Palladium-Catalyzed Weakly Coordinating Lactone-Directed C-H Bond Functionalization of 3-Arylcoumarins: Synthesis of Bioactive Coumestan Derivatives

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Palladium-Catalyzed Weakly Coordinating Lactone-Directed C−H

Bond Functionalization of 3‑Arylcoumarins: Synthesis of Bioactive

Coumestan Derivatives

Vikki N. Shinde, Krishnan Rangan, Dalip Kumar, and Anil Kumar*

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ABSTRACT: A palladium-catalyzed highly regioselective ortho-

selective C−H functionalization of 3-arylcoumarins has been

developed. The method utilizes the weakly coordinating lactone as

a directing group. The versatility of the strategy is highlighted by

developing methodologies for alkenylation, halogenation, ﬂuo-

roalkoxylation, and hydroxylation. Diﬀerent functional groups were

well tolerated, and functionalized coumarins were obtained in

moderate to high yields. The method also showed good selectivity for monofunctionalization versus difunctionalization. The

generated ortho-hydroxy derivatives were cyclized in the presence of DDQ, thus developing a simple and fast method for the

synthesis of bioactive coumestan from 3-arylcoumarins.

tion of this key scaﬀold might open a new avenue in drug

discovery. As part of our research program toward the

development of new methods for the synthesis and function-

alization of heterocyclic compounds,¹³we herein report a

lactone-directed, Pd-catalyzed C(sp²)−H bond functionaliza-

tion of 3-arylcoumarins (Scheme 1). Moreover, this method has

provided direct access to coumestan derivatives in a short

synthetic path under mild reaction conditions.

INTRODUCTION

■

Transition-metal-catalyzed direct C−H bond functionalization

has emerged as one of the most elegant approaches for the

synthesis of synthetic building blocks from simple substrates as

well as late-stage functionalization.¹In this approach, substrate-

directed functionalization through ortho-C−H bond activation

continues to be an area of intense interest for synthetic organic

chemists as it oﬀers step- and atom-economic, cost-eﬀective,

green, and sustainable methodology to construct complex

molecules.²Most commonly strong coordinating functionalities

(nitrogen-, sulfur-, or phosphorus-containing groups) are used

as directing groups (DGs) in these transition-metal-catalyzed

C−H functionalization reactions.³The intermediate metalla-

cycle of these strongly coordinating groups are thermodynami-

cally stable and are less reactive in the subsequent functionaliza-

tion step and, thus, impede the eﬃcacy and versatility of the

process. To facilitate the reaction at a faster rate and improve

selectivity, weakly coordinating groups (oxygen-containing

groups) have gained importance in directed C−H functionaliza-

tion reactions.⁴A large number of weak coordinating groups

such as Weinreb amides,⁵ketone,⁶carbamates,⁷oxazolidinone,⁸

carboxylic acids,⁹and esters¹⁰have been explored as DGs for

C−H functionalization. However, there are very few examples in

literature utilizing the weak coordinating feature of lactones.¹¹

On the other hand, a coumarin (2H-chromen-2-one) skeleton

is present in many biologically active agents, drug molecules, and

natural products.¹²3-Arylcoumarins contain an aromatic ring

neighboring to the lactone group that makes them a potential

substrate for the directed C−H bond activation. We were

intrigued by the potential yet unraveled role of the lactone group

in coumarins as a weak coordinating group in C−H bond

functionalization reactions. Regioselective C−H functionaliza-

Scheme 1. Pd-Catalyzed C(sp²)−H Bond Functionalization

of 3-Arylcoumarins

RESULTS AND DISCUSSION

■

We began our investigation to optimize the reaction conditions

by selecting 3-phenyl-2H-chromen-2-one (1a) and methyl

acrylate (2a) as model substrates. Initially, the reaction of 1a

(0.23 mmol) and 2a (0.90 mmol) in the presence of Pd(OAc)₂

(10 mol %), K₂S₂O₈(2 equiv) in triﬂuoroacetic acid (TFA) and

Received: May 10, 2021

Published: June 28, 2021

https://doi.org/10.1021/acs.joc.1c01097

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a

Table 1. Optimization of the Reaction Conditions for ortho-Alkenylation

b

entry

catalyst

oxidant

K₂S₂O₈

solvent

T (°C)

yield (%)

1

2

3

4

5

6

7

8

Pd(OAc)₂

TFA/HFIP (1:9)

HFIP

TFA

AcOH

PivOH

TfOH

TFAA

TFA/TFAA (1:1)

TFA/TFAA (3:1)

TFA/TFAA (6:1)

TFA/TFAA (9:1)

90

80

70

110

90

39

NR

41

35

27

26

39

45

52

68

88

66

56

61

52

48

32

45

46

31

61

64

52

41

56

59

NR

K₂S₂O₈

IBD

Pd(OAc)₂

PdCl₂

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

TBHP

MnO₂

Cu(OAc)₂

AgOAc

AgNO₃

Na₂S₂O₈

(NH₄)₂S₂O₈

K₂S₂O₈

Pd(PPh)₃Cl₂

Pd(CH₃CN)₂Cl₂

Pd₂(dba)₃

Ru(p-cymene)₂Cl₂

Co(OAc)₂·4H₂O

Mn(OAc)₂·4H₂O

a

b

Reaction conditions: 1a (0.23 mmol), 2a (0.90 mmol), catalyst (10 mol %), oxidant (2 equiv), solvent (2 mL), T = 70−110 °C for 3 h. Isolated

yields after column chromatography.

hexaﬂuoroisopropanol (HFIP) mixture (2 mL, 1:9 v/v) for 3 h

gave methyl 3-(2-(2-oxo-2H-chromen-3-yl)phenyl)acrylate

(3aa) in 39% yield. The molecular structure of 3aa was

(41−59%) of 3aa were obtained from PdCl₂, Pd(PPh)₃Cl₂,

Pd(CH₃CN)₂Cl₂, and Pd₂(dba)₃, while no product formation

was observed using Ru(p-cymene)₂Cl₂, Co(OAc)₂·4H₂O, and

Mn(OAc)₂·4H₂O as the catalyst. On the basis of these studies,

we conclude that the optimal reaction condition for the

alkenylation of 3-phenylcoumarin (1a) using methyl acrylate

(2a) involves Pd(OAc)₂(10 mol %) and K₂S₂O₈(2 equiv) in a

mixture of TFA and TFAA (2 mL, 9:1 v/v) at 90 °C for 3 h

(Table 1, entry 13).

The scope and limitations of the alkenylation protocol are

outlined in Table 2. The reaction of 1a with ethyl, octadecyl,

cyclohexyl, and phenyl acrylates (2b−e) aﬀorded corresponding

alkenylated products 3ab−ae in moderate to good yields (45−

76%). Unfortunately, tert-butyl acrylate, acrylamide, and vinyl

acetate failed to produce the desired product under the

optimized conditions. Next, the scope for 3-arylcoumarins

with a substituent on both the C3-phenyl ring and the benzene

ring of a coumarin scaﬀold (1b−h) was evaluated, and to our

satisfaction, corresponding alkenylated products (3ba−hd)

were obtained in moderate to high yields (44−90%).

Interestingly, better yields of alkenylated products were

1

elucidated with the help of H NMR, ¹³C{¹H} NMR, HRMS,

and single-crystal X-ray analysis (CCDC no. 1989999). In the

absence of either oxidant or palladium catalyst, the reaction did

not proceed (Table 1, entries 2 and 3). Next, we examined the

eﬀect of various solvents on the yield of 3aa employing

Pd(OAc)₂as the catalyst and K₂S₂O₈as an oxidant under

standard conditions (Table 1, entries 4−13). Switching the

solvent from TFA/HFIP mixture to pure HFIP was unfruitful.

Among all screened solvents mixture of TFA and triﬂuoroacetic

anhydride (TFAA) in 9:1 (v/v) ratio provided the highest yield

(88%) of 3aa (Table 1, entry 13). Further, no improvement in

the yield of 3aa was observed by changing the reaction

temperature (Table 1, entries 14−16). The yield of the product

did not improve on varying the oxidizing agent from K₂S₂O₈to

IBD, TBHP, MnO₂, Cu(OAc)₂, AgOAc, AgNO₃, Na₂S₂O₈, and

(NH₄)₂S₂O₈(Table 1, entries 17−24). In order to improve the

yield of 3aa, the model reaction was also carried out with

diﬀerent catalysts (Table 1, entries 25−31). Moderate yields

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a b

,

Table 2. ortho-Alkenylation of 3-Arylcoumarins

a

b

Reaction condition: 1 (0.23 mmol), 2 (0.90 mmol), Pd(OAc)₂(10 mol %), K₂S₂O₈(2 equiv), TFA/TFAA (2 mL, 9:1 v/v), 90 °C, 3 h. Yields

for isolated products.

obtained from 3-arylcoumarins having C3-phenyl substituted

with deactivating groups (compare 3ea and 3ba vs 3ca).

Pleasingly, 2-phenyl-3H-benzo[f ]-chromen-3-one (1i) also

reacted with 2a and 2d under optimized conditions to furnish

corresponding alkenylated products 3ia and 3id in 78% and 63%

yields, respectively. It is noteworthy that, in the case of low

yields, we isolated an unreacted substrate, while, in some cases,

traces of byproducts were formed possibly by double ortho-

functionalization, which could not be isolated in enough

quantities to characterize.

After successful implementation of the ortho-selective C−H

alkenylation of 3-arylcoumarins, we studied their halogenation

with slight modiﬁcation in the reaction conditions (Table 3).

The reaction of 1a with N-bromosuccinimide (NBS, 4a) using

Pd(OAc)₂(10 mol %) as the catalyst, K₂S₂O₈(2 equiv) as

anoxidant, and TfOH (2 equiv) as the acidic additive in 1,2-

dichloroethane (DCE) at 80 °C for 24 h aﬀorded 3-(2-

bromophenyl)-2H-chromen-2-one (5aa) in 73% yield. Various

functional groups such as chloro, ﬂuoro, methyl, and methoxy

on both the C3-phenyl ring and benzene ring of the coumarin

scaﬀold were well tolerated, and the corresponding brominated

compounds (5ba−ia) were obtained in good yields. Further, the

use of N-chlorosuccinimide (NCS, 4b) also resulted in ortho-

chlorinated products (5ab−ib) in good to excellent yields. The

molecular structure of 5ab was conﬁrmed by single-crystal X-ray

analysis (CCDC no. 2071538). Interestingly, the protocol could

introduce a halo substituent at the meta-position to ortho-

directing groups.

The incorporation of a ﬂuorine atom in organic molecules

imparts enhanced bioavailability and metabolic stability, and

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a b

,

Table 3. ortho-Halogenation of 3-Arylcoumarins

a

Reaction condition: 1 (0.23 mmol), 4 (0.25 mmol), Pd(OAc)₂(10 mol %), K₂S₂O₈(2 equiv), TfOH (0.45 mmol), DCE (2 mL), 80 °C, 24 h.

b

Yields for isolated products.

a b

,

Table 4. ortho-Triﬂuoroethoxylation of 3-Arylcoumarins

a

b

Reaction condition: 1 (0.23 mmol), Pd(OAc)₂(10 mol %), K₂S₂O₈(2 equiv), TFA (0.45 mmol), TFE (6, 2 mL), 80 °C, 24 h. Yields for isolated

products.

thus, ﬂuorine-containing compounds continue to receive

considerable attention in pharmaceuticals and agrochemicals.¹⁴

We decided to explore direct C−H ﬂuoroalkoxylation of 3-

arylcoumarins. To our satisfaction, the reaction of 1a with

triﬂuoroethanol (TFE, 6) using Pd(OAc)₂(10 mol %) as the

catalyst, K₂S₂O₈(2 equiv) as the oxidant, and TFA (2 equiv) as

the acidic additive at 80 °C for 24 h aﬀorded 3-(2-(2,2,2-

triﬂuoroethoxy)phenyl)-2H-chromen-2-one (7a) in 69% yield.

Similarly, the reaction of 3-arylcoumarins (1b−e) bearing

substituents on both C3-phenyl ring as well as on the benzene

ring of the coumarin scaﬀold reacted with TFE to aﬀord the

corresponding ortho-triﬂuoroethoxylated products (7b−i) in

moderate to good yields (54−63%) as shown in Table 4. The

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a b

,

Table 5. ortho-Hydroxylation of 3-Arylcoumarins

a

b

Reaction conditions: 1 (0.23 mmol), K₂S₂O₈(2 equiv), Pd(OAc)₂(10 mol %), TFA (2 mL), 90 °C, 1 h. Yields for isolated products.

a b

,

Table 6. Synthesis of Coumestan Derivatives

a

b

Reaction condition: 8 (0.21 mmol), DDQ (2 equiv), toluene (2 mL), reﬂux, 24 h. Yields for isolated products.

mechanism of the reaction is believed to involve a Pd(II)/

Pd(IV) cycle.¹⁵

yields, respectively, using monomeric [Ru(p-cymene)-

(CF₃CO₂)₂(H₂O)] as the catalyst and PhI(CF₃CO₂)₂as an

oxidant.^11bNext, various 3-arylcoumarins (1b−i) with diﬀerent

functional groups were subjected to the reaction under

optimized conditions to aﬀord the corresponding ortho-

hydroxylated derivatives (8b−i) in good to excellent (58−

96%) yields as indicated in Table 5. Notably, synthetically useful

halo groups remained intact under these conditions, which can

be used for further manipulations.

The furan-fused coumarin derivatives, coumestan, are widely

found in nature and display a wide range of biological

activities.¹⁹Due to their signiﬁcant bioactivities, several

synthetic methods have been developed for coumestan

derivatives.²⁰We, therefore, decided to cyclize the ortho-

hydroxylated derivatives (8) to obtain coumestans 9. Recently

reported copper-catalyzed intramolecular cross-dehydrogen-

A hydroxyl group on 3-arylcoumarin moieties has been found

in several natural products and pharmaceutically important

compounds.¹⁶Also, several bioactive compounds can be

achieved through the chemical transformation of a hydroxyl

group. Thus, we examined ortho-hydroxylation of 2-arylcoumar-

ins using TFA as an oxygen source.¹⁷The reaction of 1a using

Pd(OAc)₂(10 mol %) as the catalyst, K₂S₂O₈(2 equiv) as an

oxidant in TFA at 90 °C for 1 h aﬀorded 3-(2′-hydroxyphenyl)-

coumarin (8a) in 93% yield. The structure of 8a¹⁸was

conﬁrmed by NMR, HRMS and single-crystal X-ray diﬀraction

analysis (CCDC no. 2071530). Hong et al. reported ortho-

hydroxylation of 3-phenyl-2H-chromen-2-one to aﬀord a

mixture of 3-(2-hydroxyphenyl)-2H-chromen-2-one and 3-

(2,6-dihydroxyphenyl)-2H-chromen-2-one in 71% and 25%

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Scheme 2. Gram-Scale Synthesis and Synthetic Transformation of 3aa, 5aa, and 8a

ative coupling^20dfailed to produce the desired coumestans from

3-(2′-hydroxyaryl)coumarins in our hand. We then moved to

DDQ-mediated oxidative cyclization in toluene.²¹Interestingly,

various 3-(2′-hydroxyaryl)coumarins (8) containing substitu-

ents both on C3-phenyl ring as well as on benzene ring of

coumarin scaﬀold aﬀorded good yields of the corresponding

coumestans (Table 6). Thus, the lactone-directed C−H

functionalization protocol is successfully used to develop a

simple and rapid method for the total synthesis of coumestans.

The scalability of the developed protocols was demonstrated

by gram-scale alkenylation, bromination, and hydroxylation of

1a (1 g, 4.5 mmol) (Scheme 2a). The desired products 3aa, 5aa,

and 8a were isolated in 79% (1.08 g), 72% (0.96 g), and 84%

(0.90 g) yields, respectively. In addition, the synthetic utility of

the ortho-functionalized 3-arylcoumarins was demonstrated by

transforming the functional groups through synthetic manipu-

lations. For instance, compound 8a was transformed to

compound 12 via sequential triﬂuoromethylsulfonylation and

Sonogashira coupling (Scheme 2b). Product 3ab could be easily

hydrolyzed to give corresponding acid 13 in 78% yield, and

bromination of 3ab by adding bromine in CHCl₃aﬀorded

dibromo compound 14 in 93% yield (Scheme 2c). Product 5aa

was converted to synthetically useful compounds 15 and 17

through copper-catalyzed cyanation and Suzuki coupling in 76%

and 90% yields, respectively (Scheme 2d).

To gain insight into the reaction mechanism, we performed a

few control experiments (Scheme 3). A competitive experiment

between 1c and 1e for alkenylation with 2a under optimized

conditions gave corresponding products 3ca and 3ea in a 1:2.96

ratio (Scheme 3a). The result is incompatible with Friedel−

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Scheme 3. Control Experiments

Scheme 4. Proposed Mechanism for ortho-Hydroxylation

Crafts-type electrophilic aromatic substitution (S_EAr) reactivity.

Similarly, a competitive experiment between 1g and 1h

produced corresponding products 3ga and 3ha in a 2:1 ratio

(Scheme 3b). No signiﬁcant reduction in the yield of 3aa was

observed when the reaction of 1a with 2a was performed in the

presence of radical scavengers 2,2,6,6-tetramethylpiperidine-1-

oxy (TEMPO) and butylated hydroxytoluene (BHT) under

optimized conditions (Scheme 3c), ruling out the possibility of

the radical mechanism.

On the basis of the experimental results and related

literature,^6d,15,17b,cit is proposed that the possible mechanism

for the palladium-catalyzed weakly coordinating lactone-

directed C−H bond functionalization of 3-arylcoumarins

might involve a Pd(II)−Pd(IV) redox cycle. A proposed

mechanism for hydroxylation of 3-arylcoumarins is shown in

Scheme 4. Initially, lactone-directed C−H activation of 1a

generates palladacycle A, which then gets converted to

cyclopalladium(II) dimeric intermediate B. Next, intermediate

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Methyl (E)-3-(2-(2-Oxo-2H-chromen-3-yl)phenyl)acrylate (3aa).

The title compound 3aa was synthesized following method A: R_f= 0.6;

white solid (62 mg, 88%); mp = 168−170 °C; H NMR (400 MHz,

CDCl₃) δ 7.76−7.73 (m, 1H), 7.71 (d, J = 16.0 Hz, 1H), 7.67 (s, 1H),

7.63−7.59 (m, 1H), 7.55 (dd, J = 7.8, 1.4 Hz, 1H), 7.49−7.47 (m, 2H),

7.45−7.42 (m, 2H), 7.37−7.33 (m, 1H), 6.47 (d, J = 16.0 Hz, 1H), 3.76

(s, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 167.0, 160.4, 154.0,

143.0, 142.4, 135.4, 133.7, 132.0, 130.8, 130.0, 129.2, 128.1, 127.5,

126.9, 124.7, 119.8, 119.1, 116.8, 51.7; HRMS (ESI) m/z [M + H]⁺

calcd for C₁₉H₁₅O₄⁺307.0965, found 307.0937.

B in the presence of an external oxidant oxidizes to Pd(IV)

intermediate C.²²Finally, double reductive elimination from

intermediate C provides triﬂuoroacetate intermediate D, which

upon hydrolysis gets converted into a hydroxylated coumarin 5.

In the case of ortho-alkenylation, the reaction possibly proceeds

through oxidative Heck reaction from intermediate A or B.²³

1

CONCLUSIONS

■

In conclusion, a uniﬁed strategy is described for the palladium-

catalyzed, weakly coordinating lactone-directed C−H bond

functionalization of 3-arylcoumarins. The strategy allowed facile

access to regioselective alkenylation, halogenation, ﬂuoroalkox-

ylation, and hydroxylation. The reaction mechanism is proposed

to involve oxidative palladium catalysis via a Pd(II)−Pd(IV)

redox cycle. The developed protocol showed a broad substrate

scope and aﬀorded good to excellent yields of functionalized

coumarins. The 3-(2′-hydroxyaryl)coumarins generated by the

ortho-hydroxylation of 3-arylcoumarins were cyclized using

DDQ to obtain coumestan derivatives in good yields. Given that

the lactone functionality is present in a wide range of drug

molecules and natural products, the developed method should

allow their late-stage C−H functionalization under mild

conditions.

Ethyl (E)-3-(2-(2-Oxo-2H-chromen-3-yl)phenyl)acrylate (3ab).

The title compound 3ab was synthesized following method A. The

product was puriﬁed by using ethyl acetate/hexane (1.5:8.5 v/v) as an

eluent: R_f= 0.7; white solid (56 mg, 76%); mp = 147−149 °C; ¹H NMR

(400 MHz, CDCl₃) δ 7.76−7.73 (m, 1H), 7.71 (d, J = 15.6 Hz, 1H),

7.66 (s, 1H), 7.63−7.58 (m, 1H), 7.55 (dd, J = 7.8, 1.4 Hz, 1H), 7.50−

7.41 (m, 4H), 7.36−7.32 (m, 1H), 6.46 (d, J = 15.6 Hz, 1H), 4.22 (q, J =

7.1 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H); ¹³C{¹H} NMR (100 MHz,

CDCl₃) δ 166.6, 160.4, 154.0, 143.1, 142.1, 135.3, 133.7, 132.0, 130.8,

129.9, 129.2, 128.1, 127.4, 126.9, 124.7, 120.2, 119.1, 116.7, 60.5, 14.3;

+

HRMS (ESI) m/z [M + H]⁺calcd for C₂₀H₁₇O₄321.1121, found

321.1108.

Octadecyl (E)-3-(2-(2-Oxo-2H-chromen-3-yl)phenyl)acrylate

(3ac). The title compound 3ac was synthesized following method A.

The product was puriﬁed by using ethyl acetate/hexane (1:9 v/v) as an

eluent: R_f= 0.8; white solid (94 mg, 75%); mp = 95−97 °C; ¹H NMR

(400 MHz, CDCl₃) δ 7.78−7.75 (m, 1H), 7.71 (d, J = 15.6 Hz, 1H),

7.66 (s, 1H), 7.62−7.58 (m, 1H), 7.55 (dd, J = 7.8, 1.4 Hz, 1H), 7.49−

7.45 (m, 3H), 7.43 (d, J = 8.4 Hz, 1H), 7.36−7.32 (m, 1H), 6.47 (d, J =

15.6 Hz, 1H), 4.15 (t, J = 6.7 Hz, 2H), 1.67−1.61 (m, 3H), 1.36−1.27

(m, 29H), 0.90 (t, J = 6.7 Hz, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃)

δ 166.7, 160.4, 154.0, 143.0, 142.1, 135.3, 133.7, 131.9, 130.8, 129.9,

129.2, 128.1, 127.4, 126.9, 124.6, 120.2, 119.1, 116.8, 64.7, 31.9, 29.7,

29.7, 29.6, 29.5, 29.4, 29.3, 28.7, 25.9, 22.7, 14.1; HRMS (ESI) m/z [M

+ H]⁺calcd for C₃₆H₄₉O₄⁺545.3625, found 545.3583.

EXPERIMENTAL SECTION

■

General Information. Unless otherwise stated, all commercially

available materials were used without further puriﬁcation. Palladium-

(II) acetate was purchased from Alfa Aesar. Potassium persulfate was

bought from SD Fine Chemicals Ltd., India. All acrylates were obtained

from TCI (India). Triﬂuoroacetic acid (TFA) was procured from

Sigma-Aldrich. Triﬂuoroacetic anhydride (TFAA) and triﬂuorometha-

nesulfonic acid (triﬂic acid, TfOH) were received from Spectrochem,

India. The 3-arylcoumarins (1a−i) were prepared by the reaction of

salicylaldehyde and arylacetonitriles following literature procedures.²⁴

Acrylates (2a−e), NBS (4a), NCS (4b), and HFIP (6) are

commercially available and were purchased from Spectrochem, India.

All reactions were performed in a pressure tube under air with magnetic

stirring. Column chromatography was performed on silica gel (100−

200 mesh, Merck) using n-hexane and ethyl acetate as an eluent, and

TLC was performed on Merck aluminum TLC sheets (silica gel 60

Cyclohexyl (E)-3-(2-(2-Oxo-2H-chromen-3-yl)phenyl)acrylate

(3ad). The title compound 3ad was synthesized following method A.

The product was puriﬁed by using ethyl acetate/hexane (2:8 v/v) as an

eluent: R_f= 0.7; white solid (46 mg, 54%); mp = 150−152 °C; ¹H NMR

(400 MHz, CDCl₃) δ 7.77−7.75 (m, 1H), 7.71 (d, J = 15.8 Hz, 1H),

7.66 (s, 1H), 7.62−7.58 (m, 1H), 7.55 (dd, J = 7.8, 1.5 Hz, 1H), 7.50−

7.42 (m, 4H), 7.34 (t, J = 7.4 Hz, 1H), 6.46 (d, J = 15.8 Hz, 1H), 4.88−

4.82 (m, 1H), 1.88−1.82 (m, 2H), 1.73−1.65 (m, 2H), 1.55−1.43 (m,

3H), 1.41−1.32 (m, 2H), 1.30−1.20 (m, 1H); ¹³C{¹H} NMR (100

MHz, CDCl₃) δ 166.0, 160.4, 153.9, 143.1, 141.8, 135.3, 133.7, 131.9,

130.7, 129.8, 129.2, 128.1, 127.4, 126.8, 124.6, 120.7, 119.1, 116.7, 72.6,

1

F₂₅₄). The H NMR (400 MHz) and ¹³C{¹H} NMR (100 MHz)

spectra were recorded using CDCl₃(TMS as an internal standard) or

DMSO-d₆as the solvent. Chemical shifts (δ) and coupling constants (J)

are reported in parts per million (ppm) and hertz, respectively. The

chemical multiplicities were reported as singlet (s), doublet (d), triplet

(t), quartet (q), and multiplet (m) and their combinations as well. The

¹³C{¹H} shifts were referenced at 77.6 ppm for CDCl₃and 40.5 ppm for

DMSO-d₆, respectively. High-resolution mass spectra (HRMS) were

recorded in an electrospray ionization (ESI) mode on a Q-TOF LC-MS

spectrometer. X-ray crystal structures were obtained with a Rigaku

Oxford XtaLAB AFC12 (RINC): Kappa dual home/near diﬀrac-

tometer, and the thermal ellipsoids are drawn to the 50% probability

level. Melting points were determined in open capillary tubes on an

automated apparatus and were uncorrected.

Representative Procedure for ortho-Alkenylation (Method

A). An oven-dried 10 mL round-bottom ﬂask was charged with 3-

phenyl-2H-chromen-2-one 1a (0.23 mmol, 51 mg), methyl acrylate 2a

(0.9 mmol, 81 μL), Pd(OAc)₂(10 mol %, 5.15 mg), K₂S₂O₈(2 equiv,

124 mg), and TFA/TFAA (2 mL, 9:1 v/v). The reaction mixture was

reﬂuxed with stirring in an oil bath at 90 °C for 3 h. The reaction

mixture was cooled to an ambient temperature, basiﬁed with aqueous

NaHCO₃solution (5 mL), and then extracted with ethyl acetate (3 × 5

mL). The combined organic layer was washed with water (2 × 5 mL)

and dried over anhydrous Na₂SO₄, and the solvent was evaporated

under reduced pressure. The resulting residue was puriﬁed by column

chromatography over silica gel 60 (100−200 mesh size) using n-

hexane/ethyl acetate as an eluting system to give 62 mg (88%) of 3aa.

+

31.6, 25.4, 23.6; HRMS (ESI) m/z [M + H]⁺calcd for C₂₄H₂₃O₄

375.1591, found 375.1564.

Phenyl (E)-3-(2-(2-Oxo-2H-chromen-3-yl)phenyl)acrylate (3ae).

The title compound 3ae was synthesized following method A. The

crude product was puriﬁed by using 2.0:8.0 ethyl acetate/hexane as an

eluent: R_f= 0.7; white solid (38 mg, 45%); mp = 144−146 °C; ¹H NMR

(400 MHz, CDCl₃) δ 7.89 (d, J = 15.9 Hz, 1H), 7.85−7.82 (m, 1H),

7.71 (s, 1H), 7.62−7.47 (m, 5H), 7.44−7.32 (m, 4H), 7.28 (s, 1H),

7.24 (t, J = 7.4 Hz, 1H), 7.14 (d, J = 7.9 Hz, 2H), 6.67 (d, J = 15.8 Hz,

1H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 165.0, 160.4, 154.0, 150.7,

144.0, 143.1, 135.7, 133.5, 132.0, 130.9, 130.4, 129.4, 129.3, 128.1,

127.4, 127.0, 125.8, 124.7, 121.6, 119.2, 119.1, 116.8; HRMS (ESI) m/

z [M + H]⁺calcd for C₂₄H₁₇O₄⁺369.1121, found 369.1104.

Methyl (E)-3-(5-Methyl-2-(2-oxo-2H-chromen-3-yl)phenyl)-

acrylate (3ba). The title compound 3ba was synthesized following

method A. The product was puriﬁed by using 1.5:8.5 ethyl acetate/

hexane as an eluent: R_f= 0.7; white solid (51 mg, 69%); mp = 151−153

°C; ¹H NMR (400 MHz, CDCl₃) δ 7.69 (d, J = 15.8 Hz, 1H), 7.63 (s,

1H), 7.62−7.53 (m, 3H), 7.42 (d, J = 8.2 Hz, 1H), 7.36−7.28 (m, 3H),

6.45 (d, J = 15.8 Hz, 1H), 3.76 (s, 3H), 2.45 (s, 3H); ¹³C{¹H} NMR

(100 MHz, CDCl₃) δ 167.1, 160.5, 153.9, 142.8, 142.5, 139.1, 133.4,

132.6, 131.8, 130.9, 130.7, 128.0, 127.5, 127.4, 124.6, 119.5, 119.2,

+

116.7, 51.7, 21.3; HRMS (ESI) m/z [M + H]⁺calcd for C₂₀H₁₇O₄

321.1121, found 321.1129.

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Article

Ethyl (E)-3-(5-Methyl-2-(2-oxo-2H-chromen-3-yl)phenyl)acrylate

(3bb). The title compound 3bb was synthesized following method A.

The crude product was puriﬁed by using 1.5:8.5 ethyl acetate/hexane as

an eluent: R_f= 0.7; white solid (51 mg, 67%); mp = 130−132 °C; ¹H

NMR (400 MHz, CDCl₃) δ 7.69 (d, J = 15.8 Hz, 1H), 7.63 (s, 1H),

7.61−7.53 (m, 3H), 7.42 (d, J = 8.3 Hz, 1H), 7.36−7.33 (m, 2H),

7.31−7.30 (m, 1H), 6.46 (d, J = 15.8 Hz, 1H), 4.22 (q, J = 7.1 Hz, 2H),

2.4 (s, 3H),1.29 (t, J = 7.1 Hz, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃)

δ 166.7, 160.6, 153.9, 142.8, 142.3, 139.1, 133.5, 132.6, 131.8, 130.8,

130.7, 128.0, 127.4, 127.4, 124.6, 119.9, 119.2, 116.7, 60.5, 21.3, 14.3;

122.0, 118.9, 116.8, 72.9, 31.5, 25.4, 23.6; HRMS (ESI) m/z [M + H]⁺

calcd for C₂₄H₂₂ClO₄⁺409.1201, found 409.1170.

Phenyl (E)-3-(5-Chloro-2-(2-oxo-2H-chromen-3-yl)phenyl)-

acrylate (3de). The title compound 3de was synthesized following

method A. The crude product was puriﬁed by using 2.0:8.0 ethyl

acetate/hexane as an eluent: R_f= 0.6; white solid (41 mg, 44%); mp =

192−194 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.82−7.78 (m, 2H), 7.69

(s, 1H), 7.64−7.55 (m, 2H), 7.50 (dd, J = 8.3, 2.1 Hz, 1H), 7.45−7.33

(m, 5H), 7.27−7.23 (m, 1H), 7.16−7.12 (m, 2H), 6.67 (d, J = 15.8 Hz,

1H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 164.6, 160.2, 154.0, 150.6,

143.4, 142.7, 135.4, 135.2, 133.9, 132.3, 132.2, 130.3, 129.4, 128.2,

127.0, 126.3, 125.9, 124.8, 121.5, 120.5, 118.9, 116.9; HRMS (ESI) m/

z [M + H]⁺calcd for C₂₄H₁₆ClO₄⁺403.0732, found 403.0699.

Methyl (E)-3-(5-Fluoro-2-(2-oxo-2H-chromen-3-yl)phenyl)-

acrylate (3ea). The title compound 3ea was synthesized following

method A. The crude product was puriﬁed by using 1.5:8.5 ethyl

acetate/hexane as an eluent: R_f= 0.5; white solid (67 mg, 90%); mp =

143−145 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.66−7.60 (m, 3H), 7.56

(dd, J = 7.6, 1.6 Hz, 1H), 7.46−7.41 (m, 3H), 7.36 (td, J = 7.6, 1.2 Hz,

1H), 7.19 (td, J = 8.0, 2.4 Hz, 1H), 6.45 (d, J = 16.0 Hz, 1H), 3.77 (s,

3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 165.8 (d, J = 250 Hz), 162.7,

154.0, 143.3, 141.2 (d, J = 2.5 Hz), 135.9 (d, J = 7.9 Hz), 132.7 (d, J =

8.4 Hz), 132.1, 131.4 (d, J = 3.2 Hz), 128.1, 126.5, 124.8, 120.9, 119.0,

117.1 (d, J = 21.7 Hz), 116.8, 113.4 (d, J = 22.5 Hz), 51.8; HRMS (ESI)

m/z [M + H]⁺calcd for C₁₉H₁₄FO₄⁺325.0871, found 325.0852.

Cyclohexyl (E)-3-(5-Fluoro-2-(2-oxo-2H-chromen-3-yl)phenyl)-

acrylate (3ed). The title compound 3ed was synthesized following

method A. The crude product was puriﬁed by using 2.0:8.0 ethyl

acetate/hexane as an eluent: R_f= 0.4; white solid (54 mg, 60%); mp =

+

HRMS (ESI) m/z [M + H]⁺calcd for C₂₁H₁₉O₄335.1278, found

335.1256.

Cyclohexyl (E)-3-(5-Methyl-2-(2-oxo-2H-chromen-3-yl)phenyl)-

acrylate (3bd). The title compound 3bd was synthesized following

method A. The crude product was puriﬁed by using 2.0:8.0 ethyl

acetate/hexane as an eluent: R_f= 0.6; white solid (49 mg, 55%); mp =

135−137 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.69 (d, J = 15.8 Hz, 1H),

7.63 (s, 1H), 7.61−7.53 (m, 3H), 7.42 (d, J = 8.3 Hz, 1H), 7.39−7.28

(m, 3H), 6.45 (d, J = 15.9 Hz, 1H), 4.89−4.82 (m, 1H), 2.44 (s, 3H),

1.88−1.83 (m, 2H), 1.74−1.45 (m, 2H), 1.51−1.22 (m, 6H); ¹³C{¹H}

NMR (100 MHz, CDCl₃) δ 166.1, 160.6, 153.9, 142.9, 141.9, 139.1,

133.5, 132.6, 131.8, 130.7, 130.6, 128.0, 127.4, 124.6, 120.4, 119.2,

116.7, 72.6, 31.6, 25.4, 23.6, 21.3; HRMS (ESI) m/z [M + H]⁺calcd for

C₂₅H₂₅O₄⁺389.1747, found 389.1730.

Methyl (E)-3-(5-Methoxy-2-(2-oxo-2H-chromen-3-yl)phenyl)-

acrylate (3ca). The title compound 3ca was synthesized following

method A. The crude product was puriﬁed by using 2.5:7.5 ethyl

acetate/hexane as an eluent: R_f= 0.6; white solid (54 mg, 70%); mp =

218−220 °C; ¹H NMR (400 MHz, CDCl₃) δ 8.04 (d, J = 16.2 Hz, 1H),

7.87 (d, J = 2.4 Hz, 1H), 7.82−7.80 (m, 2H), 7.59−7.53 (m, 2H), 7.40

(d, J = 8.6 Hz, 1H), 7.34 (td, J = 7.5, 1.1 Hz, 1H), 7.03 (d, J = 8.7 Hz,

1H), 6.63 (d, J = 16.2 Hz, 1H), 3.97 (s, 3H), 3.84 (s, 3H); ¹³C{¹H}

NMR (100 MHz, CDCl₃) δ 167.8, 160.6, 158.8, 153.4, 139.8, 138.9,

131.8, 131.3, 129.1, 127.8, 127.3, 127.2, 124.6, 123.5, 119.7, 119.1,

116.5, 111.2, 55.6, 51.7; HRMS (ESI)m/z [M + H]⁺calcd for

C₂₀H₁₇O₅⁺337.1071, found 337.1053.

Cyclohexyl (E)-3-(5-Methoxy-2-(2-oxo-2H-chromen-3-yl)phenyl)-

acrylate (3cd). The title compound 3 cd was synthesized following

method A. The product was puriﬁed by using 2.0:8.0 ethyl acetate/

hexane as an eluent: R_f= 0.5; white solid (44 mg, 48%); mp = 178−180

°C; ¹H NMR (400 MHz, CDCl₃) δ 7.68 (d, J = 15.6 Hz, 1H), 7.61 (s,

1H), 7.58−7.52 (m, 2H), 7.41 (d, J = 8.4 Hz, 1H), 7.32 (t, J = 7.6 Hz,

1H), 7.24 (d, J = 2.4 Hz, 1H), 7.03 (dd, J = 8.8, 2.8 Hz, 1H), 6.44 (d, J =

15.6 Hz, 1H), 4.89−4.82 (m, 1H), 3.90 (s, 3H), 1.87−1.82 (m, 2H),

1.73−1.65 (m, 3H), 1.54−1.32 (m, 6H); ¹³C{¹H} NMR (100 MHz,

CDCl₃) δ 166.0, 160.8, 160.0, 153.8, 142.8, 141.9, 135.0, 132.0, 131.7,

127.9, 127.0, 124.6, 120.8, 119.2, 116.7, 116.1, 111.4, 72.7, 55.5, 31.6,

25.4, 23.6; HRMS (ESI) m/z [M + H]⁺calcd for C₂₅H₂₅O₅⁺405.1697,

found 405.1692.

1

167−169 °C; H NMR (400 MHz, CDCl₃) δ 7.83−7.72 (m, 1H),

7.66−7.65 (m, 1H), 7.63−7.58 (m, 1H), 7.58−7.54 (m, 1H), 7.48−

7.42 (m, 3H), 7.37−7.33 (m, 1H), 7.21−7.14 (m, 1H), 6.44 (d, J = 16.0

Hz, 1H), 4.89−4.83 (m, 1H), 1.88−1.83 (m, 2H), 1.72−1.68 (m, 2H),

1.53−1.43 (m, 2H), 1.44−1.32 (m, 3H), 1.30−1.27 (m, 1H); ¹³C{¹H}

NMR (100 MHz, CDCl₃) δ 165.7, 162.7 (d, J = 230.0 Hz), 154.0,

143.3, 140.7 (d, J = 2.4 Hz), 136.0 (d, J = 8.3 Hz), 132.7 (d, J = 8.6 Hz),

132.1, 131.5, 131.3, 128.1, 126.4, 124.7, 121.9, 119.0, 117.0 (d, J = 22.0

Hz), 116.8, 116.6, 116.5, 113.4 (d, J = 22.4 Hz), 72.9, 31.5, 25.4, 23.6;

+

HRMS (ESI) m/z [M + H]⁺calcd for C₂₄H₂₂FO₄393.1497, found

393.1496.

Methyl (E)-3-(2-(6-Methyl-2-oxo-2H-chromen-3-yl)phenyl)-

acrylate (3fa). The title compound 3fa was synthesized following

method A. The crude product was puriﬁed by using 1.5:8.5 ethyl

acetate/hexane as an eluent: R_f= 0.7; white solid (59.5 mg, 81%); mp =

164−166 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.75−7.73 (m, 1H), 7.71

(d, J = 15.9 Hz, 1H), 7.60 (s, 1H), 7.50−7.39 (m, 4H), 7.33−7.31 (m,

2H), 6.46 (d, J = 15.8 Hz, 1H), 3.76 (s, 3H), 2.45 (s, 3H); ¹³C{¹H}

NMR (100 MHz, CDCl₃) δ 167.0, 160.6, 152.1, 143.1, 142.4, 135.6,

134.4, 133.7, 133.0, 130.8, 129.9, 129.1, 127.9, 127.3, 126.9, 119.7,

118.9, 116.5, 51.7, 20.8; HRMS (ESI) m/z [M + H]⁺calcd for

C₂₀H₁₇O₄⁺321.1121, found 321.1092.

Cyclohexyl (E)-3-(2-(6-Methyl-2-oxo-2H-chromen-3-yl)phenyl)-

acrylate (3fd). The title compound 3fd was synthesized following

method A. The crude product was puriﬁed by using 2.0:8.0 ethyl

acetate/hexane as an eluent: R_f= 0.7; white solid (53.5 mg, 60%); mp =

146−148 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.77−7.75 (m, 1H), 7.71

(d, J = 15.8 Hz, 1H), 7.60 (s, 1H), 7.48−7.43 (m, 3H), 7.40 (dd, J = 8.8,

2.1 Hz, 1H), 7.33−7.31 (m, 2H), 6.45 (d, J = 15.8 Hz, 1H), 4.89−4.83

(m, 1H), 2.45 (s, 3H), 1.88−1.82 (m, 2H), 1.73−1.66 (m, 2H), 1.56−

1.43 (m, 3H), 1.42−1.32 (m, 2H), 1.30−1.20 (m, 1H); ¹³C{¹H} NMR

(100 MHz, CDCl₃) δ 166.1, 160.7, 152.1, 143.1, 141.9, 135.5, 134.3,

133.7, 133.0, 130.8, 129.8, 129.1, 127.8, 127.1, 126.8, 120.6, 118.8,

116.4, 72.6, 31.6, 25.4, 23.6, 20.8; HRMS (ESI) m/z [M + H]⁺calcd for

C₂₅H₂₅O₄⁺389.1747, found 389.1715.

Methyl (E)-3-(5-Chloro-2-(2-oxo-2H-chromen-3-yl)phenyl)-

acrylate (3da). The title compound 3da was synthesized following

method A. The crude product was puriﬁed by using 1.5:8.5 ethyl

acetate/hexane as an eluent: R_f= 0.7; white solid (57 mg, 73%); mp =

185−187 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.70 (d, J = 2.1 Hz, 1H),

7.65−7.60 (m, 3H), 7.56 (dd, J = 7.8, 1.6 Hz, 1H), 7.46−7.40 (m, 3H),

7.38−7.33 (m, 1H), 6.45 (d, J = 15.8 Hz, 1H), 3.77 (s, 3H); ¹³C{¹H}

NMR (100 MHz, CDCl₃) δ 166.6, 160.2, 154.0, 143.3, 141.0, 135.4,

135.3, 133.6, 132.2, 132.1, 129.9, 128.2, 126.9, 126.4, 124.8, 121.0,

+

119.0, 116.8, 51.9; HRMS (ESI) m/z [M + H]⁺calcd for C₁₉H₁₄ClO₄

341.0575, found 341.0545.

Cyclohexyl (E)-3-(5-Chloro-2-(2-oxo-2H-chromen-3-yl)phenyl)-

acrylate (3dd). The title compound 3dd was synthesized following

method A. The crude product was puriﬁed by using 1.5:8.5 ethyl

acetate/hexane as an eluent: R_f= 0.7; white solid (49 mg, 52%); mp =

177−179 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.73 (d, J = 2.0 Hz, 1H),

7.65−7.59 (m, 3H), 7.55 (dd, J = 7.8, 1.6 Hz, 1H), 7.46−7.40 (m, 3H),

7.35 (td, J = 7.5, 1.1 Hz, 1H), 6.46 (d, J = 15.8 Hz, 1H), 4.88−4.82 (m,

1H), 1.88−1.82 (m, 2H), 1.74−1.67 (m, 2H), 1.51−1.21 (m, 6H);

¹³C{¹H} NMR (100 MHz, CDCl₃) δ 165.6, 160.2, 154.0, 143.3, 140.4,

Methyl (E)-3-(2-(6-Methoxy-2-oxo-2H-chromen-3-yl)phenyl)-

acrylate (3ga). The title compound 3ga was synthesized following

method A. The crude product was puriﬁed by using 2.5:7.5 ethyl

acetate/hexane as an eluent: R_f= 0.3; white solid (59 mg, 76%); mp =

142−144 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.76−7.73 (m, 1H), 7.70

(d, J = 15.6 Hz, 1H), 7.61 (s, 1H), 7.50−7.42 (m, 3H), 7.35 (d, J = 8.8

135.5, 135.3, 133.6, 132.2, 132.1, 129.8, 128.1, 126.8, 126.3, 124.7,

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Hz, 1H), 7.18 (dd, J = 8.8, 2.8 Hz, 1H), 6.97 (d, J = 2.8 Hz, 1H), 6.46 (d,

J = 16.0 Hz, 1H), 3.88 (s, 3H), 3.76 (s, 3H); ¹³C{¹H} NMR (100 MHz,

CDCl₃) δ 167.0, 160.5, 156.3, 148.4, 142.9, 142.4, 135.5, 133.6, 130.8,

130.0, 129.2, 127.8, 126.9, 119.8, 119.7, 119.4, 117.8, 110.1, 55.9, 51.7;

Representative Procedure for ortho-Halogenation (Method

B). An oven-dried 10 mL round-bottom ﬂask was charged with 3-

phenyl-2H-chromen-2-one 1a (0.23 mmol, 51 mg), NBS 4a (0.25

mmol, 45 mg), Pd(OAc)₂(10 mol %, 5.15 mg), K₂S₂O₈(2 equiv, 124

mg), TfOH (2 equiv, 41 μL), and 1,2-dichloroethane (2 mL). The

reaction mixture was heated with stirring in an oil bath at 80 °C for 24 h.

After completion of the reaction, the reaction mixture was cooled to an

ambient temperature, basiﬁed with aqueous NaHCO₃solution, and

then extracted with ethyl acetate (3 × 5 mL). The combined organic

layer was washed with water (2 × 5 mL), dried over anhydrous Na₂SO₄,

and concentrated under reduced pressure. The resulting residue was

puriﬁed by column chromatography over silica gel 60 (100−200 mesh

size) using n-hexane/ethyl acetate as an eluting system to give 5aa (50

mg, 73%).

+

HRMS (ESI) m/z [M + H]⁺calcd for C₂₀H₁₇O₅337.1071, found

337.1065.

Cyclohexyl (E)-3-(2-(6-Methoxy-2-oxo-2H-chromen-3-yl)phenyl)-

acrylate (3gd). The title compound 3gd was synthesized following

method A. The crude product was puriﬁed by using 2.5:7.5 ethyl

acetate/hexane as an eluent: R_f= 0.3; white solid (59.5 mg, 64%); mp =

143−145 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.78−7.75 (m, 1H), 7.71

(d, J = 15.6 Hz, 1H), 7.61 (s, 1H), 7.50−7.42 (m, 3H), 7.36 (d, J = 8.8

Hz, 1H), 7.18 (dd, J = 9.2, 2.8 Hz, 1H), 6.97 (d, J = 3.2 Hz, 1H), 6.46 (d,

J = 16.0 Hz, 1H), 4.89−4.83 (m, 1H), 3.88 (s, 3H), 1.88−1.83 (m, 2H),

1.73−1.68 (m, 2H), 1.56−1.44 (m, 3H), 1.42−1.43 (m, 1H), 1.31−

1.23 (m, 1H), 0.92−0.86 (m, 1H); ¹³C{¹H} NMR (100 MHz, CDCl₃)

δ 166.1, 160.6, 156.2, 148.4, 142.9, 141.8, 135.4, 133.7, 130.7, 129.8,

129.1, 127.7, 126.8, 120.7, 119.7, 119.4, 117.8, 110.0, 72.6, 55.9, 31.6,

25.4, 23.6; HRMS (ESI) m/z [M + H]⁺calcd for C₂₅H₂₅O₅⁺405.1697,

found 405.1692.

Methyl (E)-3-(2-(6-Chloro-2-oxo-2H-chromen-3-yl)phenyl)-acryl-

ate (3ha). The title compound 3ha was synthesized following method

A. The crude product was puriﬁed by using 1.5:8.5 ethyl acetate/hexane

as an eluent: R_f= 0.7; white solid (39 mg, 50%); mp = 209−211 °C; ¹H

NMR (400 MHz, CDCl₃) δ 7.76−7.73 (m, 1H), 7.67 (d, J = 15.9 Hz,

1H), 7.58 (s, 1H), 7.57−7.53 (m, 2H), 7.52−7.47 (m, 2H), 7.45−7.41

(m, 1H), 7.38 (d, J = 8.6 Hz, 1H), 6.47 (d, J = 15.8 Hz, 1H), 3.78 (s,

3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 167.0, 159.8, 152.3, 142.1,

141.7, 134.8, 133.7, 131.9, 130.7, 130.0, 130.0, 129.5, 128.7, 127.3,

127.0, 120.1, 120.0, 118.2, 51.8; HRMS (ESI) m/z [M + H]⁺calcd for

C₁₉H₁₄ClO₄⁺341.0575, found 341.0543.

3-(2-Bromophenyl)-2H-chromen-2-one (5aa).²⁵The title com-

pound 5aa was synthesized following method B: R_f= 0.3; white solid

(50 mg, 73%); mp = 181−183 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.76

(s, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.62−7.56 (m, 2H), 7.44−7.42 (m,

3H), 7.35 (t, J = 8.0 Hz, 1H), 7.32−7.30 (m, 1H); ¹³C{¹H} NMR (100

MHz, CDCl₃) δ 159.8, 154.0, 142.5, 135.8, 133.1, 131.9, 131.3, 130.2,

128.8, 128.1, 127.5, 124.6, 123.6, 119.0, 116.8; HRMS (ESI) m/z [M +

H]⁺calcd for C₁₅H₁₀BrO₂⁺300.9859, found 300.9843.

3-(2-Bromo-4-methylphenyl)-2H-chromen-2-one (5ba). The title

compound 5ba was synthesized following method B. The crude

product was puriﬁed by using 1.5:8.5 ethyl acetate/hexane as an eluent:

R_f= 0.5; white solid (48 mg, 67%); mp = 156−158 °C; ¹H NMR (400

MHz, CDCl₃) δ 7.73 (s, 1H), 7.61−7.53 (m, 3H), 7.41 (d, J = 8.4 Hz,

1H), 7.35−7.28 (m, 2H), 7.23−7.20 (m, 1H), 2.40 (s, 3H); ¹³C{¹H}

NMR (100 MHz, CDCl₃) δ 159.9, 153.9, 142.4, 140.6, 133.6, 132.8,

131.7, 131.0, 128.7, 128.3, 128.1, 124.5, 123.3, 119.1, 116.7, 20.9;

HRMS (ESI) m/z [M + H]⁺calcd for C₁₆H₁₂BrO₂⁺315.0015, found

315.0012.

Cyclohexyl (E)-3-(2-(6-Chloro-2-oxo-2H-chromen-3-yl)phenyl)-

acrylate (3hd). The title compound 3hd was synthesized following

method A. The crude product was puriﬁed by using 1.5:8.5 ethyl

acetate/hexane as an eluent: R_f= 0.7; white solid (41 mg, 44%); mp =

182−184 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.78−7.72 (m, 1H), 7.67

(d, J = 15.8 Hz, 1H), 7.58 (s, 1H), 7.56−7.53 (m, 2H), 7.51−7.43 (m,

3H), 7.38−7.43 (m, 1H), 6.46 (d, J = 15.8 Hz, 1H), 4.89−4.83 (m,

1H), 1.90−1.84 (m, 2H), 1.74−1.68 (m, 2H), 1.57−1.46 (m, 3H),

1.44−1.34 (m, 2H), 1.31−1.21 (m, 1H); ¹³C{¹H} NMR (100 MHz,

CDCl₃) δ 166.0, 159.8, 152.3, 141.7, 141.5, 134.8, 133.7, 131.8, 130.6,

129.9, 129.9, 129.4, 128.6, 127.2, 126.9, 120.9, 120.1, 118.2, 72.7, 31.6,

3-(2-Bromo-4-methoxyphenyl)-2H-chromen-2-one (5ca). The

title compound 5ca was synthesized following method B. The crude

product was puriﬁed by using 2.5:7.5 ethyl acetate/hexane as an eluent:

R_f= 0.4; white solid (44 mg, 58%); mp = 148−150 °C; ¹H NMR (400

MHz, CDCl₃) δ 7.93 (d, J = 2.0 Hz, 1H), 7.81 (s, 1H), 7.75 (dd, J = 8.8,

2.4 Hz, 1H), 7.56 (t, J = 7.6 Hz, 2H), 7.39 (d, J = 8.4 Hz, 1H), 7.33 (td, J

= 7.6, 1.2 Hz, 1H), 7.00 (d, J = 8.0 Hz, 1H), 3.97 (s, 3H); ¹³C{¹H}

NMR (100 MHz, CDCl₃) δ 160.4, 156.4, 153.4, 139.1, 133.2, 131.4,

129.0, 128.4, 127.9, 126.5, 124.6, 119.6, 116.5, 111.7, 111.6, 56.4;

HRMS (ESI) m/z [M + H]⁺calcd for C₁₆H₁₂BrO₃⁺330.9964, found

330.9932.

3-(2-Bromo-4-chlorophenyl)-2H-chromen-2-one (5da). The title

compound 5da was synthesized following method B. The crude

product was puriﬁed by using 1.5:8.5 ethyl acetate/hexane as an eluent:

R_f= 0.6; white solid (48.5 mg, 63%); mp = 167−169 °C; ¹H NMR (400

MHz, CDCl₃) δ 7.75 (s, 1H), 7.72 (d, J = 2.0 Hz, 1H), 7.63−7.61 (m,

1H), 7.58−7.56 (m, 1H), 7.43−7.41 (m, 1H), 7.40−7.37 (m, 2H),

7.36−7.33 (m, 1H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 159.6, 154.0,

142.9, 135.4, 134.3, 132.8, 132.1, 132.1, 129.8, 128.2, 127.8, 124.7,

124.1, 118.8, 116.8; HRMS (ESI) m/z [M + H]⁺calcd for

C₁₅H₉BrClO₂⁺334.9469, found 334.9439.

+

25.4, 23.6; HRMS (ESI) m/z [M + H]⁺calcd for C₂₄H₂₂ClO₄

409.1201, found 409.1197.

Methyl (E)-3-(2-(3-Oxo-3H-benzo[f]chromen-2-yl)phenyl)-acryl-

ate (3ia). The title compound 3ia was synthesized following method A.

The crude product was puriﬁed by using 1.5:8.5 ethyl acetate/hexane as

an eluent: R_f= 0.7; white solid (64 mg, 78%); mp = 232−234 °C; ¹H

NMR (400 MHz, CDCl₃) δ 8.46 (s, 1H), 8.22 (d, J = 8.4 Hz, 1H), 8.07

(d, J = 9.0 Hz, 1H), 7.97 (dd, J = 8.1, 1.3 Hz, 1H), 7.80−7.68 (m, 3H),

7.63−7.50 (m, 5H), 6.50 (d, J = 15.8 Hz, 1H), 3.73 (s, 3H); ¹³C{¹H}

NMR (100 MHz, CDCl₃) δ 168.0, 160.4, 153.8, 142.5, 139.0, 135.8,

133.8, 133.4, 130.9, 130.4, 130.1, 129.3, 129.2, 129.1, 128.4, 127.0,

126.4, 126.2, 121.4, 119.9, 116.9, 113.3, 51.7; HRMS (ESI) m/z [M +

H]⁺calcd for C₂₃H₁₇O₄⁺357.1121, found 357.1090.

Cyclohexyl (E)-3-(2-(3-Oxo-3H-benzo[f ]chromen-2-yl)phenyl)-

acrylate (3id). The title compound 3id was synthesized following

method A. The crude product was puriﬁed by using 2.0:8.0 ethyl

acetate/hexane as an eluent: R_f= 0.7; white solid (61.5 mg, 63%); mp =

198−200 °C; ¹H NMR (400 MHz, CDCl₃) δ 8.45 (s, 1H), 8.21 (d, J =

8.4 Hz, 1H), 8.06 (d, J = 9.0 Hz, 1H), 7.97 (d, J = 8.1 Hz, 1H), 7.81−

7.76 (m, 2H), 7.69 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 7.62−7.48 (m, 5H),

6.49 (d, J = 15.8 Hz, 1H), 4.85−4.79 (m, 1H), 1.82−1.75 (m, 2H),

1.65−1.57 (m, 2H), 1.50−1.36 (m, 3H), 1.34−1.24 (m, 2H), 1.20−

1.11 (m, 1H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 166.0, 160.5, 153.8,

141.9, 139.1, 135.7, 133.9, 133.3, 130.8, 130.4, 129.9, 129.2, 129.2,

129.1, 128.4, 126.9, 126.2, 126.1, 121.4, 120.8, 116.8, 113.3, 72.6, 31.5,

25.3, 23.5; HRMS (ESI) m/z [M + H]⁺calcd for C₂₈H₂₅O₄⁺425.1747,

found 425.1713.

3-(2-Bromo-4-ﬂuorophenyl)-2H-chromen-2-one (5ea). The title

compound 5ea was synthesized following method B. The crude

product was puriﬁed by using 2.0:8.0 ethyl acetate/hexane as an eluent:

R_f= 0.4; white solid (52 mg, 71%); mp = 157−159 °C; ¹H NMR (400

MHz, CDCl₃) δ 7.75 (s, 1H), 7.63−7.56 (m, 2H), 7.47−7.39 (m, 3H),

7.35 (td, J = 7.6, 1.2 Hz, 1H), 7.14 (td, J = 8.4, 2.8 Hz, 1H); ¹³C{¹H}

NMR (100 MHz, CDCl₃) δ 162.38 (d, J = 251.3 Hz), 159.8, 154.0,

142.9, 132.4 (d, J = 8.7 Hz), 132.0, 131.9 (d, J = 3.7 Hz), 128.1, 127.8,

124.7, 124.0 (d, J = 9.7 Hz), 120.5 (d, J = 24.4 Hz), 118.9, 116.8, 114.8

+

(d, J = 21.2 Hz); HRMS (ESI) m/z [M + H]⁺calcd for C₁₅H₉BrFO₂

318.9764, found 318.9749.

3-(2-Bromophenyl)-6-methyl-2H-chromen-2-one (5fa).²⁶The

title compound 5fa was synthesized following method B. The crude

product was puriﬁed by using 1.5:8.5 ethyl acetate/hexane as an eluent:

R_f= 0.5; white solid (53.5 mg, 74%); mp = 137−139 °C (lit.²⁶mp 141−

1

142 °C); H NMR (400 MHz, CDCl₃) δ 7.70 (d, J = 6.8 Hz, 2H),

7.42−7.38 (m, 3H), 7.35−7.31 (m, 2H), 7.29−7.27 (m, 1H), 2.45 (s,

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https://doi.org/10.1021/acs.joc.1c01097

J. Org. Chem. 2021, 86, 9755−9770

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 160.0, 152.1, 142.6, 135.9,

154.0, 143.0, 134.7 (d, J = 10.4 Hz), 132.5 (d, J = 8.9 Hz), 132.1, 129.9

(d, J = 3.7 Hz), 128.1, 126.1, 124.6, 118.9, 117.4 (d, J = 24.7 Hz), 116.8,

114.3 (d, J = 21.3 Hz); HRMS (ESI) m/z [M + H]⁺calcd for

C₁₅H₉ClFO₂⁺275.0270, found 275.0249.

134.3, 133.1, 132.9, 131.4, 130.1, 128.6, 127.9, 127.4, 123.6, 118.8,

+

116.4, 20.8; HRMS (ESI) m/z [M + H]⁺calcd for C₁₆H₁₂BrO₂

315.0015, found 315.0012.

3-(2-Bromophenyl)-6-chloro-2H-chromen-2-one (5ha). The title

compound 5ha was synthesized following method B. The crude

product was puriﬁed by using 1.5:8.5 ethyl acetate/hexane as an eluent:

R_f= 0.5; white solid (51 mg, 66%); mp = 165−167 °C; ¹H NMR (400

MHz, CDCl₃) δ 7.71 (d, J = 8.0 Hz, 1H), 7.68 (s, 1H), 7.55−7.53 (m,

2H), 7.47−7.36 (m, 3H), 7.34−7.30 (m, 1H); ¹³C{¹H} NMR (100

MHz, CDCl₃) δ 159.2, 152.3, 141.2, 135.3, 133.2, 131.8, 131.2, 130.5,

130.0, 129.9, 127.5, 127.3, 123.4, 120.0, 118.2; HRMS (ESI) m/z [M +

H]⁺calcd for C₁₅H₉BrClO₂⁺334.9469, found 334.9449.

3-(2-Chlorophenyl)-6-methyl-2H-chromen-2-one (5fb). The title

compound 5fb was synthesized following method B. The crude product

was puriﬁed by using 2.0:8.0 ethyl acetate/hexane as an eluent: R_f= 0.5;

white solid (50.5 mg, 81%); mp = 149−151 °C; ¹H NMR (400 MHz,

CDCl₃) δ 7.72 (s, 1H), 7.53−7.50 (m, 1H), 7.45−7.42 (m, 1H), 7.41−

7.34 (m, 4H), 7.32 (d, J = 8.4 Hz, 1H); ¹³C{¹H} NMR (100 MHz,

CDCl₃) δ 160.1, 152.1, 142.7, 134.3, 133.9, 133.7, 132.9, 131.4, 130.0,

129.9, 127.9, 126.9, 126.8, 118.8, 116.4, 20.8; HRMS (ESI) m/z [M +

H]⁺calcd for C₁₆H₁₂ClO₂⁺271.0520, found 271.0530.

3-(2-Chlorophenyl)-6-methoxy-2H-chromen-2-one (5gb). The

title compound 5gb was synthesized following method B. The crude

product was puriﬁed by using 2.5:7.5 ethyl acetate/hexane as an eluent:

R_f= 0.3; white solid (49.5 mg, 75%); mp = 169−171 °C; ¹H NMR (400

MHz, CDCl₃) δ 7.73 (s, 1H), 7.53−7.50 (m, 1H), 7.45−7.42 (m, 1H),

7.38−7.34 (m, 3H), 7.17 (dd, J = 8.8, 2.8 Hz, 1H), 6.99 (d, J = 2.8 Hz,

1H), 3.88 (s, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 160.0, 156.2,

148.4, 142.5, 133.8, 133.6, 131.4, 130.0, 129.9, 127.4, 126.8, 119.7,

119.4, 117.7, 110.1, 55.9; HRMS (ESI) m/z [M + H]⁺calcd for

C₁₆H₁₂ClO₃⁺287.0469, found 287.0443.

6-Chloro-3-(2-chlorophenyl)-2H-chromen-2-one (5hb). The title

compound 5hb was synthesized following method B. The crude

product was puriﬁed by using 1.5:8.5 ethyl acetate/hexane as an eluent:

R_f= 0.6; white solid (38 mg, 57%); mp = 182−184 °C; ¹H NMR (400

MHz, CDCl₃) δ 7.78 (s, 1H), 7.63−7.56 (m, 2H), 7.45−7.42 (m, 2H),

7.35 (td, J = 7.6, 1.2 Hz, 1H), 7.29−7.26 (m, 1H), 7.12−7.07 (m, 1H);

¹³C{¹H} NMR (100 MHz, CDCl₃) δ 159.2, 152.3, 141.4, 133.6, 133.3,

131.8, 131.3, 130.3, 130.0, 129.9, 128.3, 127.3, 126.9, 120.1, 118.2;

HRMS (ESI) m/z [M + H]⁺calcd for C₁₅H₉Cl₂O₂⁺290.9974, found

290.9964.

2-(2-Bromophenyl)-3H-benzo[f ]chromen-3-one (5ia).²⁵The title

compound 5ia was synthesized following method B. The crude product

was puriﬁed by using 1.5:8.5 ethyl acetate/hexane as an eluent: R_f= 0.6;

1

white solid (56 mg, 70%); mp = 162−164 °C; H NMR (400 MHz,

CDCl₃) δ 8.56 (s, 1H), 8.26 (d, J = 8.0 Hz, 1H), 8.05 (d, J = 9.2 Hz,

1H), 7.96 (d, J = 8.0 Hz, 1H), 7.75 (dd, J = 8.0, 1.2 Hz, 1H), 7.73−7.69

(m, 1H), 7.63−7.59 (m, 1H), 7.55 (d, J = 8.8 Hz, 1H), 7.52 (dd, J = 7.6,

1.6 Hz, 1H), 7.46 (td, J = 7.2, 1.2 Hz, 1H), 7.33 (td, J = 8.0, 2.0 Hz, 1H);

¹³C{¹H} NMR (100 MHz, CDCl₃) δ 159.8, 153.8, 138.6, 136.1, 133.2,

131.5, 130.4, 130.2, 129.2, 129.1, 128.4, 127.6, 127.6, 126.1, 123.7,

+

121.5, 116.9, 113.2; HRMS (ESI) m/z [M + H]⁺calcd for C₁₉H₁₂BrO₂

351.0015, found 350.9994.

3-(2-Chlorophenyl)-2H-chromen-2-one (5ab).²⁷The title com-

pound 5ab was synthesized following method B. The crude product was

puriﬁed by using 2.0:8.0 ethyl acetate/hexane as an eluent: R_f= 0.4;

white solid (43.5 mg, 74%); mp = 135−137 °C (lit.²⁷mp 138 °C); ¹H

NMR (400 MHz, CDCl₃) δ 7.78 (s, 1H), 7.62−7.55 (m, 2H), 7.53−

7.51 (m, 1H), 7.45−7.40 (m, 2H), 7.39−7.32 (m, 3H); ¹³C{¹H} NMR

(100 MHz, CDCl₃) δ 159.8, 154.0, 142.7, 133.78, 133.7, 131.9, 131.4,

130.1, 129.9, 128.1, 127.1, 126.8, 124.6, 119.1, 116.7; HRMS (ESI) m/

z [M + H]⁺calcd for C₁₅H₁₀ClO₂⁺257.0364, found 257.0341.

3-(2-Chloro-4-methylphenyl)-2H-chromen-2-one (5bb). The title

compound 5bb was synthesized following method B. The crude

product was puriﬁed by using 2.0:8.0 ethyl acetate/hexane as an eluent:

R_f= 0.5; white solid (42 mg, 68%); mp = 138−140 °C; ¹H NMR (400

MHz, CDCl₃) δ 7.76 (s, 1H), 7.60−7.54 (m, 2H), 7.41 (d, J = 8.0 Hz,

1H), 7.35−7.33 (m, 2H), 7.31 (s, 1H), 7.18−7.16 (m, 1H), 2.40 (s,

3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 160.0, 153.9, 142.5, 140.5,

133.2, 131.7, 131.1, 130.7, 130.4, 128.0, 127.7, 127.1, 124.5, 119.1,

2-(2-Chlorophenyl)-3H-benzo[f]chromen-3-one (5ib). The title

compound 5ib was synthesized following method B. The crude product

was puriﬁed by using 2.0:8.0 ethyl acetate/hexane as an eluent: R_f= 0.5;

1

white solid (62 mg, 88%); mp = 160−162 °C; H NMR (400 MHz,

CDCl₃) δ 8.58 (s, 1H), 8.27 (d, J = 8.4 Hz, 1H), 8.06 (d, J = 8.8 Hz,

1H), 7.97 (d, J = 8.4 Hz, 1H), 7.71 (t, J = 7.2 Hz, 1H), 7.61 (t, J = 7.6

Hz, 1H), 7.58−7.52 (m, 3H), 7.44−7.39 (m, 2H); ¹³C{¹H} NMR (100

MHz, CDCl₃) δ 159.9, 153.8, 138.7, 134.1, 133.8, 133.2, 131.5, 130.4,

130.1, 130.0, 129.2, 129.1, 128.3, 126.9, 126.1, 126.0, 121.5, 116.9,

113.2; HRMS (ESI) m/z [M + H]⁺calcd for C₁₉H₁₂ClO₂⁺307.0520,

found 307.0492.

+

116.7, 21.0; HRMS (ESI) m/z [M + H]⁺calcd for C₁₆H₁₂ClO₂

271.0520, found 271.0530.

3-(2-Chloro-4-methoxyphenyl)-2H-chromen-2-one (5cb). The

title compound 5cb was synthesized following method B. The crude

product was puriﬁed by using 2.5:7.5 ethyl acetate/hexane as an eluent:

R_f= 0.4; white solid (37 mg, 56%); mp = 155−157 °C; ¹H NMR (400

MHz, CDCl₃) δ 7.81 (s, 1H), 7.77 (d, J = 2.4 Hz, 1H), 7.70 (dd, J = 8.6,

2.2 Hz, 1H), 7.58−7.54 (m, 2H), 7.41−7.39 (m, 1H), 7.35−7.31 (m,

1H), 7.03 (d, J = 8.4 Hz, 1H), 3.98 (s, 3H); ¹³C{¹H} NMR (100 MHz,

CDCl₃) δ 155.5, 139.1, 131.4, 130.2, 130.2, 128.2, 127.9, 127.8, 126.7,

124.6, 122.7, 119.6, 116.5, 115.1, 111.8, 56.3; HRMS (ESI) m/z [M +

H]⁺calcd for C₁₆H₁₂ClO₃⁺287.0469, found 287.0469.

Representative Procedure for ortho-Triﬂuoroethoxylation

(Method C). An oven-dried 10 mL round-bottom ﬂask was charged

with 3-phenyl-2H-chromen-2-one 1a (0.23 mmol, 51 mg), Pd(OAc)₂

(10 mol %, 5.15 mg), K₂S₂O₈(2 equiv, 124 mg), and TFA (0.45 mmol,

35 μL) and TFE (2 mL). The reaction mixture was heated with stirring

in an oil bath at 80 °C for 24 h and then cooled to room temperature.

The reaction mixture was basiﬁed with aqueous NaHCO₃solution and

then extracted with ethyl acetate (3 × 5 mL). The organic layer was

washed with water (2 × 5 mL) and dried over anhydrous Na₂SO₄and

the solvent was evaporated under reduced pressure. The resulting

residue was puriﬁed by column chromatography over silica gel 60

(100−200 mesh size) using n-hexane/ethyl acetate as the eluent to give

7a in 69% (51 mg) yield.

3-(2-(2,2,2-Triﬂuoroethoxy)phenyl)-2H-chromen-2-one (7a). The

title compound 7a was synthesized following method C: R_f= 0.5; white

solid (51 mg, 69%); mp = 181−183 °C; ¹H NMR (400 MHz, CDCl₃) δ

7.82 (s, 1H), 7.59−7.53 (m, 2H), 7.49−7.45 (m, 1H), 7.43−7.40 (m,

2H), 7.33 (t, J = 7.6 Hz, 1H), 7.18 (t, J = 7.6 Hz, 1H), 7.03 (d, J = 8.4

Hz, 1H), 4.44 (q, J = 8.0 Hz, 2H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ

160.3, 155.2, 153.8, 142.2, 131.4 (d, J = 12.6 Hz), 130.4, 127.9, 125.4

(d, J = 5.3 Hz), 124.4, 123.3 (q, J = 260.0 Hz), 122.9, 119.4, 116.6,

113.8, 67.0 (q, J = 35.2 Hz); HRMS (ESI) m/z [M + H]⁺calcd for

C₁₇H₁₂F₃O₃⁺321.0733, found 321.0704.

3-(2,4-Dichlorophenyl)-2H-chromen-2-one (5db).²⁸The title

compound 5db was synthesized following method B. The crude

product was puriﬁed by using 2.0:8.0 ethyl acetate/hexane as an eluent:

R_f= 0.4; white solid (51 mg, 77%); mp = 181−183 °C (lit.²⁸mp 187−

189 °C); ¹H NMR (400 MHz, CDCl₃) δ 7.78 (s, 1H), 7.63−7.58 (m,

1H), 7.58−7.53 (m, 2H), 7.42 (d, J = 8.4 Hz, 1H), 7.40−7.33 (m, 3H);

¹³C{¹H} NMR (100 MHz, CDCl₃) δ 159.7, 154.0, 143.0, 135.4, 134.5,

132.3, 132.2, 132.2, 129.8, 128.2, 127.2, 126.0, 124.7, 118.9, 116.8;

HRMS (ESI) m/z [M + H]⁺calcd for C₁₅H₉Cl₂O₂⁺290.9974, found

290.9985.

3-(2-Chloro-4-ﬂuorophenyl)-2H-chromen-2-one (5eb). The title

compound 5eb was synthesized following method B. The crude

product was puriﬁed by using 1.5:7.5 ethyl acetate/hexane as an eluent:

R_f= 0.7; white solid (44 mg, 70%); mp = 182−184 °C; ¹H NMR (400

MHz, CDCl₃) δ 7.71 (s, 1H), 7.55−7.52 (m, 3H), 7.44−7.36 (m, 4H);

¹³C{¹H} NMR (100 MHz, CDCl₃) δ 162.58 (d, J = 260.2 Hz), 159.8,

3-(4-Methyl-2-(2,2,2-triﬂuoroethoxy)phenyl)-2H-chromen-2-one

(7b). The title compound 7b was synthesized following method C. The

crude product was puriﬁed by using 1.5:8.5 ethyl acetate/hexane as an

9765

https://doi.org/10.1021/acs.joc.1c01097

J. Org. Chem. 2021, 86, 9755−9770

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

eluent: R_f= 0.6; white solid (42 mg, 54%); mp = 175−179 °C; ¹H NMR

(400 MHz, CDCl₃) δ 7.80 (s, 1H), 7.58−7.55 (m, 1H), 7.54−7.51 (m,

1H), 7.40 (d, J = 8.4 Hz, 1H), 7.37 (d, J = 7.6 Hz, 1H), 7.34−7.30 (m,

1H), 7.00−6.98 (m, 1H), 6.84 (s, 1H), 4.42 (q, J = 8.2 Hz, 2H), 2.43 (s,

3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 160.5, 155.1, 153.7, 141.9,

140.8, 131.3, 131.1, 127.8, 125.3, 124.4, 123.6, 123.5 (q, J = 217.1 Hz),

122.3, 119.5, 116.6, 114.7, 66.8 (q, J = 35.5 Hz), 21.6; HRMS (ESI) m/

z [M + H]⁺calcd for C₁₈H₁₄F₃O₃⁺335.0890, found 335.0861.

MHz, CDCl₃) δ 7.97 (s, 1H), 7.64 (td, J = 7.6, 1.6 Hz, 2H), 7.50−7.48

(m, 1H), 7.43−7.33 (m, 3H), 7.10 (dd, J = 8.0, 1.2 Hz, 1H), 7.06 (td, J

= 7.6, 1.2 Hz, 1H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 163.2, 155.0,

153.1, 143.8, 132.2, 131.1, 130.7, 128.2, 127.4, 125.2, 123.2, 121.4,

+

119.6, 119.5, 116.7; HRMS (ESI) m/z [M + H]⁺calcd for C₁₅H₁₁O₃

239.0703, found 239.0685.

3-(2-Hydroxy-4-methylphenyl)-2H-chromen-2-one (8b). The title

compound 8b was synthesized following method D. The crude product

was puriﬁed by using 2.5:7.5 ethyl acetate/hexane as an eluent: R_f= 0.2;

white solid (51.5 mg, 89%); mp = 201−203 °C; ¹H NMR (400 MHz,

CDCl₃) δ 7.93 (s, 1H), 7.69 (s, 1H), 7.64−7.60 (m, 2H), 7.47 (d, J =

8.4 Hz, 1H), 7.40 (t, J = 7.6 Hz, 1H), 7.22 (d, J = 7.6 Hz, 1H), 6.91 (s,

1H), 6.87 (d, J = 8.0 Hz, 1H), 2.38 (s, 3H); ¹³C{¹H} NMR (100 MHz,

CDCl₃) δ 163.4, 154.8, 153.0, 143.1, 141.6, 131.9, 130.5, 128.1, 127.4,

125.2, 122.3, 120.2, 120.1, 119.6, 116.6, 21.1; HRMS (ESI) m/z [M +

H]⁺calcd for C₁₆H₁₃O₃⁺253.0859, found 253.0835.

6-Methyl-3-(2-(2,2,2-triﬂuoroethoxy)phenyl)-2H-chromen-2-one

(7f). The title compound 7f was synthesized following method C. The

crude product was puriﬁed by using 2.0:8.0 ethyl acetate/hexane as an

eluent: R_f= 0.5; white solid (48 mg, 63%); mp = 161−163 °C; ¹H NMR

(400 MHz, CDCl₃) δ 7.76 (s, 1H), 7.47 (d, J = 7.7 Hz, 1H), 7.42 (td, J =

7.9, 1.8 Hz, 1H), 7.37 (d, J = 8.3 Hz, 1H), 7.29 (d, J = 8.6 Hz, 2H), 7.18

(t, J = 7.5 Hz, 1H), 7.03 (d, J = 8.3 Hz, 1H), 4.43 (q, J = 8.2 Hz, 2H),

2.45 (s, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 160.5, 155.3, 151.9,

142.2, 134.1, 132.5, 131.4, 130.2, 127.7, 125.6, 125.2, 123.4 (q, J = 256.3

Hz), 122.9, 119.1, 116.3, 113.9, 67.1 (q, J = 35.0 Hz), 20.8; HRMS

(ESI) m/z [M + H]⁺calcd for C₁₈H₁₄F₃O₃⁺335.0890, found 335.0861.

6-Methoxy-3-(2-(2,2,2-triﬂuoroethoxy)phenyl)-2H-chromen-2-

one (7g). The title compound 7g was synthesized following method C.

The crude product was puriﬁed by using 2.5:7.5 ethyl acetate/hexane as

an eluent: R_f= 0.3; white solid (46 mg, 57%); mp = 153−155 °C. ¹H

NMR (400 MHz, CDCl₃) δ 7.76 (s, 1H), 7.49−7.41 (m, 2H), 7.34 (d, J

= 9.2 Hz, 1H), 7.20−7.13 (m, 2H), 7.03 (dd, J = 8.4, 1.2 Hz, 1H), 6.96

(d, J = 2.8 Hz, 1H), 4.44 (q, J = 8.4 Hz, 2H), 3.89 (s, 3H); ¹³C{¹H}

NMR (100 MHz, CDCl₃) δ 160.5, 156.1, 155.3, 148.2, 142.0, 131.4,

130.3, 125.7, 125.4, 123.3 (q, J = 263.3 Hz), 122.9, 119.7, 119.2, 117.6,

113.9, 110.0, 67.3 (q, J = 35.5 Hz), 55.9; HRMS (ESI) m/z [M + H]⁺

calcd for C₁₈H₁₄F₃O₄⁺351.0839, found 351.0807.

3-(2-Hydroxy-4-methoxyphenyl)-2H-chromen-2-one (8c).³⁰The

title compound 8c was synthesized following method D. The crude

product was puriﬁed by using 2.5:7.5 ethyl acetate/hexane as an eluent:

R_f= 0.3; white solid (37 mg, 60%); mp = 173−175 °C (lit.³⁰mp 171−

172 °C); ¹H NMR (400 MHz, CDCl₃) δ 7.79 (s, 1H), 7.57−7.51 (m,

2H), 7.38 (d, J = 8.0 Hz, 1H), 7.35−7.32 (m, 1H), 7.31 (t, J = 1.8 Hz,

1H), 7.29 (d, J = 1.2 Hz, 1H), 6.95 (d, J = 8.4 Hz, 1H), 3.97 (s, 3H);

¹³C{¹H} NMR (100 MHz, CDCl₃) δ 160.6, 153.3, 147.2, 145.5, 138.8,

131.1, 128.0, 127.7, 124.4, 120.9, 119.8, 116.4, 114.7, 110.5, 100.0,

56.1; HRMS (ESI) m/z [M + H]⁺calcd for C₁₆H₁₃O₄⁺269.0808, found

269.0804.

3-(4-Chloro-2-hydroxyphenyl)-2H-chromen-2-one (8d). The title

compound 8d was synthesized following method D. The crude product

was puriﬁed by using 2.0:8.0 ethyl acetate/hexane as an eluent: R_f= 0.4;

6-Chloro-3-(2-(2,2,2-triﬂuoroethoxy)phenyl)-2H-chromen-2-one

(7h). The title compound 7h was synthesized following method C. The

crude product was puriﬁed by using 1.5:8.5 ethyl acetate/hexane as an

1

white solid (41 mg, 66%); mp = 215−217 °C; H NMR (400 MHz,

CDCl₃) δ 7.96 (s, 1H), 7.68−7.64 (m, 2H), 7.49 (d, J = 8.8 Hz, 1H),

7.45−7.41 (m, 1H), 7.28 (d, J = 2.8 Hz, 1H), 7.11 (d, J = 2.0 Hz, 1H),

7.04 (dd, J = 8.4, 2.0 Hz, 1H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ

163.3, 155.8, 153.1, 143.9, 136.6, 132.4, 131.4, 128.3, 126.5, 125.4,

121.8, 121.6, 119.9, 119.4, 116.7; HRMS (ESI) m/z [M + H]⁺calcd for

C₁₅H₁₀ClO₃⁺273.0313, found 273.0320.

1

eluent: R_f= 0.4; white solid (49.5 mg, 61%); mp = 147−149 °C; H

NMR (400 MHz, CDCl₃) δ 7.74 (s, 1H), 7.54−7.50 (m, 2H), 7.48−

7.42 (m, 2H), 7.36−7.34 (m, 1H), 7.19 (t, J = 7.6 Hz, 1H), 7.03 (d, J =

8.4 Hz, 1H), 4.44 (q, J = 8.1 Hz, 2H); ¹³C{¹H} NMR (100 MHz,

CDCl₃) δ 159.7, 155.2, 152.1, 140.8, 131.4, 131.3, 130.6, 129.7, 127.1,

126.6, 124.8, 123.3 (q, J = 270.0 Hz), 122.9, 120.4, 118.0, 113.7, 66.9

3-(4-Fluoro-2-hydroxyphenyl)-2H-chromen-2-one (8e). The title

compound 8e was synthesized following method D. The crude product

was puriﬁed by using 2.5:7.5 ethyl acetate/hexane as an eluent: R_f= 0.5;

+

(q, J = 35.7 Hz); HRMS (ESI) m/z [M + H]⁺calcd for C₁₇H₁₁ClF₃O₃

355.0343, found 355.0310.

1

white solid (45 mg, 77%); mp = 166−168 °C; H NMR (400 MHz,

2-(2-(2,2,2-Triﬂuoroethoxy)phenyl)-3H-benzo[f ]-chromen-3-one

(7i). The title compound 7i was synthesized following method C. The

crude product was puriﬁed by using 2.0:8.0 ethyl acetate/hexane as an

eluent: R_f= 0.4; white solid (53 mg, 62%); mp = 182−184 °C; ¹H NMR

(400 MHz, CDCl₃) δ 8.66 (s, 1H), 8.27 (d, J = 8.4 Hz, 1H), 8.03 (d, J =

9.2 Hz, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.70 (t, J = 7.6 Hz, 1H), 7.60 (t, J

= 7.4 Hz, 2H), 7.55 (d, J = 8.8 Hz, 1H), 7.46 (t, J = 7.6 Hz, 1H), 7.23 (t,

J = 7.6 Hz, 1H), 7.07 (d, J = 8.4 Hz, 1H), 4.48 (q, J = 8.2 Hz, 2H);

¹³C{¹H} NMR (100 MHz, CDCl₃) δ 160.5, 155.2, 153.4, 138.3, 132.8,

131.6, 130.4, 130.3, 129.2, 129.0, 128.2, 126.0, 125.5, 124.7, 123.3 (q, J

= 276.6 Hz), 122.9, 121.4, 116.9, 113.7, 113.5, 66.9 (q, J = 35.6 Hz);

HRMS (ESI) m/z [M + H]⁺calcd for C₂₁H₁₄F₃O₃⁺371.0890, found

371.0859.

CDCl₃) δ 8.06 (s, 1H), 7.94 (s, 1H), 7.67−7.63 (m, 2H), 7.49 (d, J =

8.8 Hz, 1H), 7.42 (t, J = 7.6 Hz, 1H), 7.32−7.30 (m, 1H), 6.83−6.75

(m, 2H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 164.7 (d, J = 247.6 Hz),

156.8 (d, J = 12.2 Hz), 153.0, 143.6, 132.4, 132.3, 131.8 (d, J = 10.3 Hz),

128.2, 126.6, 125.4, 119.4, 119.4, 116.7, 108.6 (d, J = 21.6 Hz), 106.8

+

(d, J = 23.4 Hz); HRMS (ESI) m/z [M + H]⁺calcd for C₁₅H₁₀FO₃

257.0608, found 257.0607.

3-(2-Hydroxyphenyl)-6-methyl-2H-chromen-2-one (8f).³¹The

title compound 8f was synthesized following method D. The crude

product was puriﬁed by using 2.5:7.5 ethyl acetate/hexane as an eluent:

R_f= 0.2; white solid (42 mg, 72%); mp = 163−165 °C (lit.³¹mp 167−

168 °C); ¹H NMR (400 MHz, CDCl₃) δ 7.91 (s, 1H), 7.76 (bs, 1H),

7.45−7.40 (m, 2H), 7.38−7.35 (m, 2H), 7.32 (dd, J = 7.6, 1.6 Hz, 1H),

7.09 (dd, J = 8.0, 1.2 Hz, 1H), 7.05 (td, J = 7.6, 1.2 Hz, 1H), 2.48 (s,

3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 163.5, 155.0, 151.3, 143.8,

135.1, 133.3, 131.0, 130.7, 127.9, 127.2, 123.3, 121.3, 119.6, 119.3,

116.3, 20.8; HRMS (ESI) m/z [M + H]⁺calcd for C₁₆H₁₃O₃⁺253.0859,

found 253.0835.

Representative Procedure for ortho-Hydroxylation (Method

D). An oven-dried 10 mL round-bottom ﬂask was charged with 3-

phenyl-2H-chromen-2-one 1a (0.23 mmol, 51 mg), Pd(OAc)₂(10 mol

%, 5.15 mg), and K₂S₂O₈(2 equiv, 124 mg). Subsequently, TFA (2 mL)

was added to the ﬂask and reﬂuxed in an oil bath at 90 °C for 1 h. After

completion of the reaction, the reaction mixture was cooled to an

ambient temperature, basiﬁed with aqueous NaHCO₃solution, and

extracted with ethyl acetate (3 × 5 mL). The combined organic layer

was washed with water (2 × 5 mL), dried over anhydrous Na₂SO₄, and

concentrated under reduced pressure. The resulting residue was

puriﬁed by column chromatography over silica gel 60 (100−200 mesh

size) using n-hexane/ethyl acetate as the eluent to give 8a in 93% (51

mg) yield.

3-(2-Hydroxyphenyl)-6-methoxy-2H-chromen-2-one (8g).³²The

title compound 8g was synthesized following method D. The crude

product was puriﬁed by using 3.0:7.0 ethyl acetate/hexane as an eluent:

R_f= 0.2; white solid (50 mg, 81%); mp = 146−148 °C (lit.³²mp 144−

145 °C); ¹H NMR (400 MHz, CDCl₃) δ 7.92 (s, 1H), 7.80 (s, 1H),

7.42−7.37 (m, 2H), 7.33 (d, J = 7.6 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H),

7.11−7.05 (m, 2H), 3.91 (s, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ

163.4, 156.7, 155.1, 147.7, 143.6, 131.1, 130.7, 127.8, 123.3, 121.4,

120.3, 119.9, 119.6, 117.7, 109.8, 55.9: HRMS (ESI) m/z [M + H]⁺

calcd for C₁₆H₁₃O₄⁺269.0808, found 269.0804.

3-(2-Hydroxyphenyl)-2H-chromen-2-one (8a)..^18,29The title com-

pound 8a was synthesized following method D: R_f= 0.2; white solid (51

mg, 93%); mp = 214−216 °C (lit.²⁹mp 212−213 °C); ¹H NMR (400

9766

https://doi.org/10.1021/acs.joc.1c01097

J. Org. Chem. 2021, 86, 9755−9770

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

6-Chloro-3-(2-hydroxyphenyl)-2H-chromen-2-one (8h).²⁹The

title compound 8h was synthesized following method D. The crude

product was puriﬁed by using 2.0:8.0 ethyl acetate/hexane as an eluent:

R_f= 0.3; white solid (36 mg, 58%); mp = 226−228 °C (lit.²⁹mp 230−

231 °C); ¹H NMR (400 MHz, CDCl₃) δ 7.88 (s, 1H), 7.62 (d, J = 2.4

Hz, 1H), 7.58 (dd, J = 8.8, 2.4 Hz, 1H), 7.44−7.38 (m, 2H), 7.32 (dd, J

= 7.6, 1.6 Hz, 1H), 7.11−7.05 (m, 2H); ¹³C{¹H} NMR (100 MHz,

CDCl₃) δ 162.5, 154.9, 151.5, 142.2, 132.0, 131.4, 130.7, 130.6, 128.7,

127.3, 122.8, 121.5, 120.5, 119.5, 118.1; HRMS (ESI) m/z [M + H]⁺

124.8, 122.5 (d, J = 10.0 Hz), 121.8, 119.8 (d, J = 1.8 Hz), 117.6, 113.6

(d, J = 23.6 Hz), 112.5, 105.7, 100.1 (d, J = 27.3 Hz); HRMS (ESI) m/z

[M + H]⁺calcd for C₁₅H₈FO₃⁺255.0452, found 255.0459.

2-Methyl-6H-benzofuro[3,2-c]chromen-6-one (9f).³⁸The title

compound 9f was synthesized following method E. The crude product

was puriﬁed by using 1.0:9.0 ethyl acetate/hexane as an eluent: R_f= 0.8;

white solid (35 mg, 67%); mp = 158−160 °C (lit.³⁸mp 166−168 °C);

¹H NMR (400 MHz, CDCl₃) δ 8.04−8.00 (m, 2H), 7.64−7.59 (m,

1H), 7.53−7.48 (m, 2H), 7.44−7.40 (m, 1H), 7.31−7.29 (m, 1H), 2.56

(s, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 159.6, 158.2, 156.0,

153.5, 137.5, 131.6, 126.6, 124.6, 121.7, 121.3, 120.8, 117.4, 112.8,

+

calcd for C₁₅H₁₀ClO₃: 273.0313, found 273.0320.

2-(2-Hydroxyphenyl)-3H-benzo[f]chromen-3-one (8i).³³The title

compound 8i was synthesized following method D. The crude product

was puriﬁed by using 2.0:8.0 ethyl acetate/hexane as an eluent: R_f= 0.4;

white solid (63.5 mg, 96%); mp = 213-215 °C (lit.³³mp 216−217 °C);

¹H NMR (400 MHz, CDCl₃) δ 8.75 (s, 1H), 8.37 (d, J = 8.4 Hz, 1H),

+

112.0, 105.9, 21.9; HRMS (ESI) m/z [M + H]⁺calcd for C₁₆H₁₁O₃

251.0703, found 251.0681.

2-Methoxy-6H-benzofuro[3,2-c]chromen-6-one (9g).³⁹The title

compound 9g was synthesized following method E. The crude product

was puriﬁed by using 1.5:8.5 ethyl acetate/hexane as an eluent: R_f= 0.6;

white solid (38.5 mg, 69%); mp = 154−156 °C (lit.³⁹mp 155−157

8.09 (d, J = 8.8 Hz, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.86 (s, 1H), 7.84−

7.74 (m, 1H), 7.68−7.64 (m, 1H), 7.60 (d, J = 9.2 Hz, 1H), 7.46−7.41

(m, 2H), 7.15−7.09 (m, 2H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ

163.3, 155.3, 153.0, 139.7, 133.7, 131.1, 130.8, 130.6, 129.2, 129.0,

128.6, 126.6, 126.4, 123.6, 121.6, 121.5, 119.7, 116.5, 114.0; HRMS

(ESI) m/z [M + H]⁺calcd for C₁₉H₁₃O₃⁺289.0859, found 289.0844.

Representative Procedure for the Synthesis of Coumestan

(Method E). An oven-dried 10 mL round-bottom ﬂask was charged

with 3-(2-hydroxyphenyl)-2H-chromen-2-one 8a (0.21 mmol, 50 mg),

DDQ (0.42 mmol, 95 mg), and toluene (2 mL). The reaction mixture

was reﬂuxed in an oil bath at 120 °C for 24 h. After completion of the

reaction, the reaction mixture was cooled to an ambient temperature

and diluted with water (15 mL). The mixture was extracted with ethyl

acetate (3 × 5 mL). The combined organic layer was dried over

anhydrous Na₂SO₄and concentrated under reduced pressure. The

resulting residue was puriﬁed by column chromatography over silica gel

60 (100−200 mesh size) using n-hexane/ethyl acetate as the eluent to

aﬀord 9a in 78% (38.5 mg) yield.

1

°C); H NMR (400 MHz, CDCl₃) δ 8.17−8.15 (m, 1H), 7.69−7.67

(m, 1H), 7.52−7.42 (m, 4H), 7.18 (dd, J = 9.2, 2.8 Hz, 1H), 3.95 (s,

3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 159.9, 158.2, 156.4, 155.5,

148.2, 126.8, 125.2, 123.6, 121.9, 120.3, 118.7, 112.8, 111.7, 106.0,

103.4, 56.0; HRMS (ESI) m/z [M + H]⁺calcd for C₁₆H₁₁O₄⁺267.0652,

found 267.0628.

2-Chloro-6H-benzofuro[3,2-c]chromen-6-one (9h).⁴⁰The title

compound 9h was synthesized following method E. The crude product

was puriﬁed by using 1.5:8.5 ethyl acetate/hexane as an eluent: R_f= 0.7;

white solid (45 mg, 80%); mp = 231−233 °C (lit.⁴⁰mp 236−238 °C);

¹H NMR (400 MHz, CDCl₃) δ 8.19−8.17 (m, 1H), 8.05 (d, J = 2.4 Hz,

1H), 7.72−7.70 (m, 1H), 7.60−7.55 (m, 2H), 7.53−7.51 (m, 1H), 7.48

(d, J = 8.8 Hz, 1H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 158.7, 157.5,

155.7, 152.0, 131.9, 130.3, 127.3, 125.5, 123.2, 122.0, 121.4, 119.0,

+

113.8, 111.9, 106.6; HRMS (ESI) m/z [M + H]⁺calcd for C₁₅H₈ClO₃

271.0156, found 271.0183.

6H-Benzofuro[3,2-c]chromen-6-one (9a).³⁴The title compound

9a was synthesized following method E: R_f= 0.6; white solid (38.5 mg,

8H-Benzo[f ]benzofuro[3,2-c]chromen-8-one (9i).⁴⁰The title

compound 9i was synthesized following method E. The crude product

was puriﬁed by using 1.0:9.0 ethyl acetate/hexane as an eluent: R_f= 0.7;

white solid (45 mg, 75%); mp = 206−208 °C (lit.⁴⁰mp 210−212 °C);

¹H NMR (400 MHz, CDCl₃) δ 9.20 (d, J = 8.4 Hz, 1H), 8.23−8.20 (m,

1H), 8.02 (d, J = 9.2 Hz, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.81−7.77 (m,

2H), 7.64−7.59 (m, 2H), 7.57−7.49 (m, 2H); ¹³C{¹H} NMR (100

MHz, CDCl₃) δ 161.4, 158.1, 155.5, 153.9, 133.1, 130.4, 128.8, 128.8,

127.5, 126.8, 126.4, 125.5, 125.4, 122.9, 121.9, 117.4, 111.7, 107.1,

78%); mp = 184−186 °C (lit.³⁴mp 187−188 °C); H NMR (400

1

MHz, CDCl₃) δ 8.19−8.15 (m, 1H), 8.07 (dd, J = 7.6, 1.6 Hz, 1H),

7.72−7.69 (m, 1H), 7.66−7.62 (m, 1H), 7.55−7.49 (m, 3H), 7.47−

7.42 (m, 1H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 160.0, 158.1, 155.6,

153.7, 131.9, 126.8, 125.2, 124.7, 123.5, 121.9, 121.9, 117.5, 112.7,

+

111.8, 105.9; HRMS (ESI) m/z [M + H]⁺calcd for C₁₅H₉O₃

237.0546, found 237.0542.

9-Methyl-6H-benzofuro[3,2-c]chromen-6-one (9b).³⁵The title

compound 9b was synthesized following method E. The crude product

was puriﬁed by using 1.0:8.0 ethyl acetate/hexane as an eluent: R_f= 0.7;

white solid (32 mg, 61%); mp = 196−198 °C (lit.³⁵mp 199−200 °C);

¹H NMR (400 MHz, CDCl₃) δ 8.18−8.13 (m, 1H), 7.83 (s, 1H), 7.69−

7.65 (m, 1H), 7.52−7.45 (m, 2H), 7.42−7.41 (m, 2H), 2.51 (s, 3H);

¹³C{¹H} NMR (100 MHz, CDCl₃) δ 160.0, 158.3, 155.5, 151.9, 134.6,

133.0, 126.6, 125.2, 123.6, 121.8, 121.5, 117.2, 112.3, 111.7, 105.8,

21.0; HRMS (ESI) m/z [M + H]⁺calcd for C₁₆H₁₁O₃⁺251.0703, found

251.0682.

+

106.1. HRMS (ESI) m/z [M + H]⁺calcd for C₁₉H₁₁O₃287.0703,

found 287.0681.

Synthesis of 2-(2-Oxo-2H-chromen-3-yl)phenyl Triﬂuorome-

thanesulfonate (10). To a solution of compound 8a (0.21 mmol, 50

mg) in dry dichloromethane was added Et₃N (0.32 mmol, 45 μL) at 0

°C, and the mixture was stirred for 15 min. Triﬂic anhydride (0.42

mmol, 2 equiv) was added with stirring, the reaction ﬂask was brought

to room temperature, and the mixture continued stirring for 4 h. The

reaction was quenched with saturated aqueous NaHCO₃solution and

extracted with dichloromethane (2 × 5 mL). The combined layer was

dried over anhydrous Na₂SO₄, and the solvent was evaporated under

reduced pressure to get the crude product. The obtained compound

was triturated by diethyl ether (1 mL) to get compound 10: R_f= 0.5;

9-Chloro-6H-benzofuro[3,2-c]chromen-6-one (9d).³⁶The title

compound 9d was synthesized following method E. The crude product

was puriﬁed by using 1.5:8.5 ethyl acetate/hexane as an eluent: R_f= 0.7;

white solid (49 mg, 86%); mp = 230−232 °C (lit.³⁶mp 239 °C); ¹H

NMR (400 MHz, CDCl₃) δ 8.08 (d, J = 8.4 Hz, 1H), 8.05 (dd, J = 8.0,

1.6 Hz, 1H), 7.71 (d, J = 1.6 Hz, 1H), 7.68−7.64 (m, 1H), 7.54 (dd, J =

8.4, 0.8 Hz, 1H), 7.49−7.44 (m, 2H); ¹³C{¹H} NMR (100 MHz,

CDCl₃) δ 160.5, 157.7, 155.5, 153.8, 132.7, 132.3, 126.1, 124.8, 122.4,

122.2, 121.9, 117.6, 112.5, 112.4, 105.7; HRMS (ESI) m/z [M + H]⁺

calcd for C₁₅H₈ClO₃⁺271.0156, found 271.0138.

1

white solid (61 mg, 79%); mp = 164−166 °C; H NMR (400 MHz,

CDCl₃) δ 7.86 (s, 1H), 7.64−7.56 (m, 3H), 7.48−7.55 (m, 2H), 7.45−

7.42 (m, 2H), 7.38−7.34 (m, 1H); ¹³C{¹H} NMR (100 MHz, CDCl₃)

δ 159.5, 154.0, 147.1, 143.7, 132.4, 132.2, 130.7, 128.8, 128.5, 128.3,

124.8, 123.6, 122.0, 118.7, 118.4 (q, J = 320 Hz), 116.8; HRMS (ESI)

m/z [M + H]⁺calcd for C₁₆H₁₀F₃O₅S⁺371.0196, found 371.0163.

Synthesis of 3-(2-((4-Propylphenyl)ethynyl)phenyl)-2H-

chromen-2-one (12). Compound 10 (0.13 mmol, 48 mg), 1-

ethynyl-4-propylbenzene 11 (0.20 mmol, 1.5 equiv), Pd(OAc)₂(10

mol %, 3.0 mg), PPh₃(20 mol %, 68 mg), and K₃PO₄(0.20 mmol, 42

mg) were taken in a reaction pressure tube, and 2 mL of DMSO was

added under a N₂atmosphere. The reaction mixture was stirred for 24 h

at 80 C in an oil bath. After completion of the reaction, the reaction

mixture was diluted by water (10 mL) and extracted with ethyl acetate

(3 × 5 mL). The combined organic layer was dried over anhydrous

9-Fluoro-6H-benzofuro[3,2-c]chromen-6-one (9e).³⁷The title

compound 9e was synthesized following method E. The crude product

was puriﬁed by using 1.0:9.0 ethyl acetate/hexane as an eluent: R_f= 0.8;

white solid (37 mg, 69%); mp = 233−235 °C (lit.³⁷mp 240−241 °C);

¹H NMR (400 MHz, CDCl₃) δ 8.11 (dd, J = 8.6, 5.5 Hz, 1H), 8.05 (dd,

J = 7.6, 1.6 Hz, 1H), 7.67−7.63 (m, 1H), 7.54 (dd, J = 8.8, 1.2 Hz, 1H),

7.48−7.42 (m, 2H), 7.28−7.23 (m, 1H); ¹³C{¹H} NMR (100 MHz,

CDCl₃) δ 161.9 (d, J = 254.2 Hz), 160.7, 160.6, 157.9, 153.6, 132.0,

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Na₂SO₄and concentrated under reduced pressure to get crude product.

The obtained crude was puriﬁed by column using ethyl acetate/n-

hexane (1.5:8.5 v/v) as an eluent: R_f= 0.5; oﬀ white solid (40 mg, 84%);

mp = 110−112 °C; ¹H NMR (400 MHz, CDCl₃) δ 8.07 (s, 1H), 7.69−

7.67 (m, 1H), 7.62−7.56 (m, 3H), 7.44−7.41 (m, 2H), 7.35−7.31 (m,

1H), 7.27−7.24 (m, 2H), 7.09 (d, J = 8.4 Hz, 2H), 2.57 (t, J = 7.6 Hz,

2H), 1.65−1.59 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H); ¹³C{¹H} NMR (100

MHz, CDCl₃) δ 160.4, 153.9, 143.4, 142.5, 136.4, 132.8, 131.6, 131.3,

129.9, 128.5, 128.5, 128.1, 127.9, 127.4, 124.5, 122.8, 120.1, 119.3,

116.6, 93.9, 87.5, 37.9, 24.3, 13.7; HRMS (ESI) m/z [M + H]⁺calcd for

C₂₆H₂₁O₂⁺365.1536, found 365.1506.

Synthesis of (E)-3-(2-(2-Oxo-2H-chromen-3-yl)phenyl)acrylic

Acid (13). Compound 3ab (0.16 mmol, 51 mg) was added to a solution

of KOH in MeOH (2 mL, 20% w/v), and the reaction mixture was

stirred overnight at room temperature. After complete consumption of

the starting material, methanol was removed in a vacuum, and the

obtained crude product was puriﬁed by column using methanol/DCM

(1:9, v/v) as an eluent: R_f= 0.1; white solid (36.5 mg, 78%); mp = 220−

222 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 8.09 (s, 1H), 7.93−7.91 (m,

1H), 7.80 (dd, J = 8.0, 1.6 Hz, 1H), 7.71−7.67 (m, 1H), 7.54−7.40 (m,

6H), 6.52 (d, J = 16.0 Hz, 1H); ¹³C{¹H} NMR (100 MHz, DMSO-d₆)

δ 168.0, 160.1, 153.8, 143.9, 141.6, 136.0, 133.6, 132.6, 131.4, 130.4,

129.5, 129.2, 127.3, 127.0, 125.3, 121.2, 119.5, 116.6; HRMS (ESI) m/

z [M + H]⁺calcd for C₁₈H₁₃O₄⁺293.0808, found 293.0784.

Synthesis of Ethyl 2,3-Dibromo-3-(2-(2-oxo-2H-chromen-3-

yl)phenyl)propanoate (14). Compound 3ab (0.16 mmol, 51 mg)

was dissolved in CHCl₃(2 mL) and cooled to 0 °C for 10 min, and then

1 M bromine in DCM solution (32 μL) was added dropwise. The

reaction mixture was brought to room temperature and stirred for 12 h,

and a sodium thiosulfate solution was added . The organic layer was

separated, dried over anhydrous Na₂SO₄, and concentrated under

reduced pressure to get the crude product. The crude product was

triturated by diethyl ether (0.5 mL) to obtain compound 14 (71 mg,

93%) as a white solid: mp = 110−112 °C; ¹H NMR (400 MHz, CDCl₃)

δ 7.85 (s, 1H), 7.65−7.52 (m, 4H), 7.48−7.44 (m, 2H), 7.38−7.34 (m,

2H), 5.43 (s, 1H), 4.89 (s, 1H), 4.31 (q, J = 7.2, 2H), 1.32 (t, J = 7.2 Hz,

3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 167.7, 160.3, 154.0, 134.7,

132.1, 130.9, 130.8, 130.7, 129.9, 129.8, 129.8, 129.2, 128.2, 124.7,

119.0, 116.8, 62.7, 49.6, 42.0, 13.8; HRMS (ESI) m/z [M + H]⁺calcd

for C₂₀H₁₇Br₂O₄⁺478.9488, found 478.9508.

149.1, 142.5, 139.1, 133.4, 131.7, 130.8, 130.0, 129.3, 128.7, 128.7,

127.9, 124.6, 123.8, 119.0, 116.7; HRMS (ESI) m/z [M + H]⁺calcd for

C₂₀H₁₄NO₂⁺300.1019, found 300.0995.

Procedure for the Competition Experiment. An oven-dried 10 mL

round-bottom ﬂask was charged with a magnetic stir bar, 3-(4-

methoxyphenyl)-2H-chromen-2-one 1c (0.23 mmol, 58 mg), 3-(4-

ﬂuorophenyl)-2H-chromen-2-one 1e (0.23 mmol, 55 mg), 2a (0.9

mmol, 81 μL), Pd(OAc)₂(10 mol %, 5.15 mg), K₂S₂O₈(2 equiv, 124

mg), and TFA/TFAA (2 mL, 9:1 v/v). The reaction mixture was

reﬂuxed with stirring in an oil bath at 90 °C for 3 h. After completion of

reaction, the reaction mixture was cooled to an ambient temperature,

basiﬁed with aqueous NaHCO₃solution, and extracted with ethyl

acetate (3 × 5 mL). The organic layer was washed with water (2 × 5

mL), and the combined organic layer was dried over anhydrous Na₂SO₄

and concentrated under reduced pressure. The resulting residue was

puriﬁed by column chromatography on silica gel (100−200 mesh size)

using n-hexane/ethyl acetate as the eluent, and a mixture of 3ca and 3ea

was analyzed by ¹H NMR. The ratio of two 3ca and 3ea was found to be

1:2.7.

A similar procedure was followed for the competition experiment

between 1g and 1h by taking 6-methoxy-3-phenyl-2H-chromen-2-one

1g (0.23 mmol, 58 mg) and 6-chloro-3-phenyl-2H-chromen-2-one 1h

(0.23 mmol, 59 mg). The mixture of 3ga and 3ha obtained was

analyzed by the ¹H NMR. The ratio of two 3ga and 3ha was found to be

2:1.

Procedure for Radical Scavenging Experiment. An oven-dried

10 mL round-bottom ﬂask was charged with 3-phenyl-2H-chromen-2-

one 1a (0.23 mmol, 51 mg), methyl acrylate 2a (0.9 mmol, 81 μL),

Pd(OAc)₂(10 mol %, 5.15 mg), K₂S₂O₈(2 equiv, 124 mg), TEMPO or

BHT (2 equiv) and TFA/TFAA (2 mL, 9:1 v/v), and TEMPO or BHT

(2 equiv). The reaction mixture was reﬂuxed with stirring in an oil bath

at 90 °C for 3 h. The reaction mixture was cooled to an ambient

temperature, basiﬁed with aqueous NaHCO₃solution (5 mL), and then

extracted with ethyl acetate (3 × 5 mL). The combined organic layer

was washed with water (2 × 5 mL) and dried over anhydrous Na₂SO₄,

and the solvent was evaporated under reduced pressure. The resulting

residue was puriﬁed by column chromatography over silica gel 60

(100−200 mesh size) using n-hexane/ethyl acetate as an eluting system

to give 3aa in 77% (using TEMPO) and 76% (using BHT).

Synthesis of 2-(2-Oxo-2H-chromen-3-yl)benzonitrile (15). To

an oven-dried pressure tube (10 mL) were added 5aa (0.17 mmol, 51

mg), CuCN (0.20 mmol, 18 mg), and DMF (2 mL). The vial was

capped, and the reaction mixture was heated at 155 °C for 16 h in an oil

bath. After complete consumption of the starting material, the reaction

mixture was dissolved in ethyl acetate and washed with chilled water (2

× 5 mL). The organic layer was dried over anhydrous Na₂SO₄and

concentrated under reduced pressure to get the crude product. The

crude product was puriﬁed by a column using ethyl acetate/n-hexane

(2.0:8.0 v/v) as an eluent: R_f= 0.3; white solid (32 mg, 76%); mp =

190−192 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.97 (s, 1H), 7.84−7.81

(m, 1H), 7.74−7.69 (m, 2H), 7.66−7.61 (m, 2H), 7.57−7.53 (m, 1H),

7.44 (d, J = 8.8 Hz, 1H), 7.39−7.35 (m, 1H); ¹³C{¹H} NMR (100

MHz, CDCl₃) δ 159.9, 154.1, 143.3, 138.2, 133.5, 132.6, 132.6, 130.9,

129.1, 128.5, 125.3, 124.8, 118.8, 117.8, 116.8, 112.4; HRMS (ESI) m/

z [M + H]⁺calcd for C₁₆H₁₀NO₂⁺248.0706, found 248.0684.

ASSOCIATED CONTENT

* Supporting Information

The Supporting Information is available free of charge at

https://pubs.acs.org/doi/10.1021/acs.joc.1c01097.

■

sı

1

Copies of H, ¹³C{¹H} NMR, and single-crystal X-ray

analysis of 3aa, 5ab, and 8a (PDF)

Accession Codes

CCDC 1989999, 2071530, and 2071538 contain the supple-

mentary 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.

Synthesis of 3-(2-(Pyridin-4-yl)phenyl)-2H-chromen-2-one

(17). To an oven-dried pressure tube (10 mL) were added compound

5aa (0.17 mmol, 51 mg), pyridin-4-ylboronic acid (0.25 mmol, 30 mg),

K₂CO₃(0.34 mmol, 47 mg), and toluene/water/2-propanol (2 mL,

9:0.5:0.5 v/v). The mixture was purged with nitrogen for 10 min at

room temperature, and thereafter, Pd(dppf)Cl₂(10 mol %, 12.5 mg)

was added. The mixture was again purged with nitrogen for 10 min. The

vial was capped and heated at 85 °C for 16 h in an oil bath. After

completion of the reaction, the solvent was removed in a vacuum, and

the obtained crude product was puriﬁed by column using ethyl acetate/

n-hexane (7:3 v/v) as an eluent: R_f= 0.2; white solid (46 mg, 90%); mp

= 222−224 °C; ¹H NMR (400 MHz, CDCl₃) δ 8.54 (d, J = 5.2 Hz, 2H),

7.57−7.50 (m, 5H), 7.48−7.40 (m, 2H), 7.35−7.30 (m, 1H), 7.28−

7.25 (m, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 160.1, 153.7, 149.8,

AUTHOR INFORMATION

Corresponding Author

■

Anil Kumar − Department of Chemistry, Birla Institute of

Technology and Science Pilani, Rajasthan 333031, India;

orcid.org/0000-0003-4699-3178; Email: anilkumar@

pilani.bits-pilani.ac.in

Authors

Vikki N. Shinde − Department of Chemistry, Birla Institute of

Technology and Science Pilani, Rajasthan 333031, India

Krishnan Rangan − Department of Chemistry, Birla Institute of

Technology and Science Pilani, Telangana 500078, India

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The Journal of Organic Chemistry

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Article

(II)-catalyzed C −H imidation: Access to primary aminoketones by

weak coordination. ACS Catal. 2016, 6, 3172−3175. (c) Thirunavuk-

karasu, V. S.; Ackermann, L. Ruthenium-catalyzed C −H bond

oxygenations with weakly coordinating ketones. Org. Lett. 2012, 14,

6206−6209. (d) Sun, X.; Shan, G.; Sun, Y.; Rao, Y. Regio- and

Chemoselective C −H chlorination/bromination of electron-deficient

arenes by weak coordination and study of relative directing-group

abilities. Angew. Chem., Int. Ed. 2013, 52, 4440−4444.

Dalip Kumar − Department of Chemistry, Birla Institute of

Technology and Science Pilani, Rajasthan 333031, India

Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.joc.1c01097

Author Contributions

The manuscript was written through contributions of all

authors. V.N.S. conducted all of the experimental work and

collected spectral data. R.K. recorded and analyzed single-crystal

X-ray data. V.N.S., D.K., and A.K. analyzed the spectral data.

A.K. proposed and supervised the research work. All authors

discussed the results, corrected the manuscript, and have given

approval to the ﬁnal version of the manuscript.

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Bhonoah, Y.; Williams, I. H.; Frost, C. G. Ruthenium (II)-catalyzed C −

H Functionalization using the oxazolidinone heterocycle as a weakly

coordinating directing group: Experimental and computational in-

sights. ACS Catal. 2016, 6, 5520−5529.

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acids mediated by a weakly coordination-directing auxiliary. Eur. J. Org.

Chem. 2017, 2017, 4749−4752.

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olefination of arene esters via C-H bond activation. Org. Lett. 2011, 13,

2372−2375. (b) Yang, Y.; Lin, Y.; Rao, Y. Ruthenium (II)-catalyzed

synthesis of hydroxylated arenes with ester as an effective directing

group. Org. Lett. 2012, 14, 2874−2877.

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Ruthenium (II) catalyzed regiospecific C −H/O −H annulations of

directing arenes via weak coordination. Org. Lett. 2015, 17, 5678−5681.

(b) Kim, K.; Choe, H.; Jeong, Y.; Lee, J. H.; Hong, S. Ru (II)-catalyzed

site-selective hydroxylation of flavone and chromone derivatives: The

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Org. Lett. 2015, 17, 2550−2553.

(12) Stefanachi, A.; Leonetti, F.; Pisani, L.; Catto, M.; Carotti, A.

Coumarin: A natural, privileged and versatile scaffold for bioactive

compounds. Molecules 2018, 23, 250.

(13) (a) Kaswan, P.; Pericherla, K.; Kumar, A. Synthesis of 3-

aroylimidazo[1, 2-a ]pyridines via CuCl₂catalyzed tandem dual

carbon −nitrogen bonding. Tetrahedron 2014, 70, 8539−8544. (b) Dhi-

man, S.; Pericherla, K.; Nandwana, N. K.; Kumar, D.; Kumar, A.

Synthesis of aza-fused isoquinolines through domino cross-aldol

condensation and palladium-catalyzed intramolecular direct arylation.

J. Org. Chem. 2014, 79, 7399−7404. (c) Nandwana, N. K.; Pericherla,

K.; Kaswan, P.; Kumar, A. Synthesis of novel azole-fused quinazolines

via one-pot, sequential Ullmann-type coupling and intramolecular

dehydrogenative C −N bonding. Org. Biomol. Chem. 2015, 13, 2947−

2950. (d) Dhiman, S.; Nandwana, N. K.; Saini, H. K.; Kumar, D.;

Rangan, K.; Robertson, K. N.; Jha, M.; Kumar, A. Nickel-catalyzed

tandem Knoevenagel condensation and intramolecular direct arylation:

Synthesis of pyrazolo[5,1-a ]isoquinoline derivatives. Adv. Synth. Catal.

2018, 360, 1973−1983. (e) Pandey, K.; Rangan, K.; Kumar, A. One-Pot

Tandem amidation, Knoevenagel condensation, and palladium-

catalyzed wacker type oxidation/C −O coupling: Synthesis of

chromeno-annulated imidazopyridines. J. Org. Chem. 2018, 83,

8026−8035. (f) Shinde, V. N.; Kanchan Roy, T.; Jaspal, S.; Nipate,

D. S.; Meena, N.; Rangan, K.; Kumar, D.; Kumar, A. Rhodium(III)-

catalyzed annulation of 2-arylimidazo[1,2-a ]pyridines with maleimides:

Synthesis of 1 H -benzo[e ]pyrido[1 ′,2 ′:1,2]imidazo[4,5-g ]isoindole-

1,3(2 H )-diones and their photophysical studies. Adv. Synth. Catal.

2020, 362, 5751−5764. (g) Shinde, V. N.; Rangan, K.; Kumar, D.;

Kumar, A. Rhodium(III)-catalyzed dehydrogenative annulation and

spirocyclization of 2-arylindoles and 2-(1 H -Pyrazol-1-yl)-1 H -indoles

with maleimides: A facile access to isogranulatimide alkaloid analogues.

J. Org. Chem. 2021, 86, 2328−2338.

Notes

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

■

We gratefully acknowledge Science and Engineering Research

Board (SERB), New Delhi (CRG/2020/002220), for ﬁnancial

support. We thank DST FIST [SR/FST/CSI-270/2015] for the

HRMS facility and BITS Pilani, CAL, for NMR analysis. V.N.S.

thanks the Council of Scientiﬁc and Industrial Research (CSIR)

for a senior research fellowship (SRF).

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https://doi.org/10.1021/acs.joc.1c01097

J. Org. Chem. 2021, 86, 9755−9770

Article Doi

Palladium-Catalyzed Weakly Coordinating Lactone-Directed C-H Bond Functionalization of 3-Arylcoumarins: Synthesis of Bioactive Coumestan Derivatives

DOI: 10.1021/acs.joc.1c01097

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Full text of DOI:10.1021/acs.joc.1c01097

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