Palladium Cascade Catalysis: Construction of

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N-Heterocyclic Carbene/Palladium Cascade Catalysis: Construction of 2,2-Disubstitiuted Benzofuranones from the Reaction of 3-(2-Formylphenoxy)propenoates with Allylic Esters Yu-Jie Liu, Ya-Li Ding, Shuang-Shuo Niu, Jin-Tao Ma, and Ying Cheng J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02849 • Publication Date (Web): 10 Jan 2018 Downloaded from http://pubs.acs.org on January 10, 2018

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The Journal of Organic Chemistry

N-Heterocyclic Carbene/Palladium Cascade Catalysis: Construction of 2,2-Disubstitiuted Benzofuranones from the Reaction of 3-(2-Formylphenoxy)propenoates with Allylic Esters Yu-Jie Liu, Ya-Li Ding, Shuang-Shuo Niu, Jin-Tao Ma and Ying Cheng* College of Chemistry, Beijing Normal University, Beijing 100875, China E-mail: [email protected]

Abstract: The cascade catalysis involving N-heterocyclic carbene (NHC) and palladium/ligand was demonstrated. In the presence of triazolium salt, palladium catalyst and base, the reaction of 3-(2-formylphenoxy)propenoates and allylic esters proceeded efficiently under mild conditions to afford 2-allylbenzofuran-3-one-2-acetates in moderated to good yields. An asymmetric cascade catalysis was achieved when (R)-BINAP was employed as a chiral ligand, producing enantiomerically enriched 2,2-disubstitiuted benzofuran-3-one derivatives with ee up to 81%.

Introduction Over the last decade, the multicatalysis including cooperative catalysis and cascade catalysis by means of the combination of an organocatalyst and a transition metal catalyst has emerged as a powerful and very promising strategy for the development of new reactions which cannot be achieved by either of them individually.1, 2 Despite of the great achievement of organocatalysis of N-heterocyclic carbenes (NHCs) in organic reactions, especially in the Umpolung reactions of carbonyl compounds,3 however, the successful merger of a NHC with a late transition metal catalyst in 1

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Page 2 of 30

one-pot multicatalytic reactions still remains a challenge due to the strong donor property of NHCs to many transition metals, which as a general consequence results in the inhibition of either or both catalysts. Only a few satisfactory integrations of NHCs with metal catalysts have been reported to date. For example, the cooperative NHC/palladium catalysis has been realized in the intramolecular and intermolecular reactions between an unsaturated aldehyde and an allylic esters pecies.4 The cascade Benzoin/allylation and allylic amination/Stetter reactions have been achieved by the combination of NHC and palladium catalysis.5 In addition, the cooperative NHC/Ru(II) and NHC/Fe(II) redox catalysis has been utilized in the esterification of aldehydes,6 while the photoredox -acylation of tertiary amines with aldehydes has been carried out by the cooperative NHC and Ru(II)-based catalysis.7 Furthermore, the direct synthesis of acyloins from olefins has been effected by the tandem NHC/rhodium catalysis.8 Since N-heterocyclic carbenes and late transition metal catalysts can activate, respectively, various and totally different substrates, the NHC/transition metal tandem catalysis would provide chemists with great opportunities and unique tools in organic synthesis. Benzofuran-3-one derivatives, especially the 2,2-disubstituted benzofuran-3-ones, are known to exhibit strong and a broad spectrum of biological activities, such as anticancer,9a–9c, antipsychotic (Alzheimer’s disease),9d antiviral,9e antibacterial and antifungal properties.9f The 2,2-disubstituted benzofuran-3-one core is also found in various

natural

products

including

Griseofulvin10a

(antifungal

agent),

Spiroapplanatumines (Kinase inhibitors)10e and Armeniaspirols A-C (antibiotic activity)10d (Figure 1).

2


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O

NH OH

O

R

O

O

O N H

O

R

A B A, B: Histone deacetylase inhibitors

O

NH2 OH O

O O

MeO

H3CO

N NH

N

O O

Cl (+)-Griseofulvin

R E: HCV RdRp inhibitor

R

CHO

HO

O HO

O HO2C

O

MeO

CH2N

D: AChE inhibitor

C: PIM1 inhibitor OMe O OMe

N

O

H3CO

HN

O

HO

Spiroapplanatumine G

OH

O MeO2C Spiroapplanatumine K

HO

O Me N

O

R1

O (CH2)3 Cl

R2

Armeniaspirols A-C

Cl

Figure 1. Some biological active synthetic and natural 2,2-disubstituted benzofuran-3-one derivatives.

Because of their potential applications in medicinal chemistry, the synthesis of benzofuran-3-one derivatives has been drawing great attention. A number of methods, including the N-heterocyclic carbene-catalyzed reactions, have been developed for the construction of benzofuran-3-ones containing a quaternary stereocenter at C2.11,12 Although many of the known methods provide the access to 2,2-disubstituted benzofuran-3-one products in good yield, most of them need multiple steps to prepare the substrates. To address this problem, multicatalytic cascade reactions starting from simple materials is a good choice. In 2010, Rovis and co-workers, for instance, developed

an

efficient

and

enantioselective

2-(carboxylmethyl)benzofuran-3-one-2-carboxylates

synthesis via

of cascade

tert-amine/NHC-catalyzed reaction of salicyladehydes with electron-deficient alkynes (Scheme 1, equ. 1).12d Later on, Glorius and co-workers reported a NHC and base cascade catalyzed reaction of o-propargyloxybenzaldehydes with aldehydes, leading to the formation of 2-(carbonylmethyl)-2-methyl-benzofuran-3-one derivatives (Scheme 1, equ. 2).12e Recently, Xu and co-workers reported an asymmetric rhodium/palladium relay catalysis for the synthesis of 2,2-diaryl benzofuran-3-ones from the reaction of 1,2-diaryl--diketones with arylboronic acids (Scheme 1, equ. 3).11b In these cascade catalytic methods, the 2,2-disubstituted benzofuran-3-one products

didn't

been

derived

from

benzofuranone

intermediates. 3



3-(2-Formylphenoxy)propenoates

are

known

to

Page 4 of 30

undergo

a

NHC-catalyzed

intramolecular Stetter reaction to form benzofuran-3-one-2-acetates.13 Inspired by this benzofuran-3-one formation reaction, we have recently developed a cascade NHC/base-catalyzed N-bocarylimines

reaction and

between

furnished

3-(2-formylphenoxy)propenoates the

high

yield

synthesis

and of

2-((aryl)(carbonylamino)methyl)benzofuran-3-one-2-acetates (Scheme 1, equ. 4).12f We envisioned that the combination of the NHC-catalyzed benzofuranone formation with the C2-substitution reactions of benzofuranones might provide new route to various 2,2-disubstituted benzofuran-3-one derivates. As a continuation of our research on the development of highly efficient cascade catalysis methods for the construction of multifunctional complexed molecules, we undertook the current study on the NHC/Pd-catalyzed reaction of 3-(2-formylphenoxy)propenoates with allylic esters.

Scheme 1. Examples for the synthesis of 2,2-disubstituted benzofuran-3-ones via the multicatalytic cascade reactions.

4


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Results and Discussion As a prelude of the investigation, 3-(2-formylphenoxy)propenoate 1a and cinnamyl acetate 2a were chosen as the model substrates. We commenced our study by the treatment of 3-(2-formylphenoxy)propenoate 1a with cinnamyl acetate 2a under the catalysis of a variety of N-heterocyclic carbenes 3' in combination with Pd(PPh3)4 in dichloromethane at ambient temperature (about 25-30

o

C). The N-heterocyclic

carbenes were generated in situ from deprotonation of the corresponding azolium salts 3 with Cs2CO3. It was found that, in the presence of a thiazolium salt 3a (20 mol%), Pd(PPh3)4 (10 mol%) and Cs2CO3 (2 equiv.), the reaction of aldehyde 1a (1 equiv.) with

allylacetate

2a

(2

equiv.)

afforded

the

expected

2-cinnamylbenzofuran-3-one-2-acetate 4a in a low yield (26%) along with a trace amount of isomers 5a and 6a (Table 1, entry 1). The replacement of thiazolium 3a by cyclohepta[d]thiazolium salt 3b increased the yield of 4a to 62% (Table 1, entry 2). Under the same reaction conditions, the reaction using imidazolinium 3c as the NHC precatalyst provided product 4a in 56% yield. When triazolium salts 3d-3g were employed

as

NHC

precursors,

1,3,4-triphenyltriazolium

3d

and

N-phenylpyrrolo[2,1-c]triazoium 3e worked similarly to give product 4a in 52-55% yields (Table 1, entries 4 and 5). In contrast, N-mesitylpyrrolo[2,1-c]triazolium 3f was virtually ineffective. Gratifyingly, N-perfluorophenylpyrrolo[2,1-c]triazolium 3g acted as the most efficient and suitable NHC precatalyst. Combined with Pd(PPh3)4 and Cs2CO3, it catalyzed the reaction of 3-(2-formylphenoxy)propenoate 1a with cinnamyl acetate 2a to produce 4a in good yield (70%) (Table 1, entry 7). With the use of triazolium 3g as an optimized NHC precatalyst, we found the action of the base used in this cascade catalysis was crucial, dictating not only for the generation of carbene catalyst, but also for the allylation of benzofuran-3-one intermediates. As summarized in entries 10-12 in Table 1, bases such as t-BuOK, NaH and DBU led to reduced yields of product 4a. Replacement of Cs2CO3 by K2CO3 significantly improved the yield of 4a to 80% (entry 8). It should be noted that, however, the decrease of base loading of K2CO3 to 1.5 equivalents decreased dramatically the yield 5



Page 6 of 30

of 4a to 37% (entry 9). The outcome indicated clearly that the excess of base was necessary for this reaction. To seek an optimal metal catalyst, different palladium catalysts were then examined. Varying Pd(PPh3)4 to [Pd(C3H5)Cl)]2, Pd2(dba)3 and Pd2(dba)3/dppp resulted in the inhibition of the reaction. On the other hand, the Pd2(dba)3/dppb Pd2(dba)3/dppf and [Pd(C3H5)Cl)]2/dppf were able to catalyze the formation of 4a but in diminished yields (43-69%) (Table 1, entries 13-18). It was also noteworthy that the reaction media and temperature played decisive roles on the cascade catalysis in question. While changing the solvent from dichloromethane to dichloroethane, 1,4-dioxane and toluene under the otherwise identical conditions did not show a beneficial effect, the yield of product 4a was heavily decreased when a polar solvent acetonitrile was tested (Table 1, entries 19-22). The reaction conducted in refluxing dichloromethane and at room temperature gave similar results. In stark contrast, the reaction at 0 oC only yielded 15% of product. Finally, under the conditions of optimized catalysts, base, solvent and temperature, respective reducing the loading of cinnamyl acetate 2a to 1.5 equiv. and Pd(PPh3)4 to 5 mol% led to diminished yields of product 4a (Table 1, entries 25 and 26). In addition to the major product 4a, two diastereoisomeric byproducts 5a and 6a were also detected both below 10% yields (4a:5a:6a ~ 69:15:16‒87:7:6) in most of the aforementioned reactions. X-ray diffraction analysis confirmed that the major product 4 and the minor 6 were constitutional isomers that were derived from two different regioselective reactions between 1 and 2 (See X-ray structures of 4a and 6e in Supporting Information). The 1H NMR spectra indicated that the two minor products 5a an 6a were the syn- and anti-stereoisomers. Table 1. Optimization of reaction conditions.

6


Page 7 of 30


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Entry

3

Base

MLn

Solvent

T. (oC)

T (h)

(mol%)

Yield of

4a:5a:6ab

a

(mol%)

(equiv.)

1

3a (20)

Cs2CO3 (2)

Pd(PPh3)4 (10)

DCM

25-30

8

26

72:14:14

2

3b (20)

Cs2CO3 (2)

Pd(PPh3)4 (10)

DCM

25-30

8

62

85:7:8

3

3c (20)

Cs2CO3 (2)

Pd(PPh3)4 (10)

DCM

25-30

8

56

83:9:8

4

3d (20)

Cs2CO3 (2)

Pd(PPh3)4 (10)

DCM

25-30

8

52

82:9:8

5

3e (20)

Cs2CO3 (2)

Pd(PPh3)4 (10)

DCM

25-30

8

55

87:7:6

6

3f (20)

Cs2CO3 (2)

Pd(PPh3)4 (10)

DCM

25-30

24

9

80:10:10

7

3g (20)

Cs2CO3 (2)

Pd(PPh3)4 (10)

DCM

25-30

8

70

81:10:9

8

3g (20)

K2CO3 (2)

Pd(PPh3)4 (10)

DCM

25-30

8

80

83:9:8

9

3g (20)

K2CO3 (1.5)

Pd(PPh3)4 (10)

DCM

25-30

12

37

80:10:10

10

3g (20)

t-BuOK

Pd(PPh3)4 (10)

DCM

25-30

8

20

70:13:17

4a

(2) 11

3g (20)

NaH (2)

Pd(PPh3)4 (10)

DCM

25-30

8

45

76:8:16

12

3g (20)

DBU (2)

Pd(PPh3)4 (10)

DCM

25-30

11

11

78:10:12

13

3g (20)

K2CO3 (2)

[Pd(C3H5)Cl)]2

DCM

25-30

24

-

DCM

25-30

24

-

DCM

25-30

8

-

DCM

25-30

8

43

76:12:12

DCM

25-30

8

69

76:13:11

DCM

25-30

8

67

76:12:12

(10) 14

3g (20)

K2CO3 (2)

Pd2(dba)3 (10)

15

3g (20)

K2CO3 (2)

Pd2(dba)3/dpppc

3g (20)

K2CO3 (2)

Pd2(dba)3/dppbd

(10) 16

(10) 17

3g (20)

K2CO3 (2)

Pd2(dba)3/dppfe (10)

18

3g (20)

K2CO3 (2)

[Pd(C3H5)Cl)]2 e

/dppf (10) 19

3g (20)

K2CO3 (2)

Pd(PPh3)4 (10)

DCE

25-30

8

73

81:9:10

20

3g (20)

K2CO3 (2)

Pd(PPh3)4 (10)

toluene

25-30

8

77

84:6:10

21

3g (20)

K2CO3 (2)

Pd(PPh3)4 (10)

dioxane

25-30

8

71

82:7:11

22

3g (20)

K2CO3 (2)

Pd(PPh3)4 (10)

CH3CN

25-30

8

26

73:11:8

23

3g (20)

K2CO3 (2)

Pd(PPh3)4 (10)

DCM

40

8

80

86:7:7

24

3g (20)

K2CO3 (2)

Pd(PPh3)4 (10)

DCM

0

8

15

69:15:16

7



25

3g (20)

26

3g (20)

a

K2CO3 (2) K2CO3 (2) b

1

Page 8 of 30

Pd(PPh3)4 (10)

DCM

25-30

8

61 f

89:5:6

Pd(PPh3)4 (5)

DCM

25-30

24

70

81：9：10

c

Isolated yields. Determined by H NMR. dppp = 1,3-bis(diphenylphosphino) propane;

d

dppb = 1,4-bis(diphenylphosphino)butane; edppf = 1,1'-bis(diphenyphosphino)ferrocene. fIn this reaction, the

loading of cinnamyl acetate 2a was 1.5 equiv..

With the optimized conditions established, we surveyed the scope of the reaction by employing various 3-(2-formylphenoxy)propenoates 1 and allylic esters 2 as reaction substrates (Table 2). It was revealed that the substituents on the aldehydes 1 have a negligible effect to the outcomes of the reaction. Substrates 1b-1g bearing an electron-donating (methoxy and methyl) or an electron-withdrawing group (bromine atom) on the para- or meta-position of aldehyde underwent highly regioselective cascade reactions with cinnamyl acetate 2a, affording the corresponding products 4b-4g in good yields (69-87%), and only a trace amount of minor isomers 5b-5g and 6b-6g were formed (4:5:6 ~ 81:10:9-86:9:5) (Table 2, entries 2-7). In sharp contrast to the substrates 1, the structures of allylic esters 2 significantly influenced the reactivity and regioselectivity of the reaction. For instance, cinnamyl acetates 2b and 2c bearing a electron-withdrawn bromine and carboxylate groups on the para-position of phenyl ring reacted with aldehyde 1a to produce 4h and 4i in 61-65% yields with excellent regioselectivity (4:5:6 ~ 87:4:9-93:2:5) (Table 2, entries 8 and 9). Meanwhile, the reactions of electron-donating p-methoxy and p-methyl substituted cinnamyl acetate 2d and 2f with aldehyde 1a yielded products 4j and 4l also in moderate yields (50-62%), but exhibited lower regioselectivity (4:5:6 ~ 68:16:6-74:12:14) (Table 2, entries 10 and 12). When ortho-substituted cinnamyl acetate was used, however, the reaction of o-methylcinnamyl 2e with 1a provided product 4k in good yield (73%) with excellent regioselectivity (4:5:6 ~ 93:3:4) (Table 2, entry 11). On the other hand, the reaction of non-substituted allylic ester 2g with 1a produced 4m as a sole product in 79% yield (Table 2, entry 13). In addition, when alkyl substituted allylic esters were employed, the reaction was obviously less efficient than that of aryl substituted allylic esters. After reacting with 1a for 24h, 2-hexenyl acetate 2h provided 63% of 4n with excellent regioselectivity (4n:5n:6n ~ 90:5:5), where as 2-cyclohexenyl acetate 2i produced the sole product 4o in only 40% 8


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yield (Table 2, entries 14 and 15). Finally, different esters of cinnamic alcohol were employed in the reaction with aldehyde 1a. It was found that the cinnamyl carbonate 2j gave product 4a in similar yield and regioselectivity (83% yield, 4a:5a:6a ~ 82:6:12) as that of cinnamyl acetate 2a, where as the cinnamyl benzoate 2k produced 4a in a lower yield with higher regioselectivity (70% yield, 4a:5a:6a ~ 89:7:4) (see Table 2, entries 1, 16 and 17). Table 2. Scope of the developed protocol on various substrates.

entry

1: X

2: R, R1

T (h)

1

1a: H

2a: Ph, Me

2

1b: 5-Br

3

Yield (%)a

4:5:6b

8

80

83:9:8

2a: Ph, Me

8

69

85:8:7

1c: 5-Me

2a: Ph, Me

8

86

85:8:7

4

1d: 5-OMe

2a: Ph, Me

8

87

86:9:5

5

1e: 4-Br

2a: Ph, Me

8

74

81:10:9

6

1f: 4-Me

2a: Ph, Me

8

77

84:8:8

4

O Me Ph 4f

O CO2Me

7

1g: 4-OMe

2a: Ph, Me

8

78

81:9:10

8

1a: H

2b: p-C6H4CO2Me, Me

24

65

93:2:5

9

1a: H

2c: p-C6H4Br, Me

24

61

87:4:9

10

1a: H

2d: p-C6H4Me, Me

24

50

74:12:14

11

1a: H

2e: o-C6H4Me, Me

24

73

93:3:4

12

1a: H

2f: p-C6H4OMe,

24

62

68:16:16

9

79

-

Me 13

1a: H

2g: H, Me

9



14

1a: H

15

1a: H

2h: n-propyl, Me

Page 10 of 30

24

63

90:5:5

24

40

-

2i:

16

1a: H

2j: Ph, OMe

8

4a

83

82:6:12

17

1a: H

2k: Ph, Ph

8

4a

70c

89:7:4

Isolated yields. bThe ratios of 4:5:6 were determined by 1H NMR. Except 5a, 6a, 5e and 6e that were

a

isolated and characterized, other by-products were detected by TLC and 1H NMR without isolation. c In this reaction, 11% yield of intermediate 10a was detected in the crude products determined by 1H NMR.

A most plausible catalytic cycle for the NHC/Pd-catalyzed tandem reaction of 3-(2-formylphenoxy)propenoates 1 with allylic esters 2 is depicted in Figure 2. The addition of a NHC catalyst to aldehydes 1 forms the Breslow intermediates 7. An intramolecular Stetter reaction of intermediates 7 yields the carbanion intermediates 8. Carbanions 8 undergo a proton transformation followed by the elimination of NHC species to produce the benzofuran-3-one-2-acetates 10. In the presence of a base catalyst, deprotonation of intermediates 10 forms the enolates 11. The enolates 11 undergo nucleophilic attack to the palladium -allyl complexes derived from allylic esters 2 and the palladium catalyst to provide 2,2-disubstituted benzofuran-3-one products. The major products 4, and the minor ones 5 and 6 were derived respectively from the regioselective addition to the terminal and substituted carbons of palladium -allyl complexes. This cascade catalytic mechanism has been confirmed by the Pd(PPh3)4/K2CO3-catalyzed

reaction

of

benzofuran-3-one-2-acetate

10a

with

cinnamyl acetate 2a to produce 2,2-disubstituted benzofuran-3-ones 4a, 5a and 6a.

10


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Figure 2. Proposed mechanism for the tandem reaction.

To achieve asymmetric synthesis of 2,2-disubstituted benzofuranones, the reaction between 3-(2-formylphenoxy)propenoates 1 and allylic esters 2 was then examined under the catalysis of chiral catalysts. It was found that the reaction catalyzed by a combination of a chiral NHC and Pd(PPh3)4 showed no enantioselectivity in the formation of products 4 due to the racemization of the mono-substituted benzofuranone intermediates 10 in the allylation step. Thus, we focused on the asymmetric reaction of 1a with 2a under the catalysis of triazole carbene and chiral palladium catalysts (Table 3). Since both Pd2(bda)3 and [Pd(C3H5)Cl]2 have been frequently used as palladium precatalysts in various asymmetric allylic alkylation reactions of nucleophiles with allylic esters,14 we firstly tried the reaction under the catalysis of NHC/Pd2(bda)3/(R)-BINAP (L1) and NHC/[Pd(C3H5)Cl]2/(R)-BINAP, respectively. In dichloromethane and at 25-30 oC, the combination of triazolium salt 3g, K2CO3 and Pd2(bda)3/BINAP did not appear as an efficient catalytic system. High catalytic activity was observed when [Pd(C3H5)Cl]2/BINAP was applied in the reaction promoted by the same NHC. Although product 4a was yielded in 82%, unfortunately, the enantioselectivity was rather low (33% ee) (Table 3, entry 2). To improve the enantioselectivity, the solvent effect was investigated. The reaction in 11



Page 12 of 30

dichloroethane gave similar results as that in dichloremethane, however, the use of 1,4-dioxane and toluene as solvents nearly doubled the ee values of the product 4a (Table 3, entries 3-5). Different chiral bidentate phosphine ligands L1-L8 were then studied in toluene at 25-30 oC. It was found that the DIFLUORPHOS (L3) gave comparable yield and enantioselectivity as BINAP (L1), where as the SEGPHOS (L2) and SYNPHOS (L4) gave slightly worse chiral induction than that of BINAP (Table 3, entries 5-8). The (R)-5-Cl-6-MeO-BIPHEP (L5) and (S)-P-PHOS (L6) led to the formation of product 4a in lower yields with similar enantioselectivity as that of BINAP (Table 3, entries 9 and 10). On the contrary, the bulky ligand (S)-DTBM-SEGPHOS (L7) gave excellent yield of product, but with no enantioselectivity

(Table

3,

entry

11).

In

addition

to

the

2,2'-bis(diarylphosphino)-1,1'-biaryl ligands L1-L7, the (R, R)-Trost Ligand (L8) was also examined, which gave product in a lower yield with a ee value similar as that of BINAP (see Table 3, entries 5 and 12). At 25-30 oC, the change of a base catalyst from K2CO3 to Cs2CO3 didn't benefit to the reaction. Delightfully, decreasing the reaction temperature to 0 oC improved the enantioselectivity to 73% ee (77% yield) and 75% ee (82% yield), respectively, by using K2CO3 and Cs2CO3 as the base catalyst (Table 3, entries 14 and 15). Table 3. Optimization of reaction conditions for enantioselective synthesis.

12


Page 13 of 30 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


entry

PdLn

L

Base

Solvent

T (oC)

T (h)

Yield of 4a

ee

(%)a

(%)b

1

Pd2(dba)3

L1

K2CO3

DCM

25-30

12

-c

2

[Pd(C3H5)Cl]2

L1

K2CO3

DCM

25-30

12

82

33

3

[Pd(C3H5)Cl]2

L1

K2CO3

DCE

25-30

12

74

32

4

[Pd(C3H5)Cl]2

L1

K2CO3

1,4-dioxane

25-30

12

80

63

5

[Pd(C3H5)Cl]2

L1

K2CO3

toluene

25-30

12

87

65

6

[Pd(C3H5)Cl]2

L2

K2CO3

toluene

25-30

12

90

59

7

[Pd(C3H5)Cl]2

L3

K2CO3

toluene

25-30

12

83

64

8

[Pd(C3H5)Cl]2

L4

K2CO3

toluene

25-30

12

87

51

9

[Pd(C3H5)Cl]2

L5

K2CO3

toluene

25-30

12

76

61

10

[Pd(C3H5)Cl]2

L6

K2CO3

toluene

25-30

12

50

62

11

[Pd(C3H5)Cl]2

L7

K2CO3

toluene

25-30

12

91

2

12

[Pd(C3H5)Cl]2

L8

K2CO3

toluene

25-30

12

76

67

13

[Pd(C3H5)Cl]2

L1

Cs2CO3

toluene

25-30

12

84

63

14

[Pd(C3H5)Cl]2

L1

K2CO3

toluene

0

12

77

73

15

[Pd(C3H5)Cl]2

L1

Cs2CO3

toluene

0

12

82

75

a

Isolated yields. bDetermined by chiral HPLC. cOnly benzofuran-3-one-2-acetate intermediate 10a was

isolated under these conditions.

Under the asymmetric catalytic conditions using (R)-BINAP as a chiral ligand, reactions of a number of aldehydes 1 and cinnamyl acetates 2 were studied in order to synthesize enantiomerically enriched 2,2-disubstituted benzofuran-3-ones 4. It was found

that,

in

the

[Pd(C3H5)Cl]2/(R)-BINAP

presence in

of

toluene

triazolium at

0

salt o

C,

3g,

Cs2CO3

and

the

reaction

of

3-(5-bromo-2-formylphenoxy)propenoate 1b with cinnamyl acetate 2a proceeded efficiently to give product 4b in 90% yield with 68% ee in 12h (Table 4, entry 2). Under the same conditions, however, 3-(2-formyl-5-methylphenoxy)propenoate 1c and 3-(2-formyl-5-methoxyphenoxy)propenoate 1d were less reactive than 1a and 1b, as their reactions with 2a produced 4c and 4d in 61% and 46% yields with 72% ee and 74% ee, respectively (Table 4, entries 3 and 6). An appreciable amount of 13



benzofuran-3-one-2-acetate

intermediates

10c

and

Page 14 of 30

10d

(20-46%)

remained

unconverted. By prolonging reaction time at 0 oC or both prolonging time and elevating temperature to 25-30 oC, the reaction of 1c and 2a went completion within 24h to give 4c in 82% yield (81% ee) or 85% yield (72% ee), respectively (Table 4, entries 4 and 5). At 25-30 oC, the reaction between 1d and 2a also completed in 24h to provide product 4d in 84% yield with 75% ee (Table 4, entry 7). On the other hand, the reactions of p-bromo-, p-methyl- and p-methoxy-substituted cinnamyl acetates 2c, 2d and 2f with aldehyde 1a proceeded analogously, affording products 4i, 4j and 4l in 54-79% yield with 73-79% ee in 12-24h at 0 oC (Table 4, entries 8, 10, 11). The absolute configurations of the major enantiomers have not been determined by X-ray analysis, because a pair of enantiomers precipitated from the enantioenriched products 4 during the process of recrystallization, although different products 4 and different solvents have been tried. Glorius and co-workers have reported a DBU-catalyzed rearrangement from chroman-4-ones to 2,2-disubstituted benzofuran-3-ones.12e In this work, we also found

a

DBU-catalyzed

isomerization

between

benzofuran-3-ones

4

and

chroman-4-ones 15 (Vide infra Scheme 2, equ. 3). To examine the stability of the optically

active

products

4

under

basic

reaction

conditions,

we

stirred

enantiomerically enriched benzofuran-3-one product 4h (79% ee) with 2 equv. of Cs2CO3 in dry toluene for 12h at room temperature. The product 4h was recovered with 77% ee, and no isomerized product was observed under these conditions. In addition, the asymmetric reactions of 1c with 2a and 1a with 2c have been carried out at 0 oC for 12h and 24h, and both reactions gave higher chemical yields and ee values in 24h than 12h (see Table 4, entries 3, 4; and 9, 10.). All these results indicated that the products 4 did not undergo racemization and isomerization under our chiral catalysis conditions. Table 4. Enantioselective synthesis of 2,2-disubstituted benzofuran-3-ones.

14


Page 15 of 30 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


entry

1: X

T (o C)

2: Ar

T (h)

Yield of 4a

ee (%)c

(%)a,b 1

1a: H

2a: Ph

0

12

4a: 82

75

2

1b: Br

2a: Ph

0

12

4b: 90

68

3

1c: Me

2a: Ph

0

12

4c: 61

72

4

1c: Me

2a: Ph

0

24

4c: 82

81

5

1c, Me

2a: Ph

25-30

24

4c: 85

72

6

1d: OMe

2a: Ph

0

24

4d: 46d

74

7

1d: OMe

2a: Ph

25-30

24

4d: 84

75

8

1a: H

2b: p-BrC6H4

0

12

4i: 77

79

d

9

1a: H

2c: p-MeC6H4

0

12

4j: 55

10

1a: H

2c: p-MeC6H4

0

24

4j: 79

73

11

1a: H

2d: p-OMeC6H4

0

12

4l: 54

73

d

67

a

Isolated yields. bA trace amount of by-products 5 and 6 were detected by TLC without isolation.

c

Determined by chiral HPLC. dIn these reactions, the intermediates 10 were detected in 20-46 %

yields in the products determined by 1H NMR. The yields of products 4 were calculated based on the total yields and the ratios of 4:8 in the products.

To demonstrate the synthetic utility of the resulting products, different transformations of the racemic 2-cinnamylbenzofuran-3-one-2-acetates 4 were explored. For example, the oxidative cleavage of C=C bonds of 4a and 4b with PhI(OAc)2 and catalytic OsO4 yielded aldehydes 12a and 12b in 61% and 51% yields, respectively (Scheme 2, equ. 1).15 The epoxidation of 4 with m-CPBA provided a pair of diastereomeric epoxides 13 and 14 in 42-45% and 43-47% yields (Scheme 2, equ. 2).16 In the presence of DBU, dihydrobenzofuran-3-ones 4 underwent a base-catalyzed isomerization to form the anti-substituted 2-styrylchroman-4-one-3-acetates 15 in 41-47% yields (Scheme 2, equ. 3). Although different bases, the loading of DBU, solvents, temperature and reaction time were varied, the dihydrobenzofuranones 4 were not completely transformed into chromanones 15, with 4 being recovered in 26-56% yields. This was most probably due to the equilibrium between benzofuran-3-ones 4 and 15



Page 16 of 30

chroman-4-ones 15 under the reaction conditions used. The relative configurations of compounds 13a, 14a and 15a were determined by single crystal X-ray diffraction analysis (See Supporting Information).

Scheme 2. Transformations of 2-cinnamylbenzofuran-3-one-2-acetates 4.

Conclusion In summary, we have developed a novel and efficient NHC/base/Pd cascade catalytic method for the synthesis of 2,2-disubstituted benzofuran-3-ones from the reaction of 3-(2-formylphenoxy)propenoates with allylic esters. In the presence of a combination of a triazole carbene, K2CO3 or Cs2CO3 and Pd(PPh3)4, the 3-(2-formylphenoxy)propenoates and allylic esters undergo a cascade Stetter reaction and regioselective allylation to produce 2-allylbenzofuran-3-one-2-acetates in 40-87% yields. By using [Pd(C3H5)Cl]2/(R)-BINAP as the chiral palladium catalyst, optically active 2-allylbenzofuran-3-one-2-acetates were obtained in 54-90% yield with 68-81% ee. The resulting products were easily converted into different polyfunctionalized compounds. This work has provided not only a simple and efficient strategy for the construction of 2,2-disubstituted benzofuran-3-ones, but also demonstrated an interesting example of N-heterocyclic carbene and transition metal cascade catalysis in organic synthesis.

Experimental Section 1. General procedure for the synthesis of 2-allylbenzofuran-3-one-2-acetates 4 16


Page 17 of 30 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


from NHC/Pd(PPh3)4 catalyzed reaction of 3-(2-formylphenoxy)propenoates with allylic esters. At ambient temperature (around 25 oC), Pd(PPh3)4 (57.8 mg, 0.05 mmol, 10 mol%), triazolium

salt

3g

(36.3

mg,

0.1

mmol,

20

mol%)

and

3-(2-formylphenoxy)propenoates 1 (0.5 mmol) were added to an oven-dried Schlenk tube. The test tube was then evacuated and backfilled with nitrogen (3×). The dry dichloromethane (5 mL) was added using a microsyringe and the mixture was stirred for 5 minutes. Then allylic esters (1 mmol) and K2CO3 (1 mmol) was added to the mixture under N2. The reaction mixture was then stirred for 8-24h at room temperature under nitrogen atmosphere. The K2CO3 was filtrated and washed with dichloromethane (10 mL×3). The filtrate was concentrated under reduced pressure. The residue was chromatographed on a silica gel column eluting with a mixture of petroleum ether and ethyl acetate (PE:EA from 15:1 to 10:1) to give a mixture of isomeric products 4, 5 and 6. After determining the ratios of 4:5:6 by 1H NMR, the crude products were chromatographed again on a silica gel column to give the major products 4 in 40-87% yields. Except 5a, 6a, 5e and 6e that were isolated and characterized, other minor products 5 and 6 were determined in 3-10% yields by 1H NMR without isolation. (E)-Methyl 2-cinnamylbenzofuran-3-one-2-acetate 4a: white solid, 129/134/113 mg, 80/83/70% from 1a and cinnamyl acetate 2a/cinnamyl carbonate 2j/cinnamyl benzoate 2k, respectively; mp 104-105 oC (recrystallization from AcOEt/n-hexane); IR v (cm-1) 1740, 1717, 1611; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.69 (d, J = 7.6 Hz, 1H), 7.60 (t, J = 7.4 Hz, 1H), 7.20-7.28 (m, 5H), 7.10 (d, J = 7.7 Hz, 1H), 7.08 (t, J = 7.5 Hz, 1H), 6.49 (d, J = 15.8 Hz, 1H), 6.03-6.11 (m, 1H), 3.52 (s, 3H), 3.08 (d, J = 17.0 Hz, 1H), 3.03 (d, J = 16.8 Hz, 1H), 2.64-2.73 (m, 2H); 13C NMR (100 MHz, CDCl3) δ (ppm) 202.2, 171.4, 169.1, 137.9, 136.9, 135.3, 128.6, 127.7, 126.4, 124.4, 122.1, 121.6, 121.4, 113.2, 88.3, 51.9, 40.0, 39.9; HRMS (TOF-APCI): [M + H]+ calcd for C20H19O4: 323.1277; found: 323.1272. syn-Methyl 2-(1-phenylallyl)benzofuran-3-one-2-acetate 5a: white solid, 7.4 mg, 4.6% from cinnamyl acetate 2a, mp 79-80 oC (without recrystallization); IR v (cm-1) 17



Page 18 of 30

1741, 1729, 1617; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.65 (t, J = 7.7 Hz, 1H), 7.59 (d, J = 7.4 Hz, 1H), 7.40 (d, J = 7.8 Hz, 2H), 7.33 (t, J = 7.5 Hz, 2H), 7.24-7.27 (m, 1H), 7.12 (d, J = 8.3 Hz, 1H), 7.07 (t, J = 7.4 Hz, 1H), 5.83-5.92 (m, 1H), 5.06 (d, J = 16.9 Hz, 1H), 4.91 (d, J = 10.1 Hz, 1H), 3.70 (d, J = 9.2 Hz, 1H), 3.41 (s, 3H), 2.98 (d, J = 16.7 Hz, 1H), 2.69 (d, J = 16.7 Hz, 1H);

13

C NMR (100 MHz, CD3Cl) δ (ppm)

202.5, 171.9, 169.0, 138.3, 137.6, 133.9, 129.0, 128.7, 127.5, 123.8, 122.9, 122.0, 118.8, 112.6, 90.3, 56.8, 51.8, 40.3; HRMS (TOF-APCI): [M + H]+ calcd for C20H19O4: 323.1277; found: 323.1283. anti-Methyl 2-(1-phenylallyl)benzofuran-3-one-2-acetate 6a: white solid, 8.6 mg, 5.3%, mp 65-66 oC (recrystallization from AcOEt/n-hexane); IR v (cm-1) 1745, 1722, 1614; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.43 (t, J = 8.2 Hz, 1H), 7.31 (d, J = 7.6 Hz, 1H), 7.12 (d, J = 7.6 Hz, 2H), 6.96-7.04 (m, 4H), 6.83 (t, J = 7.3 Hz, 1H), 6.39 (dt, J = 16.9, 10.1 Hz, 1H), 5.33 (d, J = 11.5 Hz, 1H), 5.29 (d, J = 18.2 Hz, 1H), 3.68 (d, J = 10.1 Hz, 1H), 3.46 (s, 3H), 3.23 (d, J = 16.6 Hz, 1H), 3.10 (d, J = 16.6 Hz, 1H); 13C NMR (100 MHz, CD3Cl) δ (ppm) 202.2, 172.0, 169.1, 137.4, 136.8, 135.1, 129.1, 128.1, 127.2, 123.7, 122.7, 121.6, 119.8, 112.4, 89.8, 56.2, 51.9, 40.2; HRMS (TOF-ESI): [M + Na]+ calcd for C20H18O4Na: 345.1097; found: 345.1093. (E)-Methyl 6-bromo-2-cinnamylbenzofuran-3-one-2-acetate 4b: white solid, 137 mg, 69%, mp 126-127 oC (recrystallization from AcOEt/n-hexane); IR v (cm-1) 1738, 1717, 1605; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.54 (d, J = 8.2 Hz, 1H), 7.21-7.31 (m, 7H), 6.49 (d, J = 15.8 Hz, 1H), 6.00-6.08 (m, 1H), 3.54 (s, 3H), 3.08 (d, J = 16.9 Hz, 1H), 3.04 (d, J = 16.8 Hz, 1H), 2.62-2.71 (m, 2H); 13C NMR (100 MHz, CDCl3) δ (ppm) 200.9, 171.3, 169.0, 136.6, 135.5, 132.6, 128.6, 127.7, 126.3, 125.8, 125.1, 121.0, 120.5, 116.7, 89.1, 52.0, 39.9, 39.8; HRMS (TOF-APCI): [M + H]+ calcd for C20H18BrO4: 401.0382; found: 401.0385. (E)-Methyl 2-cinnamyl-6-methylbenzofuran-3-one-2-acetate 4c: white solid, 145 mg, 86%, mp 124-125 oC (recrystallization from AcOEt/n-hexane); IR v (cm-1) 1738, 1713, 1616; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.57 (d, J = 8.0 Hz, 1H), 7.20-7.29 (m, 5H), 6.90 (s, 1H), 6.89 (d, J = 7.0 Hz, 1H), 6.48 (d, J = 15.8 Hz, 1H), 6.04-6.11 (m, 1H), 3.53 (s, 3H), 3.04 (d, J = 16.8 Hz, 1H), 3.00 (d, J = 16.6 Hz, 1H), 2.62-2.72 18


Page 19 of 30 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(m, 2H), 2.41 (s, 3H);

13

C NMR (100 MHz, CDCl3) δ (ppm) 201.5, 171.8, 169.1,

149.9, 136.8, 135.1, 128.5, 127.6, 126.3, 124.0, 123.7, 121.7, 118.9, 113.2, 88.4, 51.9, 39.9, 39.8, 22.6; HRMS (TOF-APCI): [M + H]+ calcd for C21H21O4: 337.1434; found: 337.1439. (E)-Methyl 2-cinnamyl-6-methoxybenzofuran-3-one-2-acetate 4d: white solid, 153 mg, 87%, mp 149-150 oC (recrystallization from AcOEt/n-hexane); IR v (cm-1) 1742, 1705, 1611; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.58 (d, J = 8.6 Hz, 1H), 7.20-7.29 (m, 5H), 6.63 (d, J = 8.6 Hz, 1H), 6.53 (s, 1H), 6.49 (d, J = 15.8 Hz, 1H), 6.04-6.11 (m, 1H), 3.86 (s, 3H), 3.54 (s, 3H), 3.03 (d, J = 17.2 Hz, 1H), 2.98 (d, J = 17.2 Hz, 1H), 2.64-2.75 (m, 2H);

13


168.2, 136.8, 135.1, 128.5, 127.6, 126.3, 125.4, 121.7, 114.3, 111.6, 96.1, 89.1, 55.8, 51.9, 39.9, 39.7; HRMS (TOF-APCI): [M + H]+ calcd for C21H21O5: 353.1383; found: 353.1387. (E)-Methyl 5-bromo-2-cinnamylbenzofuran-3-one-2-acetate 4e: white solid, 147.8 mg, 74%, mp 104-105 oC (without recrystallization); IR v (cm-1) 1744, 1719, 1607; 1

H NMR (400 MHz, CDCl3) δ (ppm) 7.81 (s, 1H), 7.67 (d, J = 8.8 Hz, 1H), 7.21-7.30

(m, 5H), 7.01 (d, J = 8.7 Hz, 1H), 6.49 (d, J = 15.8 Hz, 1H), 6.01-6.08 (m, 1H), 3.54 (s, 3H), 3.10 (d, J = 16.9 Hz, 1H), 3.04 (d, J = 16.9 Hz, 1H), 2.62-2.74 (m, 2H); 13C NMR (100 MHz, CDCl3) δ (ppm) 200.8, 169.9, 169.0, 140.3, 136.6, 135.6, 128.6, 127.8, 126.9, 126.3, 123.2, 120.9, 114.8, 114.5, 89.1, 52.0, 40.0, 39.8; HRMS (TOF-APCI): [M + H]+ calcd for C20H18BrO4: 401.0382; found: 401.0387. syn-Methyl 5-bromo-2-(1-phenylallyl)benzofuran-3-one-2-acetate 5e: white solid, 7.5 mg, 3.7%, mp 112-113 oC (recrystallization from AcOEt/n-hexane); IR v (cm-1) 1743, 1727, 1609; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.75 (d, J = 1.8 Hz, 1H), 7.65 (dd, J = 8.7, 2.0 Hz, 1H), 7.36 (d, J = 7.0 Hz, 2H), 7.32 (t, J = 7.6 Hz, 2H), 7.26 (t, J = 8.2 Hz, 1H), 7.02 (d, J = 8.7 Hz, 1H), 5.86 (dt, J = 16.9, 9.6 Hz, 1H), 5.06 (d, J = 16.9 Hz, 1H), 4.94 (d, J = 10.1 Hz, 1H), 3.67 (d, J = 9.2 Hz, 1H), 3.44 (s, 3H), 2.99 (d, J = 17.0 Hz, 1H), 2.70 (d, J = 17.0 Hz, 1H); 13C NMR (100 MHz, CD3Cl) δ (ppm) 201.1, 170.5, 168.9, 140.0, 138.0, 133.6, 128.9, 128.8, 127.7, 126.4, 124.8, 119.2, 114.5, 19



Page 20 of 30

114.3, 91.2, 56.9, 51.8, 40.4; HRMS (TOF-ESI): [M + Na]+ calcd for C20H17O4BrNa: 423.0202; found: 423.0195. anti-Methyl 5-bromo-2-(1-phenylallyl)benzofuran-3-one-2-acetate 6e: white solid, 8.7 mg, 4.3%, mp 129-130 oC (recrystallization from AcOEt); IR v (cm-1) 1732, 1720, 1607; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.49 (dd, J = 8.7, 2.1 Hz, 1H), 7.44 (d, J = 2.1 Hz, 1H), 7.00-7.10 (m, 5H), 6.87 (d, J = 8.7 Hz, 1H), 6.35 (dt, J = 17.0, 10.1 Hz, 1H), 5.34 (d, J = 10.1 Hz, 1H), 5.29 (d, J = 17.0 Hz, 1H), 3.66 (d, J = 10.1 Hz, 1H), 3.49 (s, 3H), 3.23 (d, J = 16.9 Hz, 1H), 3.09 (d, J = 16.9 Hz, 1H);

13

C NMR (100

MHz, CD3COCD3) δ (ppm) 199.8, 170.7, 168.7, 139.4, 137.0, 135.3, 129.1, 127.9, 127.1, 125.3, 124.9, 119.2, 114.7, 113.1, 90.6, 55.8, 51.1, 40.0; HRMS (TOF-ESI): [M + H]+ calcd for C20H18O4Br: 401.0382; found: 401.0387. (E)-Methyl 2-cinnamyl-5-methylbenzofuran-3-one-2-acetate 4f: white solid, mp 66-67 oC (without recrystallization), 130 mg, 77%; IR v (cm-1) 1745, 1717, 1620; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.46 (s, 1H), 7.41 (dd, J = 8.5, 1.8 Hz, 1H), 7.18-7.29 (m, 5H), 7.00 (d, J = 8.4 Hz, 1H), 6.48 (d, J = 15.8 Hz, 1H), 6.04-6.11 (m, 1H), 3.52 (s, 3H), 3.05 (d, J = 16.5 Hz, 1H), 3.00 (d, J = 16.5 Hz, 1H), 2.62-2.72 (m, 2H), 2.34 (s, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 202.2, 169.7, 169.1, 139.1, 136.8, 135.1, 131.6, 128.5, 127.5, 126.3, 123.8, 121.6, 121.2, 112.6, 88.3, 51.8, 39.9, 39.8, 20.6; HRMS (TOF-APCI): [M + H]+ calcd for C21H20O4Na: 359.1253; found: 359.1259. (E)-Methyl 2-cinnamyl-5-methoxybenzofuran-3-one-2-acetate 4g: colourless oil, 136.9 mg, 78%; IR v (cm-1) 1744, 1715, 1602; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.18-7.29 (m, 6H), 7.08 (d, J = 2.8 Hz, 1H), 7.03 (d, J = 8.9 Hz, 1H), 6.49 (d, J = 15.8 Hz, 1H), 6.04-6.11 (m, 1H), 3.80 (s, 3H), 3.53 (s, 3H), 3.06 (d, J = 16.5 Hz, 1H), 3.01 (d, J = 16.6 Hz, 1H), 2.62-2.73 (m, 2H); 13C NMR (100 MHz, CDCl3) δ (ppm) 202.4, 169.1, 166.6, 154.9, 136.8, 135.1, 128.5, 127.7, 127.6, 126.3, 121.6, 121.2, 114.0, 104.2, 88.8, 55.8, 51.8, 40.0, 39.9; HRMS (TOF-APCI): [M + Na]+ calcd for C21H20O5Na: 375.1202; found: 375.1204. (E)-Methyl 2-(3-(p-(methoxycarbonyl)phenyl)allyl)benzofuran-3-one-2-acetate 4h: white solid, 124 mg, 65%, mp 95-96 oC (recrystallization from CH2Cl2/petroleum 20


Page 21 of 30 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


ether); IR v (cm-1) 1742, 1719, 1612; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.92 (d, J = 8.4 Hz, 2H), 7.69 (dd, J = 7.6, 0.7 Hz, 1H), 7.60 (td, J = 8.4, 1.4 Hz, 1H), 7.27 (d, J = 9.0 Hz, 2H), 7.07-7.12 (m, 2H), 6.52 (d, J = 15.8 Hz, 1H), 6.14-6.22 (m, 1H), 3.89 (s, 3H), 3.53 (s, 3H), 3.08 (d, J = 16.5 Hz, 1H), 3.02 (d, J = 16.6 Hz, 1H), 2.66-2.77 (m, 2H);

13

C NMR (100 MHz, CDCl3) δ (ppm) 202.0, 171.2, 168.9, 166.8, 141.1,

138.0, 134.3, 129.8, 129.0, 126.1, 124.4, 124.3, 122.1, 121.2, 113.1, 88.0, 52.1, 51.9, 39.9, 39.7; HRMS (TOF-ESI): [M + H]+ calcd for C22H21O6: 381.1332; found: 381.133. (E)-Methyl 2-(3-(p-bromophenyl)allyl)benzofuran-3-one-2-acetate 4i: white solid, 121.5 mg, 61%, mp 80-81 oC (recrystallization from AcOEt/n-hexane); IR v (cm-1) 1743, 1721, 1614; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.68 (d, J = 7.6 Hz, 1H), 7.60 (t, J = 7.8 Hz, 1H), 7.37 (d, J = 8.3 Hz, 2H), 7.07-7.11 (m, 4H), 6.42 (d, J = 15.8 Hz, 1H), 6.01-6.08 (m, 1H), 3.52 (s, 3H), 3.06 (d, J = 16.5 Hz, 1H), 3.01 (d, J = 16.4 Hz, 1H), 2.63-2.73 (m, 2H);

13


137.9, 135.6, 134.0, 131.6, 127.8, 124.3, 122.4, 122.1, 121.4, 121.3, 113.1, 88.0, 51.9, 39.9, 39.7; HRMS (TOF-ESI): [M + Na]+ calcd for C20H17BrO4Na: 423.0202; found: 423.0208. (E)-Methyl 2-(3-(p-methylphenyl)allyl)benzofuran-3-one-2-acetate 4j: colourless oil, 83.5 mg, 50%; IR v (cm-1) 1745, 1722, 1614; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.69 (d, J = 7.6 Hz, 1H), 7.60 (t, J = 7.5 Hz, 1H), 7.06-7.15 (m, 6H), 6.45 (d, J = 15.7 Hz, 1H), 5.98-6.05 (m, 1H), 3.51 (s, 3H), 3.07 (d, J = 17.0 Hz, 1H), 3.03 (d, J = 18.9 Hz, 1H), 2.62-2.71 (m, 2H), 2.31 (s, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 202.2, 171.3, 169.0, 137.8, 137.4, 135.1, 134.0, 129.1, 126.2, 124.3, 121.9, 121.4, 120.4, 113.0, 88.2, 51.8, 39.9, 39.8, 21.1; HRMS (TOF-ESI): [M + Na]+ calcd for C21H20O4Na: 359.1253; found: 359.1258. (E)-Methyl 2-(3-(o-methylphenyl)allyl)benzofuran-3-one-2-acetate 4k: white solid, 123 mg, 73%, mp 61-62 oC (recrystallization from acetone/n-hexane); IR v (cm-1) 1744, 1721, 1612; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.69 (d, J = 7.6 Hz, 1H), 7.60 (td, J = 8.5, 1.4 Hz, 1H), 7.04-7.13 (m, 6H), 6.67 (d, J = 15.6 Hz, 1H), 5.85-5.92 (m, 1H), 3.53 (s, 3H), 3.09 (d, J = 16.5 Hz, 1H), 3.03 (d, J = 16.5 Hz, 1H), 21



2.67-2.78 (m, 2H), 2.26 (s, 3H);

Page 22 of 30

13

C NMR (100 MHz, CD3COCD3) δ (ppm) 201.2,

171.3, 168.8, 137.6, 136.2, 135.0, 133.0, 130.0, 127.4, 125.9, 125.6, 123.7, 123.2, 121.9, 121.8, 112.9, 88.2, 51.0, 39.8, 39.7, 18.9; HRMS (TOF-ESI): [M + H]+ calcd for C21H21O4: 337.1434; found: 337.1436. (E)-Methyl 2-(3-(p-methoxyphenyl)allyl)benzofuran-3-one-2-acetate 4l: white solid, 109.2 mg, 62%, mp 78-79 oC (without recrystallization); IR v (cm-1) 1736, 1722, 1614; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.69 (d, J = 7.6 Hz, 1H), 7.59 (t, J = 8.4 Hz, 1H), 7.17 (d, J = 8.6 Hz, 2H), 7.10 (d, J = 8.2 Hz, 1H), 7.07 (t, J = 7.4 Hz, 1H), 6.79 (d, J = 8.7 Hz, 2H), 6.42 (d, J = 15.8 Hz, 1H), 5.88-5.96 (m, 1H), 3.78 (s, 3H), 3.51 (s, 3H), 3.07 (d, J = 16.6 Hz, 1H), 3.02 (d, J = 16.6 Hz, 1H), 2.61-2.70 (m, 2H); 13

C NMR (100 MHz, CD3COCD3) δ (ppm) 201.2, 171.2, 168.8, 159.4, 137.6, 134.3,

129.7, 127.3, 123.7, 121.8, 121.7, 119.2, 113.8, 112.9, 88.2, 54.6, 51.0, 39.7, 39.6; HRMS (TOF-ESI): [M + Na]+ calcd for C21H20O5Na: 375.1202; found: 375.1208. (E)-Methyl 2-allylbenzofuran-3-one-2-acetate 4m: colourless oil, 97.2 mg, 79%; IR v (cm-1) 1747, 1722, 1614; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.69 (d, J = 7.8 Hz, 1H), 7.60 (t, J = 7.8 Hz, 1H), 7.09 (t, J = 7.1 Hz, 1H), 7.08 (d, J = 8.4 Hz, 1H), 5.62-5.72 (m, 1H), 5.15 (d, J = 17.0 Hz, 1H), 5.09 (d, J = 10.1 Hz, 1H), 3.51 (s, 3H), 3.03 (d, J = 16.6 Hz, 1H), 2.98 (d, J = 16.6 Hz, 1H), 2.49-2.59 (m, 2H);

13

C NMR

(100 MHz, CDCl3) δ (ppm) 202.2, 171.3, 169.0, 137.8, 130.0, 124.2, 121.9, 121.4, 120.5, 113.0, 87.9, 51.8, 40.5, 39.9; HRMS (TOF-ESI): [M + H]+ calcd for C14H15O4: 247.0964; found: 247.0963. (E)-Methyl 2-(2-hexen-1-yl)benzofuran-3-one-2-acetate 4n: colourless oil, 90.2 mg, 63%; IR v (cm-1) 1746, 1722, 1614; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.67 (dd, J = 8.1, 1.4 Hz, 1H), 7.58 (td, J = 8.0, 1.4 Hz, 1H), 7.04-7.08 (m, 2H), 5.52-5.56 (m, 1H), 5.24-5.28 (m, 1H), 3.51 (s, 3H), 3.01 (d, J = 16.5 Hz, 1H), 2.96 (d, J = 16.4 Hz, 1H), 2.46-2.49 (m, 2H), 1.87 (q, J = 7.2 Hz, 2H), 1.21-1.26 (m, 2H), 0.76 (t, J = 7.4 Hz, 3H);

13

C NMR (100 MHz, CDCl3) δ (ppm) 202.4, 171.3, 169.1, 137.6, 136.6,

124.1, 121.7, 121.6, 121.3, 112.9, 88.3, 51.7, 40.0, 39.5, 34.4, 22.1, 13.4; HRMS (TOF-ESI): [M + H]+ calcd for C17H21O4: 289.1434; found: 289.1432. 22


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(E)-Methyl 2-(2-cyclohex-1-yl)benzofuran-3-one-2-acetate 4o: colourless oil, 58 mg, 40%; IR v (cm-1) 1746, 1721, 1614; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.68 (dd, J = 7.9, 1.2 Hz, 1H), 7.58 (td, J = 7.4, 1.4 Hz, 1H), 7.07 (t, J = 7.1 Hz, 1H), 7.08 (d, J = 8.6 Hz, 1H), 5.79-5.83 (m, 1H), 5.50 (d, J = 10.2 Hz, 1H), 3.47 (s, 3H), 3.10 (d, J = 16.2 Hz, 1H), 3.04 (d, J = 16.2 Hz, 1H), 2.59-2.62 (m, 1H), 1.91-1.98 (m, 3H), 1.76-1.84 (m, 1H), 1.39-1.52 (m, 2H);

13

C NMR (100 MHz, CDCl3) δ (ppm) 202.4,

171.5, 169.3, 137.5, 131.4, 124.5, 124.0, 122.2, 121.7, 112.9, 89.9, 51.7, 42.2, 38.0, 24.9, 23.2, 21.6; HRMS (TOF-ESI): [M + Na]+ calcd for C17H18O4Na:309.1097; found: 309.1093. 2.

General

procedure

for

the

enantioselective

synthesis

of

2-cinnamylbenzofuran-3-one-2-acetates 4: The palladium catalyst was first prepared in a glove box by mixing [Pd(C3H5)Cl]2 (0.04 mmol) and (R)-BINAP (0.08 mmol) in dry toluene (1 mL) in an oven-dried test tube for 1h at room temperature. To a separate Schlenk tube was added 3-(2-formylphenoxy)propenoates 1 (0.4 mmol), triazolium salt 3g (0.08 mmol) and Cs2CO3 (0.8 mmol). After the mixture in Schlenk tube was evacuated and backfilled with nitrogen (3×), dry toluene (2 mL) and cinnamyl acetates 2 (0.8 mmol) were added using a microsyringe. This Schlenk tube was then moved into the glove box, and pre-prepared palladium-BINAP complex solution was added. To make sure the complete transfer of the Pd-catalyst, the test tube was washed with 1 mL of dry toluene and add to the reaction mixture. The resulting reaction mixture was kept stirring for 12-24 h at 0 oC or at 25-30 oC (see Table 4) under nitrogen atmosphere. After the reaction, the Cs2CO3 was filtrated and washed with toluene (10 mL×3). The filtrate was concentrated under vacuum. The residue was chromatographed on a silica gel column eluting with a mixture of petroleum ether and ethyl acetate (PE:EA from 15:1 to 10:1) to give products 4 in 54-90% yield with 68-81% ee. 4a: 82% yield, 75% ee (HPLC data: OD-H column, 95:5 hexane : IPA, flow rate 1 mL/min, 254 nm, 25 °C, Rt. 22.067 min), []20D = -99.8o (c = 0.50, CH2Cl2). 4b: 90% yield, 68% ee (HPLC data: AD-H column, 95:5 hexane : IPA, flow rate 1 mL/min, 254 nm, 25 °C, Rt. 13.851 min), []20D = -39.6o (c = 0.50, CH2Cl2). 23



Page 24 of 30

4c: 82% yield, 81% ee (HPLC data: OD-H column, 95:5 hexane : IPA, flow rate 1 mL/min, 254 nm, 25 °C, Rt. 20.862 min), []20D = -78.6o (c = 0.50, CH2Cl2). 4d: 84% yield, 75% ee (HPLC data: AD-H column, 95:5 hexane : IPA, flow rate 1 mL/min, 254 nm, 25 °C, Rt. 37.974 min), []20D = -26.2o (c = 0.50, CH2Cl2). 4i: 77% yield, 79% ee (HPLC data: AD-H column, 95:5 hexane : IPA, flow rate 1 mL/min, 254 nm, 25 °C, Rt. 20.013 min), []20D = -91o (c = 0.50, CH2Cl2). 4j: 79% yield, 73% ee (HPLC data: OD-H column, 95:5 hexane : IPA, flow rate 1 mL/min, 254 nm, 25 °C, Rt. 16.135 min), []20D = -106.8o (c = 0.50, CH2Cl2). 4l: 54% yield, 73% ee (HPLC data: OD-H column, 95:5 hexane : IPA, flow rate 1 mL/min, 254 nm, 25 °C, Rt. 29.669 min), []20D = -90.8o (c = 0.50, CH2Cl2). 3. Oxidation of 2-cinnamylbenzofuran-3-one-2-acetates 4 with PhI(OAc)2 and catalytic OsO4. In a flask, the 2-cinnamylbenzofuran-3-one-2-acetates 4 (0.3 mmol) was dissolved in a mixture of THF (3 mL) and water (0.1 mL) with stirring. To this solution, the 2,6-lutidine (0.75 mmol), OsO4 (0.012 mmol) and PhI(OAc)2 (0.69 mmol) were added. The reaction mixture was stirred at room temperature untill the substrates 4 were consumed (about 12h). The reaction was quenched by adding of saturated aqueous solution of Na2S2O3 (10 mL). The reaction mixture was then extracted with ethyl acetate (10 mL×3). The extract was washed by saturated aqueous solution of CuSO4 (10 mL×2), and then was dried over anhydrous Na2SO4. After removal of Na2SO4, the solvent was evaporated under vacuum. The residue was chromatographed on a silica gel column eluting with a mixture of petroleum ether and ethyl acetate (PE:EA 5:1) to give the aldehydes 12 in 51-61% yield. Methyl 2-(2-oxoethyl)benzofuran-3-one-2-acetate 12a: colourless oil, 45 mg, 61%, IR v (cm-1) 1724, 1614; 1H NMR (400 MHz, CDCl3) δ (ppm) 9.64 (t, J = 0.9 Hz, 1H), 7.73 (d, J = 7.7 Hz, 1H), 7.64 (td, J = 7.1, 1.4 Hz, 1H), 7.14 (t, J = 7.4 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 3.58 (s, 3H), 3.18 (dd, J = 17, 2.2 Hz, 1H), 3.03 (d, J = 16.2 Hz, 1H), 2.97 (dd, J = 16.9, 0.7 Hz, 1H), 2.95 (d, J = 16.2 Hz, 1H); 13C NMR (100 MHz, CD3Cl) δ (ppm) 200.8, 196.6, 170.9, 168.6, 138.1, 124.6, 122.5, 120.6, 113.3,

24


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85.0, 52.1, 48.2, 39.9; HRMS (TOF-ESI): [M + H]+ calcd for C13H13O5: 249.0757; found: 249.0758. Methyl 6-bromo-2-(2-oxoethyl)benzofuran-3-one-2-acetate 12b: colourless oil, 50 mg, 51%, IR v (cm-1) 1724, 1605; 1H NMR (400 MHz, CDCl3) δ (ppm) 9.62 (d, J = 1.0 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.27-7.30 (m, 2H), 3.61 (s, 3H), 3.21 (dd, J = 17.3, 2.0 Hz, 1H), 2.93-3.05 (m, 3H);

13

C NMR (100 MHz, CDCl3) δ (ppm) 199.5,

196.0, 170.9, 168.4, 132.8, 126.3, 125.3, 119.9, 116.8, 85.7, 52.1, 48.2, 39.9; HRMS (TOF-ESI): [M + H]+ calcd for C13H12 BrO5: 326.9862; found: 326.9865. 4. Epoxidation of 2-cinnamylbenzofuran-3-one-2-acetates 4 with m-CPBA: In a flask, the 2-cinnamylbenzofuran-3-one-2-acetates 4 (0.2 mmol) were dissolved in dry dichloromethane (1 mL). The solution of m-CPBA (85% by wt, 0.4 mmol) in DCM (1 mL) was added dropwise to the flask cooled in a ice-bath. The resultant mixture was stirred at room temperature for 8-10h untill the substrates 4 were consumed. The reaction was quenched by the addition of saturated aqueous solution of NaHCO3 (10 mL). The organic layer was seperated. The aqueous phase was extracted with DCM (10 mL×2). The combined organic solution was dried over anhydrous Mg2SO4. After removal of Mg2SO4, the solvent was evaporated under vacuum. The residue was chromatographed on a silica gel column eluting with a mixture of petroleum ether and ethyl acetate (PE:EA 10:1) to give a pair of diastereomeric epoxides 13 and 14 in 42-45% and 43-47% yields. Epoxide 13a: white solid, 30 mg, 45%, mp 73-74 oC (recrystallization from DCM/n-hexane); IR v (cm-1) 1744, 1721, 1611; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.67 (d, J = 7.8 Hz, 1H), 7.56 (td, J = 8.4, 1.8 Hz, 1H), 7.22-7.28 (m, 3H), 7.12 (d, J = 7.2 Hz, 2H), 7.06 (d, J = 9 Hz, 1H), 7.04 (t, J = 7.2 Hz, 1H), 3.57 (s, 1H), 3.54 (s, 3H), 3.24 (d, J = 16.8 Hz, 1H), 3.12 (d, J = 16.8 Hz, 1H), 3.02 (td, J = 7.2, 1.2 Hz, 1H), 2.22 (dd, J = 14.4, 6.0 Hz, 1H), 2.09 (dd, J = 14.4, 5.4 Hz, 1H); 13C NMR (100 MHz, CD3Cl) δ (ppm) 201.9, 171.2, 169.0, 138.1, 136.6, 128.4, 128.3, 125.5, 124.5, 122.3, 121.0, 113.2, 87.5, 57.9, 57.8, 52.0, 40.1, 39.1; HRMS (TOF-ESI): [M + H]+ calcd for C20H19O5: 339.1227; found: 339.1228. Epoxide 14a: white solid, 29 mg, 43%, mp 133-134 oC (recrystallization from 25



Page 26 of 30

DCM/n-hexane); IR v (cm-1) 1738, 1721, 1612; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.68 (d, J = 8 Hz, 1H), 7.58 (t, J = 7.6 Hz, 1H), 7.22-7.28 (m, 3H), 7.04-7.12 (d, 4H), 3.62 (s, 1H), 3.55 (s, 3H), 3.14 (d, J = 16.4 Hz, 1H), 3.03 (d, J = 15.6 Hz, 1H), 2.99 (d, J = 5.6 Hz, 1H), 2.28 (dd, J = 14.4, 6.0 Hz, 1H), 2.20 (dd, J = 14.4, 5.6 Hz, 1H); 13C NMR (100 MHz, CD3Cl) δ (ppm) 201.5, 171.2, 168.8, 138.0, 136.5, 128.4, 128.3, 125.6, 124.6, 122.3, 121.0, 113.2, 86.9, 58.5, 57.1, 52.0, 40.4, 39.1; HRMS (TOF-ESI): [M + H]+ calcd for C20H19O5: 339.1227; found: 339.1226. Epoxide 13b: white solid, 35 mg, 42%, mp 109-110 oC (recrystallization from AcOEt/petroleum ether); IR v (cm-1) 1738, 1715, 1601; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.52 (d, J = 8.2 Hz, 1H), 7.27-7.31 (m, 4H), 7.19 (dd, J = 8.2, 1.3 Hz, 1H), 7.12-7.14 (m, 2H), 3.57 (s, 1H), 3.56 (s, 3H), 3.26 (d, J = 17.0 Hz, 1H), 3.14 (d, J = 17.0 Hz, 1H), 3.01 (td, J = 6.6, 2.0 Hz, 1H), 2.17 (dd, J = 14.5, 6.6 Hz, 1H), 2.09 (dd, J = 14.5, 4.9 Hz, 1H);

13

C NMR (100 MHz, CD3Cl) δ (ppm) 200.5, 171.1, 168.8,

136.3, 132.7, 128.4, 128.3, 126.0, 125.4, 125.1, 120.1, 116.7, 88.2, 57.8, 57.5, 52.0, 39.9, 39.0; HRMS (TOF-ESI): [M + H]+ calcd for C20H18O5Br: 417.0332; found: 417.0330. Epoxide 14b: white solid, 40 mg, 47%, mp 146-147 oC (recrystallization from AcOEt/petroleum ether); IR v (cm-1) 1736, 1721, 1605; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.52 (d, J = 8.2 Hz, 1H), 7.26-7.31 (m, 4H), 7.19 (dd, J = 8.2, 1.4 Hz, 1H), 7.08-7.10 (m, 2H), 3.60 (d, J = 1.9 Hz, 1H), 3.57 (s, 3H), 3.11 (d, J = 16.7 Hz, 1H), 3.03 (d, J = 16.7 Hz, 1H), 2.95 (td, J = 6.0, 2.0 Hz, 1H), 2.25 (dd, J = 14.4, 6.2 Hz, 1H), 2.19 (dd, J = 14.4, 5.7 Hz, 1H);

13

C NMR (100 MHz, CD3Cl) δ (ppm) 200.1,

171.1, 168.6, 136.2, 132.7, 128.4, 128.3, 126.0, 125.4, 125.2, 120.2, 116.7, 87.8, 58.3, 56.8, 52.0, 40.3, 39.1; HRMS (TOF-ESI): [M + H]+ calcd for C20H18O5Br: 417.0332; found: 417.0334. 5. Base-catalyzed isomerization of 2-cinnamylbenzofuran-3-one-2-acetates 4 to 2-styrylchroman-4-one-3-acetates 15. Under nitrogen atmosphere, the 2-cinnamylbenzofuran-3-one-2-acetates 4 (0.2 mmol) and DBU (0.2 mmol) were dissolved in dry dichloroethane (2 mL). The reaction mixture was stirred at room temperature for 24 h. After removal of the solvent, the 26


Page 27 of 30 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


residue was chromatographed on a silica gel column eluting with a mixture of petroleum

ether

and

ethyl

acetate

(PE:EA

15:1)

to

give

anti-2-styrylchroman-4-one-3-acetates 15 in 41-47% yields, along with 26-56% of reactants 4 were recovered. (anti and E)-Methyl 2-styrylchroman-4-one-3-acetate 15a: white solid, 28 mg, 44%, mp 114-115 oC (recrystallization from AcOEt/petroleum ether); IR v (cm-1) 1728, 1695, 1605; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.90 (dd, J = 7.8, 1.6 Hz, 1H), 7.50 (td, J = 8.6, 1.7 Hz, 1H), 7.43 (d, J = 7.0 Hz, 2H), 7.28-7.38 (m, 3H), 7.05 (t, J = 7.3 Hz, 1H), 7.02 (d, J = 8.3 Hz, 1H), 6.74 (d, J = 15.9 Hz, 1H), 6.36 (dd, J = 15.9, 8.4 Hz, 1H), 4.99 (dd, J = 15.9, 12.1 Hz, 1H), 3.58 (s, 3H), 3.32-3.38 (m, 1H), 2.90 (dd, J = 17.0, 5.1 Hz, 1H), 2.58 (dd, J = 17.0, 6.3 Hz, 1H);

13

C NMR (100 MHz,

CD3Cl) δ (ppm) 192.4, 172.2, 161.1, 136.1, 135.7, 135.5, 128.7, 128.7, 127.3, 126.9, 125.0, 121.6, 120.3, 117.9, 82.8, 51.9, 47.3, 30.1; HRMS (TOF-ESI): [M + H]+ calcd for C20H19O4: 323.1277; found: 323.1276. (anti and E)-Methyl 7-bromo-2-styrylchroman-4-one-3-acetate 15b: white solid, 38 mg, 47%, mp 118-119 oC (recrystallization from DCM/n-hexane); IR v (cm-1) 1726, 1697, 1591; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.75 (d, J = 8.4 Hz, 1H), 7.43 (d, J = 8.6 Hz, 2H), 7.29-7.38 (m, 3H), 7.23 (d, J = 2.0 Hz, 1H), 7.18 (dd, J = 8.8, 1.6 Hz, 1H), 6.74 (d, J = 16.0 Hz, 1H), 6.32 (dd, J = 16.0, 8.4 Hz, 1H), 5.01 (dd, J = 12.0, 8.8 Hz, 1H), 3.59 (s, 3H), 3.28-3.34 (m, 1H), 2.87 (dd, J = 17.2, 4.8 Hz, 1H), 2.60 (dd, J = 16.8, 6.0 Hz, 1H);

13

C NMR (100 MHz, CD3Cl) δ (ppm) 191.7, 172.1, 161.4,

136.2, 135.4, 130.7, 128.9, 128.8, 128.6, 127.0, 125.4, 124.6, 121.2, 119.3, 83.2, 52.0, 47.3, 30.1; HRMS (TOF-ESI): [M + H]+ calcd for C20H18O4Br: 401.0382; found: 401.0384. (anti and E)-Methyl 2-(p-bromostyryl)chroman-4-one-3-acetate 15l: white solid, 33 mg, 41%, mp 109-110 oC (recrystallization from DCM/n-hexane); IR v (cm-1) 1724, 1697, 1607; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.90 (dd, J = 8.4, 2.0 Hz, 1H), 7.50 (td, J = 6.8, 1.6 Hz, 1H), 7.48 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8.4 Hz, 2H), 7.05 (t, J = 8.0 Hz, 1H), 7.01 (d, J = 8.0 Hz, 1H), 6.68 (d, J = 16.0 Hz, 1H), 6.35 (dd, J = 16.0, 8.4 Hz, 1H), 4.97 (dd, J = 12.0, 8.4 Hz, 1H), 3.0 (s, 3H), 3.31-3.37 (m, 1H), 2.92 27



(dd, J = 16.8, 4.4 Hz, 1H), 2.56 (dd, J = 16.8, 6.4 Hz, 1H);

Page 28 of 30

13

C NMR (100 MHz,

CD3Cl) δ (ppm) 191.2, 172.2, 161.0, 136.3, 134.6, 134.4, 132.0, 128.4, 127.5, 126.0, 122.7, 121.8, 120.3, 117.9, 82.6, 52.0, 47.4, 30.2; HRMS (TOF-ESI): [M + H]+ calcd for C20H18O4Br: 401.0382; found: 401.0380.

ASSOCIATED CONTENT Supporting Information Available. The copies of 1H NMR,13C NMR spectra for the products 4a-4o, 5a, 5e, 6a, 6e, 12a, 12b, 13a, 13b, 14a, 14b, 15a, 15b and 15i, and HPLC chromatographs for enantiomerically enriched 4a-4d, 4i, 4j and 4l; single crystal data of rac-4a, rac-6e, rac-13a, rac-14a and rac-15a (CIF). This material is available free of charge via the Internet at http://pubs.acs.org AUTHOR INFORMATION Corresponding Author： E-mail: [email protected] Notes： The authors declare no competing financial interest. Acknowledgements This work was supported by the National Natural Science Foundation of China (No. 21772015). Reference： 1. Some reviews on tandem catalysis: (a) Zhou, J. Chem. Asian J. 2010, 5, 422-434. (b) Wasilke, J. C.; Obrey, S. J.; Baker, R. T.; Bazan, G. C. Chem. Rev. 2005, 105, 1001-1020. (c) Chapman, C. J.; Frost, C. G. Synthesis 2007, 1-21. 2. (a) Du, Z.; Shao, Z. Chem. Soc. Rev., 2013, 42, 1337-1378. (b) Shao, Z.; Zhang, H. Chem. Soc. Rev. 2009, 38, 2745–2755. 3. Some reviews for NHCs organocatalysis: (a) Enders, D.; Niemeier, O.; Henseler, A. Chem. Rev. 2007, 107, 5606-5655. (b) Marion, N.; Diez-Gonzalez, S.; Nolan, S. P. Angew. Chem., Int. Ed. 2007, 46, 2988-3000. (c) Grossmann, A.; Enders, D. Angew. Chem. Int. Ed. 2012, 51, 314-325. 4. (a) Liu, K.; Hovey, M. T.; Scheidt, K. A.Chem. Sci., 2014, 5, 4026–4031. (b) Guo, C.; Fleige, 28


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Palladium Cascade Catalysis: Construction of

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