J = 8.6
Hz, 1H), 6.83 (d, J = 8.8 Hz, 2H), 3.82 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 190.0,
164.2, 158.2, 153.7, 151.9, 131.9, 131.7, 129.6, 129.1, 128.8, 128.6, 128.5, 127.9,
126.6, 126.2, 120.3, 118.5, 113.9, 55.4. HRMS (ESI): calcd for C23H16BrO4+ [M+H]+
m/z 435.0226, found 435.0231.
3-(4-Methoxybenzoyl)-4-phenyl-6-trifluoromethyl-2H-chromen-2-one (4h): 57.2
mg, 54%; yellow solid; mp 141-142 °C. 1H NMR (400 MHz, CDCl3): δ 7.75 (d, J =
8.8 Hz, 2H), 7.70 (s, 3H), 7.47 (d, J = 8.4 Hz, 1H), 7.42 (d, J = 8.2 Hz, 1H), 7.37-7.35
(m, 3H), 7.27-7.26 (m, 2H), 6.83 (d, J = 8.8 Hz, 2H), 3.82 (s, 3H). 13C NMR (100
MHz, CDCl3): δ 189.6, 164.3, 157.9, 153.2, 151.1, 133.9 (d, JC-F = 33.4 Hz), 132.3,
131.7, 130.2, 129.8, 128.7, 128.7, 128.6, 122.2, 123.0 (d, JC-F = 271.3 Hz), 121.0 (d,
JC-F = 3.5 Hz), 114.5 (d, JC-F = 4.0 Hz), 114.0, 113.7, 55.5. HRMS (ESI): calcd for
+
C24H16F3O4 [M+H]+ m/z 425.0995, found 425.0997.
5,7-Dimethyl-3-(4-methoxybenzoyl)-4-phenyl-2H-chromen-2-one (4i): 54.7 mg,
57%; yellow solid; mp 188-189 °C. 1H NMR (400 MHz, CDCl3): δ 7.76 (d, J = 8.8
Hz, 2H), 7.33-7.31 (m, 3H), 7.27-7.24 (m, 3H), 6.85 (s, 1H), 6.81 (d, J = 8.9 Hz, 1H),
3.80 (s, 3H), 2.49 (s, 3H), 2.67 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 190.8, 163.9,
159.1, 152.7, 150.1, 134.9, 133.6, 132.7, 131.7, 129.4, 129.1, 128.6, 128.3, 126.2,
+
125.8, 125.2, 118.9, 113.7, 55.4, 20.8, 15.5. HRMS (ESI): calcd for C25H21O4
[M+H]+ m/z 385.1434, found 385.1436.
3-(4-Methoxybenzoyl)-7-methyl-4-phenyl-2H-chromen-2-one
(4k)
and
3-(4-Methoxybenzoyl)-5-methyl-4-phenyl-2H-chromen-2-one (4k’): 78.6 mg, 85%;
yellow solid. 1H NMR (400 MHz, CDCl3): δ 7.77 (d, J = 8.8 Hz, 2H), 7.76 (d, J = 8.8
Hz, 2H), 7.45-7.38 (m, 2H), 7.35-7.30 (m, 7H), 7.30-7.26 (m, 4H), 7.15-7.08 (m, 2H),
7.03 (s, 1H), 6.82 (d, J = 8.8 Hz, 4H), 3.80 (s, 3H), 2.53 (s, 3H), 2.31 (s, 3H). 13C
NMR (100 MHz, CDCl3): δ 190.6, 190.6, 164.1, 159.0, 158.9, 152.8, 152.4. 151.9,
151.8, 134.4, 133.8, 133.5, 132.8, 132.6, 131.7, 131.7, 129.4, 129.3, 129.2, 128.6,
128.5, 128.4, 127.5, 126.6, 126.1, 125.6, 123.9, 119.2, 119.2, 116.9, 113.8, 113.8,
+
55.4, 20.9, 15.7. HRMS (ESI): calcd for C24H19O4 [M+H]+ m/z 371.1278, found
371.1281.
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3-(4-Methoxybenzoyl)-7-methoxyl-4-phenyl-2H-chromen-2-one (4l): 73.3 mg, 76%;
1
yellow solid; mp 158 °C. H NMR (400 MHz, CDCl3): δ 7.75 (d, J = 8.8 Hz, 2H),
7.36 (d, J = 8.8 Hz, 1H), 7.32-7.26 (m, 4H), 7.16 (dd, J1 = 8.8 Hz, J2 = 2.9 Hz, 1H),
6.80 (d, J = 8.8 Hz, 2H), 6.68 (d, J = 2.9 Hz, 1H), 3.78 (s, 3H), 3.68 (s, 3H). 13C NMR
(100 MHz, CDCl3): δ 190.5, 164.0, 158.9, 156.1, 152.1, 147.9, 132.4, 131.6, 129.4,
129.3, 128.5, 126.4, 119.9, 119.6, 117.9, 113.8, 110.6, 55.7, 55.4. HRMS (ESI): calcd
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for C24H19O5 [M+H]+ m/z 387.1227, found 387.1230.
+
3-(4-Methoxybenzoyl)-4-(4-methoxyphenyl)-2H-chromen-2-one (4m): 57.8 mg,
1
60%, yellow solid; mp 150-151 °C. H NMR (400 MHz, CDCl3): δ 7.77 (d, J = 8.7
Hz, 2H), 7.60-7.56 (m, 1H), 7.43 (d, J = 8.2 Hz, 1H), 7.35 (d, J = 7.8 Hz, 1H),
7.24-7.20 (m, 3H), 6.85-6.80 (m, 4H), 3.80 (s, 3H), 3.76 (s, 3H). 13C NMR (100 MHz,
CDCl3): δ 190.7, 164.0, 160.3, 158.9, 153.6, 152.2, 132.4, 131.7, 130.2, 129.3, 127.9,
125.9, 124.5 (2H), 119.6, 117.1, 114.0, 113.8, 55.4, 55.2. HRMS (ESI): calculated for
+
C24H19O5 [M+H]+ m/z 387.1227, found 387.1228.
3-(4-Methoxybenzoyl)-4-(4-methylphenyl)-2H-chromen-2-one (4n): 64.7 mg, 70%,
1
yellow solid; mp 132-133 °C. H NMR (400 MHz, CDCl3): δ 7.79 (d, J = 8.8 Hz,
2H), 7.61-7.57 (m, 1H), 7.44 (d, J = 8.3 Hz, 1H), 7.34-7.31 (m, 1H), 7.27-7.22 (m,
1H), 7.18-7.12 (m, 4H), 6.84 (d, J = 8.9 Hz, 2H), 3.82 (s, 3H), 2.31 (s, 3H). 13C NMR
(100 MHz, CDCl3): δ 190.7, 164.2, 159.0, 153.7, 152.8, 139.6, 132.5, 131.8, 129.5,
129.5, 129.3, 128.7, 128.0, 126.1, 124.6, 119.7, 117.2, 113.9, 55.5, 21.4. HRMS
+
(ESI): calculated for C24H19O4 [M+H]+ m/z 371.1278, found 371.1279.
4-(4-Acetylphenyl)-3-(4-methoxybenzoyl)-2H-chromen-2-one (4o): 52.7 mg, 53%,
1
yellow solid; mp 157 °C. H NMR (400 MHz, CDCl3): δ 7.94 (d, J = 8.0 Hz, 2H),
7.78 (d, J = 8.6 Hz, 2H), 7.65-7.60 (m, 1H), 7.47 (d, J = 8.3 Hz, 1H), 7.41-7.39 (m,
2H), 7.25 (d, J = 7.4 Hz, 1H), 7.18 (d, J = 7.7 Hz, 2H), 6.85 (d, J = 8.6 Hz, 2H), 3.83
(s, 3H), 2.58 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 197.2, 190.0, 164.4, 158.6,
153.7, 151.4, 137.6, 137.2, 132.8, 131.8, 129.2, 129.1, 128.5, 127.6, 126.6, 124.8,
+
119.1, 117.3, 114.1, 55.5, 26.6. HRMS (ESI): calculated for C25H19O5 [M+H]+ m/z
399.1227, found 399.1227.
3-(4-Methoxybenzoyl)-4-(2-methylphenyl)-2H-chromen-2-one (4p): 74.0 mg, 80%,
yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.77 (d, J = 8.8 Hz, 2H), 7.60-7.56 (m, 1H),
7.45 (d, J = 8.0 Hz, 1H), 7.24-7.18 (m, 3H), 7.11-6.98 (m, 3H), 6.84 (d, J = 8.8 Hz,
2H), 3.81 (s, 3H), 2.14 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 190.0, 164.1, 159.0,
153.4, 153.2, 135.8, 132.5, 131.9, 131.5, 130.2, 129.3, 129.3, 128.2, 127.4, 126.5,
+
125.7, 124.7, 119.3, 117.0, 113.8, 55.4, 19.9. HRMS (ESI): calculated for C24H19O4
[M+H]+ m/z 371.1278, found 371.1279.
Intramolecular Kinetic Isotope Effect (KIE) Study (Scheme 3). To a 25 mL
dried Schlenk tube were added alkynoate [D1]-1a (0.25 mmol), TBAB (0.25 mmol),
K2S2O8 (0.5 mmol), benzaldehyde 2b (1.0 mmol), and DCE (1.5 mL) under a N2
o
atmosphere. After sealing the tube, the reaction mixture was stirred at 90 C for 6
hours after which time the reaction mixture was concentrated under reduced pressure.
The residue was purified by chromatography on silica gel to give the desired product
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in 46% yield. The ratio of deuterium to hydrogen was determined from the H NMR
relative integration values of Ha (7.26 ppm) based on Hb (7.61 ppm). (see Figure S1)
Intermolecular Kinetic Isotope Effect (KIE) Study (Scheme 3). To a 25mL
dried Schlenk tube were added alkynoate 1a (0.125 mmol), [D1]-1a (0.125 mmol),
TBAB (0.25 mmol), K2S2O8 (0.5 mmol), benzaldehyde 2b (1.0 mmol), and DCE (1.5
mL) under a N2 atmosphere. After sealing the tube, the reaction mixture was stirred at
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o
90 C for 6 hours after which time the reaction mixture was concentrated under
reduced pressure. The residue was purified by chromatography on silica gel to give
the desired product in 46% yield. The ratio of deuterium to hydrogen was determined
1
from the H NMR relative integration values of Hb (7.61 ppm) based on Ha’ (7.79
ppm). (see Figure S2)
Radical-trapping Experiments (Scheme 3). Two equivalents of radical
scavenger (2,2,6,6-tetramethylpiperidinooxy or 2,6-di-tert-butyl-4-methylphenol) was
added to the reaction of 1a with 2a in the standard conditions. After two hours, the
reaction mixture was cooled to room temperature. The crude reaction mixture was
detected by ESI-MS, and no peak of the desired product was found. An adduct of
aldehyde with radical scavenger was detected shown in Figure S3 and S4.
ASSOCIATED CONTENT
Supporting Information
13
1H and C NMR spectra of compounds 3 and 4 and crystal structure and data of 3a.
This material is available free of charge via the Internet at http://pubs.acs.org.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGEMENTS
This work was supported by the National Natural Science Foundation (NSF) of China
(no. 21172200 and 21302172).
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