One-Pot Multicomponent Mechanosynthesis of Polysubstituted trans-2

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One-Pot Multi-Component Mechanosynthesis of Polysubstituted trans-2,3Dihydropyrroles and Pyrroles from Amines, Alkyne Esters, and Chalcones Hui Xu, Hong-Wei Liu, Kuan Chen, and Guan-Wu Wang J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00665 • Publication Date (Web): 10 May 2018 Downloaded from http://pubs.acs.org on May 10, 2018

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is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

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The Journal of Organic Chemistry

One-Pot Multi-Component Mechanosynthesis of Polysubstituted trans-2,3-Dihydropyrroles and Pyrroles from Amines, Alkyne Esters, and Chalcones

Hui Xu,† Hong-Wei Liu,† Kuan Chen,† and Guan-Wu Wang*,†,‡

†

CAS Key Laboratory of Soft Matter Chemistry, iChEM (Collaborative Innovation

Center of Chemistry for Energy Materials), Hefei National Laboratory for Physical Sciences at Microscale, and Department of Chemistry, University of Science and Technology of China, Hefei, Anhui 230026, P. R. China E-mail: [email protected]; ‡

State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou, Gansu 730000, P. R. China

ABSTRACT

An efficient and practical one-pot multi-component reaction of amines with alkyne esters and chalcones promoted by I2/PhI(OAc)2 has been developed under solvent-free ball-milling

conditions

to

afford

a

variety

1

ACS Paragon Plus Environment

of

polysubstituted

The Journal of Organic Chemistry 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

Page 2 of 61

trans-2,3-dihydropyrroles in moderate to good yields. The present method features short reaction time, mild reaction conditions, broad substrate scope, and feasibility of large-scale synthesis. Intriguingly, this protocol can also furnish the corresponding synthetically more attractive pyrroles with the addition of an oxidant in a one-pot way.

INTRODUCTION Polysubstituted

2,3-dihydropyrroles

are

a

vital

class

of

five-membered

nitrogen-containing heterocycles as they are present in numerous bioactive compounds and pharmaceuticals, such as sibiromycin,1 anthramycin,2 serotonin reuptake inhibitor,3 and thienamycin.4 Furthermore, 2,3-dihydropyrroles can be used as versatile synthetic intermediates for the synthesis of natural products.5 Therefore, considerable efforts have been devoted to the synthesis of these heterocyclic motifs, and numerous synthetic methods have been established. Among them, the commonly used approaches are cyclization reactions catalyzed/promoted by various metal catalysts, including Pd,6 Rh,7 Cu,8 Au,9 and Ni.10 In addition, some non-metallic reagents such as phosphines,11 thiourea,12 and iodine13 catalyzed/promoted reactions have also been reported. Pyrrole motifs are also ubiquitous in natural products,14 pharmaceuticals,15 agrochemicals,16 dyes,17 and functional materials.18 In light of their numerous applications, extensive attention has been paid to develop methods for the efficient construction of such privileged molecules. Current strategies to access such frameworks are mainly based on Knorr,19 Paal-Knorr20, and Hantzsch reactions.21 2


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In general, most of these methods for 2,3-dihydropyrroles and pyrroles are very useful, but they often suffer from some drawbacks, such as the use of expensive metal catalysts, special or complicated starting materials, toxic organic solvents, harsh reaction conditions, and so on. Thus, the development of more efficient and environmentally friendly strategies towards such frameworks directly from readily available starting materials is of great importance and highly desirable. On the other hand, solvent-free reactions have drawn increasing attention over the past few decades because they supply environmentally benign protocols and provide green as well as efficient organic processes in modern synthetic chemistry. Among the current solvent-free techniques, ball-milling is an attractive and practical tool to promote solvent-free reactions.22 In many cases, reactions performed under ball-milling conditions lead to higher yields compared to the liquid-phase counterparts. Furthermore, the mechanochemical protocols can even alter the chemical selectivity, providing unexpected products that cannot be generated by the analogous solution-based reactions.23 Therefore, the ball-milling technique has been extensively utilized in synthetic chemistry.24 In light of our successful studies in this field25 and the above-mentioned importance of 2,3-dihydropyrroles and pyrroles, herein we present

a

one-pot

multi-component

mechanosynthesis

of

polysubstituted

2,3-dihdropyrroles via I2/PhI(OAc)2-promoted cyclization of amines with alkyne esters and chalcones under solvent-free ball-milling conditions. Subsequently, it is found that the addition of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) to the reaction system provides a variety of the corresponding pyrroles. To the best of our 3



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knowledge, this is the first attempt of I2/PhI(OAc)2-promoted synthesis of 2,3-dihydropyrroles and pyrroles from readily available amines, alkyne esters, and chalcones.

RESULTS AND DISCUSSION The reaction of p-toluidine (1a) with diethyl acetylenedicarboxylate (2a) and chalcone (3a) was chosen as the model reaction to screen the optimal reaction conditions. Firstly, a mixture of 1a (0.2 mmol) and 2a (0.2 mmol) together with four stainless steel balls (5 mm in diameter) were introduced into a stainless steel jar (5 mL). The reaction vessel along with another identical empty vessel were closed and fixed on the vibration arms of a ball-milling apparatus (Retsch MM200 mixer mill, Retsch GmbH, Haan, Germany) and were vibrated vigorously at a rate of 1800 rounds per minute (30 Hz) at room temperature for 10 min in order to quantitatively generate the corresponding enamine. Then, 3a (0.2 mmol) and I2 (0.2 mmol) were added and milled at 30 Hz for 30 min. As a result, the desired product, i.e., diethyl 2-benzoyl-3-phenyl-1-(p-tolyl)-2,3-dihydro-1H-pyrrole-4,5-dicarboxylate

4a,

was

obtained in 25% yield (Table 1, entry 1). The coupling constant (J = 4.0 Hz) of the two protons on the dihydropyrrole moiety of 4a in its 1H NMR spectrum indicated that the product was in the trans form.11a,13,26 Encouraged by this initial result, we began to optimize the reaction conditions by screening different molar ratios of the starting materials, additives as well as reaction times, and the results are summarized in Table 1. The effect of the amounts of 1a and 2a on the product yield was firstly examined. When the amounts of 1a and 2a were increased simultaneously to 1.5 equiv, 4


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the yield of product 4a was improved to 31% (Table 1, entry 2). Delightedly, a higher yield was obtained when 2.0 equiv of 2a and 3a were used (Table 1, entry 3). However, further increasing the dosages of 1a and 2a to 2.5 equiv led to a decreased yield (Table 1, entry 4). The effect of the dosage of I2 on the product yield was also investigated, and the results indicated that 2.0 equiv of I2 was optimal to afford product 4a in 49% yield (Table 1, entry 6 vs entries 5 and 7). According to these results, the molar ratio of 1a, 2a, 3a, and I2 was fixed at 2:2:1:2 to further optimize the reaction conditions. It is found that bases are frequently employed in I2-promoted cyclization reactions and can facilitate the transformations to some extent.13,27 Thus, various inorganic and organic bases including Na2CO3, K2CO3, KF, K3PO4, DMAP, and DABCO were attempted. Unfortunately, all of these bases were detrimental to this reaction. (Table 1, entries 8−13). It was accidentally found that the yield of dihydropyrrole 4a was increased to 55% when 1.0 equiv of PhI(OAc)2 was used (Table 1, entry 14). Further optimization by adjusting the amount of PhI(OAc)2 showed that 0.5 equiv of PhI(OAc)2 was the best choice, affording 4a in 62% yield (Table 1, entry 15 vs entries 14 and 16). To identify whether the amounts of 1a and 2a could be reduced in the presence of PhI(OAc)2, the reaction was carried out with 1.5 equiv of 1a and 2a, and the yield of 4a was dramatically increased to 74% (Table 1, entry 17). But further reducing the dosages of 1a and 2a afforded product 4a in a decreased yield (Table 1, entry 18). It should be noted that a significantly decreased yield (53%) was obtained when the amount of I2 was decreased from 2.0 equiv to 1.5 equiv (Table 1, entry 17 vs entry 19). Furthermore, the influence of the reaction time 5



Page 6 of 61

on the product yield was investigated. As the reaction time was extended to 40 min, the yield of 4a was increased to 80% (Table 1, entry 20). However, a longer reaction time of 50 min led to a slightly decreased yield (Table 1, entry 21). In addition, some other

halogenating

agents

including

trimethylphenylammonium

tribromide,

dibromoisocyanuric acid, 1,3-diiodo-5,5-dimethylhydantoin, and N-iodosuccinimide (NIS) were also investigated. Unfortunately, all of these halogenating agents only gave a trace amount of 4a (Table 1, entries 22−25). However, the addition of NIS along with 0.2 equiv of BF3·Et2O as a Lewis acid could afford 4a in 26% yield (Table 1, entry 26), indicating that I2 may also play a role of Lewis acid in this transformation. On the other hand, the liquid-assisted grinding (LAG) protocol has demonstrated as a power tool to promote mechanochemical reactions.25b,28 Accordingly,

several

liquids

such

as

toluene,

tetrahydrofuran

(THF),

1,2-dichloroethane (DCE), acetonitrile (MeCN), ethanol (EtOH), N,N-dimethyl formamide (DMF), and dimethyl sulfoxide (DMSO) were added in the second step. It was found that the addition of EtOH, DMF, and DMSO were detrimental to this reaction (Table 1, entries 31−33), while toluene, THF, DCE, and MeCN gave 4a in similar yields (Table 1, entries 27−30). Although the addition of a liquid could not further improve the yield of product 4a, the reaction time could be slightly shortened from 40 min to 30 min when DCE was used (Table 1, entry 34 vs entries 30 and 35). Nevertheless, a grinding liquid would not be employed in order to make the experimental process simpler.

6


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Table 1. Optimization of the Reaction Conditionsa

molar ratio of

additive

t2

yield

1a:2a:3a:I2

(equiv)

(min)

(%)b

entry

1

1:1:1:1

—

30

25

2

1.5:1.5:1:1

—

30

31

3

2:2:1:1

—

30

37

4

2.5:2.5:1:1

—

30

30

5

2:2:1:1.5

—

30

44

6

2:2:1:2

—

30

49

7

2:2:1:2.5

—

30

48

8

2:2:1:2

Na2CO3 (1.0)

30

16

9

2:2:1:2

K2CO3 (1.0)

30

12

10

2:2:1:2

KF (1.0)

30

13

11

2:2:1:2

K3PO4 (1.0)

30

8

12

2:2:1:2

DMAP (1.0)

30

trace

13

2:2:1:2

DABCO (1.0)

30

7

14

2:2:1:2

PhI(OAc)2 (1.0)

30

55

15

2:2:1:2

PhI(OAc)2 (0.5)

30

62

7



Page 8 of 61

16

2:2:1:2

PhI(OAc)2 (0.25)

30

60

17

1.5:1.5:1:2

PhI(OAc)2 (0.5)

30

74

18

1:1:1:2

PhI(OAc)2 (0.5)

30

58

19

1.5:1.5:1:1.5

PhI(OAc)2 (0.5)

30

53

20c

1.5:1.5:1:2

PhI(OAc)2 (0.5)

40

80

21

1.5:1.5:1:2

PhI(OAc)2 (0.5)

50

76

40

trace

40

trace

40

trace

trimethylphenylammonium 22

1.5:1.5:1:0 tribromide (2.0)

23

1.5:1.5:1:0

dibromoisocyanuric acid (2.0) 1,3-diiodo-5,5-dimethylhydantoin

24

1.5:1.5:1:0 (2.0)

25

1.5:1.5:1:0

NIS (2.0)

40

trace

26

1.5:1.5:1:0

NIS (2.0), BF3·Et2O (0.2)

40

26

27d,e

1.5:1.5:1:2

PhI(OAc)2 (0.5)

40

81

28d,f

1.5:1.5:1:2

PhI(OAc)2 (0.5)

40

80

29d,g

1.5:1.5:1:2

PhI(OAc)2 (0.5)

40

81

30d,h

1.5:1.5:1:2

PhI(OAc)2 (0.5)

40

78

31d,i

1.5:1.5:1:2

PhI(OAc)2 (0.5)

40

38

32d,j

1.5:1.5:1:2

PhI(OAc)2 (0.5)

40

23

33d,k

1.5:1.5:1:2

PhI(OAc)2 (0.5)

40

25

34d,g

1.5:1.5:1:2

PhI(OAc)2 (0.5)

30

81

35d,g

1.5:1.5:1:2

PhI(OAc)2 (0.5)

20

71

8


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a

Unless otherwise noted, the reactions were carried out with 0.2 mmol of 3a in a

Retsch MM200 mixer mill. bYield based on 3a. c5% of 3a was recovered. dA liquid (26 µL, ƞ = 0.1 µL/mg) was added in the second step as a LAG agent. eToluene was added. fTHF was added. gDCE was added. hMeCN was added. iEtOH was added. j

DMF was added. kDMSO was added.

For the purpose of comparing the present solvent-free reaction with its liquid-phase counterpart, this one-pot two-step protocol was also carried out in several organic solvents including toluene, THF, DCE, MeCN, EtOH, DMF, and DMSO (Table 2). It was found that the enamine could be quantitatively formed within 30 min in these solvents. Thus, the reaction temperature for the second step was first fixed at 50 oC, toluene, THF, DCE, MeCN, and DMF as the solvents delivered 4a in poor yields (6−38%, Table 2, entries 1−4 and entry 6), and EtOH and DMSO as the solvents were even worse and only gave a trace amount of 4a (Table2, entries 5 and 7). Subsequently, the liquid-phase reactions in DCE and MeCN were carried out at a higher temperature of 80 oC for the second step. The starting materials were almost consumed after a reaction time of 12 h, but lower yields was obtained due to formation of many byproducts (Table 2, entries 8 and 9).

Table 2. One-Pot Two-Step Synthesis of 2,3-Dihydropyrrole 4a in Organic Solventsa

9



entry

a

solvent

temp (oC)

Page 10 of 61

yield (%)b

t2 (h)

1

toluene

50

24

23

2

THF

50

24

24

3

DCE

50

24

27

4

MeCN

50

24

38

5

EtOH

50

24

trace

6

DMF

50

24

6

7

DMSO

50

24

trace

8

DCE

80

12

16

9

MeCN

80

12

13

Reaction conditions: a mixture of 1a (0.3 mmol) and 2a (0.3 mmol) in an organic

solvent (2 mL) was stirred at 50 oC for 0.5 h, then 3a (0.2 mmol), I2 (0.4 mmol), and PhI(OAc)2 were added and stirred at 50 oC or 80 oC. bYield based on 3a.

The one-pot reaction without a stepwise operation in a ball mill or in an organic solvent was also investigated. A mixture of 1a, 2a, 3a, I2, and PhI(OAc)2 was milled directly at 30 Hz for 40 min gave product 4a only in a poor yield of 18%, accompanied with significant amounts of unreacted 3a and byproducts. In addition, 10


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the reaction of 1a with 2a and 3a in MeCN at 50 oC for 24 h provided 4a in 36% yield, which was similar to the yield (38%) from the one-pot two-step protocol (Table 2, entry 4). By comparing the results from the mechanochemical reaction and its liquid-phase counterpart, it can be obviously found that the mechanical protocol has prominent advantages, including significantly higher yield and much shorter reaction time. Therefore, the optimal reaction conditions were established as follows: 1a (0.3 mmol) was firstly milled with 2a (0.3 mmol) at 30 Hz for 10 min, then 3a (0.2 mmol), I2 (0.4 mmol), and PhI(OAc)2 (0.1 mmol) were added and milled at 30 Hz for 40 min (Table 1, entry 20). It should be noted that 4a was obtained in 80% yield, along with 5% of recovered 3a, 4% of the in situ formed enamine, and a small amount of an unknown byproduct under the optimal reaction conditions. As for other entries with lower product yields of 4a in Table 1, significant amounts of unreacted 3a and the in situ formed enamine could also be isolated. With the optimized reaction conditions in hand, the scope and generality of this reaction were explored (Table 3). Firstly, a variety of anilines were investigated under the ball-milling conditions. Anilines with other para-substituted electron-donating groups (i-Pr, t-Bu, and OMe) gave products 4b−d in 70−75% yields. It was worth mentioning that the meta- or ortho-methyl-substituted anilines still exhibited high reactivity, affording the corresponding products 4e and 4f in good yields of 75% and 78%, respectively. In addition, 3,4-dimethyl-substituted aniline and unsubstituted aniline proceeded smoothly in this transformation to provide products 4g and 4h in 71% and 72% yields, respectively. Aniline with the para-substituted electron-withdrawing 11



Page 12 of 61

group (F) was also investigated, and product 4i was obtained in a moderate yield of 62%. Furthermore, various alkylamines were employed in this one-pot reaction, affording the corresponding products 4j−n in 63−84% yields. When the diethyl ester was replaced by the dimethyl ester in the alkyne ester, the desired product 4o was obtained in nearly the same yield (79%). To further explore the substrate scope and limitations, a vast variety of chalcone derivatives were employed. Chalcones with the phenyl ring in R3 bearing electron-donating groups at the para-position exhibited a relatively higher efficiency than those containing electron-withdrawing groups (4p and

4q

vs

4t

and

4u).

Chalcones

with

either

electron-donating

or

electron-withdrawing groups on the phenyl ring adjacent to the carbonyl group reacted well and afforded 4v−bʹ in 64−82% yields. Gratifyingly, when the benzoyl group of chalcones was replaced by the acetyl or 2-naphthoyl group, the corresponding products 4cʹ and 4dʹ were obtained in 62% and 74% yields, respectively. The stereochemistry of dihydropyrroles 4 was further unambiguously confirmed by single-crystal X-ray diffraction analysis of 4e as an example (See the Supporting Information for details),29 showing that the phenyl ring and the benzoyl group on the dihydropyrrole moiety were in the trans form.

Table 3. One-Pot Two-Step Synthesis of trans-2,3-Dihydropyrroles from Amines 1, Alkyne Esters 2, and Chalcones 3 under Ball-Milling Conditionsa,b

12


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a

Unless otherwise noted, the reactions were performed with 1 (0.3 mmol), 2 (0.3 13



mmol), 3 (0.2 mmol), I2 (0.4 mmol), and PhI(OAc)2 (0.1 mmol) in a Retsch MM200 mixer mill. bYields based on 3. c0.5 mmol of I2 was used. dReaction time of the second step was 30 min.

Interestingly, the diamines 5 were also compatible for this protocol to provide bis-dihydropyrroles 6a and 6b in 59% and 61% yields (based on 3a), respectively (Scheme 1). Such dual cyclizations may serve as a potential route to construct mechanically interlocked molecular architectures such as rotaxanes.30

Scheme 1. Synthesis of Bis-Dihydropyrroles 6

To demonstrate the practical application of the present protocol, a scale-up reaction of p-toluidine 1a (6 mmol) with diethyl acetylenedicarboxylate 2a (6 mmol) and chalcone 3a (4 mmol) was carried out (Scheme 2). To our delight, product 4a was obtained in a satisfactory yield of 79% (1.53 g), which indicated that the present method could be easily adopted for a larger-scale preparation.

Scheme 2. Gram-Scale Synthesis of 4a 14


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Considering that dihydropyrroles can be oxidized to corresponding pyrroles via dehydrogenative aromatization process, we further attempted a one-pot three-step synthesis of polysubstituted pyrroles under ball-milling conditions. To our delight, when DDQ was added into the above-synthesized 2,3-dihydropyrroles and milled vigorously in the ball mill, the synthetically more attractive polysubstituted pyrroles 7 were isolated in good yields (Table 4). As seen from Table 3, both arylamines and alkylamines reacted smoothly under the ball-milling conditions, providing the corresponding products 7a−m in 61−83% yields. Dimethyl acetylenedicarboxylate was also compatible in the one-pot protocol and afforded the desired polysubstituted pyrroles 7n−q in 71−78% yields. In addition, chalcones with different substituents on the two phenyl rings were investigated, and products 7r−w were obtained in 69−75% yields.

Table 4. One-Pot Three-Step Synthesis of Pyrroles from Amines 1, Alkyne Esters 2, and Chalcones 3 under Ball-Milling Conditionsa,b

15



a

Unless otherwise noted, the reactions were performed with 1 (0.3 mmol), 2 (0.3

mmol), 3 (0.2 mmol), I2 (0.4 mmol), PhI(OAc)2 (0.1 mmol), and DDQ (0.8 mmol) in a Retsch MM200 mixer mill. bYields based on 3. cReaction time of the third step was 90 min. 16


Page 16 of 61

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To gain insight into the reaction mechanism, control experiments were carried out (Scheme 3). When pre-prepared enamine 8a was allowed to react with chalcone 1a in the presence of I2 and PhI(OAc)2, product 4a was obtained in 82% yield (Scheme 3a), which was similar to the yield (80%) from the one-pot two-step reaction. Notably, the reaction of the pre-prepared enamine 8a with chalcone 1a in the absence of I2 gave no product (Scheme 3b). These results indicated that the enamine 8 should be a key intermediate, and I2 was crucial in this transformation. In addition, the reaction of 8a with 1a in the absence of PhI(OAc)2 delivered 4a only in a poor yield of 40% (Scheme 3c), demonstrating that PhI(OAc)2 played an essential role for a significant improvement on the product yield.

Scheme 3. Control Experiments

17



On the basis of the above experimental results and the previous literature,13,31 a plausible reaction mechanism is proposed in Scheme 4. At first, amine 1 reacts with alkyne ester 2 to give β-enamino ester 8. Then, a Michael addition reaction occurs between 8 and the subsequently added chalcone 3 to generate intermediate A, which may prefer to form a hydrogen bond between the NH moiety and the carbonyl group connected to the R4 group, and then reacts with I2 or the in situ generated AcOI32 from I2 and PhI(OAc)2 to afford iodide B with the indicated configuration. Subsequently, an intramolecular SN2-type nucleophilic substitution of iodide B takes place with the elimination of HI, affording the polysubstitued trans-2,3-dihydropyrrole 4. Finally, 4 undergoes dehydrogenation aromatization in the presence of DDQ to give the 18


Page 18 of 61

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corresponding pyrrole 7.

Scheme 4. Proposed Reaction Mechanism

CONCLUSIONS In summary, we have successfully developed a novel one-pot method for the efficient

multi-component

synthesis

of

a

variety

of

polysubstituted

trans-2,3-dihydropyrroles via I2/PhI(OAc)2-promoted cyclization of amines with alkyne esters and chalcones under solvent-free ball-milling conditions. Afterward oxidation with DDQ can afford synthetically more attractive pyrroles in a one-pot way. A plausible reaction mechanism is proposed to explain the product formation. This protocol features high efficiency, mild reaction conditions, broad substrate scope, and feasibility for large-scale synthesis. These merits make the present method a potential 19



and

practical

alternative

to

the

efficient

synthesis

Page 20 of 61

of

polysubstituted

2,3-dihydropyrroles and pyrroles.

EXPERIMENTAL SECTION General Information. All reagents were obtained from commercial sources and used without further purification. NMR spectra were recorded on a 400 MHz NMR spectrometer (400 MHz for 1H NMR; 101 MHz for

13

C NMR). 1H NMR chemical

shifts were determined relative to internal TMS at δ 0.0 ppm.

13

C NMR chemical

shifts were determined relative to CDCl3 at δ 77.16 ppm. Data for 1H NMR and

13

C

NMR are reported as follows: chemical shift (δ, ppm), multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet, q = quartet, sept = septet). High-resolution mass spectra (HRMS) were measured with ESI-TOF in a positive mode. Ball-milling reactions were performed in a MM200 mixer mill (Retsch GmbH, Haan, Germany), using a 5 mL stainless steel jar and were milled vigorously at a rate of 1800 rounds per minute (30 Hz) at room temperature (~25 oC). General

Procedure

for

the

One-Pot

Two-Step

Synthesis

of

trans-2,3-Dihydropyrroles 4 from Amines 1, Alkyne Esters 2, and Chalcones 3 under Ball-Milling Conditions. A mixture of 1 (0.3 mmol) and 2 (0.3 mmol) together with four stainless steel balls (5 mm in diameter) were introduced into a stainless steel jar (5 mL). The reaction vessel and another identical empty vessel were closed and fixed on the vibration arms of a MM200 mixer mill, and were vibrated vigorously at a rate of 1800 revolutions per minute (30 Hz) at room temperature for 20


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10 min. Then, 3a (0.2 mmol), I2 (0.4 mmol) and PhI(OAc)2 (0.1 mmol) were added and milled at 30 Hz for 40 min. After completion of the reaction, the resulting mixture was extracted with ethyl acetate, and the combined solution was evaporated to remove the solvent in vacuo. The residue was separated by flash column chromatography on silica gel with ethyl acetate/petroleum ether as the eluent to afford 4. Diethyl 2-benzoyl-3-phenyl-1-p-tolyl-trans-2,3-dihydro-1H-pyrrole-4,5-dicarboxylate

(4a).

Ethyl acetate/petroleum ether = 1:6 as eluent. Yellow solid (mp 101–102 oC), 80% yield (77.5 mg). 1H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 7.4 Hz, 2H), 7.61 (t, J = 7.4 Hz, 1H), 7.45 (t, J = 7.8 Hz, 2H), 7.40–7.29 (m, 5H), 7.06 (s, 4H), 5.52 (d, J = 4.0 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 4.18 (d, J = 4.0 Hz, 1H), 3.99 (dq, J = 10.8, 7.1 Hz, 1H), 3.93 (dq, J = 10.8, 7.1 Hz, 1H), 2.27 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H), 1.05 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 193.4, 164.1, 162.7, 150.2, 142.4, 138.1, 135.4, 134.1, 133.5, 130.0 (2C), 129.2 (2C), 129.1 (2C), 129.0 (2C), 127.8, 127.4 (2C), 122.6 (2C), 107.0, 77.6, 62.5, 59.7, 51.2, 21.0, 14.2, 14.0; HRMS (ESI-TOF) calcd for C30H30NO5 [M + H]+ 484.2124, found 484.2115. Diethyl 2-benzoyl-1-(4-isopropylphenyl)-3-phenyl-trans-2,3-dihydro-1H-pyrrole-4,5-dicarbox ylate (4b). Ethyl acetate/petroleum ether = 1:8 as eluent. Yellow solid (mp 68–69 oC), 75% yield (76.8 mg),. 1H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 7.5 Hz, 2H), 7.61 (t, J = 7.4 Hz, 1H), 7.46 (t, J = 7.7 Hz, 2H), 7.40–7.29 (m, 5H), 7.11 (d, J = 8.7 Hz, 2H), 7.08 (d, J = 8.7 Hz, 2H), 5.52 (d, J = 3.8 Hz, 1H), 4.43–4.40 (m, 2H), 4.17 (d, J = 3.8 21



Hz, 1H), 3.99 (dq, J = 10.8, 7.1 Hz, 1H), 3.93 (dq, J = 10.8, 7.1 Hz, 1H), 2.83 (sept, J = 6.9 Hz, 1H), 1.28 (t, J = 7.1 Hz, 3H), 1.18 (d, J = 6.9 Hz, 6H), 1.05 (t, J = 7.1 Hz, 3H);

13

C{1H} NMR (101 MHz, CDCl3) δ 193.4, 164.1, 162.7, 150.1, 146.2, 142.3,

138.3, 134.1, 133.5, 129.2 (2C), 129.11 (2C), 129.05 (2C), 127.8, 127.4 (4C), 122.3 (2C), 107.0, 77.5, 62.5, 59.7, 51.1, 33.7, 24.0 (2C), 14.2, 14.0; HRMS (ESI-TOF) calcd for C32H34NO5 [M + H]+ 512.2437, found 512.2438. Diethyl 2-benzoyl-1-(4-tert-butylphenyl)-3-phenyl-trans-2,3-dihydro-1H-pyrrole-4,5-dicarbox ylate (4c). Ethyl acetate/petroleum ether = 1:8 as eluent. Yellow solid (mp 95–96 oC), 73% yield (76.9 mg). 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 7.6 Hz, 2H), 7.62 (t, J = 7.4 Hz, 1H), 7.46 (t, J = 7.7 Hz, 2H), 7.40–7.29 (m, 5H), 7.26 (d, J = 8.6 Hz, 2H), 7.07 (d, J = 8.6 Hz, 2H), 5.53 (d, J = 3.8 Hz, 1H), 4.44–4.31 (m, 2H), 4.17 (d, J = 3.8 Hz, 1H), 3.99 (dq, J = 10.8, 7.1 Hz, 1H), 3.94 (dq, J = 10.8, 7.1 Hz, 1H), 1.29 (t, J = 7.2 Hz, 3H), 1.25 (s, 9H), 1.05 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 193.3, 164.1, 162.8, 149.9, 148.3, 142.3, 137.9, 134.1, 133.4, 129.2 (2C), 129.10 (2C), 129.06 (2C), 127.8, 127.4 (2C), 126.4 (2C), 121.6 (2C), 107.2, 77.3, 62.5, 59.7, 51.1, 34.5, 31.4 (3C), 14.2, 14.0; HRMS (ESI-TOF) calcd for C33H36NO5 [M + H]+ 526.2593, found 526.2587. Diethyl 2-benzoyl-1-(4-methoxyphenyl)-3-phenyl-trans-2,3-dihydro-1H-pyrrole-4,5-dicarboxy late (4d). Ethyl acetate/petroleum ether = 1:4 as eluent. Yellow solid (mp 87–88 oC), 70% yield (70.1 mg). 1H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 7.4 Hz, 2H), 7.59 (t, 22


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J = 7.4, Hz, 1H), 7.43 (t, J = 7.7 Hz, 2H), 7.41–7.29 (m, 5H), 7.21 (d, J = 8.9 Hz, 2H), 6.80 (d, J = 8.9 Hz, 2H), 5.46 (d, J = 4.3 Hz, 1H), 4.31 (q, J = 7.1 Hz, 2H), 4.20 (d, J = 4.3 Hz, 1H), 3.99 (dq, J = 10.8, 7.1 Hz, 1H), 3.92 (dq, J = 10.8, 7.1 Hz, 1H), 3.75 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H), 1.04 (t, J = 7.1 Hz, 3H);

13

C{1H} NMR (101 MHz,

CDCl3) δ 193.7, 164.1, 162.6, 158.0, 151.1, 142.7, 134.0, 133.7, 133.4, 129.2 (2C), 129.1 (2C), 129.0 (2C), 127.7, 127.5 (2C), 125.9 (2C), 114.6 (2C), 105.7, 78.2, 62.3, 59.6, 55.6, 51.4, 14.2, 14.0; HRMS (ESI-TOF) calcd for C30H30NO6 [M + H]+ 500.2073, found 500.2074. Diethyl 2-benzoyl-3-phenyl-1-m-tolyl-trans-2,3-dihydro-1H-pyrrole-4,5-dicarboxylate

(4e).

Ethyl acetate/petroleum ether = 1:6 as eluent. Yellow solid (mp 83–84 oC), 75% yield (72.5 mg). 1H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 7.5 Hz, 2H), 7.61 (t, J = 7.4 Hz, 1H), 7.46 (t, J = 7.7 Hz, 2H), 7.40–7.28 (m, 5H), 7.14 (t, J = 8.1 Hz, 1H), 6.97–6.92 (m, 2H), 6.91 (d, J = 7.6 Hz, 1H), 5.55 (d, J = 3.8 Hz, 1H), 4.43–4.31 (m, 2H), 4.18 (d, J = 3.8 Hz, 1H), 3.99 (dq, J = 10.8, 7.1 Hz, 1H), 3.94 (dq, J = 10.8, 7.1 Hz, 1H), 2.26 (s, 3H), 1.31 (t, J = 7.1 Hz, 3H), 1.05 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 193.3, 164.1, 162.7, 149.7, 142.2, 140.6, 139.4, 134.1, 133.4, 129.3, 129.2 (2C), 129.1 (2C), 129.0 (2C), 127.8, 127.4 (2C), 126.1, 122.5, 119.0, 107.7, 77.3, 62.5, 59.8, 51.2, 21.5, 14.2, 14.0; HRMS (ESI-TOF) calcd for C30H30NO5 [M + H]+ 484.2124, found 484.2119. Diethyl 2-benzoyl-3-phenyl-1-o-tolyl-trans-2,3-dihydro-1H-pyrrole-4,5-dicarboxylate 23


(4f).


Ethyl acetate/petroleum ether = 1:6 as eluent. Yellow oil, 78% yield (75.7 mg). 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 7.6 Hz, 2H), 7.61–7.53 (m, 2H), 7.42–7.29 (m, 7H), 7.17–7.11 (m, 3H), 5.42 (d, J = 5.2 Hz, 1H), 4.39 (d, J = 5.2 Hz, 1H), 4.25–4.13 (m, 2H), 4.00 (dq, J = 10.8, 7.1 Hz, 1H), 3.92 (dq, J = 10.8, 7.1 Hz, 1H), 2.34 (s, 3H), 1.11 (t, J = 7.1 Hz, 3H), 1.01 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 193.6, 164.2, 162.3, 153.4, 142.6, 137.8, 136.8, 134.1, 133.9, 131.1, 130.7, 129.1 (2C), 129.0 (2C), 128.9 (2C), 128.5, 127.7 (2C), 127.6, 126.7, 103.1, 76.2, 62.1, 59.5, 51.8, 18.6, 14.2, 13.9; HRMS (ESI-TOF) calcd for C30H30NO5 [M + H]+ 484.2124, found 484.2130. Diethyl 2-benzoyl-1-(3,4-dimethylphenyl)-3-phenyl-trans-2,3-dihydro-1H-pyrrole-4,5-dicarbo xylate (4g). Ethyl acetate/petroleum ether = 1:6 as eluent. Yellow solid (mp 111–112 o

C), 71% yield (70.7 mg). 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 7.4 Hz, 2H),

7.60 (t, J = 7.4 Hz, 1H), 7.45 (t, J = 7.7 Hz, 2H), 7.40–7.28 (m, 5H), 7.01 (d, J = 8.1 Hz, 1H), 6.94 (d, J = 2.3 Hz, 1H), 6.92 (dd, J = 8.1, 2.3 Hz, 1H), 5.53 (d, J = 4.0 Hz, 1H), 4.36 (q, J = 7.1 Hz, 2H), 4.18 (d, J = 4.0 Hz, 1H), 3.99 (dq, J = 10.8, 7.1 Hz, 1H), 3.93 (dq, J = 10.8, 7.1 Hz, 1H), 2.17 (s, 6H), 1.31 (t, J = 7.1 Hz, 3H), 1.04 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 193.5, 164.1, 162.7, 150.2, 142.4, 138.3, 137.8, 134.1, 134.0, 133.5, 130.4, 129.2 (2C), 129.1 (2C), 129.0 (2C), 127.7, 127.4 (2C), 123.6, 120.0, 106.8, 77.5, 62.4, 59.7, 51.2, 20.0, 19.3, 14.2, 14.0; HRMS (ESI-TOF) calcd for C31H32NO5 [M + H]+ 498.2280, found 498.2273. Diethyl 2-benzoyl-1,3-diphenyl-trans-2,3-dihydro-1H-pyrrole-4,5-dicarboxylate 24


Page 24 of 61

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(4h). Ethyl acetate/petroleum ether = 1:6 as eluent. Yellow solid (mp 99–100 oC), 72% yield (67.7 mg). 1H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 7.4 Hz, 2H), 7.62 (t, J = 7.4 Hz, 1H), 7.46 (t, J = 7.7 Hz, 2H), 7.40–7.29 (m, 5H), 7.26 (t, J = 7.9 Hz, 2H), 7.14 (d, J = 7.7 Hz, 2H), 7.09 (t, J = 7.3 Hz, 1H), 5.56 (d, J = 3.8 Hz, 1H), 4.42–4.30 (m, 2H), 4.19 (d, J = 3.8 Hz, 1H), 4.00 (dq, J = 10.8, 7.1 Hz, 1H), 3.94 (dq, J = 10.8, 7.1 Hz, 1H), 1.29 (t, J = 7.1 Hz, 3H), 1.05 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 193.2, 164.0, 162.7, 149.6, 142.1, 140.7, 134.2, 133.4, 129.5 (2C), 129.2 (2C), 129.14 (2C), 129.07 (2C), 127.8, 127.4 (2C), 125.3, 121.9 (2C), 108.0, 77.4, 62.5, 59.8, 51.2, 14.2, 14.0; HRMS (ESI-TOF) calcd for C29H28NO5 [M + H]+ 470.1967, found 470.1961. Diethyl 2-benzoyl-1-(4-fluorophenyl)-3-phenyl-trans-2,3-dihydro-1H-pyrrole-4,5-dicarboxylat e (4i). Ethyl acetate/petroleum ether = 1:6 as eluent. Yellow solid (mp 87–88 oC), 62% yield (60.3 mg). 1H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 7.8 Hz, 2H), 7.61 (t, J = 7.4 Hz, 1H), 7.45 (t, J = 7.7 Hz, 2H), 7.42–7.30 (m, 5H), 7.22 (dd, J = 8.8, 4.6 Hz, 2H), 6.97 (t, J = 8.5 Hz, 2H), 5.50 (d, J = 4.0 Hz, 1H), 4.33 (q, J = 7.1 Hz, 2H), 4.21 (d, J = 4.0 Hz, 1H), 3.99 (dq, J = 10.7, 7.1 Hz, 1H), 3.93 (dq, J = 10.7, 7.1 Hz, 1H), 1.27 (t, J = 7.1 Hz, 3H), 1.04 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 193.4, 164.0, 162.5, 160.6 (d, J = 246.0 Hz, 1C), 150.2, 142.2, 136.7 (d, J = 2.9 Hz, 1C), 134.2, 133.4, 129.21 (2C), 129.18 (2C), 129.1 (2C), 127.9, 127.4 (2C), 125.5 (d, J = 8.5 Hz, 2C), 116.3 (d, J = 22.8 Hz, 2C), 107.2, 77.9, 62.5, 59.8, 51.3, 14.2, 14.0; 19

F NMR (376 MHz, CDCl3) δ -115.63–-115.73 (m, 1F); HRMS (ESI-TOF) calcd for 25



Page 26 of 61

C29H27FNO5 [M + H]+ 488.1873, found 488.1877. Diethyl 2-benzoyl-3-phenyl-1-propyl-trans-2,3-dihydro-1H-pyrrole-4,5-dicarboxylate

(4j).

Ethyl acetate/petroleum ether = 1:8 as eluent. Yellow oil, 71% yield (61.7 mg). 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 7.4 Hz, 2H), 7.62 (t, J = 7.4 Hz, 1H), 7.46 (t, J = 7.7 Hz, 2H), 7.35 (t, J = 7.2 Hz, 2H), 7.32–7.26 (m, 3H), 5.11 (d, J = 4.3 Hz, 1H), 4.53–4.41 (m, 2H), 4.12 (d, J = 4.3 Hz, 1H), 3.94 (dq, J = 10.8, 7.1 Hz, 1H), 3.88 (dq, J = 10.8, 7.1 Hz, 1H), 3.24 (dt, J = 14.3, 7.8 Hz, 1H), 3.12 (dt, J = 14.3, 7.0 Hz, 1H), 1.59–1.48 (m, 2H), 1.45 (t, J = 7.2 Hz, 3H), 1.01 (t, J = 7.1 Hz, 3H), 0.90 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 194.1, 164.2, 163.1, 153.8, 143.0, 134.1, 133.7, 129.2 (2C), 129.00 (2C), 128.98 (2C), 127.5, 127.4 (2C), 101.4, 74.6, 62.5, 59.3, 51.0, 48.7, 21.8, 14.2 (2C), 11.4; HRMS (ESI-TOF) calcd for C26H30NO5 [M + H]+ 436.2124, found 436.2117. Diethyl 2-benzoyl-1-butyl-3-phenyl-trans-2,3-dihydro-1H-pyrrole-4,5-dicarboxylate

(4k).

Ethyl acetate/petroleum ether = 1:8 as eluent. Yellow oil, 84% yield (75.3 mg). 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 7.3 Hz, 2H), 7.62 (t, J = 7.4 Hz, 1H), 7.46 (t, J = 7.8 Hz, 2H), 7.36 (t, J = 7.1 Hz, 2H), 7.32–7.25 (m, 3H), 5.11 (d, J = 4.4 Hz, 1H), 4.47 (q, J = 7.2 Hz, 2H), 4.12 (d, J = 4.4 Hz, 1H), 3.94 (dq, J = 10.8, 7.1 Hz, 1H), 3.88 (dq, J = 10.8, 7.1 Hz, 1H), 3.35–3.26 (m, 1H), 3.18–3.09 (m, 1H), 1.56–1.42 (m, 2H), 1.45 (t, J = 7.2 Hz, 3H), 1.38–1.25 (m, 2H), 1.01 (t, J = 7.1 Hz, 3H), 0.88 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 194.0, 164.1, 163.0, 153.7, 143.0, 26


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134.0, 133.6, 129.1 (2C), 129.0 (2C), 128.9 (2C), 127.5, 127.4 (2C), 101.3, 74.5, 62.5, 59.2, 50.9, 46.7, 30.5, 20.0, 14.2 (2C), 13.7; HRMS (ESI-TOF) calcd for C27H32NO5 [M + H]+ 450.2280, found 450.2277. Diethyl 2-benzoyl-1-isobutyl-3-phenyl-trans-2,3-dihydro-1H-pyrrole-4,5-dicarboxylate

(4l).

Ethyl acetate/petroleum ether = 1:8 as eluent. Yellow oil, 81% yield (72.9 mg). 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 7.5 Hz, 2H), 7.63 (t, J = 7.4 Hz, 1H), 7.48 (t, J = 7.7 Hz, 2H), 7.40–7.33 (m, 2H), 7.33–7.27 (m, 3H), 5.11 (d, J = 4.0 Hz, 1H), 4.53– 4.41 (m, 2H), 4.13 (d, J = 4.0 Hz, 1H), 3.94 (dq, J = 10.8, 7.1 Hz, 1H), 3.88 (dq, J = 10.8, 7.1 Hz, 1H), 3.05 (dd, J = 14.3, 8.6 Hz, 1H), 2.97 (dd, J = 14.3, 6.3 Hz, 1H), 1.80–1.68 (m, 1H), 1.45 (t, J = 7.1 Hz, 3H), 1.02 (t, J = 7.1 Hz, 3H), 0.93 (d, J = 6.6 Hz, 3H), 0.86 (d, J = 6.6 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 193.8, 164.2, 163.0, 154.3, 142.7, 134.1, 133.6, 129.2 (2C), 129.01 (2C), 128.99 (2C), 127.5, 127.4 (2C), 101.1, 74.9, 62.4, 59.3, 54.7, 51.0, 27.6, 20.3, 20.2, 14.2 (2C); HRMS (ESI-TOF) calcd for C27H32NO5 [M + H]+ 450.2280, found 450.2279. Diethyl 2-benzoyl-1-benzyl-3-phenyl-trans-2,3-dihydro-1H-pyrrole-4,5-dicarboxylate

(4m).

Ethyl acetate/petroleum ether = 1:6 as eluent. Yellow oil, 77% yield (74.4 mg). 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 7.5 Hz, 2H), 7.57 (t, J = 7.4 Hz, 1H), 7.39 (t, J = 7.7 Hz, 2H), 7.32–7.21 (m, 8H), 7.16–7.11 (m, 2H), 4.87 (d, J = 4.8 Hz, 1H), 4.59 (d, J = 15.0 Hz, 1H), 4.45 (q, J = 7.1 Hz, 2H), 4.22 (d, J = 15.0 Hz, 1H), 4.09 (d, J = 4.8 Hz, 1H), 3.96 (dq, J = 10.8, 7.1 Hz, 1H), 3.89 (dq, J = 10.8, 7.1 Hz, 1H), 1.43 (t, J 27



Page 28 of 61

= 7.1 Hz, 3H), 1.02 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 194.3, 164.2, 163.1, 153.0, 142.7, 135.5, 134.0, 133.7, 129.1 (2C), 128.93 (2C), 128.90 (2C), 128.80 (2C), 128.76 (2C), 128.3, 127.5 (2C), 127.4, 102.0, 73.6, 62.7, 59.4, 50.9 (2C), 14.2 (2C); HRMS (ESI-TOF) calcd for C30H30NO5 [M + H]+ 484.2124, found 484.2120. Diethyl 2-benzoyl-1-isopropyl-3-phenyl-trans-2,3-dihydro-1H-pyrrole-4,5-dicarboxylate (4n). Ethyl acetate/petroleum ether = 1:6 as eluent. Yellow oil, 63% yield (54.6 mg). 1H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 7.5 Hz, 2H), 7.61 (t, J = 7.4 Hz, 1H), 7.46 (t, J = 7.7 Hz, 2H), 7.34 (t, J = 7.3 Hz, 2H), 7.28 (t, J = 7.2 Hz, 1H), 7.21 (d, J = 7.1 Hz, 2H), 4.98 (d, J = 5.3 Hz, 1H), 4.50 (dq, J = 10.7, 7.1 Hz, 1H), 4.44 (dq, J = 10.7, 7.1 Hz, 1H), 4.06 (d, J = 5.3 Hz, 1H), 3.95 (dq, J = 10.8, 7.1 Hz, 1H), 3.88 (dq, J = 10.8, 7.1 Hz, 1H), 3.73 (sept, J = 6.6 Hz, 1H), 1.45 (t, J = 7.1 Hz, 3H), 1.28 (d, J = 6.6 Hz, 3H), 1.03 (d, J = 6.6 Hz, 3H). 1.00 (t, J = 7.1 Hz, 3H);

13

C{1H} NMR (101 MHz,

CDCl3) δ 195.5, 164.2, 163.5, 153.3, 143.2, 133.9 (2C), 129.2 (2C), 128.93 (2C), 128.87 (2C), 127.5 (2C), 127.4, 101.5, 71.9, 62.5, 59.3, 51.3, 49.6, 21.5, 20.9, 14.2 (2C); HRMS (ESI-TOF) calcd for C26H30NO5 [M + H]+ 436.2124, found 436.2125. Dimethyl 2-benzoyl-3-phenyl-1-p-tolyl-trans-2,3-dihydro-1H-pyrrole-4,5-dicarboxylate

(4o).

Ethyl acetate/petroleum ether = 1:4 as eluent. Yellow solid (mp 115–116 oC), 79% yield (72.4 mg). 1H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 7.5 Hz, 2H), 7.61 (t, J = 7.4 Hz, 1H), 7.46 (t, J = 7.7 Hz, 2H), 7.41–7.29 (m, 5H), 7.06 (d, J = 8.5 Hz, 2H), 28


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7.02 (d, J = 8.5 Hz, 2H), 5.51 (d, J = 3.7 Hz, 1H), 4.18 (d, J = 3.7 Hz, 1H), 3.89 (s, 3H), 3.50 (s, 3H), 2.26 (s, 3H);

13

C{1H} NMR (101 MHz, CDCl3) δ 193.2, 164.5,

163.2, 150.1, 142.1, 138.0, 135.3, 134.2, 133.4, 130.2 (2C), 129.2 (4C), 129.1 (2C), 127.8, 127.3 (2C), 122.0 (2C), 107.1, 77.6, 53.3, 51.2, 51.0, 20.9; HRMS (ESI-TOF) calcd for C28H26NO5 [M + H]+ 456.1811, found 456.1810. Diethyl 2-benzoyl-1,3-dip-tolyl-trans-2,3-dihydro-1H-pyrrole-4,5-dicarboxylate (4p). Ethyl acetate/petroleum ether = 1:6 as eluent. Yellow solid (mp 100–101 oC), 81% yield (80.8 mg). 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 7.4 Hz, 2H), 7.60 (t, J = 7.4 Hz, 1H), 7.45 (t, J = 7.7 Hz, 2H), 7.24 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 8.0 Hz, 2H), 7.06 (s, 4H), 5.49 (d, J = 3.9 Hz, 1H), 4.34 (q, J = 7.1 Hz, 2H), 4.15 (d, J = 3.9 Hz, 1H), 3.99 (dq, J = 10.9, 7.1 Hz, 1H), 3.94 (dq, J = 10.9, 7.1 Hz, 1H), 2.36 (s, 3H), 2.26 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H), 1.06 (t, J = 7.1 Hz, 3H);

13

C{1H} NMR (101

MHz, CDCl3) δ 193.5, 164.2, 162.8, 149.9, 139.4, 138.2, 137.4, 135.3, 134.0, 133.5, 130.0 (2C), 129.8 (2C), 129.2 (2C), 129.0 (2C), 127.3 (2C), 122.5 (2C), 107.1, 77.7, 62.4, 59.7, 50.9, 21.3, 21.0, 14.2, 14.0; HRMS (ESI-TOF) calcd for C31H32NO5 [M + H]+ 498.2280, found 498.2277. Diethyl 2-benzoyl-3-(4-methoxyphenyl)-1-p-tolyl-trans-2,3-dihydro-1H-pyrrole-4,5-dicarboxy late (4q). Ethyl acetate/petroleum ether = 1:4 as eluent. Yellow solid (mp 124–125 oC), 76% yield (77.6 mg). 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 7.4 Hz, 2H), 7.60 (t, J = 7.4 Hz, 1H), 7.45 (t, J = 7.7 Hz, 2H), 7.27 (d, J = 8.6 Hz, 2H), 7.06 (s, 4H), 6.90 (d, J = 8.6 Hz, 2H), 5.48 (d, J = 4.0 Hz, 1H), 4.40–4.28 (m, 2H), 4.15 (d, J = 4.0 Hz, 29



Page 30 of 61

1H), 3.99 (dq, J = 10.8, 7.1 Hz, 1H), 3.94 (dq, J = 10.8, 7.1 Hz, 1H), 3.82 (s, 3H), 2.27 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H), 1.07 (t, J = 7.1 Hz, 3H);

13

C{1H} NMR (101

MHz, CDCl3) δ 193.5, 164.2, 162.8, 159.1, 149.8, 138.2, 135.3, 134.6, 134.0, 133.5, 130.0 (2C), 129.2 (2C), 129.0 (2C), 128.5 (2C), 122.5 (2C), 114.4 (2C), 107.2, 77.8, 62.4, 59.7, 55.4, 50.6, 20.9, 14.2, 14.0; HRMS (ESI-TOF) calcd for C31H32NO6 [M + H]+ 514.2230, found 514.2225. Diethyl 2-benzoyl-3-m-tolyl-1-p-tolyl-trans-2,3-dihydro-1H-pyrrole-4,5-dicarboxylate

(4r).

Ethyl acetate/petroleum ether = 1:6 as eluent. Yellow solid (mp 95–96 oC), 71% yield (70.3 mg). 1H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 7.4 Hz, 2H), 7.60 (t, J = 7.4 Hz, 1H), 7.45 (t, J = 7.7 Hz, 2H), 7.26 (t, J = 7.7 Hz, 1H), 7.16–7.10 (m, 3H), 7.06 (s, 4H), 5.51 (d, J = 4.1 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 4.15 (d, J = 4.1 Hz, 1H), 4.00 (dq, J = 10.8, 7.1 Hz, 1H), 3.94 (dq, J = 10.8, 7.1 Hz, 1H), 2.36 (s, 3H), 2.27 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H), 1.06 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 193.5, 164.2, 162.8, 150.1, 142.3, 138.6, 138.2, 135.4, 134.1, 133.6, 130.0 (2C), 129.3 (2C), 129.0 (3C), 128.5, 128.2, 124.5, 122.5 (2C), 107.0, 77.7, 62.5, 59.7, 51.2, 21.7, 21.0, 14.2, 14.0; HRMS (ESI-TOF) calcd for C31H32NO5 [M + H]+ 498.2280, found 498.2275. Diethyl 2-benzoyl-3-o-tolyl-1-p-tolyl-trans-2,3-dihydro-1H-pyrrole-4,5-dicarboxylate

(4s).

Ethyl acetate/petroleum ether = 1:6 as eluent. Yellow oil, 68% yield (67.6 mg). 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 7.4 Hz, 2H), 7.58 (t, J = 7.4 Hz, 1H), 7.51 (d, J = 7.4 Hz, 1H), 7.40 (t, J = 7.8 Hz, 2H), 7.28 (t, J = 7.3 Hz, 1H), 7.18 (t, J = 7.3 Hz, 30


Page 31 of 61 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


1H), 7.13–7.04 (m, 5H), 5.58 (d, J = 4.9 Hz, 1H), 4.49 (d, J = 4.9 Hz, 1H), 4.40–4.28 (m, 2H), 3.96 (dq, J = 10.4, 7.1 Hz, 1H), 3.93 (dq, J = 10.4, 7.1 Hz, 1H), 2.27 (s, 3H), 2.10 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H), 1.03 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 193.6, 164.1, 162.7, 150.2, 141.5, 138.2, 135.52, 135.46, 134.1, 133.9, 130.3, 130.0 (2C), 129.0 (4C), 127.4 (2C), 127.1, 122.7 (2C), 107.8, 77.9, 62.4, 59.7, 46.4, 21.0, 19.4, 14.1, 14.0; HRMS (ESI-TOF) calcd for C31H32NO5 [M + H]+ 498.2280, found 498.2289. Diethyl 2-benzoyl-3-(4-chlorophenyl)-1-p-tolyl-trans-2,3-dihydro-1H-pyrrole-4,5-dicarboxyla te (4t). Ethyl acetate/petroleum ether = 1:6 as eluent. Yellow solid (mp 122–123 oC), 68% yield (70.7 mg). 1H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 7.4 Hz, 2H), 7.61 (t, J = 7.4 Hz, 1H), 7.45 (t, J = 7.7 Hz, 2H), 7.34 (d, J = 8.4 Hz, 2H), 7.28 (d, J = 8.4 Hz, 2H), 7.07 (s, 4H), 5.48 (d, J = 4.1 Hz, 1H), 4.34 (q, J = 7.1 Hz, 2H), 4.17 (d, J = 4.1 Hz, 1H), 4.00 (dq, J = 10.8, 7.1 Hz, 1H), 3.94 (dq, J = 10.8, 7.1 Hz, 1H), 2.27 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H), 1.07 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 193.1, 163.9, 162.5, 150.4, 140.9, 137.8, 135.7, 134.2, 133.5, 133.4, 130.0 (2C), 129.2 (2C), 129.1 (2C), 129.0 (2C), 128.8 (2C), 122.7 (2C), 106.3, 77.3, 62.5, 59.8, 50.6, 20.9, 14.2, 14.0; HRMS (ESI-TOF) calcd for C30H2935ClNO5 [M + H]+ 518.1734, found 518.1730. Diethyl 2-benzoyl-3-(4-bromophenyl)-1-p-tolyl-trans-2,3-dihydro-1H-pyrrole-4,5-dicarboxyla te (4u). Ethyl acetate/petroleum ether = 1:6 as eluent. Yellow solid (mp 125–127 oC), 31



65% yield (73.2 mg). 1H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 7.4 Hz, 2H), 7.62 (t, J = 7.4 Hz, 1H), 7.50 (d, J = 8.3 Hz, 2H), 7.46 (t, J = 7.7 Hz, 2H), 7.22 (d, J = 8.3 Hz, 2H), 7.06 (s, 4H), 5.46 (d, J = 4.1 Hz, 1H), 4.34 (q, J = 7.1 Hz, 2H), 4.15 (d, J = 4.1 Hz, 1H), 4.00 (dq, J = 10.9, 7.1 Hz, 1H), 3.95 (dq, J = 10.9, 7.1 Hz, 1H), 2.27 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H), 1.07 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 193.1, 164.0, 162.5, 150.5, 141.5, 137.8, 135.7, 134.2, 133.4, 132.2 (2C), 130.1 (2C), 129.15 (2C), 129.14 (2C), 129.11 (2C), 122.8 (2C), 121.7, 106.3, 77.3, 62.5, 59.8, 50.7, 21.0, 14.2, 14.0; HRMS (ESI-TOF) calcd for C30H2979BrNO5 [M + H]+ 562.1229, found 562.1224. Diethyl 2-(4-methylbenzoyl)-3-phenyl-1-p-tolyl-trans-2,3-dihydro-1H-pyrrole-4,5-dicarboxyla te (4v). Ethyl acetate/petroleum ether = 1:6 as eluent. Yellow solid (mp 93–94 oC), 82% yield (81.7 mg). 1H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 8.2 Hz, 2H), 7.40–7.28 (m, 5H), 7.25 (d, J = 8.4 Hz, 2H), 7.06 (s, 4H), 5.49 (d, J = 4.0 Hz, 1H), 4.41–4.29 (m, 2H), 4.17 (d, J = 4.0 Hz, 1H), 3.98 (dq, J = 10.8, 7.1 Hz, 1H), 3.93 (dq, J = 10.8, 7.1 Hz, 1H), 2.41 (s, 3H), 2.26 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H), 1.04 (t, J = 7.1 Hz, 3H); 13

C{1H} NMR (101 MHz, CDCl3) δ 193.1, 164.1, 162.8, 150.1, 145.1, 142.5, 138.1,

135.3, 130.9, 130.0 (2C), 129.7 (2C), 129.3 (2C), 129.1 (2C), 127.7, 127.5 (2C), 122.5 (2C), 107.0, 77.5, 62.4, 59.7, 51.3, 21.8, 21.0, 14.2, 14.0; HRMS (ESI-TOF) calcd for C31H32NO5 [M + H]+ 498.2280, found 498.2285. Diethyl 2-(4-methoxybenzoyl)-3-phenyl-1-p-tolyl-trans-2,3-dihydro-1H-pyrrole-4,5-dicarboxy 32


Page 32 of 61

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late (4w). Ethyl acetate/petroleum ether = 1:4 as eluent. Yellow solid (mp 94–95 oC), 64% yield (65.9 mg),. 1H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 8.8 Hz, 2H), 7.40– 7.28 (m, 5H), 7.05 (s, 4H), 6.91 (d, J = 8.8 Hz, 2H), 5.47 (d, J = 4.1 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 4.18 (d, J = 4.1 Hz, 1H), 3.99 (dq, J = 10.8, 7.1 Hz, 1H), 3.93 (dq, J = 10.8, 7.1 Hz, 1H), 3.86 (s, 3H), 2.26 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H), 1.04 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 192.1, 164.3, 164.1, 162.8, 150.1, 142.6, 138.2, 135.2, 131.5 (2C), 130.0 (2C), 129.1 (2C), 127.7, 127.5 (2C), 126.4, 122.4 (2C), 114.2 (2C), 107.0, 77.4, 62.4, 59.6, 55.7, 51.5, 20.9, 14.2, 14.0; HRMS (ESI-TOF) calcd for C31H32NO6 [M + H]+ 514.2230, found 514.2231. Diethyl 2-(3-methylbenzoyl)-3-phenyl-1-p-tolyl-trans-2,3-dihydro-1H-pyrrole-4,5-dicarboxyla te (4x). Ethyl acetate/petroleum ether = 1:6 as eluent. Yellow solid (mp 84–55 oC), 82% yield (82.0 mg). 1H NMR (400 MHz, CDCl3) δ 7.66–7.62 (m, 2H), 7.43–7.28 (m, 7H), 7.10–7.03 (m, 4H), 5.50 (d, J = 4.2 Hz, 1H), 4.41–4.29 (m, 2H), 4.18 (d, J = 4.2 Hz, 1H), 3.99 (dq, J = 10.8, 7.1 Hz, 1H), 3.93 (dq, J = 10.8, 7.1 Hz, 1H), 2.34 (s, 3H), 2.27 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H), 1.04 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 193.6, 164.1, 162.7, 150.3, 142.5, 138.9, 138.2, 135.4, 134.8, 133.5, 130.0 (2C), 129.9, 129.0 (2C), 128.9, 127.7, 127.5 (2C), 126.4, 122.6 (2C), 106.8, 77.8, 62.4, 59.7, 51.3, 21.4, 21.0, 14.2, 14.0; HRMS (ESI-TOF) calcd for C31H32NO5 [M + H]+ 498.2280, found 498.2284. Diethyl 2-(2-methylbenzoyl)-3-phenyl-1-p-tolyl-trans-2,3-dihydro-1H-pyrrole-4,5-dicarboxyla 33



te (4y). Ethyl acetate/petroleum ether = 1:6 as eluent. Yellow oil, 80% yield (79.8 mg). 1

H NMR (400 MHz, CDCl3) δ 7.41 (t, J = 7.8 Hz, 2H), 7.35–7.26 (m, 4H), 7.22 (d, J

= 7.3 Hz, 2H), 7.16 (t, J = 7.6 Hz, 1H), 7.06 (s, 4H), 5.42 (d, J = 4.2 Hz, 1H), 4.34 (q, J = 7.1 Hz, 2H), 4.18 (d, J = 4.2 Hz, 1H), 4.01 (dq, J = 10.6, 7.1 Hz, 1H), 3.95 (dq, J = 10.6, 7.1 Hz, 1H), 2.53 (s, 3H), 2.27 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H), 1.05 (t, J = 7.1 Hz, 3H);

13

C NMR (101 MHz, CDCl3) δ 196.8, 164.2, 162.7, 150.4, 142.7, 140.7,

138.2, 135.5, 133.8, 132.6, 132.4, 130.0 (2C), 129.2, 129.0 (2C), 127.5, 127.2 (2C), 125.7, 122.7 (2C), 106.2, 78.9, 62.4, 59.7, 50.9, 21.8, 21.0, 14.2, 14.0; HRMS (ESI-TOF) calcd for C31H32NO5 [M + H]+ 498.2280, found 498.2274. Diethyl 2-(4-fluorobenzoyl)-3-phenyl-1-p-tolyl-trans-2,3-dihydro-1H-pyrrole-4,5-dicarboxylat e (4z). Ethyl acetate/petroleum ether = 1:6 as eluent. Yellow solid (mp 86–87 oC), 78% yield (78.4 mg). 1H NMR (400 MHz, CDCl3) δ 7.87 (dd, J = 8.8, 5.3 Hz, 2H), 7.41– 7.29 (m, 5H), 7.12 (t, J = 8.6 Hz, 2H), 7.06 (s, 4H), 5.47 (d, J = 4.3 Hz, 1H), 4.40– 4.28 (m, 2H), 4.17 (d, J = 4.3 Hz, 1H), 3.99 (dq, J = 10.8, 7.1 Hz, 1H), 3.93 (dq, J = 10.8, 7.1 Hz, 1H), 2.27 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H), 1.05 (t, J = 7.1 Hz, 3H); 13

C{1H} NMR (101 MHz, CDCl3) δ 192.1, 166.3 (d, J = 256.8 Hz,), 164.1, 162.6,

150.2, 142.3, 138.0, 135.6, 131.9 (d, J = 9.5 Hz, 2C), 130.1 (2C), 130.0 (d, J = 3.0 Hz), 129.2 (2C), 127.8, 127.4 (2C), 122.7 (2C), 116.3 (d, J = 21.9 Hz, 2C), 106.9, 77.6, 62.5, 59.8, 51.4, 21.0, 14.2, 14.0;

19

F NMR (376 MHz, CDCl3) δ -103.09–

-103.19 (m, 1F); HRMS (ESI-TOF) calcd for C30H29FNO5 [M + H]+ 502.2030, found 502.2033. 34


Page 34 of 61

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Diethyl 2-(4-chlorobenzoyl)-3-phenyl-1-p-tolyl-trans-2,3-dihydro-1H-pyrrole-4,5-dicarboxyla te (4y). Ethyl acetate/petroleum ether = 1:6 as eluent. Yellow solid (mp 120–122 oC), 76% yield (78.7 mg). 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.7 Hz, 2H), 7.42 (d, J = 8.7 Hz, 2H), 7.40–7.29 (m, 5H), 7.06 (s, 4H), 5.46 (d, J = 4.3 Hz, 1H), 4.35 (dq, J = 10.8, 7.1 Hz, 1H), 4.32 (dq, J = 10.8, 7.1 Hz, 1H), 4.16 (d, J = 4.3 Hz, 1H), 3.99 (dq, J = 10.8, 7.1 Hz, 1H), 3.93 (dq, J = 10.8, 7.1 Hz, 1H), 2.27 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H), 1.04 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 192.4, 164.0, 162.6, 150.2, 142.2, 140.7, 138.0, 135.6, 131.8, 130.6 (2C), 130.1 (2C), 129.4 (2C), 129.2 (2C), 127.9, 127.4 (2C), 122.7 (2C), 106.9, 77.7, 62.5, 59.8, 51.3, 21.0, 14.2, 14.0; HRMS (ESI-TOF) calcd for C30H2935ClNO5 [M + H]+ 518.1734, found 518.1737. Diethyl 2-(4-bromobenzoyl)-3-phenyl-1-p-tolyl-trans-2,3-dihydro-1H-pyrrole-4,5-dicarboxyla te (4bʹ). Ethyl acetate/petroleum ether = 1:6 as eluent. Yellow solid (mp 130–131 oC), 75% yield (87.4 mg). 1H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 8.5 Hz, 2H), 7.59 (d, J = 8.5 Hz, 2H), 7.41–7.29 (m, 5H), 7.06 (s, 4H), 5.46 (d, J = 4.3 Hz, 1H), 4.40–4.28 (m, 2H), 4.16 (d, J = 4.3 Hz, 1H), 3.99 (dq, J = 10.8, 7.1 Hz, 1H), 3.93 (dq, J = 10.8, 7.1 Hz, 1H), 2.27 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H), 1.04 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 192.7, 164.0, 162.6, 150.2, 142.2, 138.0, 135.6, 132.4 (2C), 132.3, 130.6 (2C), 130.1 (2C), 129.5, 129.2 (2C), 127.9, 127.4 (2C), 122.7 (2C), 106.9, 77.6, 62.5, 59.7, 51.3, 21.0, 14.1, 14.0; HRMS (ESI-TOF) calcd for C30H2979BrNO5 [M + H]+ 562.1229, found 562.1241. 35



Page 36 of 61

Diethyl 2-acetyl-3-phenyl-1-p-tolyl-trans-2,3-dihydro-1H-pyrrole-4,5-dicarboxylate

(4cʹ).

Ethyl acetate/petroleum ether = 1:6 as eluent. Colorless oil, 62% yield (51.6 mg). 1H NMR (400 MHz, CDCl3) δ 7.37–7.29 (m, 4H), 7.28–7.23 (m, 1H), 7.09 (d, J = 8.3 Hz, 2H), 6.96 (d, J = 8.3 Hz, 2H), 4.53 (d, J = 4.7 Hz, 1H), 4.36 (dq, J = 10.9, 7.2 Hz, 1H), 4.31 (dq, J = 10.9, 7.2 Hz, 1H), 4.20 (d, J = 4.7 Hz, 1H), 4.04 (dq, J = 10.8, 7.1 Hz, 1H), 3.99 (dq, J = 10.8, 7.1 Hz, 1H), 2.29 (s, 3H), 2.27 (s, 3H), 1.28 (t, J = 7.2 Hz, 3H), 1.08 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 205.4, 164.0, 162.6, 149.5, 142.6, 138.1, 135.4, 130.2 (2C), 129.0 (2C), 127.6, 127.1 (2C), 121.4 (2C), 107.4, 81.3, 62.5, 59.9, 50.7, 25.9, 20.9, 14.2, 13.9; HRMS (ESI-TOF) calcd for C25H28NO5 [M + H]+ 422.1967, found 422.1958. Diethyl 2-(2-naphthoyl)-3-phenyl-1-p-tolyl-trans-2,3-dihydro-1H-pyrrole-4,5-dicarboxylate (4dʹ). Ethyl acetate/petroleum ether = 1:6 as eluent. Yellow solid (mp 131–133 oC), 74% yield (78.3 mg). 1H NMR (400 MHz, CDCl3) δ 8.25 (s, 1H), 8.00 (dd, J = 8.6, 1.7 Hz, 1H), 7.91 (d, J = 8.9 Hz, 1H), 7.88 (d, J = 8.3 Hz, 1H), 7.75 (d, J = 8.1 Hz, 1H), 7.63 (ddd, J = 8.1, 6.9, 1.2 Hz, 1H), 7.54 (ddd, J = 8.1, 7.0, 1.1 Hz, 1H), 7.43–7.33 (m, 5H), 7.12 (d, J = 8.4 Hz, 2H), 7.06 (d, J = 8.4 Hz, 2H), 5.68 (d, J = 4.4 Hz, 1H), 4.38 (dq, J = 10.8, 7.1 Hz, 1H), 4.35 (dq, J = 10.8, 7.1 Hz, 1H), 4.28 (d, J = 4.4 Hz, 1H), 3.98 (dq, J = 10.9, 7.1 Hz, 1H), 3.93 (dq, J = 10.9, 7.1 Hz, 1H), 2.26 (s, 3H), 1.31 (t, J = 7.1 Hz, 3H), 1.03 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 193.5, 164.1, 162.8, 150.4, 142.6, 138.2, 136.0, 135.5, 132.4, 131.4, 130.8, 130.1 (2C), 129.7, 129.2, 129.1 36


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(2C), 129.0, 128.0, 127.8, 127.7 (2C), 127.2, 124.5, 122.7 (2C), 106.9, 78.0, 62.5, 59.7, 51.7, 21.0, 14.2, 14.1; HRMS (ESI-TOF) calcd for C34H32NO5 [M + H]+ 534.2280, found 534.2274. General

Procedure

for

the

One-Pot

Two-Step

Synthesis

of

Double-Dihydropyrroles 6 from Diamines 5, Alkyne Ester 2a, and Chalcone 3a under Ball-Milling Conditions. A mixture of 5 (0.2 mmol) and 2a (0.4 mmol) together with four stainless steel balls (5 mm in diameter) were introduced into a stainless steel jar (5 mL). The reaction vessel along with another identical empty vessel were closed and fixed on the vibration arms of a MM200 mixer mill, and were vibrated vigorously at a rate of 30 Hz at room temperature for 10 min. Then, 3a (0.2 mmol), I2 (0.5 mmol), and PhI(OAc)2 (0.1 mmol) were added and milled at 30 Hz for 40 min. After completion of the reaction, the resulting mixture was extracted with ethyl acetate, and the combined solution was evaporated to remove the solvent in vacuo. The residue was separated by flash column chromatography on silica gel with acetone/petroleum ether as the eluent to afford 6. Tetraethyl 1,1'-(hexane-1,6-diyl)bis(2-benzoyl-3-phenyl-trans-2,3-dihydro-1H-pyrrole-4,5-dicar boxylate) (6a). Acetone/petroleum ether = 1:4 as eluent. Yellow oil, 59% yield (50.9 mg). 1H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 7.3 Hz, 4H), 7.61 (t, J = 7.4 Hz, 2H), 7.46 (t, J = 7.7 Hz, 4H), 7.36–7.22 (m, 10H), 5.07 (d, J = 4.1 Hz, 2H), 4.43 (q, J = 7.1 Hz, 4H), 4.10 (d, J = 4.1 Hz, 2H), 3.93 (dq, J = 10.8, 7.1 Hz, 2H), 3.87 (dq, J = 10.8, 7.1 Hz, 2H), 3.29–3.20 (m, 2H), 3.15–3.06 (m, 2H), 1.53–1.39 (m, 4H), 1.421 (t, J = 37



Page 38 of 61

7.1 Hz, 3H), 1.415 (t, J = 7.1 Hz, 3H), 1.29–1.21 (m, 4H), 1.00 (t, J = 7.1 Hz, 6H); 13

C{1H} NMR (101 MHz, CDCl3) δ 194.0 (2C), 164.1 (2C), 163.0 (2C), 153.58,

153.56, 142.9 (2C), 134.1 (2C), 133.6 (2C), 129.2 (4C), 129.0 (8C), 127.6 (2C), 127.3 (4C), 101.5 (2C), 74.6, 74.5, 62.5 (2C), 59.3 (2C), 50.9 (2C), 46.9, 46.8, 28.4 (2C), 26.4 (2C), 14.3 (2C), 14.2 (2C); HRMS (ESI-TOF) calcd for C52H57N2O10 [M + H]+ 869.4013; found 869.4008. Tetraethyl 1,1'-(octane-1,8-diyl)bis(2-benzoyl-3-phenyl-trans-2,3-dihydro-1H-pyrrole-4,5-dicarb oxylate) (6b). Acetone/petroleum ether = 1:4 as eluent. Yellow oil, 61% yield (54.3 mg). 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 7.4 Hz, 4H), 7.62 (t, J = 7.4 Hz, 2H), 7.46 (t, J = 7.8 Hz, 4H), 7.37–7.31 (m, 4H), 7.31–7.24 (m, 6H), 5.08 (d, J = 4.3 Hz, 2H), 4.45 (q, J = 7.1 Hz, 4H), 4.11 (d, J = 4.3 Hz, 2H), 3.94 (dq, J = 10.8, 7.1 Hz, 2H), 3.87 (dq, J = 10.8, 7.1 Hz, 2H), 3.31–3.22 (m, 2H), 3.15–3.07 (m, 2H), 1.54–1.41 (m, 4H), 1.44 (t, J = 7.1 Hz, 6H), 1.29–1.17 (m, 8H), 1.01 (t, J = 7.1 Hz, 6H);

13

C{1H}

NMR (101 MHz, CDCl3) δ 194.0 (2C), 164.1 (2C), 163.1 (2C), 153.6 (2C), 142.9 (2C), 134.1 (2C), 133.6 (2C), 129.2 (4C), 128.99 (4C), 128.95 (4C), 127.5 (2C), 127.4 (4C), 101.4 (2C), 74.6, 74.5, 62.5 (2C), 59.3 (2C), 50.9 (2C), 46.93, 46.90, 29.2 (2C), 28.44, 28.43, 26.7 (2C), 14.3 (2C), 14.2 (2C); HRMS (ESI-TOF) calcd for C54H61N2O10 [M + H]+ 897.4326; found 897.4338. General

Procedure

for

the

Gram-Scale

Synthesis

of

trans-2,3-Dihydropyrrole 4a under Ball-Milling Conditions. A mixture of 1a (510 mg, 3 mmol) and 2a (321 mg, 3 mmol) together with two stainless steel balls (10 mm 38


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in diameter) were introduced into a stainless steel jar (10 mL). The same mixture was also introduced into another parallel jar. The two reaction vessels were closed and fixed on the vibration arms of a MM200 mixer mill, and were vibrated vigorously at a rate of 30 Hz at room temperature for 10 min. Then, 3a (416 mg, 2 mmol), I2 (1016 mg, 4 mmol), and PhI(OAc)2 (322 mg, 1 mmol) were added to each vessel and milled at 30 Hz for 60 min. After completion of the reaction, the resulting mixtures were extracted with ethyl acetate, and the combined solution was evaporated to remove the solvent in vacuo. The residue was separated by flash column chromatography on silica gel with ethyl acetate/petroleum ether as the eluent to afford 4a (1.53 g, 79%). General Procedure for the One-Pot Three-Step Synthesis of Pyrroles 7 from Amines 1, Alkyne Esters 2, and Chalcones 3 under Ball-Milling Conditions. A mixture of 1 (0.3 mmol) and 2 (0.3 mmol) together with a stainless steel ball (8 mm in diameter) were introduced into a stainless steel jar (5 mL). The reaction vessel along with another identical empty vessel were closed and fixed on the vibration arms of a MM200 mixer mill, and were vibrated vigorously at a rate of 30 Hz at room temperature for 10 min. Then, 3a (0.2 mmol), I2 (0.4 mmol), and PhI(OAc)2 (0.1 mmol) were added and milled at 30 Hz for 40 min. Subsequently, DDQ (0.8 mmol) was added into the mixture and milled at 30 Hz for 60 min. After completion of the reaction, the resulting mixture was extracted with acetone, and the combined solution was evaporated to remove the solvent in vacuo. The residue was separated by flash column chromatography on silica gel with ethyl acetate/petroleum ether as the eluent to afford 7. 39



Diethyl 2-benzoyl-3-phenyl-1-p-tolyl-1H-pyrrole-4,5-dicarboxylate (7a). Ethyl acetate/petroleum ether = 1:8 as eluent. White solid (mp 81–82 oC), 73% yield (70.2 mg). 1H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 7.3 Hz, 2H), 7.28 (t, J = 7.4 Hz, 1H), 7.21 (dd, J = 7.7, 1.5 Hz, 2H), 7.18 (d, J = 8.4 Hz, 2H), 7.16–7.03 (m, 7H), 4.22 (q, J = 7.2 Hz, 2H), 4.18 (q, J = 7.2 Hz, 2H), 2.33 (s, 3H), 1.18 (t, J = 7.2 Hz, 3H), 1.15 (t, J = 7.2 Hz, 3H);

13

C{1H} NMR (101 MHz, CDCl3) δ 188.4, 164.9, 160.3, 138.9,

137.4, 135.1, 133.1, 133.0, 132.3, 130.1 (2C), 129.7 (2C), 129.3 (2C), 128.4, 128.0 (3C), 127.8 (2C), 127.4, 127.3 (2C), 119.8, 61.5, 61.2, 21.3, 14.0, 13.9; HRMS (ESI-TOF) calcd for C30H28NO5 [M + H]+ 482.1967; found 482.1968. Diethyl 2-benzoyl-1-(4-isopropylphenyl)-3-phenyl-1H-pyrrole-4,5-dicarboxylate (7b). Ethyl acetate/petroleum ether = 1:8 as eluent. White solid (mp 148–149 oC), 70% yield (71.7 mg). 1H NMR (400 MHz, CDCl3) δ 7.51 (d, J = 7.3 Hz, 2H), 7.27 (t, J = 7.4 Hz, 1H), 7.25–7.18 (m, 4H), 7.16 (d, J = 8.4 Hz, 2H), 7.13–7.04 (m, 5H), 4.22 (q, J = 7.1 Hz, 2H), 4.16 (q, J = 7.1 Hz, 2H), 2.89 (sept, J = 6.9 Hz, 1H), 1.21 (d, J = 6.9 Hz, 6H), 1.17 (t, J = 7.1 Hz, 3H), 1.08 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 188.5, 164.8, 160.4, 149.6, 137.6, 135.3, 133.1, 133.0, 132.3, 130.1 (2C), 129.7 (2C), 128.6, 128.4, 128.0 (2C), 127.8 (2C), 127.5 (3C), 126.7 (2C), 119.7, 61.5, 61.2, 33.9, 23.9 (2C), 14.0, 13.8; HRMS (ESI-TOF) calcd for C32H32NO5 [M + H]+ 510.2280; found 510.2285. Diethyl 2-benzoyl-1-(4-tert-butylphenyl)-3-phenyl-1H-pyrrole-4,5-dicarboxylate (7c). Ethyl acetate/petroleum ether = 1:8 as eluent. White solid (mp 127–128 oC), 70% yield (73.2 mg). 1H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 7.4 Hz, 2H), 7.31 (d, J = 40


Page 40 of 61

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8.5 Hz, 2H), 7.29–7.18 (m, 5H), 7.13–7.04 (m, 5H), 4.22 (q, J = 7.1 Hz, 2H), 4.15 (q, J = 7.1 Hz, 2H), 1.28 (s, 9H), 1.17 (t, J = 7.1 Hz, 3H), 1.06 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 188.5, 164.8, 160.4, 151.8, 137.6, 135.0, 133.0, 132.9, 132.3, 130.1 (2C), 129.6 (2C), 128.6, 128.4, 128.0 (2C), 127.7 (2C), 127.4, 127.1 (2C), 125.5 (2C), 119.6, 61.5, 61.2, 34.8, 31.3 (3C), 14.0, 13.7; HRMS (ESI-TOF) calcd for C33H34NO5 [M + H]+ 524.2437; found 524.2435. Diethyl

2-benzoyl-1-(4-fluorophenyl)-3-phenyl-1H-pyrrole-4,5-dicarboxylate

(7d). Ethyl acetate/petroleum ether = 1:8 as eluent. Colorless oil, 61% yield (59.4 mg). 1

H NMR (400 MHz, CDCl3) δ 7.52 (d, J = 7.2 Hz, 2H), 7.33–7.26 (m, 3H), 7.24–7.19

(m, 2H), 7.13 (d, J = 7.8 Hz, 2H), 7.11–7.06 (m, 3H), 7.03 (t, J = 8.5 Hz, 2H), 4.23 (q, J = 7.1 Hz, 2H), 4.18 (q, J = 7.1 Hz, 2H), 1.19 (t, J = 7.1 Hz, 3H), 1.16 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 188.3, 164.9, 162.5 (d, J = 249.3 Hz), 160.0, 137.2, 133.7 (d, J = 3.1 Hz), 133.3, 133.2, 132.0, 130.0 (2C), 129.7 (2C), 129.6 (d, J = 8.9 Hz, 2C), 128.5, 128.1 (2C), 127.9 (2C), 127.6, 127.5, 120.7, 115.6 (d, J = 23.2 Hz, 2C), 61.6, 61.4, 14.0, 13.9; 19F NMR (376 MHz, CDCl3) δ -111.74–-111.83 (m, 1F); HRMS (ESI-TOF) calcd for C29H25FNO5 [M + H]+ 486.1717; found 486.1719. Diethyl 2-benzoyl-3-phenyl-1-propyl-1H-pyrrole-4,5-dicarboxylate (7e). Ethyl acetate/petroleum ether = 1:10 as eluent. Colorless oil, 70% yield (60.6 mg). 1H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 7.4 Hz, 2H), 7.28 (t, J = 7.4 Hz, 1H), 7.12 (t, J = 7.7 Hz, 2H), 7.11–7.07 (m, 2H), 7.05–6.96 (m, 3H), 4.48–4.42 (m, 2H), 4.38 (q, J = 7.1 Hz, 2H), 4.17 (q, J = 7.1 Hz, 2H), 1.84–1.73 (m, 2H), 1.38 (t, J = 7.1 Hz, 3H), 1.15 (t, J = 7.1 Hz, 3H), 0.89 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 189.5, 41



165.6, 160.6, 137.6, 133.0, 132.6, 131.8, 130.0 (2C), 129.9 (2C), 128.7, 128.0 (2C), 127.7 (2C), 127.2, 125.2, 121.2, 61.5, 61.2, 48.3, 25.4, 14.2, 14.1, 11.2; HRMS (ESI-TOF) calcd for C26H27NO5Na [M + Na]+ 456.1787; found 456.1785. Diethyl 2-benzoyl-1-butyl-3-phenyl-1H-pyrrole-4,5-dicarboxylate (7f). Ethyl acetate/petroleum ether = 1:10 as eluent. Colorless oil, 81% yield (72.7 mg). 1H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 7.3 Hz, 2H), 7.28 (t, J = 7.4 Hz, 1H), 7.12 (t, J = 7.8 Hz, 2H), 7.11–7.07 (m, 2H), 7.05–6.96 (m, 3H), 4.52–4.45 (m, 2H), 4.38 (q, J = 7.1 Hz, 2H), 4.17 (q, J = 7.1 Hz, 2H), 1.79–1.70 (m, 2H), 1.38 (t, J = 7.1 Hz, 3H), 1.36– 1.26 (m, 2H), 1.15 (t, J = 7.1 Hz, 3H), 0.87 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 189.5, 165.6, 160.6, 137.6, 133.0, 132.6, 131.8, 130.0 (2C), 129.9 (2C), 128.8, 128.0 (2C), 127.7 (2C), 127.2, 125.2, 121.2, 61.5, 61.2, 46.7, 34.2, 20.0, 14.1, 14.0, 13.7; HRMS (ESI-TOF) calcd for C27H30NO5 [M + H]+ 448.2124; found 448.2121. Diethyl 2-benzoyl-1-pentyl-3-phenyl-1H-pyrrole-4,5-dicarboxylate (7g). Ethyl acetate/petroleum ether = 1:8 as eluent. Colorless oil, 83% yield (76.8 mg). 1H NMR (400 MHz, CDCl3) δ 7.57 (d, J = 7.3 Hz, 2H), 7.28 (t, J = 7.4 Hz, 1H), 7.12 (t, J = 7.8 Hz, 2H), 7.11–7.07 (m, 2H), 7.05–6.96 (m, 3H), 4.51–4.44 (m, 2H), 4.38 (q, J = 7.1 Hz, 2H), 4.18 (q, J = 7.1 Hz, 2H), 1.81–1.71 (m, 2H), 1.38 (t, J = 7.1 Hz, 3H), 1.33– 1.21 (m, 4H), 1.15 (t, J = 7.1 Hz, 3H), 0.82 (t, J = 6.8 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 189.5, 165.6, 160.6, 137.6, 133.0, 132.6, 131.8, 130.0 (2C), 129.9 (2C), 128.7, 128.0 (2C), 127.7 (2C), 127.2, 125.2, 121.2, 61.5, 61.2, 46.9, 31.8, 28.9, 22.3, 14.1, 14.03, 13.97; HRMS (ESI-TOF) calcd for C28H31NO5Na [M + Na]+ 42


Page 42 of 61

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484.2100; found 484.2100. Diethyl 2-benzoyl-1-hexyl-3-phenyl-1H-pyrrole-4,5-dicarboxylate (7h). Ethyl acetate/petroleum ether = 1:8 as eluent. Colorless oil, 80% yield (76.3 mg). 1H NMR (400 MHz, CDCl3) δ 7.57 (d, J = 7.2 Hz, 2H), 7.28 (t, J = 7.4 Hz, 1H), 7.12 (t, J = 7.8 Hz, 2H), 7.11–7.07 (m, 2H), 7.05–6.96 (m, 3H), 4.51–4.44 (m, 2H), 4.38 (q, J = 7.1 Hz, 2H), 4.18 (q, J = 7.1 Hz, 2H), 1.80–1.71 (m, 2H), 1.38 (t, J = 7.1 Hz, 3H), 1.32– 1.19 (m, 6H), 1.15 (t, J = 7.1 Hz, 3H), 0.82 (t, J = 6.8 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 189.5, 165.6, 160.6, 137.6, 133.0, 132.6, 131.8, 130.0 (2C), 129.9 (2C), 128.7, 128.0 (2C), 127.7 (2C), 127.2, 125.2, 121.2, 61.5, 61.2, 46.9, 32.1, 31.3, 26.5, 22.6, 14.1, 14.0 (2C); HRMS (ESI-TOF) calcd for C29H33NO5Na [M + Na]+ 498.2256; found 498.2255. Diethyl 2-benzoyl-1-isobutyl-3-phenyl-1H-pyrrole-4,5-dicarboxylate (7i). Ethyl acetate/petroleum ether = 1:10 as eluent. White solid (mp 56–57 oC), 80% yield (71.6 mg). 1H NMR (400 MHz, CDCl3) δ 7.57 (d, J = 7.6 Hz, 2H), 7.28 (t, J = 7.3 Hz, 1H), 7.12 (t, J = 7.7 Hz, 2H), 7.12–7.07 (m, 2H), 7.04–6.96 (m, 3H), 4.44 (d, J = 7.6 Hz, 2H), 4.37 (q, J = 7.1 Hz, 2H), 4.16 (q, J = 7.1 Hz, 2H), 1.99–1.88 (m, 1H), 1.38 (t, J = 7.1 Hz, 3H), 1.13 (t, J = 7.1 Hz, 3H), 0.82 (d, J = 6.7 Hz, 6H); 13C{1H} NMR (101 MHz, CDCl3) δ 189.5, 165.4, 160.9, 137.6, 133.0, 132.6, 131.9, 130.2 (2C), 129.9 (2C), 129.2, 128.0 (2C), 127.7 (2C), 127.2, 126.1, 121.1, 61.6, 61.2, 53.0, 30.8, 19.9 (2C), 14.1, 14.0; HRMS (ESI-TOF) calcd for C27H30NO5 [M + H]+ 448.2124; found 448.2121. Diethyl 2-benzoyl-1-benzyl-3-phenyl-1H-pyrrole-4,5-dicarboxylate (7j). Ethyl 43



acetate/petroleum ether = 1:8 as eluent. Colorless oil, 76% yield (73.4 mg). 1H NMR (400 MHz, CDCl3) δ 7.41 (d, J = 7.3 Hz, 2H), 7.21 (t, J = 7.5 Hz, 1H), 7.19 (t, J = 7.6 Hz, 2H), 7.15–7.06 (m, 5H), 7.06–6.96 (m, 5H), 5.81 (s, 2H), 4.31 (q, J = 7.1 Hz, 2H), 4.17 (q, J = 7.1 Hz, 2H), 1.28 (t, J = 7.1 Hz, 3H), 1.14 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 189.6, 165.3, 160.7, 137.5, 137.4, 132.9, 132.4, 132.1, 130.1 (2C), 129.8 (2C), 129.4, 128.6 (2C), 127.8 (2C), 127.7 (2C), 127.6, 127.3, 127.1 (2C), 126.1, 121.2, 61.7, 61.2, 49.4, 14.0 (2C); HRMS (ESI-TOF) calcd for C30H28NO5 [M + H]+ 482.1967; found 482.1974. Diethyl

2-benzoyl-1-(4-chlorobenzyl)-3-phenyl-1H-pyrrole-4,5-dicarboxylate

(7k). Ethyl acetate/petroleum ether = 1:8 as eluent. White solid (mp 103–104 oC), 78% yield (80.1 mg). 1H NMR (400 MHz, CDCl3) δ 7.41 (d, J = 7.8 Hz, 2H), 7.23 (t, J = 7.4 Hz, 1H), 7.17 (d, J = 8.3 Hz, 2H), 7.12–6.96 (m, 9H), 5.78 (s, 2H), 4.31 (q, J = 7.1 Hz, 2H), 4.17 (q, J = 7.1 Hz, 2H), 1.30 (t, J = 7.1 Hz, 3H), 1.14 (t, J = 7.1 Hz, 3H); 13

C{1H} NMR (101 MHz, CDCl3) δ 189.5, 165.3, 160.6, 137.2, 136.1, 133.4, 133.0,

132.2, 132.0, 130.0 (2C), 129.8 (2C), 129.4, 128.7 (2C), 128.6 (2C), 127.9 (2C), 127.8 (2C), 127.4, 125.5, 121.8, 61.7, 61.3, 48.8, 14.0 (2C); HRMS (ESI-TOF) calcd for C30H2735ClNO5 [M + H]+ 516.1578, found 516.1574. Diethyl

2-benzoyl-1-(2-chlorobenzyl)-3-phenyl-1H-pyrrole-4,5-dicarboxylate

(7l). Ethyl acetate/petroleum ether = 1:8 as eluent. White solid (mp 90–91 oC), 73% yield (75.6 mg). 1H NMR (400 MHz, CDCl3) δ 7.49 (d, J = 7.3 Hz, 2H), 7.30 (dd, J = 7.4, 1.7 Hz, 1H), 7.23 (t, J = 7.4 Hz, 1H), 7.18–7.09 (m, 4H), 7.09–6.99 (m, 5H), 6.70 (dd, J = 7.1, 1.9 Hz, 1H), 5.86 (s, 2H), 4.25 (q, J = 7.1 Hz, 2H), 4.21 (q, J = 7.1 Hz, 44


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2H), 1.22 (t, J = 7.1 Hz, 3H), 1.17 (t, J = 7.1 Hz, 3H);

13

C{1H} NMR (101 MHz,

CDCl3) δ 188.9, 165.3, 160.1, 137.2, 135.8, 133.0, 132.4, 132.3, 131.8, 130.1 (2C), 129.9 (2C), 129.32, 129.28, 128.4, 127.9 (2C), 127.8 (2C), 127.5, 127.1, 126.8, 126.0, 122.1, 61.7, 61.4, 48.2, 14.1, 13.9; HRMS (ESI-TOF) calcd for C30H2735ClNO5 [M + H]+ 516.1578, found 516.1580. Diethyl

2-benzoyl-1-phenethyl-3-phenyl-1H-pyrrole-4,5-dicarboxylate

(7m).

Ethyl acetate/petroleum ether = 1:10 as eluent. White solid (mp 100–101 oC), 76% yield (75.2 mg). 1H NMR (400 MHz, CDCl3) δ 7.48 (d, J = 7.8 Hz, 2H), 7.29–7.20 (m, 5H), 7.19–7.12 (m, 1H), 7.12–7.05 (m, 4H), 7.05–6.96 (m, 3H), 4.73–4.66 (m, 2H), 4.39 (q, J = 7.1 Hz, 2H), 4.18 (q, J = 7.1 Hz, 2H), 3.18–3.11 (m, 2H), 1.38 (t, J = 7.1 Hz, 3H), 1.16 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 189.4, 165.6, 160.5, 138.0, 137.6, 132.9, 132.6, 131.9, 130.0 (2C), 129.9 (2C), 129.1 (2C), 128.8, 128.7 (2C), 127.9 (2C), 127.8 (2C), 127.3, 126.8, 124.8, 121.9, 61.6, 61.3, 48.5, 38.4, 14.2, 14.1; HRMS (ESI-TOF) calcd for C31H30NO5 [M + H]+ 496.2124; found 496.2135. Dimethyl 2-benzoyl-3-phenyl-1-p-tolyl-1H-pyrrole-4,5-dicarboxylate (7n). Ethyl acetate/petroleum ether = 1:6 as eluent. Colorless oil, 71% yield (64.4 mg). 1H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 7.5 Hz, 2H), 7.28 (t, J = 7.4 Hz, 1H), 7.21 (d, J = 6.4 Hz, 2H), 7.17 (d, J = 8.3 Hz, 2H), 7.15–7.04 (m, 7H), 3.75 (s, 3H), 3.73 (s, 3H), 2.33 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 188.5, 165.4, 160.8, 139.0, 137.3, 134.9, 133.3, 133.1, 132.1, 130.0 (2C), 129.7 (2C), 129.4 (2C), 128.3, 128.1 (2C), 127.9 (2C), 127.7, 127.5, 127.2 (2C), 119.6, 52.5, 52.3, 21.4; HRMS (ESI-TOF) calcd for 45



Page 46 of 61

C28H24NO5 [M + H]+ 454.1654; found 454.1657. Dimethyl 2-benzoyl-1-butyl-3-phenyl-1H-pyrrole-4,5-dicarboxylate (7o). Ethyl acetate/petroleum ether = 1:10 as eluent. White solid (mp 60–61 oC), 78% yield (65.5 mg). 1H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 7.3 Hz, 2H), 7.29 (t, J = 7.4 Hz, 1H), 7.13 (t, J = 7.7 Hz, 2H), 7.11–7.06 (m, 2H), 7.06–6.97 (m, 3H), 4.52–4.45 (m, 2H), 3.92 (s, 3H), 3.72 (s, 3H), 1.77–1.68 (m, 2H), 1.35–1.25 (m, 2H), 0.87 (t, J = 7.4 Hz, 3H);

13

C{1H} NMR (101 MHz, CDCl3) δ 189.5, 166.0, 161.0, 137.5, 133.1, 132.5,

132.0, 129.95 (2C), 129.88 (2C), 128.7, 128.1 (2C), 127.8 (2C), 127.3, 125.1, 120.9, 52.5, 52.3, 46.8, 34.2, 20.0, 13.7; HRMS (ESI-TOF) calcd for C25H25NO5Na [M + Na]+ 442.1631; found 442.1627. Dimethyl

2-benzoyl-1-isobutyl-3-phenyl-1H-pyrrole-4,5-dicarboxylate

(7p).

Ethyl acetate/petroleum ether = 1:10 as eluent. White solid (mp 90–91 oC), 76% yield (63.9 mg). 1H NMR (400 MHz, CDCl3) δ 7.57 (d, J = 7.3 Hz, 2H), 7.29 (t, J = 7.4 Hz, 1H), 7.13 (t, J = 7.7 Hz, 2H) ,7.12–7.07 (m, 2H), 7.05–6.97 (m, 3H), 4.43 (d, J = 7.6 Hz, 2H), 3.91 (s, 3H), 3.71 (s, 3H), 1.97–1.85 (m, 1H), 0.81 (d, J = 6.7 Hz, 6H);

13

C{1H} NMR (101 MHz, CDCl3) δ 189.5, 165.9, 161.3, 137.5, 133.1, 132.5,

132.1, 130.1 (2C), 129.9 (2C), 129.2, 128.1 (2C), 127.8 (2C), 127.3, 126.0, 120.8, 53.0, 52.5, 52.3, 30.9, 19.9 (2C); HRMS (ESI-TOF) calcd for C25H25NO5Na [M + Na]+ 442.1631; found 442.1627. Dimethyl 2-benzoyl-1-benzyl-3-phenyl-1H-pyrrole-4,5-dicarboxylate (7q). Ethyl acetate/petroleum ether = 1:6 as eluent. White solid (mp 98–99 oC), 76% yield (68.8 mg). 1H NMR (400 MHz, CDCl3) δ 7.40 (d, J = 7.2 Hz, 2H), 7.21 (t, J = 7.4 Hz, 1H), 46


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7.18 (t, J = 7.5 Hz, 2H), 7.15–6.96 (m, 10H), 5.81 (s, 2H), 3.85 (s, 3H), 3.71 (s, 3H); 13

C{1H} NMR (101 MHz, CDCl3) δ 189.6, 165.7, 161.1, 137.4, 137.2, 133.0, 132.3,

132.2, 130.0 (2C), 129.8 (2C), 129.3, 128.6 (2C), 127.9 (2C), 127.8 (2C), 127.6, 127.4, 127.1 (2C), 125.8, 121.1, 52.6, 52.3, 49.5; HRMS (ESI-TOF) calcd for C28H23NO5Na [M + Na]+ 476.1474; found 476.1466. Diethyl

2-benzoyl-1,3-dip-tolyl-1H-pyrrole-4,5-dicarboxylate

(7r).

Ethyl

acetate/petroleum ether = 1:8 as eluent. White solid (mp 82–83 oC), 75% yield (74.4 mg). 1H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 7.8 Hz, 2H), 7.29 (t, J = 7.4 Hz, 1H), 7.16 (d, J = 8.2 Hz, 2H), 7.15–7.08 (m, 6H), 6.90 (d, J = 7.8 Hz, 2H), 4.23 (q, J = 7.1 Hz, 2H), 4.17 (q, J = 7.1 Hz, 2H), 2.32 (s, 3H), 2.18 (s, 3H), 1.21 (t, J = 7.1 Hz, 3H), 1.15 (t, J = 7.1 Hz, 3H);

13

C{1H} NMR (101 MHz, CDCl3) δ 188.6, 165.1, 160.3,

138.8, 137.4, 137.1, 135.1, 133.1, 133.0, 129.9 (2C), 129.7 (2C), 129.3 (2C), 129.1, 128.6 (2C), 128.3, 128.0 (2C), 127.6, 127.4 (2C), 120.0, 61.5, 61.3, 21.3, 21.2, 14.1, 13.9; HRMS (ESI-TOF) calcd for C31H30NO5 [M + H]+ 496.2124; found 496.2131. Diethyl

3-benzoyl-3-(4-methoxyphenyl)-1-p-tolyl-1H-pyrrole-4,5-dicarboxylate

(7s). Ethyl acetate/petroleum ether = 1:6 as eluent. White solid (mp 84–85 oC), 70% yield (71.4 mg). 1H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 7.3 Hz, 2H), 7.29 (t, J = 7.4 Hz, 1H), 7.20–7.09 (m, 8H), 6.63 (d, J = 8.6 Hz, 2H), 4.23 (q, J = 7.1 Hz, 2H), 4.17 (q, J = 7.1 Hz, 2H), 3.68 (s, 3H), 2.32 (s, 3H), 1.22 (t, J = 7.1 Hz, 3H), 1.15 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 188.6, 165.0, 160.4, 159.0, 138.9, 137.4, 135.2, 133.0 (2C), 131.3 (2C), 129.7 (2C), 129.3 (2C), 128.2, 128.0 (2C), 127.9, 127.4 (2C), 124.6, 119.8, 113.3 (2C), 61.5, 61.2, 55.2, 21.3, 14.1, 13.9; HRMS 47



(ESI-TOF) calcd for C31H30NO6 [M + H]+ 512.2073; found 512.2072. Diethyl

2-(4-methylbenzoyl)-3-phenyl-1-p-tolyl-1H-pyrrole-4,5-dicarboxylate

(7t). Ethyl acetate/petroleum ether = 1:8 as eluent. White solid (mp 87–88 oC), 71% yield (70.5 mg). 1H NMR (400 MHz, CDCl3) δ 7.45 (d, J = 8.1 Hz, 2H), 7.25–7.20 (m, 2H), 7.16 (d, J = 8.3 Hz, 2H), 7.14–7.05 (m, 5H), 6.92 (d, J = 8.0 Hz, 2H), 4.23 (q, J = 7.1 Hz, 2H), 4.17 (q, J = 7.1 Hz, 2H), 2.32 (s, 3H), 2.23 (s, 3H), 1.19 (t, J = 7.1 Hz, 3H), 1.15 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 188.3, 165.1, 160.3, 144.1, 138.9, 135.2, 134.9, 133.5, 132.4, 130.0 (4C), 129.3 (2C), 128.8 (2C), 127.9 (2C), 127.6, 127.4 (3C), 127.3, 120.1, 61.5, 61.3, 21.7, 21.4, 14.1, 13.9; HRMS (ESI-TOF) calcd for C31H30NO5 [M + H]+ 496.2124; found 496.2125. Diethyl

2-(3-methylbenzoyl)-3-phenyl-1-p-tolyl-1H-pyrrole-4,5-dicarboxylate

(7u). Ethyl acetate/petroleum ether = 1:8 as eluent. White solid (mp 88–90 oC), 73% yield (72.2 mg). 1H NMR (400 MHz, CDCl3) δ 7.35 (d, J = 7.6 Hz, 1H), 7.32 (s, 1H), 7.21 (d, J = 6.5 Hz, 2H), 7.18 (d, J = 8.3 Hz, 2H), 7.13 (d, J = 8.3 Hz, 2H), 7.11–7.03 (m, 4H), 7.01 (t, J = 7.6 Hz, 1H), 4.22 (q, J = 7.2 Hz, 2H), 4.18 (q, J = 7.2 Hz, 2H), 2.33 (s, 3H), 2.15 (s, 3H), 1.18 (t, J = 7.2 Hz, 3H), 1.16 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 188.4, 164.9, 160.3, 138.9, 137.6, 137.2, 135.2, 133.8, 133.2, 132.5, 130.6, 130.0 (2C), 129.3 (2C), 128.4, 128.0 (2C), 127.7 (2C), 127.4, 127.3 (2C), 126.9, 119.8, 61.6, 61.2, 21.4, 21.1, 14.1, 13.9; HRMS (ESI-TOF) calcd for C31H30NO5 [M + H]+ 496.2124; found 496.2124. Diethyl

2-(4-fluorobenzoyl)-3-phenyl-1-p-tolyl-1H-pyrrole-4,5-dicarboxylate

(7v). Ethyl acetate/petroleum ether = 1:8 as eluent. White solid (mp 97–98 oC), 75% 48


Page 48 of 61

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yield (75.2 mg). 1H NMR (400 MHz, CDCl3) δ 7.55 (dd, J = 8.7, 5.4 Hz, 2H), 7.22– 7.09 (m, 9H), 6.78 (t, J = 8.6 Hz, 2H), 4.22 (q, J = 7.1 Hz, 2H), 4.18 (q, J = 7.1 Hz, 2H), 2.34 (s, 3H), 1.18 (t, J = 7.1 Hz, 3H), 1.15 (t, J = 7.1 Hz, 3H);

13

C{1H} NMR

(101 MHz, CDCl3) δ 186.8, 165.5 (d, J = 255.4 Hz), 164.8, 160.3, 139.0, 135.0, 133.8 (d, J = 2.8 Hz), 132.7, 132.4 (d, J = 9.5 Hz, 2C), 132.2, 130.1 (2C), 129.4 (2C), 128.5, 128.3, 127.9 (2C), 127.6, 127.3 (2C), 119.7, 115.2 (d, J = 22.1 Hz, 2C), 61.6, 61.3, 21.4, 14.1, 13.9;

19

F NMR (376 MHz, CDCl3) δ -104.55–-104.65 (m, 1F); HRMS

(ESI-TOF) calcd for C30H27FNO5 [M + H]+ 500.1873; found 500.1880. Diethyl

2-(4-chlorobenzoyl)-3-phenyl-1-p-tolyl-1H-pyrrole-4,5-dicarboxylate

(7w). Ethyl acetate/petroleum ether = 1:8 as eluent. White solid (mp 108–109 oC), 69% yield (71.3 mg). 1H NMR (400 MHz, CDCl3) δ 7.46 (d, J = 8.7 Hz, 2H), 7.22–7.10 (m, 9H), 7.08 (d, J = 8.7 Hz, 2H), 4.22 (q, J = 7.2 Hz, 2H), 4.18 (q, J = 7.2 Hz, 2H), 2.35 (s, 3H), 1.18 (t, J = 7.2 Hz, 3H), 1.15 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 187.1, 164.7, 160.3, 139.4, 139.1, 135.7, 135.0, 132.5, 132.1, 131.1 (2C), 130.1 (2C), 129.4 (2C), 128.7, 128.5, 128.4 (2C), 128.0 (2C), 127.7, 127.3 (2C), 119.6, 61.7, 61.3, 21.4, 14.1, 13.9; HRMS (ESI-TOF) calcd for C30H2735ClNO5 [M + H]+ 516.1578; found 516.1588.

AUTHOR INFORMATION Corresponding Author *Email: [email protected] ORCID 49



Guan-Wu Wang: 0000-0001-9287-532X Notes The authors declare no competing financial interest.

ACKNOWLEDGEMENTS We are grateful for financial support from the National Natural Science Foundation of China (No. 21372211) and the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB20000000).

ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge via the Internet at http://pubs.acs.org. The employed stainless steel jars and balls, NMR spectra of 4a‒d’, 6a, 6b, and 7a‒w (PDF) X-ray crystallography data of 4e (CIF)

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One-Pot Multicomponent Mechanosynthesis of Polysubstituted trans-2

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