Regioselective Coupling Reactions of Coumarins with Aldehydes or Di-tert-butyl Peroxide (DTBP) through a C(sp2)-H Functionalization Process

Article abstract of DOI:10.1002/ejoc.201501251

Coumarin derivatives are highly valuable compounds in drug discovery. Herein, we have developed two new coupling reactions that involve coumarins and either aldehydes or di-tert-butyl peroxide (DTBP) in the presence of inexpensive copper or iron catalysts. Both of these reactions proceed through a C(sp²)-H functionalization process to regioselectivity generate keto- or methyl-substituted coumarin derivatives in moderate to good yields These coupling reactions will enrich current coumarin chemistry.

Full text of DOI:10.1002/ejoc.201501251

DOI: 10.1002/ejoc.201501251
Full Paper
C–H Functionalization
Regioselective Coupling Reactions of Coumarins with Aldehydes
2
or Di-tert-butyl Peroxide (DTBP) through a C(sp )–H
Functionalization Process
Wannian Zhao,[
a][‡]
Lei Xu, Yingcai Ding,
[a]
[a][‡]
Ben Niu, Ping Xie, Zhaogang Bian,
[a]
[b]
[a]
[
a]
[a]
Denghong Zhang, and Aihua Zhou*
2
Abstract: Coumarin derivatives are highly valuable compounds through a C(sp )–H functionalization process to regioselectivity
in drug discovery. Herein, we have developed two new cou- generate keto- or methyl-substituted coumarin derivatives in
pling reactions that involve coumarins and either aldehydes or moderate to good yields These coupling reactions will enrich
di-tert-butyl peroxide (DTBP) in the presence of inexpensive current coumarin chemistry.
copper or iron catalysts. Both of these reactions proceed
Introduction
Coumarin derivatives are widely found in nature[1] and are a
significant class of natural products because of their remarkable
forward and highly efficient,[13] they provide a better and more
practical method for researchers to functionalize coumarin scaf-
folds.
Herein, aldehydes and di-tert-butyl peroxide (DTBP) were se-
lected as coupling partners with coumarins to generate keto-
and methyl-substituted coumarin derivatives through a radical
mechanism. This new method is different from previously re-
ported approaches, which generate keto- and methyl-substi-
tuted coumarin derivatives mainly from 2-hydroxybenzalde-
[
2]
[3]
range of biological activities, which include anticancer, anti-
oxidant, monoamine oxidase (MAO) inhibition,[5] HIV protease
[
4]
[
6]
inhibition, acetylcholinesterase (AChE) inhibition, and anti-
[
7]
hepatitis C virus (HCV) properties. They also have therapeutic
[
8]
effects on cardiovascular system diseases. Despite the fact
that coumarins have been extensively investigated, explorations
of new coumarin derivative bioactivities are still attractive to
researchers in the drug discovery community. This research is
somewhat restricted, however, by the availability of and effect-
ive modification methods for coumarin derivatives. Therefore,
new powerful modification methods that can directly install
functionality into coumarin skeletal structures are welcome.
Until now, many methods to synthesize coumarin derivatives
have been reported,
[14]
hydes (Scheme 1). Although the generation of coumarin de-
rivatives by using radical sequences can be found in the litera-
[12]
ture,
the coupling reactions of coumarins with aldehydes or
2
DTBP by using a C(sp )–H functionalization process has not
been reported.
[
9]
Results and Discussion
[
10]
but traditional methods typically re-
On the basis of previous reports,[15] we screened various metal
catalysts, oxidants, and solvents to find the suitable reaction
conditions for the couplings between the coumarins and alde-
hydes (Table 1). p-Methoxybenzaldehyde was selected as the
representative aldehyde for our optimization studies. First, TBAI
quire several steps or used prefunctionalized reactants to gen-
erate the target compounds.
[
11]
In recent years, transition-
2
3
metal-catalyzed C(sp or sp )–H functionalization has emerged
as a highly efficient and environmentally friendly method to
produce coumarin derivatives. However, these methods involve
the use of expensive metal catalysts. More recently, direct cou-
pling reactions of coumarins with a partner that proceed
through radical mechanisms have attracted increasing atten-
(tetra-n-butylammonium iodide, 10.0 mol-%) and TBHP (70 wt.-
%
in water, 2.0 equiv.) were used in the screening reaction
along with an excess amount of p-methoxybenzaldehyde
(3.0 equiv.) to promote the reaction rate and partially act as a
solvent. This reaction, however, afforded only a trace amount
of the expected product 3a (Table 1, Entry 1). A combination
of FeCl /TBHP or CuBr /TBHP still gave trace amounts of prod-
[
12]
tion. Because these C–C bond-forming reactions are straight-
[
a] Pharmacy School, Jiangsu University,
3
2
Xuefu Road 301, Zhenjiang, Jiangsu 212013, People's Republic of China
E-mail: ahz@ujs.edn.cn;
http://phar.ujs.edu.cn/teacher10zhouah.asp
uct 3a (Table 1, Entries 2 and 3), whereas using CuCl or CuO
2
as the catalyst in the presence of TBHP generated the expected
products in 50 and 61 % yield, respectively (Table 1, Entries 4
[
[
b] Scientific Information Research Institute, Jiangsu University (Library),
Xuefu Road 301, Zhenjiang, Jiangsu 212013, People's Republic of China
‡] W. Z. and Y. D. contributed equally.
and 5). When Cu(OAc) was used with TBHP as the oxidant, the
2
reaction only afforded 18 % of the coupling product (Table 1,
Entry 6). The combination of CuI/TBHP did not afford coupling
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201501251.
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Scheme 1. Previous representative methods to generate keto- and methyl-substituted coumarin derivatives (THF = tetrahydrofuran, DABCO = 1,4-diazabi-
cyclo[2.2.2]octane, DMF = N,N-dimethylformamide, TBHP = tert-butylhydroperoxide).
product 3a (Table 1, Entry 7). Using Mn(OAc) and TBHP to- (Table 1, Entry 13) or in a trace amount (Table 1, Entries 14
2
gether gave only a 14 % isolated product yield (Table 1, En- and 15). On the basis of these screening results, the suitable
try 8). Employing DTBP, instead of TBHP, in the presence of conditions for this coupling reaction include the aldehyde
CuCl generated a trace amount of product (Table 1, Entry 9). (3.0 equiv.), CuO (10 mol-%), and TBHP (2.0 equiv.) at 90 °C for
2
Different solvents were also screened, but these coupling reac- 24 h.
tions gave trace amounts of 3a (Table 1, Entries 10–12). Using
Under the optimized reaction conditions, different aldehydes
CuO as the catalyst in benzene, DMF, or 1,2-dichloroethane were then treated with the coumarin derivatives (Table 2). Most
(DCE) as the solvent generated product 3a either in 15 % yield of these reactions regioselectively gave keto-substituted coum-
arin derivatives 3 in moderate to good yields, but when iso-
Table 1. Screening to optimize reaction conditions.[a]
2
Table 2. The coupling reactions of coumarins with aldehydes through C(sp )–
H functionalization.[
a]
Entry
Catalyst
TBAI
Oxidant
Temp. [°C]
Solvent
Yield [%][b]
Entry
R
R1
Product
Yield [%][b]
1
2
3
4
5
6
7
8
9
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
DTBP
TBHP
TBHP
DTBP
TBHP
TBHP
TBHP
90
90
90
90
90
90
90
90
90
90
90
90
90
90
90
–
–
–
–
–
–
–
–
–
trace
trace
trace
50
61
18
FeCl
CuBr
3
1
2
3
4
5
6
7
8
H
6-Me
H
H
6-Me
H
6-Me
6-Me
H
4-MeO-C
4-MeO-C
4-Me-C
4-tBu-C
4-tBu-C
furan
furan
2-MeO-C
iBu
2-O
4-Br-C
4-tBu-C
4-Br-C
4-Br-C
6
6
H
H
4
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
61
58
61
67
65
65
63
61
48
trace
62
64
51
52
2
4
CuCl
CuO
2
6
H
4
6
6
H
H
4
Cu(OAc)
CuI
Mn(OAc)
2
4
trace
14
2
CuCl
CuCl
CuCl
CuCl
CuO
CuO
CuO
2
2
2
2
trace
trace
trace
trace
15
6
H
4
10
11
12
13
14
15
EtOAc
9
3
CH CN
10
11
12
13
14
H
2
N-C
H
6
H
4
EtOAc
benzene
DMF
6-MeO
6-Br
6-tBu
benzo[f]
H
6
4
6
H
4
trace
trace
6
H
H
4
DCE
6
4
1
5
C
6
H
5
68
[
a] Reagents and conditions: coumarin (1.0 equiv.), catalyst (10 mol-%), p-
methoxybenzaldehyde (3.0 equiv.), and oxidant such as TBAI (10 mol-%),
TBHP (70 wt.-% in water, 2.0 equiv.), or DTBP (2.0 equiv.). [b] Isolated yield of
product 3a was calculated by using the amount of coumarin (1a). The reac-
tion was carried out for 24 h.
[a] Reagents and conditions: coumarin (1.0 equiv.), an aldehyde (3.0 equiv.),
TBHP (70 wt.-% in water, 2.0 equiv.), and the catalysts (10 mol-%). [b] Isolated
yields of 3a–3o were calculated by using the amount of coumarin derivative
1. The reaction was carried out for 24 h.
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butyraldehyde was used, the reaction only generated a moder- (2.0 equiv.), and DABCO (0.1 equiv.) in DMF (1.0 mL) at
ate 48 % yield. The coupling of electron-deficient 2-nitrobenz- 120 °C.
aldehyde with coumarin was then explored, but this reaction
Under the optimized reaction conditions, different coumarin
failed to give the expected product 3j. On the basis of the derivatives were then treated with DTBP, and the expected pro-
chemical shifts in the 1H NMR spectra, it was clear that the ducts 5a–5g were produced in yields of 60–72 % (Table 4, En-
aldehydes were selectively added to the α-position of the dou- tries 1–7). All reactions gave the substituted coumarin deriva-
ble bond of the coumarin ester.
tives with the methyl group at the α-position. Besides coumar-
The methyl group is another important functionality in drug ins, cinnamate esters were also used as a reactant. These reac-
discovery. Because its presence can improve the pharmaceutical tions proceeded well and regioselectively generated the
properties of some bioactive molecules, the addition of a methyl-substituted products 5h–5j in isolated yields of 60–70 %
methyl function into these compounds is very popular, and (Table 4, Entries 8–10).
many researchers have spent their efforts exploring efficient
methods to incorporate it into bioactive compounds. Until now,
various methylation methods have been developed, but the use
of DTBP as a methylation reagent in the presence of a copper
or iron catalyst is a new approach. Here, we applied this strat-
egy to coumarin to make the corresponding methyl-substituted
derivatives.
Table 4. The coupling reactions of coumarins and cinnamate esters with DTBP
through C(sp )–H functionalization.
2
[a]
Hence, we examined the suitable reaction conditions for the
coupling between coumarin (1a) and DTBP. Different catalysts
and solvents were screened for the optimization study. First,
Entry
R
Product
Yield [%][b]
various copper catalysts [i.e., CuCl, CuI, CuBr, CuCl , CuO, and
2
Cu(OAc) ] were employed in DMF, but these reactions only gave
trace amounts of product 5a (Table 3, Entries 1–6). Switching
2
1
2
3
4
5
6
7
H
5a
5b
5c
5d
5e
5f
72
60
65
65
60
65
70
6-Me
6-MeO
6-tBu
6-Br
benzo[f]
6-O
the catalyst from a copper salt to FeCl greatly increased the
3
yield of 5a to 70 % (Table 3, Entry 7). When FeCl ·4H O was
2
2
used as a catalyst in dimethyl sulfoxide (DMSO), a 60 % yield of
a was obtained (Table 3, Entry 8). Changing the solvent from
5
2
N
5g
DMSO to DMF or dichloromethane (DCM) afforded the ex-
pected product 5a in 72 and 60 % yield, respectively (Table 3,
Entries 9 and 10). Using CH CN as the solvent generated a trace
3
amount of the expected product (Table 3, Entry 11). On the
basis of these screening results, the optimized reaction condi-
tions for the coupling of coumarin with DTBP include
FeCl ·4H O (10.0 mol-%), coumarin (1.0 equiv.), DTBP
8
9
10
Me
Et
Bn
5h
5i
5j
60
70
65
2
2
[
(
a] Reagents and conditions: coumarin (1.0 equiv.), DTBP (2.0 equiv.), DABCO
0.1 equiv.), and FeCl ·4H O (10 mol-%). [b] Isolated yields of 5a–5j were
2
2
Table 3. Screening for suitable reaction conditions for coupling of coumarin
calculated by using the amount of coumarin derivative 1.
[
a]
(
1a) with DTBP.
To determine if the two coupling reactions proceed through
a
radical process, TEMPO [(2,2,6,6-tetramethylpiperidin-1-
yl)oxyl] was used as a radical scavenger. In the presence of
TEMPO, 3a and 5a were not formed, which indicates that a
radical process is involved. On the basis of these and previously
[15f,16]
Entry
Catalyst
Temp. [°C]
Solvent
Yield [%][b]
reported results,
Scheme 2.
we propose the mechanism as shown in
1
2
3
4
5
6
7
8
9
CuCl
CuI
CuBr
120
120
120
120
120
120
120
120
120
120
120
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
DMF
DCM
MeCN
trace
trace
trace
trace
trace
trace
70
60
72
60
trace
Upon initial heating, TBHP can split into two radicals, which
could then extract a hydrogen atom from the aldehyde func-
tional group to generate radical A. Possible attack at the α-
and β-position of the olefin moiety of coumarin then generates
radical intermediates B and C. As benzylic radical B is more
stable than radical C, only keto-substituted coumarin derivative
CuCl
CuO
2
Cu(OAc)
2
FeCl
FeCl
FeCl
FeCl
FeCl
3
2
2
2
2
·4H
2
2
2
2
O
O
O
O
·4H
·4H
·4H
3
is regioselectively obtained after the loss of one electron to
1
1
0
1
the Cu catalyst. In the second coupling reaction, a methyl radi-
cal is generated upon heating DTBP. Possible attack by this radi-
cal to the α- and β-position of the olefin unit of coumarin gen-
erates radical intermediates D and E, respectively. Because
benzylic radical D is more stable than radical E, only methyl-
[
(
a] Reagents and conditions: coumarin (1.0 equiv.), DTBP (2.0 equiv.), DABCO
0.1 equiv.), the catalysts (10 mol-%), solvent (1.0 mL), 120 °C. [b] Isolated
yield of product 5a was calculated by using the amount of coumarin (1a).
The reaction time was 12 h.
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(2.0 equiv., 70 wt.-% in water). The mixture was stirred at 90 °C for
24 h (monitored by TLC). Then the reaction was quenched with
water, and the resulting solution was extracted with dichlorometh-
ane. The combined organic layers were washed by brine, dried with
anhydrous Na SO , and concentrated under vacuum. The residue
2
4
was purified by flash chromatography on silica gel (petroleum
ether/ethyl acetate, 15:1) to provide the desired product 3a in 64 %
yield as well as compounds 3b–3o.
General Procedure for the Synthesis of Compounds 5a–5j: To a
dry sealed tube were added coumarin (1.0 equiv.) and DTBP
(
2.0 equiv.) followed by the addition of FeCl ·4H O (10.0 mol-%),
2 2
DABCO (0.1 equiv.), and DMF (1.0 mL). The mixture was stirred at
20 °C for 12 h (monitored by TLC). Then the reaction was
1
quenched with water, and the resulting solution was extracted with
ethyl acetate. The combined organic layers were washed by brine,
dried with anhydrous Na SO , and concentrated under vacuum. The
2
4
residue was purified by flash chromatography on silica gel (petro-
leum ether/ethyl acetate, 20:1) to provide the desired product 5a
in 72 % yield as well as compounds 5b–5j.
3
-(4-Methoxybenzoyl)-2H-chromen-2-one (3a): FTIR: ν˜ = 3083,
–1 1
2919, 1716, 1647, 1607, 1260, 1176, 759 cm . H NMR (400 MHz,
CDCl ): δ = 8.05 (s, 1 H), 7.91 (d, J = 8.8 Hz, 2 H), 7.68–7.60 (m, 2 H),
3
1
3
Scheme 2. Plausible reaction mechanism.
7.44–7.35 (m, 2 H), 6.97 (d, J = 8.8 Hz, 2 H), 3.91 (s, 3 H) ppm.
C
NMR (100 MHz, CDCl ): δ = 190.0, 164.3, 158.6, 154.7, 144.6, 133.3,
3
1
32.2, 129.0, 129.0, 127.6, 124.9, 118.3, 116.9, 113.9, 55.6 ppm.
substituted coumarin derivative 5 is regioselectively generated
after the loss of one electron to the Fe catalyst.
+
+
HRMS (ESI-TOF): calcd. for C H NaO [M + Na] 303.0628; found
17
12
4
303.0626.
3
-(4-Methoxybenzoyl)-6-methyl-2H-chromen-2-one (3b): FTIR:
–1 1
ν˜ = 2919, 2843, 1720, 1650, 1618, 1574, 1256, 1175, 790 cm . H
Conclusions
NMR (400 MHz, CDCl ): δ = 7.97 (s, 1 H), 7.88 (d, J = 8.4 Hz, 2 H),
3
7
.45–7.43 (m, 1 H), 7.37 (s, 1 H), 7.29 (d, J = 8.4 Hz, 1 H), 6.95 (d, J =
In summary, we have developed two new coupling reactions
that proceed through a C(sp )–H functionalization process. The
13
2
8.0 Hz, 2 H), 3.88 (s, 3 H), 2.43 (s, 3 H) ppm. C NMR (100 MHz,
CDCl ): δ = 190.2, 164.2, 158.8, 152.8, 144.7, 134.7, 134.5, 132.2,
3
reactions between coumarins and aldehydes and coumarins
and DTBP regioselectively generated keto- and methyl-substi-
tuted coumarin derivatives, respectively, in moderate to good
yields in the presence of an inexpensive copper or iron catalyst.
The couplings will enrich current coumarin chemistry, as these
derivatives are highly valuable in drug discovery. All com-
pounds synthesized will be screened for a variety of biological
activities at the medical school of Jiangsu University.
1
29.1, 128.7, 127.5, 118.0, 116.6, 113.9, 55.6, 20.8 ppm. HRMS (ESI-
+
+
TOF): calcd. for C H NaO [M + Na] 317.0784; found 317.0783.
18
14
4
3
-(4-Methylbenzoyl)-2H-chromen-2-one (3c): FTIR: ν˜ = 3060,
–1 1
2919, 1713, 1658, 1608, 1265, 1184, 764 cm . H NMR (400 MHz,
CDCl ): δ = 8.05 (s, 1 H), 7.79 (d, J = 8.0 Hz, 2 H), 7.64–7.58 (m, 2 H),
3
7
2
.40 (d, J = 8.4 Hz, 1 H), 7.37–7.33 (m, 1 H), 7.28 (d, J = 8.0 Hz, 2 H),
.43 (s, 3 H) ppm. C NMR (100 MHz, CDCl ): δ = 191.2, 158.5, 154.7,
13
3
145.1, 145.0, 133.7, 133.5, 129.8, 129.3, 129.1, 127.3, 124.9, 118.2,
16.9, 21.8 ppm. HRMS (ESI-TOF): calcd. for C H NaO [M + Na]+
+
1
2
17 12 3
87.0679; found 287.0680.
-[4-(tert-Butyl)benzoyl]-2H-chromen-2-one (3d): FTIR: ν˜ = 3056,
Experimental Section
3
2
–
1 1
968, 1736, 1657, 1605, 1263, 1166, 762 cm . H NMR (400 MHz,
General Methods: All reactions were carried out in sealed tubes.
An oven-dried magnetic stirring bar was used to stir the reaction
mixtures. Solvents were purified by standard methods, unless other-
wise noted. Commercially available reagents were purchased from
the Aladdin Company in China and used without further purifica-
tion than that detailed below. Flash column chromatography was
performed on silica gel (200–300 mesh). All reactions were moni-
tored by TLC analysis. Deuterated solvents were purchased from
CDCl ): δ = 8.05 (s, 1 H), 7.84 (d, J = 8.0 Hz, 2 H), 7.65–7.58 (m, 2 H),
3
7
7
1
1
.50 (d, J = 8.0 Hz, 1 H), 7.41 (d, J = 8.0 Hz, 2 H), 7.37–7.33 (m, 1 H),
.33 (s, 1 H), 1.35 (s, 9 H) ppm. 13C NMR (100 MHz, CDCl ): δ = 191.2,
3
58.5, 157.8, 154.7, 145.0, 144.8, 133.5, 129.7, 129.1, 127.4, 125.6,
24.9, 118.3, 116.9, 35.3, 31.3, 31.0, 30.8 ppm. HRMS (ESI-TOF): calcd.
+
+
for C H NaO [M + Na] 329.1148; found 329.1144.
20
18
3
3-[4-(tert-Butyl)benzoyl]-6-methyl-2H-chromen-2-one (3e): FTIR:
˜
1
13
–1 1
Cambridge Isotope Laboratories. The H and C NMR spectroscopic ν = 2966, 1754, 1662, 1603, 1361, 1255, 864, 786 cm . H NMR
data were recorded with a Bruker DRX-400 spectrometer that oper- (400 MHz, CDCl ): δ = 7.99 (s, 1 H), 7.83 (dd, J = 6.8, 2.0 Hz, 2 H),
3
ated at 400 and 100 MHz, respectively. HRMS [liquid chromatogra- 7.49 (d, J = 8.0 Hz, 2 H), 7.46–7.44 (m, 1 H), 7.37 (s, 1 H), 7.30 (d, J =
phy (LC)–HRMS] was recorded on a LXQ Spectrometer (Thermo 8.4 Hz, 1 H), 2.44 (s, 3 H), 1.35 (s, 9 H) ppm. 13C NMR (100 MHz,
Scientific) with ESI-TOF (MeOH as a solvent). Coumarins derivatives
were synthesized according to the literature.
CDCl ): δ = 191.3, 158.7, 152.9, 145.0, 134.7, 134.6, 133.6, 129.7,
3
128.8, 127.3, 125.6, 118.0, 116.6, 35.3, 31.1, 20.7 ppm. HRMS (ESI-
+
+
TOF): calcd. for C H NaO [M + Na] 343.1305; found 343.1308.
21
20
3
General Procedure for the Syntheses of Compounds 3a–3o: To
a dry sealed tube were added coumarin (1.0 equiv.) and p-methoxy- 3-(Furan-2-carbonyl)-2H-chromen-2-one (3f): FTIR: ν˜ = 3132,
–
1
1
benzaldehyde (3.0 equiv.) followed by the addition of TBHP 3114, 1717, 1652, 1607, 1462, 1176, 960, 762 cm . H NMR
Eur. J. Org. Chem. 2016, 325–330
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112.7 ppm. HRMS (ESI-TOF): calcd. for C H BrNaO [M + Na]+
+
(
400 MHz, CDCl ): δ = 8.17 (s, 1 H), 7.68–7.61 (m, 3 H), 7.41 (d, J =
3
20 11
3
8
.4 Hz, 1 H), 7.38–7.36 (m, 2 H), 6.62 (dd, J = 3.6, 1.6 Hz, 1 H) ppm.
400.9784; found 400.9784.
13
C NMR (100 MHz, CDCl ): δ = 178.0, 158.0, 154.8, 151.8, 147.7,
3
3
-Benzoyl-2H-chromen-2-one (3o): FTIR: ν˜ = 3063, 1717, 1607,
1
45.5, 133.8, 129.3, 126.3, 125.0, 120.7, 118.1, 116.9, 112.8 ppm.
–1 1
1
1
2
493, 1243, 1055, 813 cm . H NMR (400 MHz, CDCl ): δ = 8.11 (s,
3
+
+
HRMS (ESI-TOF): calcd. for C H NaO [M + Na] 263.0315; found
2
1
4
8
4
H), 7.90, (d, J = 7.2 Hz, 2 H), 7.62–7.70 (m, 3 H), 7.51 (d, J = 7.6 Hz,
63.0312.
13
H), 7.36–7.49 (m, 2 H) ppm. C NMR (100 MHz, CDCl ): δ = 160.5,
3
3
-(Furan-2-carbonyl)-6-methyl-2H-chromen-2-one (3g): FTIR: ν˜ =
151.2, 137.4, 134.0, 132.0, 130.7, 127.7, 119.1, 116.1, 74.6, 69.1, 32.2,
–
1
1
+
3
131, 3114, 1714, 1650, 1575, 1462, 1183, 962, 766 cm . H NMR 26.0, 23.6, 20.8 ppm. HRMS (ESI-TOF): calcd. for C H NaO [M +
16 10 3
+
(400 MHz, CDCl ): δ = 8.11 (s, 1 H), 7.68 (d, J = 1.2 Hz, 1 H), 7.45
Na] 273.0522; found 273.0519.
-Methyl-2H-chromen-2-one (5a): FTIR: ν˜ = 3072, 2361, 1745,
3
(dd, J = 8.4, 1.6 Hz, 1 H), 7.39 (s, 1 H), 7.36–7.35 (m, 1 H), 7.30 (d,
3
1
13
J = 8.4 Hz, 1 H), 6.62 (dd, J = 3.6, 1.6 Hz, 1 H), 2.44 (s, 3 H) ppm.
NMR (100 MHz, CDCl ): δ = 178.2, 158.2, 153.0, 151.8, 147.7, 145.6,
C
–1 1
659, 1414, 1116, 885, 552 cm . H NMR (400 MHz, CDCl ): δ = 7.54
3
3
(
s, 1 H), 7.50–7.43 (m, 2 H), 7.32 (d, J = 8.4 Hz, 1 H), 7.27–7.25 (m, 1
1
34.9, 128.9, 126.1, 120.7, 117.9, 116.6, 112.7, 20.7 ppm. HRMS (ESI-
13
H), 2.23 (d, J = 1.2 Hz, 3 H) ppm. C NMR (100 MHz, CDCl ): δ =
3
+
+
TOF): calcd. for C H NaO [M + Na] 277.0471; found 277.0455.
15
10
4
1
62.2, 153.2, 139.3, 130.4, 127.0, 125.7, 124.3, 119.5, 116.4, 29.7,
+
+
3
-(2-Methoxybenzoyl)-6-methyl-2H-chromen-2-one (3h): FTIR:
17.1 ppm. HRMS (ESI-TOF): calcd. for C H NaO [M + Na] 183.0417;
9 5 2
–
1 1
ν˜ = 2930, 1840, 1726, 1653, 1620, 1575, 1258, 1172, 792 cm . H found 183.0422.
NMR (400 MHz, CDCl ): δ = 8.0 (s, 1 H), 7.90 (d, J = 8.8 Hz, 2 H), 7.46
3
3
,6-Dimethyl-2H-chromen-2-one (5b): FTIR: ν˜ = 3072, 2361, 1745,
(
(
(
dd, J = 8.4, 1.6 Hz, 1 H), 7.39 (s, 1 H), 7.32 (d, J = 8.8 Hz, 1 H), 6.97
–1 1
1659, 1323, 1244, 868, 694 cm . H NMR (400 MHz, CDCl ): δ = 7.47
d, J = 9.2 Hz, 2 H), 3.91 (s, 3 H), 2.46 (s, 3 H) ppm. 13C NMR
3
(
2
s, 1 H), 7.26 (d, J = 1.6 Hz, 1 H), 7.22–7.20 (m, 2 H), 2.40 (s, 3 H),
100 MHz, CDCl ): δ = 190.2, 164.2, 158.8, 152.8, 144.7, 134.7, 134.5,
3
13
.21 (d, J = 0.8 Hz, 3 H) ppm. C NMR (100 MHz, CDCl ): δ = 162.5,
3
1
32.2, 129.1, 128.7, 127.5, 118.0, 116.6, 113.9, 55.6, 20.8 ppm. HRMS
1
51.4, 139.9, 131.4, 126.8, 125.6, 119.3, 116.2, 29.7, 20.8, 17.2 ppm.
+
[M + Na]+ 317.0784; found
(ESI-TOF): calcd. for C H NaO
1
8
14
4
+
+
HRMS (ESI-TOF): calcd. for C H NaO [M + Na] 197.0753; found
11
10
2
3
17.0783.
197.0576.
3
-Isobutyryl-2H-chromen-2-one (3i): FTIR: ν˜ = 2955, 1866, 1776,
6
-Methoxy-3-methyl-2H-chromen-2-one (5c): FTIR: ν˜ = 2932,
–
1 1
1
653, 1322, 1172, 865, 792 cm . H NMR (400 MHz, CDCl ): δ = 8.46
3
–1 1
2361, 1745, 1659, 1244, 1116, 868, 694 cm . H NMR (400 MHz,
(s, 1 H), 7.68–7.64 (m, 2 H), 7.40–7.34 (m, 2 H), 3.91–3.84 (m, 1 H),
CDCl ): δ = 7.47 (s, 1 H), 7.23 (d, J = 9.2 Hz, 1 H), 7.03 (dd, J = 8.8,
1
3
3
1
1
1
2
.20 (d, J = 6.8 Hz, 6 H) ppm. C NMR (100 MHz, CDCl ): δ = 202.5,
58.8, 155.2, 147.6, 134.1, 129.9, 124.9, 124.8, 118.4, 116.7, 38.6,
8.3 ppm. HRMS (ESI-TOF): calcd. for C H NaO [M + Na]
39.0679; found 239.0688.
-(4-Bromobenzoyl)-6-methoxy-2H-chromen-2-one (3k): FTIR:
3
2
.8 Hz, 1 H), 6.85 (d, J = 2.8 Hz, 1 H), 3.84 (s, 3 H), 2.12 (s, 3 H) ppm.
1
3
C NMR (100 MHz, CDCl ): δ = 162.4, 156.0, 147.6, 139.1, 126.2,
+
+
3
1
3
12
3
119.9, 118.0, 117.4, 109.3, 55.8, 17.3 ppm. HRMS (ESI-TOF): calcd. for
+
+
C H NaO [M + Na] 213.0522; found 213.0525.
11
10
3
3
6
-(tert-Butyl)-3-methyl-2H-chromen-2-one (5d): FTIR: ν˜ = 2932,
–
1 1
ν˜ = 2988, 2361, 1745, 1659, 1331, 1116, 868, 783 cm . H NMR
–1 1
2361, 1745, 1659, 1244, 1116, 885, 662 cm . H NMR (400 MHz,
(400 MHz, CDCl ): δ = 8.10 (s, 1 H), 7.75 (d, J = 8.8 Hz, 2 H), 7.63 (d,
3
CDCl ): δ = 7.54–7.50 (m, 2 H), 7.40 (d, J = 2.0 Hz, 1 H), 7.26 (d, J =
3
J = 8.4 Hz, 2 H), 7.35 (d, J = 9.2 Hz, 1 H), 7.25 (dd, J = 9.2, 2.8 Hz, 1
H), 7.02 (d, J = 2.8 Hz, 1 H), 3.88 (s, 1 H) ppm. C NMR (100 MHz,
CDCl ): δ = 190.9, 158.6, 156.5, 149.4, 145.9, 135.1, 131.9, 131.0,
1
3
8.8 Hz, 1 H), 2.22 (d, J = 1.2 Hz, 3 H), 1.36 (s, 9 H) ppm. C NMR
1
3
(100 MHz, CDCl ): δ = 162.6, 151.2, 147.3, 139.8, 128.1, 125.4, 123.3,
3
3
119.0, 116.0, 34.5, 31.4, 17.2 ppm. HRMS (ESI-TOF): calcd. for
1
29.1, 126.8, 122.1, 118.4, 118.0, 110.67, 55.95 ppm. HRMS (ESI-TOF):
+
C H O [M + H] 239.1043; found 239.1046.
+
+
14 17 2
calcd. for C H NaO [M + Na] 380.9733; found 380.9725.
13
12
3
6
-Bromo-3-methyl-2H-chromen-2-one (5e): FTIR: ν˜ = 2932, 2361,
6-Bromo-3-[4-(tert-butyl)benzoyl]-2H-chromen-2-one(3l): FTIR:
–1 1
1745, 1659, 1456, 1116, 860, 694 cm . H NMR (400 MHz, CDCl ):
–
1
1
3
ν˜ = 2988, 2361, 1745, 1659, 1331, 1116, 868, 783 cm . H NMR
δ = 7.57–7.55 (m, 2 H), 7.46 (s, 1 H), 7.23–7.21 (m, 1 H), 2.25 (d, J =
(400 MHz, CDCl ): δ = 8.15 (s, 1 H), 7.76–7.72 (m, 3 H), 7.65–7.63 (m,
3
13
0.8 Hz, 3 H) ppm. C NMR (100 MHz, CDCl ): δ = 161.5, 152.1, 137.8,
3
2
H), 7.59 (d, J = 2.4 Hz, 1 H), 7.37 (d, J = 8.8 Hz, 1 H), 1.39 (s, 9
133.3, 129.3, 127.3, 121.1, 118.2, 116.8, 17.3 ppm. HRMS (ESI-TOF)
13
H) ppm. C NMR (100 MHz, CDCl ): δ = 190.6, 158.1, 157.8, 153.5,
3
+
+
m/z calculated for C H NaO [M + Na] 260.9522; found 260.9527.
10
7
2
1
3
4
43.3, 136.1, 133.2, 131.2, 129.7, 128.5, 125.7, 119.7, 118.7, 117.5,
5.3, 31.0 ppm. HRMS (ESI-TOF): calcd. for C HBrNaO [M + Na]
07.0253; found 407.0257.
+
+
2-Methyl-3H-benzo[f]chromen-3-one (5f): FTIR: ν˜ = 2932, 2361,
–1 1
2
0
3
1745, 1659, 1414, 1244, 868, 669 cm . H NMR (400 MHz, CDCl
):
3
δ = 8.27 (d, J = 1.6 Hz, 1 H), 8.22 (d, J = 8.4 Hz, 1 H), 7.92–7.89 (m,
3
-(4-Bromobenzoyl)-6-(tert-butyl)-2H-chromen-2-one
(3m):
2
2
1
1
+
H), 7.70–7.65 (m, 1 H), 7.59–7.55 (m, 1 H), 7.44 (d, J = 9.2 Hz, 1 H),
–
1 1
FTIR: ν˜ = 2932, 2361, 1745, 1659, 1323, 1116, 885, 694 cm . H NMR
.34 (d, J = 1.2 Hz, 3 H) ppm. 13C NMR (CDCl , 100 MHz): δ = 162.3,
3
(400 MHz, CDCl ): δ = 8.00 (s, 1 H), 7.83 (d, J = 8.8 Hz, 2 H), 7.73
3
52.5, 135.1, 131.6, 130.3, 129.0, 128.7, 127.9, 125.8, 125.0, 121.4,
(dd, J = 6.8, 2.0 Hz, 2 H), 7.52 (d, J = 8.4 Hz, 2 H), 7.31 (d, J = 9.6 Hz,
+
16.80, 113.5, 17.6 ppm. HRMS (ESI-TOF): calcd. for C H NaO [M
Na] 233.0573; found 233.0575.
1
3
14 10
2
1
1
1
H), 1.37 (s, 9 H) ppm. C NMR (100 MHz, CDCl ): δ = 190.9, 158.7,
3
+
53.0, 148.4, 146.7, 135.2, 131.9, 131.8, 131.0, 129.0, 126.1, 125.5,
17.6, 116.6, 34.7, 31.3 ppm. HRMS (ESI-TOF): calcd. for
3-Methyl-6-nitro-2H-chromen-2-one (5g): FTIR: ν˜ = 2932, 2361,
+
+
–1 1
C H BrNaO [M + Na] 407.0253; found 407.0257.
1745, 1659, 1244, 1107, 837, 669 cm . H NMR (400 MHz, CDCl
δ = 8.39–8.34 (m, 2 H), 7.62 (s, 1 H), 7.46 (d, J = 9.2 Hz, 1 H), 2.30
(d, J = 0.8 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl
): δ = 160.2,
56.7, 137.8, 128.7, 128.6, 125.4, 122.8, 119.6, 117.6 ppm. HRMS (ESI-
3
):
20
17
3
2
-(4-Bromobenzoyl)-3H-benzo[f]chromen-3-one (3n): FTIR: ν˜ =
–1 1
3
2
988, 2361, 1745, 1659, 1244, 1116, 868, 694 cm . H NMR
1
(400 MHz, CDCl ): δ = 9.00 (s, 1 H), 8.30 (d, J = 8.4 Hz, 1 H), 8.15 (d,
3
+
+
TOF) calcd. for C H NNaO [M + Na] 228.0267; found 228.0273.
10
7
4
J = 8.8 Hz, 1 H), 7.98 (d, J = 8.0 Hz, 1 H), 7.81–7.75 (m, 3 H), 7.67–
1
3
7
.63 (m, 3 H), 7.54 (d, J = 8.8 Hz, 1 H) ppm. C NMR (100 MHz,
Methyl (E)-2-Methyl-3-phenylacrylate (5h): FTIR: ν˜ = 2932, 2361,
–
1 1
CDCl ): δ = 191.2, 158.6, 155.7, 142.6, 135.8, 135.4, 131.9, 131.0,
1745, 1659, 1414, 1244, 885, 789 cm . H NMR (400 MHz, CDCl ):
3
3
1
30.4, 129.4, 129.3, 129.2, 129.0, 126.7, 124.8, 121.5, 116.7,
δ = 7.72 (d, J = 1.2 Hz, 1 H), 7.42 (t, J = 4.4 Hz, 4 H), 7.37–7.33 (m,
Eur. J. Org. Chem. 2016, 325–330
www.eurjoc.org
329
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
1
H), 3.85 (s, 3 H), 2.15 (d, J = 1.6 Hz, 3 H) ppm. 13C NMR (100 MHz,
CDCl ): δ = 169.2, 139.0, 135.9, 129.7, 128.4, 128.3, 77.4, 77.0, 76.7,
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+
+
5
2.1, 14.1 ppm. HRMS (ESI-TOF): calcd. for C H NaO [M + Na]
11 12 2
6
400; b) F. Pérez-Cruz, S. Vazquez-Rodriguez, M. J. Matos, A. Herrera-
1
99.0730; found 199.0740.
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–
1 1
1
745, 1659, 1323, 1116, 868, 694 cm . H NMR (400 MHz, CDCl ):
3
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8
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7
1
.30 (dd, J = 14.4, 7.2 Hz, 2 H), 2.14 (d, J = 1.6 Hz, 3 H), 1.38 (t, J =
2
2
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3
29.6, 128.7, 128.4, 128.3, 60.9, 14.3, 14.1 ppm. HRMS (ESI-TOF):
5
1, 7520.
+
+
calcd. for C H NaO [M + Na] 213.0886; found 213.0736.
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11
2
Benzyl (E)-2-Methyl-3-phenylacrylate (5j): FTIR: ν˜ = 2932, 2361,
–
1 1
1
745, 1659, 1298, 1116, 885, 694 cm . H NMR (400 MHz, CDCl ):
3
δ = 7.78 (d, J = 1.6 Hz, 1 H), 7.47–7.35 (m, 10 H), 5.30 (s, 2 H), 2.18
1
3
(d, J = 1.2 Hz, 3 H) ppm. C NMR (100 MHz, CDCl ): δ = 168.5,
3
1
1
2
39.3, 136.3, 135.9, 129.7, 128.5, 128.4, 128.3, 128.2, 128.1, 66.7,
4.1 ppm. HRMS (ESI-TOF): calcd. for C H NaO [M + Na]
+
+
1
7
16
2
75.1043; found 275.1048.
[
Supporting Information (see footnote on the first page of this
article): H and C NMR spectra of compounds.
1
13
Acknowledgments
2
957.
A. Z. acknowledges Jiangsu University for the financial support
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Published Online: November 24, 2015
Eur. J. Org. Chem. 2016, 325–330
www.eurjoc.org
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