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The Divergent Cascade Reactions of Arylalkynols with Homopropargylic Amines or Electron-deficient Olefins: Access to the Spiroisobenzofuran-b-pyrroloquinolines or Brigded-isobenzofuran Polycycles Lun Wang, Lingyan Liu, Weixing Chang, and Jing Li J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00691 • Publication Date (Web): 06 Jun 2018 Downloaded from http://pubs.acs.org on June 6, 2018

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The Journal of Organic Chemistry

The Divergent Cascade Reactions of Arylalkynols with Homopropargylic Amines or Electron-deficient Olefins: Access to the Spiro-isobenzofuran-b-pyrroloquinolines or Brigded-isobenzofuran Polycycles Lun Wang1 , Lingyan Liu*1 , Weixing Chang1 , Jing Li*1,2 1

the State Key Laboratory and Institute of Elemento-Organic Chemistry, the Co llege of Chemistry, Nan kai

University, Tianjin, 300071 (China) 2

Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Weijin Road 94#,

Nankai District, Tian jin 300071 (China)

E-mail: [email protected]; [email protected]

ACS Paragon Plus Environment

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

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ABSTRACT Two divergent cascade reactions of arylalkynols with homopropargylic amines or electron-deficient olefins were developed to synthesize the spiro- isobenzofuranb-pyrroloquinolines or bridged-isobenzofuran heterocycles in good yields, respectively. One

reaction

actually

involved

intramolecular

5-endo-dig

hydroamination

cyclization-protonation of homopropargylic amines to give cycloiminium ions and intramolecular 5-exo-dig hydroalkoxylation cyclization of arylalkynols to generate isobenzofuran with exocyclic double bond, followed by the nontypical Povarov-type reaction in the presence of PtCl2 /FeCl3 cocatalysts, the other underwent intramolecular hydroalkoxylation cycloisomerization of alkynols with the subsequent normal [4+2] cycoaddition with dienophiles. Herein, the arylalkynols acted as both “masked” electron-rich olefins and “masked” electron-rich dienes.

INTRODUCTION The development of novel cascade reactions, possessing high efficiency, atom economy, low cost and operational simplicity, has always been one of hot topic research in the organic synthetic chemistry fields and become the focus of the chemists for ever. And the new complex potential bioactive molecules can be constructed via severa l consecutive steps to form multiple new bonds from simple and easily available substrates in fast and efficient one pot cascade reaction. Obviously, the key points are the design


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and combination of applicable reactants for the cascade reactions. For insta nce, the alkynols- or alkynlamines-based cascade reactions have attracted increasing attention in chemical synthesis in recent years. 1 These cascade reactions afford the complex oxygenand nitrogen-containing spiro or bridged fused heterocycles, as well as polycyclic structural units, which may have some certain bioactivities. 2 For the arylalkynols 1, previous reports mainly focus on the simple intramolecular 5-exo-dig and 6-endo-dig hydroalkoxylation cyclizations to generate the isobenzofurans 2 (exo-cyclic enol ethers) and isobenzopyrans 3 (endo-cyclic enol) (Figure 1).3

Figure 1. The two possible Intramolecular hydroalkoxylation cyclization of arylalkynols

More recently, the less stable isobenzofurans and isobenzopyrans formed in situ have been developed as electron-rich olefins to undergo further diverse cycloadditions. 4 Liu’s research group reported many successful cascade reactions on the internal alkynols, which gave the isobenzopyrans, and followed by treating with other reactants. 5 Barluenga’s group also developed prosperous cascade reactions of alkynols to synthesize spiroisobenzofuran

polycyclic

compounds

5.6

A

typical

example

was

the

multicomponents reaction of alkynols, aldehydes and amines in one pot through



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intramolecular hydroalkoxylation of alkynols and subsequent Povarov reaction (Scheme 1a). 6d

Scheme 1. The divergent reactions of alkynols and homopropargylic amines

On the other hand, alkynyl amines, especially for the β-aminoalkynes, can generate the cycloenamines or cycloiminium ions intermediates through the

intramolecular

hydroamination cyclization or further protonation. These two intermediates can further perform various transformations. Ye’s group had made significant achievements in the


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field of hydroamination cyclization cascade reactions of N-protected β-aminoalkynes.7 Our research group also exploited some hydroamination cyclization cycloaddition cascade reactions of N-arylhomopropargylic amines.8 Among them, we had ever used electron-rich olefins 7, such as the dihydrofuran, dihydropyran or dihydropyrrole, to react with homopropargylic amines 6 (Scheme 1b).8c In this reaction, the electron-olefins were only limited to the cyclic olefins. Based on the previous literatures and as a continuous work of our group, we herein designed to employ the arylalkynols 9 as “masked” electron-olefins to react with the N-arylhomopropargylic amines 6 to deliver the complex spiroisobenzofuran-b-quinolines heterocycles. As a result, the reaction of alkynols and homopropargylic amines was expectedly occurred, providing the complex polycyclic compounds 10 in good yields (Scheme 1c). This interesting reaction actually involved an intramolecular hydroamination cyclization-protonation of homopropargylic amines to generate the cycloiminium ions and an intramolecular hydroalkoxylation of arylalkynols to produce the isobenzofurans with exocyclic double bonds, followed by an intermolecular nontypical Povarov reaction. Additionally, the isobenzofuran with exocyclic double bond can isomerize to 1- methylisobenzofuran,9 which can be easily captured by other electron-deficient dienes to perform the Diels-Alder reactions, and thus giving the bridged polycycles 11 (Scheme 1c). The divergent cascade reactions of alkynols would provide new strategies for the construction of complex nitrogen- and



oxygen-containing polycycles, as may further lay a solid foundation for synthesizing natural products or developing new bioactive molecules.

RESULTS AND DISCUSSION In our initial effort, we selected 4-chloro-N-(1-phenylbut-3-yn-1-yl)aniline 6c and (2-ethynylphenyl)methanol 9a as model substrates using 10 mol% Cu(OTf)2 as catalyst in CH3 OH solvent. As a result, a spiroisobenzofuran-b-pyrroloquinoline 10ca was obtained in moderate yield (Table 1, entry 1). Changing the methanol solvent to toluene, the yield of target molecule was slightly decreased (entry 2). Further screening the other copper salts, such as CuCl2 and CuBr2 , no improved results were obtained (entries 3-4). Using FeCl3 catalyst, no target compound was observed and the phenylalkynol 9a remained nearly untouched with small amount of homopropargylic amine 6c performing a formal self-dimerization (27% yield) (entry 5). Based on the literatures, 6 we employed PtCl2 as catalyst, the expected spiroisobenzofuran-b-quinoline 10ca could be obtained in 44% yield but with the self-dimerized side product of 6c in 51% yield (entry 6). Considering for promoting the transformation of cycloenamine formed in situ to cycloiminium ion, the cocatalysts were preferred to be used. For example, the reaction could give the 10ca in improved yields in the presence of PtCl2 /CuCl2 or PtCl2 /CuBr2 cocatalysts (entries 7 and 8). Interestingly, the yield of spiro-isobenzofuran-bpyrroloquinoline 10ca was high up to 83% or 89% when employing the PtCl2 /Fe(OTf)3


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or PtCl2 /FeCl3 as cocatalysts, respectively (entries 9 and 10). Decreasing the amount of homopropargylic amine 6c or the reaction temperature to room temperature, the reaction gave a slightly decreased yield of product 10ca in the presence of PtCl2 /FeCl3 cocatalysts (entries 11 and 12). Introducing the acidic Al2 O3 as an additive, the yield remained hardly changed yet (entry 13). In the case of PtCl2 /AgOAc, the reaction could proceed but with moderate yield of 10ca under dark conditions (entry 14). The reactions catalyzed by the PtCl2 /FeCl3 afforded no obvious improved results in other common used organic solvents, such as CH3 OH, n-PrOH, THF and CHCl3 (entries 15-18). And no reaction occurred in CH3 CN even with prolonging reaction time (entry 19). Under N2 atmosphere, similar yield of 10ca was obtained (entry 20). Increasing the reaction temperature to 80 or 100 o C, the reaction gave the decreased yields of target molecules in toluene on the contrary (Table 1, entries 21 and 22) in the presence of 5 mol% PtCl2 / 5 mol% FeCl3 . It should be noteworthy that the corresponding products 10ca were obtained with nearly 7:2:1 diastereoselectivity in all cases. In the cases of low or moderate yields of target compounds, the self-dimerization compound of homopropargylic amine 6c was observed by the 1 H NMR of crude products. Summarily, the optimal reaction conditions were 5 mol% PtCl2 / 5 mol% FeCl3 , 1.5 equiv. homopropargylic amines, 1.0 equiv. arylalkynols, 0.2 M (toluene), 50 o C for 12 h in the air. Table 1. Opti mization studies of the cascade reaction of homoproparg ylic amine 6c and phenylalkynol 9aa



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Entry

Catalyst (mol%)

Solvent

Yield (%)b

1

Cu(OTf)2 (10)

CH3 OH

49

2

Cu(OTf)2 (10)

PhMe

36

3

CuCl2 (10)

PhMe

42

4

CuBr2 (10)

PhMe

39

5

FeCl3 (5)

PhMe

0(27)

6

PtCl2 (5)

PhMe

44 (51)c

7

PtCl2 (5) / Cu Cl2 (10)

PhMe

67

8

PtCl2 (5) / Cu Br2 (10)

PhMe

58

9

PtCl2 (5) / Fe(OTf)3 (5)

PhMe

83

10

PtCl 2 (5) / FeCl 3 (5)

PhMe

89

11d

PtCl2 (5) / FeCl3 (5)

PhMe

70

12e

PtCl2 (5) / FeCl3 (5)

PhMe

72

13f

PtCl2 (5) / FeCl3 (5)

PhMe

86


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a

14g

PtCl2 (5) / AgOAc (5)

PhMe

48

15

PtCl2 (5) / FeCl3 (5)

MeOH

77

16

PtCl2 (5) / FeCl3 (5)

n-PrOH

53

17

PtCl2 (5) / FeCl3 (5)

THF

55

18h

PtCl2 (5) / FeCl3 (5)

CHCl3

61

19h

PtCl2 (5) / FeCl3 (5)

MeCN

N.R.

20i

PtCl2 (5) / FeCl3 (5)

PhMe

88

21j

PtCl2 (5) / FeCl3 (5)

PhMe

63

22k

PtCl2 (5) / FeCl3 (5)

PhMe

47

Standard procedure: The ho mopropargylic amine 6c (76.7 mg, 0.3 mmol, 1.5 equiv.) and

(2-ethynylphenyl)methanol 9a (26.4 mg, 0.2 mmo l), catalyst and solvent (1 mL) were sequentially added into the reaction tube. The reaction mixture was stirred at 50 o C for 12 h in the air; b Isolated yield; c The bracket was the yield of self-dimerized side product (counted by the loading of 6c); d 1.2 equiv. 6c; e The reaction temperature was r.t.; f 2.0 equiv. acidic A l2 O3 was added; g Under dark condition; h The reaction time was 24 h; i under N2 at mosphere;

j

The reaction temperature was 80 o C; k The reaction temperature

was 100 o C.

The scope of the nontypical Povarov-type cascade reaction was evaluated on the various homopropargylic amines 6 and alkynols 9. As shown in Table 2, all reactions



could

smoothly

proceed

and

afford

the

corresponding

Page 10 of 55

spiroisobenzofuran-

b-pyrroloquinolines in good to high yields. Moreover, the homopropargylic amines bearing with electron-withdrawing substituted aryls on N atom or C atom generally rendered better yields of corresponding products than that of electron-donating substituted aryls compounds (10ba-10da, 10ha-10ja, 10la vs 10ea-10ga, 10ka). Even for the nitro-substituted aryl substrate 3l, the reaction could also produce the 10la in 72% total yields with 9:1 dr value. In the cases of homopropargylic amines with steric hindrance naphthyl group (6m) and heteroatomic thiophenyl (6n) as well as hydrogen atom (6o), the reactions gave the corresponding spiroisobenzofuran-b-pyrroloquinolines in above moderate yields (10ma-10oa). Similarly, for the arylalkynols 9, whether bearing with electron-donating substituents or electron-withdrawing groups, the reaction afforded the target molecules in good yields (10pb, 10jc and 10jd). Notably, the small amount of self-dimerization compounds were concomitantly obtained besides the moderate yields of spiroisobenzofuran-b-pyrroloquinolines were produced (10aa, 10fa, 10ga, 10ka, 10ma and 10oa). The diastereoselectivities of most target products were good with > 9:1 dr values. And three diastereoisomers were generated at least and could not be isolated by simple silica gel column chromatography. Therefore, the single crystal could not be obtained, thus the absolute configuration of the major isomer remained unclear at present. Nevertheless, the DEPT and 2D NMR analyses of product 10aa (HMBC and HMQC) were determined and the structure was unambiguously confirmed (Figure S1-S4).


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Table 2. The hydroami nation cyclization-protonation / hydroalkoxylation nontypical Povarov-type cascade reactions of various homoproparg ylic amines 6 and arylalkynols 9 a,b

Various homopropargylic amines 6 and phenylalkynols 9a:



Other arylalk ynols 9b-9d:

a

Standard procedure: The homopropargylic amines 6 (0.3 mmol, 1.5 equiv.) and alkynols 9 (0.2

mmol), PtCl2 (2.7 mg, 0.01 mmol, 5 mol%) and FeCl3 (1.6 mg, 0.01mmol, 5 mol%) as well as toluene (2 mL) were sequentially added into the reaction tube. The reaction mixture was stirred at 50 o C for 12 h in the air;

b

Isolated yield and the diastereoisomers ratios were determined by the 1 H NMR; c The

product was self-dimerization of homopropargylic amine and the yield was counted according to the amount of homopropargylic amine.


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Since the isobenzofuran with exocyclic double bond generated from arylalkynol 9 can isomerize to 1- methylisobenzofuran, which may act as diene, we atte mpted to introduce dienophiles. The N-phenylmaleimide sa was first selected to react with the 1-(2-ethynylphenyl)ethan-1-ol 9f. As shown in Table 3, the reaction of 9f and sa (1.2 equiv.) was complicated in toluene at 50 o C with the prolonging reaction time for 4 h in the presence of 5 mol% PtI2 (Table 3, entry 1). To our delight, the expected bridged- isobenzofuran-polycycle was obtained with 55 % yield at elevating 80 o C (entry 2). Further increasing the reaction temperature to 110 o C, slightly improved yield of target molecule was generated (entry 3). Nevertheless, the reaction was messy at 130 o C in anisole (entry 4). Other solvents were then examined at 110 o C with PtI2 catalyst, no obvious improved results were obtained (entries 5-10). Adjusting the amount of the sa from 1.2 equiv. to 1.5 equiv., the product 11fa was given in increased yield of 79% (entry 11). Changing the PtI2 to PtCl2 , the reaction could also smoothly proceed with slightly decreased yield of 11fa (entry 12). The common used AuCl3 and AuCl catalysts were also investigated and the reaction was complicated with no target compound. Notably, the endo-11fa was generated as a major prodcuct in all above cases. Therefore, the optimal reaction conditions were as follows: arylalkynols 9 1.0 equiv., dienophiles 1.5 equiv., 5 mol% PtI2 , toluene (0.4 M), 110 o C for about 2 h.



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Table 3. The experimental parameters screening on the hydroalkoxylation cascade reactions of 1-(2-ethynylphenyl)ethan-1-ol 9f and N-phenylmaleimide saa

Entry

o sa (equiv.) T( C)

Solv.

1

H NMR Yield (%)[b]

1

1.2

50

toluene

complicated

2

1.2

80

toluene

55

3

1.2

110

toluene

61

4

1.2

130

anisole

complicated

5

1.2

110

anisole

48

6

1.2

110

DMF

37

7

1.2

110

1,4-dioxane

44

8

1.2

110

THF

51

9

1.2

110

MeCN

47

10

1.2

110

DCM

56

11

1.5

110

toluene

79

1.5

110

toluene

72

12

[c]


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a

Standard

procedure:

The

1-(2-ethynylphenyl)ethan-1-ol

9f

(29

mg,

0.2

mmol)

and

N-phenylmaleimide (given amount), PtI2 (2.7 mg, 0.01 mmol, 5 mol%) and solvent (0.5 mL) were sequentially added into the reaction tube. The reaction mixture was stirred under given conditions for 2 h in the air; b 1 H NMR yield of crude product using benzylbromide as an internal standard sample.

c

The catalyst was PtCl2 (5 mol%).

With the optimized reaction conditions in hand, we examined the scope of this cascade reaction with various arylalkynols and dienophiles. The results were shown in Table 4. Both electron withdrawing and electron donating substituents on the alkynols bearing aromatic ring proceeded smoothly under the standard reaction conditions and afforded the correspongding products in 72-81% yields (11aa-11da). Moreover, the large steric hindrance naphthylalkynol was also competent with N-phenylmaleimide in this reaction (11ea). Additionally, in the cases of 1-(2-ethynylphenyl)ethan-1-ol 9f, various N-alkyl- or aryl- substituted maleimides delivered the bridged heteropolycycles in 55-79% yields (11fa-11fd). Employing other dienophiles, such as quinone, benzoquinone, maleic anhydride and diethyl but-2-ynedioate, these reactions could also afford the polycycles in good yields with excellent diastereoselectivities (11fe-11fh). For the 11ga, the allenyl group

of

the

allenylalkynol

remained

untouched

in

this

hydroalkoxylation

cyclization-[4+2]-cycloaddition cascade reaction. The absolute configuration was



Page 16 of 55

unambiguously determined by the single-crystal X-ray diffraction of endo-11ga (Figure 2).10

Table

4.

The

hydroalkoxylation

cascade

reactions

of

a,b

electron-deficient olefins


various

arylalkynols

9

and

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a

Standard procedure: The arylalkynols 9 (0.4 mmol) and dienophiles (0.6 mmol, 1.5 equiv.), PtI2 (2.7

mg, 0.01 mmol, 5 mol%) and toluene (1 mL) were sequentially added into the reaction tube. The reaction mixture was stirred under given conditions for 2 h in the air; b Isolated yield.

Figure 2. The ORTEP drawing (30% thermal elli psoi ds) of endo-11ga

The gram scale of these two divergent cascade reactions between the aryalkynols and homopropargylic amines or dienophiles were then investigated. As shown in Scheme 2, the spiro-cyclic compound 10da and the bridge-cyclic mixture of 11fa and 11fa’ could be obtained in 61% and 72% yield, respectively.



Scheme 2. The gram scale of these two di vergent cascade reactions

In addition, the bridged polycyclic compounds 11 could be easily transformed to the multi-susbtituted naphthene derivatives 12 with high yields (86-91%) in the presence of Cu(OTf)2 (Table 5).

Table 5. The transformation of bridged polycycles


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Based on the previous literatures about the arylalkynols 3-6 and combined with our developed methodologies about the homopropargylic amines 8 , the possible mechanisms of these two reactions were proposed (Scheme 3). Herein, the PtCl2 mainly catalyzed the intramolecular hydroalkoxylation cyclization of the arylalkynol 9a to render the isobenzofuran intermediate III (red), and the FeCl3 preferred to catalyze the intramolecular hydroamination cyclization of homopropargylic amine 6a and followed by the protonation in the presence of trace protonic acid to give the cycloiminium ion intermediate VII. The intermediate III (red) attacked the intermediate VII to give the final product 10aa via two steps of nucleophilic addition (VII-VIII) and proton elimination processes (VIII-IX). On the other hand, the intermediate III could easily isomerize to intermediate X (blue) through the 1,5-hydrogen shift, which was followed by the normal [4+2]-cycloaddition reaction in the presence of the high reactive dienophile sa to afford the bridge-cyclic compounds 11aa and 11aa’.



Scheme 3. The possible mechanisms of these two cascade reacti ons

CONCLUSION In conclusion, the divergent cascade reactions of arylalkynols and homopropargylic amines or dienophiles were developed in the presence of PtCl2 /FeCl3 cocatalysts or PtI2 . The arylalkynols performed the intramolecular hydroalkoxylation cyclization to deliver the isobenzofurans with exocyclic double bond, which could undergo nontypical Povarov reactions with the homopropargylic amines. And the isobenzofurans can isomerize to the 1-methylisobenzofurans to act as electron-rich dienes to further react with dienophiles via normal Diels-Alder cycloaddition process. In the former, the cascade reaction actually


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involves intramolecualr hydroalkoxylation cyclization of arylalkynols and intramolecular hydroamination cyclization-protonation of homopropargylic amines as well as subsequent Povarov-type reaction. These four steps were highly efficiently achieved in one pot and four new bonds were formed, concomitant with two new stereocenters. Thus the complex spiroisobenzofuran-pyrrolo-b-quinolines fused heteropolycycles were facilely constructed. Whereas in the latter, the intramolecular hydroalkoxylation cycloisomerization of arylalkynols and [4+2]-cycloaddition processes were involved, and consequently a bridged isobenzofuran polycycles were produced with four new bonds and three new stereocenters formed in one pot. These two methodologies provide simple and highly efficient strategy for the construction of complex heteropolycyclic compounds. Further research on the synthesis of the bioactive natural products or pharmaceutical intermediates is our ongoing work.

EXPERIMENTAL SECTION 1. General Information The 1 H NMR,

13

C NMR and DEPT (Distortionless Enhancement by Polarization

Transfer) as well as HMQC (Heteronuclear Multiple Quantum Correlation) and HMBC (Heteronuclear Multiple Bond Correlation) spectra were recorded at Bruker AV 400 MHz or 600 MHz. 1 H and 13 C NMR Chemical shifts were calibrated to tetramethylsilane as an internal reference. Chemical shifts are given in (ppm) and coupling constants (J) in



Hz. The following abbreviations are used to indicate the multiplicity: s, singlet; d, doublet: t, triplet; q, quartet; m, multiplet; Infrared spectra were recorded on an Bruker Fourier transform spectrometer (FT-IR) and are reported in wave numbers. High resolution mass spectrometric (HRMS) analyses spectrum was determined on the Varian 7.0T FTMS instrument (Fourier transform ion cyclotron resonance, FTICR). 2. Synthesis and characte rization (1) Synthesis and characterization of the Imines 8d,8f A dried round-bottom flask was charged with aromatic aldehydes (20 mmol), the appropriate anilines (20 mmol), 4Å molecular sieves (1g/1.0mmol aldehyde) and dichloromethane. The reaction mixture was stirred at room temperature and traced by TLC until the reaction finished. Then the mixture was filtered and the filtrate was concentrated underreduced pressure, gave the pure imines without additional purification. (E)-N-(2-bromo-4-fluorobenzylidene)-4-methylaniline: Yellow solid; 5.8 g, yield 99%; 1

H NMR (400 MHz, Chloroform-d) δ 8.72 (s, 1H), 8.18 (dd, J = 8.8, 6.3 Hz, 1H), 7.23

(dd, J = 8.1, 2.6 Hz, 1H), 7.17 – 7.09 (m, 4H), 7.01 (td, J = 8.3, 2.6 Hz, 1H), 2.32 (s, 3H); 13

C NMR (101 MHz, CDCl3 ) δ 165.2, 162.6, 156.7, 148.9, 136.4, 131.29, 131.26, 130.6,

130.5, 129.9, 126.3, 126.18, 121.19, 120.4, 120.1, 115.5, 115.2, 21.1. (2) Synthesis and characterization of homopropargylic amines (6a-6p)8d,8f The homopropargylic amines (6a-6p) were prepared according to the known procedures. Among them, the 6g and 6h were unknown compounds.


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An aluminum amalgam was prepared from aluminum powder (0.5 g, 18.0 mmol) and a catalytic amount of mercuric chloride (10 mg) in 7.5 mL anhydrous THF by vigorously stirring at room temperature for 1 h under a N 2 atmosphere. A solution of propargylic bromide (18.0 mmol) in 12.5 mL of anhydrous THF was then slowly added to the suspension at such a rate as to maintain the temperature between 30-40 o C. After the addition, the reaction mixture was continued to stir until a dark grey solution formed. The generated propargylic aluminum sesqui-bromide solution was added to a solution of imine (6.0 mmol) in 20.0 mL of anhydrous THF at 0 o C under N 2 atmosphere. The reaction mixture was stirred at 0 o C for about 1 h, then warmed to room temperature and continued to stir for additional 3-4 h (monitored by TLC). The mixture was quenched by adding saturated NH4 Cl aqueous solution, and extracted with EtOAc (3 × 20 mL). The combined organic extracts were washed with brine and dried over MgSO 4 , and then filtered, the filtration was concentrated in vacuo to give the residue. The residue was purified by flash chromatography over silica gel (gradient elution of EtOAc/petroleum ether, PE : EA = 50 : 1). 4-methyl-N-(1-(m-tolyl)but-3-yn-1-yl)aniline (6g): Yellow oil; 1.03 g, yield 69%; 1 H NMR (400 MHz, Chloroform-d) δ 7.11 (s, 3H), 6.98 (d, J = 6.1 Hz, 1H), 6.84 (d, J = 8.2 Hz, 2H), 6.40 (d, J = 8.2 Hz, 2H), 4.37 (t, J = 6.2 Hz, 1H), 4.18 (s, 1H), 2.71 – 2.48 (m, 2H), 2.25 (s, 3H), 2.11 (s, 3H), 1.96 (t, J = 2.2 Hz, 1H). 13 C NMR (101 MHz, CDCl3 ) δ 145.1, 142.6, 138.4, 129.8, 128.7, 128.46, 127.23, 127.17, 123.6, 114.1, 80.8, 71.4, 57.0,



Page 24 of 55

28.3, 21.8, 20.6. HRMS (ESI-FT-ICR) m/z: [M + H]+ Calcd for C18 H20N 250.1596; found 250.1601. N-(1-(2-bromo-4-fluorophenyl)but-3-yn-1-yl)-4-methylaniline (6h): Yellow solid; 1.44 g, yield 72%; m.p. 52-54 o C; 1 H NMR (400 MHz, Chloroform-d) δ 7.45 (dd, J = 8.7, 6.1 Hz, 1H), 7.31 (dd, J = 8.1, 2.6 Hz, 1H), 6.96 (dd, J = 8.3, 2.5 Hz, 1H), 6.94 – 6.89 (m, 2H), 6.37 (d, J = 8.4 Hz, 2H), 4.85 (s, 1H), 4.44 (s, 1H), 2.85 (ddd, J = 17.0, 4.5, 2.7 Hz, 1H), 2.60 (ddd, J = 17.0, 6.6, 2.6 Hz, 1H), 2.19 (s, 3H), 2.08 (t, J = 2.6 Hz, 1H);

13

C

NMR (101 MHz, CDCl3 ) δ 163.0, 160.6, 144.1, 136.4, 136.3, 130.0, 129.43, 129.35, 127.6, 122.9, 122.8, 120.5, 120.2, 115.2, 115.0, 113.9, 79.7, 72.2, 54.7, 26.1, 20.6. HRMS (ESI-FT-ICR) m/z: [M + H]+ Calcd for C17 H16 BrFN 332.0450; found 332.0442. (3) Synthesis and characterization of homopropargylic amines (6o)11 The N-(but-3-yn-1-yl)aniline 6o were prepared according to the known procedures. To a solution of but-3-yn-1-ol (10 mmol, 700 mg) in DCM (30 mL) at 0 ºC was added Et3 N (20 mmol, 2. 8mL) and TsCl (13 mmol, 2.478 g). The solution was slowly warmed to room temperature and stirred for overnight. Then saturated NaHCO 3 aqueous solution was added and extracted several times with DCM. The combined organic layers were dried over Na2 SO 4 and concentrated under reduced pressure. Purification by flash chromatography (10:1

hexanes/EtOAc) provided a colorless oil but-3-yn-1-yl

4-methylbenzenesulfonate (1.90 g, 90%).


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To a solution of anilines (12.0 mmol), p-toluenesulfonate derivatives (8.0 mmol) and KI (132 mg, 0.8 mmol) in DMF (20 mL) was added K 2 CO3 (3.3 g, 24.0 mmol). The mixture was heated to 90 °C. After complete consumption of the p-toluenesulfonate derivatives, the reaction mixture was cooled to room temperature and quenched with a saturated solution of NH4 Cl. EtOAc was used to extract the product from the aqueous layer (3 × 60 mL). The combined organic layer was washed with water (3 × 50 mL), dried over Na2 SO 4 , filtered and concentrated to afford the crude product, which was purified by flash column chromatography to afford the product in moderate yield as yellow oil 6o (765 mg, 66%). (4) Synthesis and characterization of the arylalkynols (9a-9f)12 To a solution of 2-bromobenzaldehyde or its derivatives (20 mmol, 1 equiv.), PdCl2 (PPh3 )2 (702.0 mg, 5 mol%), and CuI (76.0 mg, 2 mol%) in NEt3 (40.0 mL) was added under N2 atmosphere. After being stirred for 10 min at room temperature, terminal acetylene (1.5 equiv.) was added to the mixture. The resulting mixture was heated under N 2 atmosphere at 50 °C for 6-18 hours. After the reaction was completed, the reaction mixture was quenched with distilled water and extracted with CH2 Cl2 (three times). The combined organic layer was washed with brine, dried over MgSO 4 , and concentrated in vacuo. The residue was purified by column chromatography on silica gel to afford the desired product 2-((trimethylsilyl)ethynyl)benzaldehyde derivatives S1. The 2-((trimethylsilyl)ethynyl)benzaldehyde derivatives (1.0 equiv.) was dissolved in



the mixture solution of MeOH, and treated with K 2 CO3 (2.0 equiv.). After stirring at ambient temperature for 2 h, the mixture was diluted with Et2 O, partitioned with H2 O, dried over Na2 SO 4 and concentrated in vacuo, purified by flash column chromatography to give the arylalkynyl benzaldehyde derivatives product S2. The arylalkynyl benzaldehyde derivatives (1.0 equiv.) was added to round-bottomed flask and dissolved by MeOH. At 0℃, NaBH4 (2.0 equiv.) was added to the flask in batches. After 30 minutes, the mixture was quenched with saturated NH4 Cl aqueous solution, and then was washed three times with brine, dried over MgSO 4 , and concentrated in vacuo. The residue was purified by column chromatography on silica gel to afford the desired product 9. (2-ethynylphenyl)methanol (9a) (purified by column chromatography over silica gel treated with petroleum ether/EtOAc (5:1)): Yellowish solid;1.8 g, yield 68%; m.p. 64-66 o

C; 1 H NMR (400 MHz, Chloroform-d) δ 7.48 (d, J = 7.6 Hz, 1H), 7.42 (d, J = 7.7 Hz,

1H), 7.35 (td, J = 7.6, 3.8 Hz, 1H), 7.28 – 7.19 (m, 1H), 4.80 (s, 2H), 3.32 (d, J = 1.6 Hz, 1H), 2.46 (s, 1H);

13

C NMR (101 MHz, CDCl3 ) δ 143.4, 133.0, 129.4, 127.6, 127.4,

120.3, 82.2, 81.5, 63.8; HRMS (ESI-FT-ICR) m/z: [M + H]+ Calcd for C9 H9 O 133.0653, found 133.0659. (2-ethynyl-4-methoxyphenyl)methanol (9b) (purified by column chromatography over silica gel treated with petroleum ether/EtOAc (3:1)): Red solid; 2.4 g, yield 74%; m.p. 71-73 o C; 1 H NMR (400 MHz, Chloroform-d) δ 7.31 (dd, J = 8.5, 1.8 Hz, 1H), 7.01 (t, J =


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2.3 Hz, 1H), 6.89 (dt, J = 8.6, 2.3 Hz, 1H), 4.73 (d, J = 1.9 Hz, 2H), 3.78 (d, J = 1.9 Hz, 3H), 3.31 (d, J = 1.8 Hz, 1H), 2.34 (s, 1H); 13 C NMR (101 MHz, CDCl3 ) δ 135.8, 129.3, 117.8, 113.3, 110.2, 81.7, 81.5, 63.4, 55.6; HRMS (ESI-FT-ICR) m/z: [M + H]+ Calcd for C10 H11 O2 163.0759, found 163.0755. (2-ethynyl-4-methylphenyl)methanol (9c) (purified by column chromatography over silica gel treated with petroleum ether/EtOAc (5:1)): Yellow solid; 2 g, yield 68%; m.p. 60-62 o C; 1 H NMR (400 MHz, Chloroform-d) δ 7.35 – 7.28 (m, 2H), 7.16 (d, J = 8.0 Hz, 1H), 4.77 (s, 2H), 3.29 (d, J = 2.0 Hz, 1H), 2.32 (s, 3H), 2.22 (s, 1H);

13

C NMR (101

MHz, CDCl3 ) δ 140.5 , 133.6 , 130.3 , 127.7 , 120.34 , 81.71 , 81.66 , 63.8 , 21.1. HRMS (ESI-FT-ICR) m/z: [M + H]+ Cacld for C10 H11 O 147.0810, found 147.0811. (2-ethynyl-5-fluorophenyl)methanol (9d) (purified by column chromatography over silica gel treated with petroleum ether/EtOAc (5:1)): Yellow solid; 2.3 g, yield 77%; m.p. 59-61o C; 1 H NMR (400 MHz, Chloroform-d) δ 7.46 (dd, J = 8.4, 5.5 Hz, 1H), 7.20 (dd, J = 9.4, 2.7 Hz, 1H), 6.93 (td, J = 8.4, 2.7 Hz, 1H), 4.81 (s, 2H), 3.30 (s, 1H), 2.36 (s, 1H); 13

C NMR (101 MHz, CDCl3 ) δ 164.5, 162.0, 146.5, 146.4, 134.9, 134.8, 115.92, 115.88,

114.7, 114.48, 114.46, 114.2, 82.02, 82.00, 80.4, 63.3, 29.9, 23.3; HRMS (ESI-FT-ICR) m/z: [M + H]+ Cacld for C9 H8 FO 151.0559, found 151.0561. (1-ethynylnaphthalen-2-yl)methanol (9e) (purified by column chromatography over silica gel treated with petroleum ether/EtOAc (5:1)): Yellow solid; 2.5 g, yield 69%; m.p. 87-89 o C; 1 H NMR (400 MHz, Chloroform-d) δ 8.28 (d, J = 8.3 Hz, 1H), 7.79 – 7.73 (m,



2H), 7.54 – 7.47 (m, 2H), 7.43 (ddd, J = 8.1, 6.9, 1.2 Hz, 1H), 4.96 (s, 2H), 3.67 (s, 1H), 2.10 (s, 1H); 13 C NMR (101 MHz, CDCl3 ) δ 142.6, 133.8, 132.7, 129.6, 128.4, 127.4, 126.6, 126.2, 125.3, 117.4, 87.59, 79.5, 64.4; HRMS (ESI-FT-ICR) m/z: [M + H]+ Cacld for C13 H11 O 183.0810, found 183.0822. 1-(2-ethynylphenyl)ethanol (9f) (purified by column chromatography over silica gel treated with petroleum ether/EtOAc (5:1)): Yellow liquid; 2.1 g, yield 72%; 1 H NMR (400 MHz, Chloroform-d) δ 7.46 (dd, J = 7.9, 1.3 Hz, 1H), 7.39 (dd, J = 7.6, 1.4 Hz, 1H), 7.33 – 7.26 (m, 1H), 7.19 – 7.10 (m, 1H), 5.26 (q, J = 6.5 Hz, 1H), 3.25 (s, 1H), 1.44 (d, J = 6.5 Hz, 3H); 13 C NMR (101 MHz, CDCl3 ) δ 148.4, 133.0, 129.5, 127.1, 124.9, 119.3, 82.3, 81.6, 68.3, 24.2; HRMS (ESI-FT-ICR) m/z: [M + H]+ Cacld for C10 H11 O 147.0810, found 147.0817. (5) The synthesis of allenynol 9g13 A saturated aqueous solution of ammonium chloride (10.5 mL) was added to a methanolic (33 mL) solution of 1-bromo-2-butyne (2.593 g, 19.5 mmol, 1.3 equiv.) and the 2-ethynylbenzaldehyde (1.952 g, 15 mmol, 1.0 equiv.), and the solution was cooled to 0 °C. Indium powder (100 mesh) (1.894 g, 16.5 mmol, 1.1 equiv.) was added in four portions (over 20 min), and the mixture was stirred vigorously until completion of the reaction (1 h) as evidenced by TLC. The mixture was diluted with an equal volume of Et2 O, and this was washed with brine. The brine was re-extracted with Et2 O. The combined extracts were dried with anhydrous MgSO 4 and concentrated. Column


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chromatography (SiO 2 ) of the residue was carried out with PE/EA (20:1) to afford the disired allenynol 9g as a yellow oil, 1.6 g, yield 68%. 1-(2-ethynylphenyl)-2-methylbuta-2,3-dien-1-ol

(9g)

(purified

by

column

chromatography over silica gel treated with petroleum ether/EtOAc (5:1)): Yellow oil; 1.6 g, yield 68%; 1 H NMR (400 MHz, Chloroform-d) δ 7.48 (ddd, J = 7.8, 4.4, 1.3 Hz, 2H), 7.36 (td, J = 7.7, 1.4 Hz, 1H), 7.24 (td, J = 7.5, 1.3 Hz, 1H), 5.57 (t, J = 2.8 Hz, 1H), 4.87 (dq, J = 5.1, 3.2 Hz, 2H), 3.31 (s, 1H), 2.46 (s, 1H), 1.62 (t, J = 3.2 Hz, 3H);

13

C

NMR (101 MHz, CDCl3 ) δ 205.3, 144.7, 133.2, 129.3, 127.7, 126.8, 120.8, 102.8, 82.4, 81.9, 78.4, 72.4, 15.3; HRMS (ESI-FT-ICR) m/z: [M + H]+ Cacld for C13 H13 O 185.0966, found 185.0961. (6) The characterization of products 10 1'-phenyl-2',3',3a',4'-tetrahydro-1'H,3H-spiro[isobenzofuran-1,5'-pyrrolo[1,2-a]qui noline] (10aa) (purified by column chromatography over silica gel treated with petroleum ether/EtOAc (100:1)): Yellowish solid; 40.8 mg, yield 58%; dr = 10.4:1.6:1; m.p. 85-87 o C. 1 H NMR (400 MHz, Chloroform-d) δ 7.39 – 7.17 (m, 10.23H), 7.16 – 7.05 (m, 1.51H), 6.96 (t, J = 7.7 Hz, 1.13H), 6.86 – 6.71 (m, 1.18H), 6.49 (dd, J = 7.6, 1.5 Hz, 1.05H), 6.43 (d, J = 12.3 Hz, 0.17H), 6.31 (t, J = 7.3 Hz, 0.91H), 6.16 – 6.02 (m, 1.17H), 5.30 – 5.21 (m, 0.59H), 5.20 – 5.06 (m, 1.96H), 4.76 (t, J = 7.4 Hz, 1.04H), 4.63 (s, 0.22H), 4.23 (dddd, J = 12.4, 9.0, 5.7, 3.6 Hz, 0.97H), 4.13 (ddt, J = 12.4, 9.5, 4.6 Hz, 0.16H), 3.92 – 3.81 (m, 0.09H), 2.52 (dtd, J = 11.2, 7.6, 3.5 Hz, 1.16H), 2.24 – 2.13 (m,



2.10H), 2.07 (dq, J = 10.1, 4.9 Hz, 0.23H), 1.96 – 1.75 (m, 2.72H), 1.58 (ddd, J = 19.1, 10.9, 8.2 Hz, 1.40H); 13 C NMR (101 MHz, CDCl3 ) δ 149.1, 144.9, 144.7, 144.5, 143.4, 142.9, 140.7, 138.3, 129.4, 128.9, 128.7, 128.7, 128.6, 128.5, 127.9, 127.7, 127.5, 126.9, 126.8, 126.3, 125.7, 125.3, 123.4, 123.0, 122.5, 121.1, 116.3, 115.0, 112.5, 112.3, 86.8, 86.3, 71.7, 71.0, 64.0, 61.6, 56.4, 54.9, 40.6, 36.3, 34.9, 32.5, 30.1. HRMS (ESI-FT-ICR) m/z: [M + H]+ Cacld for C25 H24NO 354.1858; found 354.1858. 7'-fluoro-1'-phe nyl-2',3',3a',4'-tetrahydro-1'H,3H-spiro[isobenzofuran-1,5'-pyrrolo[ 1,2-a]quinoline] (10ba) (purified by column chromatography over silica gel treated with petroleum ether/EtOAc (150:1)): Yellowish solid; 50.1 mg, yield 67%; dr = 11.4:3.1:1; m.p. 88-90 o C. 1 H NMR (400 MHz, Chloroform-d) δ 7.35 – 7.12 (m, 11.52H), 7.09 – 6.91 (m, 1.52H), 6.75 – 6.67 (m, 0.15H), 6.61 – 6.45 (m, 1.37H), 6.26 (ddd, J = 23.6, 9.6, 3.0 Hz, 1.14H), 6.08 – 5.91 (m, 1.37H), 5.33 – 5.07 (m, 2.84H), 4.76 – 4.53 (m, 1.40H), 4.27 – 4.16 (m, 1H), 4.14 (d, J = 9.8 Hz, 0.09H), 3.90 – 3.72 (m, 0.28H), 2.53 (dtd, J = 12.7, 7.6, 3.6 Hz, 1.15H), 2.45 – 2.30 (m, 0.62H), 2.27 – 2.06 (m, 2.48H), 2.05 – 1.89 (m, 0.60H), 1.88 – 1.75 (m, 2.56H), 1.73 – 1.66 (m, 0.29H), 1.59 (ddt, J = 11.9, 9.8, 7.7 Hz, 1.26H); 13 C NMR (101 MHz, CDCl3 ) δ 155.4, 153.1, 144.9, 144.2, 140.6, 140.1, 129.2, 129.0, 128.9, 128.8, 128.2, 128.1, 128.0, 127.8, 127.6, 127.1, 126.9, 126.4, 126.2, 125.8, 125.6, 123.92, 123.86, 122.5, 121.3, 121.2, 116.1, 115.9, 115.1, 115.0, 114.9, 112.9, 112.8, 86.2, 71.2, 71.1, 65.5, 64.5, 62.1, 56.6, 56.1, 54.9, 41.9, 40.6, 38.6, 36.3, 34.9, 32.4,


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29.9. HRMS (ESI-FT-ICR) m/z: [M + H]+ Cacld for C25 H23FNO 372.1764; found: 372.1765. 7'-chloro-1'-phenyl-2',3',3a',4'-tetrahydro-1'H,3H-spiro[isobenzofuran-1,5'-pyrrolo[ 1,2-a]quinoline] (10ca) (purified by column chromatography over silica gel treated with petroleum ether/EtOAc (150:1)): White solid; 69.0 mg, yield 89%; dr = 6.5:2.1:1; m.p. 84-86 o C. 1 H NMR (400 MHz, Chloroform-d) δ 7.34 – 7.20 (m, 7.88H), 7.20 – 7.11 (m, 4.72H), 7.04 (d, J = 7.6 Hz, 0.30H), 7.02 – 6.97 (m, 0.25H), 6.97 – 6.91 (m, 1.20H), 6.75 (dd, J = 8.8, 2.6 Hz, 1.19H), 6.70 (dd, J = 8.8, 2.6 Hz, 0.21H), 6.51 (d, J = 2.5 Hz, 0.14H), 6.44 (d, J = 2.5 Hz, 0.89H), 6.02 (d, J = 8.8 Hz, 1.21H), 5.94 (d, J = 8.8 Hz, 0.21H), 5.36 – 5.01 (m, 3.05H), 4.78 – 4.52 (m, 1.54H), 4.29 – 4.15 (m, 1H), 4.15 – 4.04 (m, 0.15H), 3.84 (dddd, J = 23.1, 12.6, 4.6, 2.2 Hz, 0.33H), 2.53 (dtd, J = 12.7, 7.5, 3.0 Hz, 1.18H), 2.43 – 2.27 (m, 0.78H), 2.19 (ddq, J = 15.2, 12.2, 3.1 Hz, 2.36H), 2.11 – 1.90 (m, 0.68H), 1.86 – 1.76 (m, 2.49H), 1.69 (ddd, J = 12.5, 10.5, 7.0 Hz, 0.45H), 1.58 (tdd, J = 11.7, 9.9, 7.3 Hz, 1.37H);

13

C NMR (101 MHz, CDCl3 ) δ 144.8, 144.7, 144.5, 144.4, 143.94,

143.89, 142.6, 142.1, 141.4, 140.5, 138.3, 129.4, 129.20, 129.16, 129.1, 128.9, 128.8, 128.5, 128.34, 128.25, 128.1, 128.0, 127.8, 127.7, 127.6, 127.2, 127.12, 127.09, 127.0, 126.3, 126.1, 125.7, 125.5, 124.6, 123.4, 122.9, 122.5, 121.5, 121.3, 121.2, 119.7, 113.8, 113.4, 112.9, 86.5, 86.0, 72.0, 71.9, 71.2, 71.1, 65.1, 64.2, 62.0, 61.8, 56.6, 56.3, 55.8, 55.0, 41.7, 40.5, 40.1, 38.5, 37.3, 36.4, 34.9, 33.6, 32.5, 30.0, 29.8, 27.1. HRMS (ESI-FT-ICR) m/z: [M + H]+ Calcd for C25 H23 ClNO 388.1468; found 388.1464.



7'-bromo-1'-phenyl-2',3',3a',4'-tetrahydro-1'H,3H-spiro[isobenzofuran-1,5'-pyrrolo[ 1,2-a]quinoline] (10da) (purified by column chromatography over silica gel treated with petroleum ether/EtOAc (150:1)): White solid; 65.8 mg, yield 76%; dr = 11:1; m.p. 93-95 o

C. 1 H NMR (400 MHz, Chloroform-d) δ 7.39 – 7.32 (m, 2.13H), 7.31 – 7.17 (m, 3.51H),

7.12 – 7.04 (m, 2.14H), 6.96 (d, J = 7.4 Hz, 1.09H), 6.85 (ddd, J = 8.6, 7.2, 1.7 Hz, 1.06H), 6.50 (dd, J = 7.6, 1.7 Hz, 1.09H), 6.34 (td, J = 7.4, 1.1 Hz, 0.95H), 6.06 (dd, J = 8.3, 1.1 Hz, 1.02H), 5.22 – 5.06 (m, 1.99H), 4.72 (t, J = 7.4 Hz, 1.06H), 4.29 – 4.15 (m, 1H), 3.92 – 3.79 (m, 0.09H), 2.53 (dtd, J = 12.7, 7.6, 3.5 Hz, 1.02H), 2.34 (dd, J = 12.5, 2.2 Hz, 0.25H), 2.19 (tdd, J = 12.2, 6.9, 3.6 Hz, 2.06H), 1.90 – 1.69 (m, 2.23H), 1.60 (dddd, J = 11.9, 10.3, 8.8, 7.3 Hz, 1.14H); 13 C NMR (101 MHz, CDCl3 ) δ 144.6, 144.1, 143.3, 140.7, 132.0, 129.5, 128.7, 128.0, 127.8, 127.6, 123.2, 122.6, 121.2, 120.4, 115.3, 112.23, 112.20, 86.3, 71.0, 63.6, 54.9, 40.6, 36.2, 32.5. HRMS (ESI-FT-ICR) m/z: [M + H]+ Cacld for C25 H23 BrNO 432.0963; found 432.0968. 7'-methyl-1'-phenyl-2',3',3a',4'-tetrahydro-1'H,3H-spiro[isobenzofuran-1,5'-pyrrolo [1,2-a]quinoline] (10ea) (purified by column chromatography over silica gel treated with petroleum ether/EtOAc (100:1)): Yellowish solid; 48.4 mg, yield 66%; dr = 15:1:1; m.p. 82-84 o C. 1 H NMR (400 MHz, Chloroform-d) δ 7.32 – 7.16 (m, 8.25H), 7.16 – 7.08 (m, 1.47H), 6.96 (d, J = 7.3 Hz, 1.01H), 6.78 (s, 0.08H), 6.65 (dd, J = 8.3, 2.2 Hz, 1.12H), 6.32 (d, J = 2.1 Hz, 0.94H), 6.03 (d, J = 8.3 Hz, 1.10H), 5.34 – 5.06 (m, 2.36H), 4.80 – 4.55 (m, 1.17H), 4.29 – 4.16 (m, 1.02H), 4.12 (ddt, J = 14.0, 9.5, 4.6 Hz, 0.07H), 3.87 –


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3.72 (m, 0.07H), 2.51 (dtd, J = 12.7, 7.6, 3.7 Hz, 1.12H), 2.17 (tq, J = 12.1, 3.8, 3.4 Hz, 2.42H), 2.03 (s, 0.20H), 1.97 (s, 0.21H), 1.93 (s, 2.95H), 1.87 – 1.72 (m, 2.32H), 1.57 (ddt, J = 11.9, 9.8, 7.6 Hz, 1.48H); 13 C NMR (101 MHz, CDCl3 ) δ 144.3, 143.9, 140.4, 139.7, 129.1, 128.1, 128.0, 127.9, 126.9, 126.7, 125.7, 124.8, 122.9, 121.9, 121.6, 120.2, 111.4, 85.5, 70.0, 63.2, 53.9, 40.0, 35.3, 31.5, 19.5. HRMS (ESI-FT-ICR) m/z: [M + H]+ Calcad for C26 H26NO 368.2014; found 368.2016. 7'-methyl-1'-(p-tolyl)-2',3',3a',4'-tetrahydro-1'H,3H-s piro[isobenzofuran-1,5'-pyrrol o[1,2-a]quinoline] (10fa) (purified by column chromatography over silica gel treated with petroleum ether/EtOAc (100:1)): Yelowish solid; 45.7 mg, yield 60%; dr = 11:2:1; m.p. 83-85 o C. 1 H NMR (400 MHz, Chloroform-d) δ 7.30 – 7.14 (m, 4.55H), 7.13 – 7.06 (m, 2.61H), 7.03 (d, J = 8.1 Hz, 2.43H), 6.96 (d, J = 7.3 Hz, 1.08H), 6.78 (d, J = 2.3 Hz, 0.15H), 6.65 (td, J = 7.2, 6.0, 2.1 Hz, 1.23H), 6.31 (d, J = 2.1 Hz, 1H), 6.07 (t, J = 8.7 Hz, 1.25H), 5.35 – 5.04 (m, 2.59H), 4.75 – 4.53 (m, 1.28H), 4.26 – 4.15 (m, 0.99H), 4.10 (ddt, J = 14.0, 9.5, 4.5 Hz, 0.18H), 3.80 (d, J = 11.4 Hz, 0.09H), 2.50 (tdd, J = 11.7, 8.1, 5.2 Hz, 1.27H), 2.27 (s, 0.52H), 2.24 (s, 3.26H), 2.16 (ddq, J = 14.4, 10.8, 3.6 Hz, 2.52H), 2.03 (s, 0.51H), 1.97 (s, 0.34H), 1.93 (s, 2.96H), 1.86 – 1.71 (m, 2.58H), 1.62 – 1.50 (m, 1.37H); 13 C NMR (101 MHz, CDCl3 ) δ 145.0, 142.2, 141.5, 140.7, 136.2, 130.1, 129.8, 129.6, 129.0, 127.9, 127.7, 125.8, 125.6, 123.8, 122.8, 122.7, 121.1, 112.4, 86.5, 77.6, 77.5, 77.3, 76.9, 71.0, 64.0, 54.8, 41.0, 36.3, 32.4, 27.1, 21.4, 21.3, 20.5. HRMS (ESI-FT-ICR) m/z: [M + H]+ Cacld for C27 H28 NO 382.2171; found 382.2181.



7'-methyl-1'-(m-tolyl)-2',3',3a',4'-tetrahydro-1'H,3H-spiro[isobenzofuran-1,5'-pyrro lo[1,2-a]quinoline] (10ga) (purified by column chromatography over silica gel treated with petroleum ether/EtOAc (100:1)): Yellowish solid; 45.9 mg, yield 60%; dr = 11.4:2:1; m.p. 83-85 o C. 1 H NMR (400 MHz, Chloroform-d) δ 7.35 – 7.15 (m, 4H), 7.14 – 7.07 (m, 2H), 7.07 – 6.90 (m, 4H), 6.72 – 6.57 (m, 1H), 6.32 (d, J = 2.1 Hz, 1H), 6.14 – 5.95 (m, 1H), 5.35 – 5.07 (m, 3H), 4.69 (t, J = 7.2 Hz, 1H), 4.22 (dddt, J = 12.2, 9.0, 5.9, 3.4 Hz, 1H), 4.12 (ddt, J = 17.1, 9.6, 4.4 Hz, 0H), 3.85 – 3.75 (m, 0H), 2.56 – 2.42 (m, 1H), 2.28 (d, J = 21.5 Hz, 4H), 2.17 (dtd, J = 12.6, 6.3, 3.5 Hz, 2H), 1.99 (d, J = 41.0 Hz, 4H), 1.90 – 1.73 (m, 3H), 1.63 – 1.53 (m, 1H); 13 C NMR (101 MHz, CDCl3 ) δ 145.4, 145.0, 141.6, 140.7, 138.5, 130.2, 129.0, 128.8, 127.9, 127.7, 127.6, 126.5, 123.9, 122.9, 122.8, 122.7, 121.2, 112.5, 86.5, 71.0, 64.5, 54.9, 41.0, 36.3, 32.4, 21.8, 20.5. HRMS (ESI-FT-ICR) m/z: [M + H]+ Cacld for C27 H28NO 382.2171; found 382.2169. 1'-(2-bromo-4-fluorophenyl)-7'-methyl-2',3',3a',4'-tetrahydro-1'H,3H-s piro[isobenz ofuran-1,5'-pyrrolo[1,2-a]quinoline] (10ha) (purified by column chromatography over silica gel treated with petroleum ether/EtOAc (150:1)): Yellowish solid; 62.1 mg, yield 67%; dr = 12:2:1; m.p. 96-98 o C. 1 H NMR (400 MHz, Chloroform-d) δ 7.37 – 7.14 (m, 5.68H), 7.09 (dd, J = 8.6, 6.1 Hz, 1.20H), 6.97 (d, J = 7.3 Hz, 1.14H), 6.84 (td, J = 8.3, 2.6 Hz, 1.12H), 6.72 – 6.60 (m, 1.12H), 6.33 (d, J = 2.1 Hz, 0.89H), 5.94 – 5.74 (m, 1.20H), 5.34 – 5.07 (m, 2.59H), 5.00 (t, J = 7.0 Hz, 1.21H), 4.22 (dddd, J = 12.0, 8.8, 5.7, 3.5 Hz, 1H), 4.16 – 4.07 (m, 0.08H), 3.91 – 3.72 (m, 0.17H), 2.72 (ddd, J = 11.8, 9.4, 5.4


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Hz, 1.06H), 2.49 – 2.29 (m, 0.44H), 2.18 (td, J = 12.2, 11.2, 4.8 Hz, 2.28H), 1.95 (s, 3.85H), 1.83 (t, J = 12.8 Hz, 1.34H), 1.64 (dddd, J = 21.4, 17.8, 7.9, 5.4 Hz, 2.41H); 13C NMR (101 MHz, CDCl3 ) δ 162.6, 160.1, 144.7, 140.8, 140.6, 139.32, 139.29, 130.3, 129.1, 128.5, 128.4, 128.0, 127.8, 127.6, 124.6, 122.7, 121.9, 121.8, 121.2, 120.4, 120.2, 115.5, 115.2, 112.5, 112.2, 86.4, 71.1, 63.3, 60.7, 56.9, 55.0, 40.9, 33.8, 33.3, 32.2, 20.5. HRMS (ESI-FT-ICR) m/z: [M + H]+ Calcd for C26 H24 BrFNO 464.1025; found 464.1029. 7'-bromo-1'-(p-tolyl)-2',3',3a',4'-tetrahydro-1'H,3H-spiro[isobenzofuran-1,5'-pyrrol o[1,2-a]quinoline] (10ia) (purified by column chromatography over silica gel treated with petroleum ether/EtOAc(150:1)): Yellowish solid; 62.3 mg, yield 70%; dr = 16:6:1; m.p. 96-98 o C. 1 H NMR (400 MHz, Chloroform-d) δ 7.33 – 7.18 (m, 4.86H), 7.16 – 6.98 (m, 7.42H), 6.94 (dd, J = 7.1, 1.6 Hz, 1.10H), 6.91 – 6.80 (m, 1.43H), 6.63 (d, J = 2.4 Hz, 0.22H), 6.56 (d, J = 2.4 Hz, 0.93H), 5.99 (dd, J = 8.8, 3.6 Hz, 1.32H), 5.91 (d, J = 8.8 Hz, 0.16H), 5.29 – 5.04 (m, 3.08H), 4.66 (h, J = 8.8 Hz, 1.45H), 4.52 (q, J = 9.3, 8.7 Hz, 0.07H), 4.17 (dddd, J = 12.5, 9.1, 5.7, 3.6 Hz, 1.05H), 4.06 (dt, J = 9.7, 5.1 Hz, 0.07H), 3.90 – 3.72 (m, 0.40H), 2.51 (dtd, J = 12.6, 7.5, 3.2 Hz, 1.23H), 2.41 – 2.31 (m, 0.88H), 2.28 (d, J = 1.6 Hz, 0.35H), 2.25 (s, 0.91H), 2.24 (s, 3.06H), 2.22 – 2.12 (m, 2.29H), 1.98 – 1.89 (m, 0.57H), 1.84 – 1.72 (m, 2.70H), 1.71 – 1.63 (m, 0.46H), 1.63 – 1.50 (m, 1.22H);

13

C NMR (101 MHz, CDCl3 ) δ 144.7, 144.0, 143.0, 142.6, 141.4, 141.3, 140.8,

140.5, 140.31, 140.27, 136.7, 136.6, 132.2, 132.04, 131.98, 131.3, 131.0, 129.7, 129.60, 129.5, 128.3, 128.1, 128.0, 127.8, 127.6, 126.2, 126.1, 125.6, 125.1, 123.5, 122.5, 121.3,



121.2, 114.8, 114.3, 113.9, 108.2, 107.8, 106.8, 86.6, 86.4, 86.0, 71.8, 71.2, 71.1, 63.9, 61.7, 61.5, 56.1, 55.7, 55.0, 41.6, 40.5, 40.0, 36.4, 34.9, 33.5, 32.5, 30.0, 29.8, 21.3. HRMS (ESI-FT-ICR) m/z: [M + H]+ Calcd for C26 H25 BrNO 446.1120; found 446.1129. 7'-chloro-1'-(4-methoxyphenyl)-2',3',3a',4'-tetrahydro-1'H,3H-spiro[isobenzofuran1,5'-pyrrolo[1,2-a]quinoline] (10ja) (purified by column chromatography over silica gel treated with petroleum ether/EtOAc(50:1)): Brown solid; 59.1 mg, yield 71%; dr = 18:4:1; m.p. 88-90 o C. 1 H NMR (400 MHz, Chloroform-d) δ 7.29 – 7.18 (m, 3.66H), 7.10 – 7.04 (m, 2.23H), 6.95 – 6.90 (m, 1.25H), 6.75 (dd, J = 8.8, 2.4 Hz, 3.37H), 6.50 (d, J = 2.5 Hz, 0.08H), 6.43 (d, J = 2.6 Hz, 0.89H), 6.07 – 5.93 (m, 1.12H), 5.34 – 5.00 (m, 2.57H), 4.65 (t, J = 7.4 Hz, 1.29H), 4.17 (dddd, J = 12.5, 9.1, 5.7, 3.5 Hz, 1H), 4.11 – 4.04 (m, 0.06H), 3.85 – 3.79 (m, 0.23H), 3.67 (d, J = 2.2 Hz, 3.38H), 2.48 (dtd, J = 12.6, 7.5, 3.2 Hz, 1.11H), 2.37 – 2.09 (m, 2.70H), 1.83 – 1.70 (m, 2.40H), 1.61 – 1.50 (m, 1.28H); 13 C NMR (101 MHz, CDCl3 ) δ 158.6, 144.0, 142.2, 140.5, 136.5, 129.2, 128.3, 128.2, 128.0, 127.3, 126.8, 124.6, 122.5, 121.29, 121.27, 119.6, 114.4, 114.3, 114.2, 113.4, 86.0, 71.1, 63.6, 55.4, 54.9, 40.5, 36.4, 32.4. HRMS (ESI-FT-ICR) m/z: [M + H]+ Calcd for C26 H25NClO 2 418.1574; found 418.1580. 1'-(p-tolyl)-2',3',3a',4'-tetrahydro-1'H,3H-spiro[isobenzofuran-1,5'-pyrrolo[1,2-a]qu inoline] (10ka) (purified by column chromatography over silica gel treated with petroleum ether/EtOAc (150:1)): Yellowish solid; 39.9 mg, yield 54%; dr = 16.3:2.1:1; m.p. 84-86 o C. 1 H NMR (400 MHz, Chloroform-d) δ 7.46 – 7.30 (m, 4.14H), 7.24 (d, J =


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8.0 Hz, 2.23H), 7.18 (d, J = 8.0 Hz, 2.13H), 7.10 (d, J = 7.4 Hz, 1.03H), 7.03 – 6.88 (m, 1.19H), 6.64 (dd, J = 7.6, 1.7 Hz, 1.12H), 6.58 – 6.42 (m, 1.17H), 6.35 – 6.18 (m, 1.17H), 5.46 – 5.36 (m, 0.44H), 5.35 – 5.22 (m, 2.02H), 4.88 (t, J = 7.4 Hz, 1.06H), 4.84 – 4.72 (m, 0.12H), 4.37 (dddd, J = 12.4, 9.0, 5.9, 3.5 Hz, 1H), 4.31 – 4.22 (m, 0.06H), 4.05 – 3.92 (m, 0.13H), 2.65 (dtd, J = 11.3, 7.6, 3.7 Hz, 1.12H), 2.54 – 2.45 (m, 0.53H), 2.42 (s, 0.39H), 2.39 (s, 3.06H), 2.38 – 2.27 (m, 2.17H), 2.09 – 1.87 (m, 2.54H), 1.79 – 1.62 (m, 1.31H); 13 C NMR (101 MHz, CDCl3 ) δ 144.8, 143.6, 142.0, 140.7, 136.3, 129.6, 129.4, 128.6, 127.9, 127.7, 125.7, 123.0, 122.6, 121.1, 114.9, 112.3, 86.4, 71.0, 63.9, 54.8, 40.7, 36.4, 32.5, 21.3. HRMS (ESI-FT-ICR) m/z: [M + H]+ Calcd for C26 H26 NO 368.2014; found 368.2015. 1'-(4-nitrophenyl)-2',3',3a',4'-tetrahydro-1'H,3H-spiro[isobenzofuran-1,5'-pyrrolo[1 ,2-a]quinoline] (10la) (purified by column chromatography over silica gel treated with petroleum ether/EtOAc (150:1)): Yellow solid; 57.2 mg, yield 72%; dr = 9:1; m.p. 103-105 o C. 1 H NMR (400 MHz, Chloroform-d) δ 8.32 – 8.16 (m, 2.24H), 7.56 – 7.46 (m, 2.35H), 7.45 – 7.31 (m, 3.29H), 7.21 – 7.05 (m, 1.36H), 7.01 – 6.87 (m, 1.14H), 6.69 – 6.58 (m, 1.10H), 6.54 – 6.42 (m, 0.98H), 6.09 (d, J = 8.2 Hz, 1.06H), 5.43 – 5.20 (m, 2.33H), 4.98 (t, J = 7.5 Hz, 1.11H), 4.48 – 4.32 (m, 1H), 4.03 (d, J = 4.4 Hz, 0.11H), 2.73 (dtd, J = 12.4, 7.4, 3.1 Hz, 1.06H), 2.35 (tdd, J = 12.1, 6.7, 3.4 Hz, 2.16H), 1.99 (t, J = 12.8 Hz, 1.36H), 1.95 – 1.84 (m, 1.07H), 1.79 (ddd, J = 11.6, 8.7, 6.2 Hz, 1.10H); 13 C NMR (101 MHz, CDCl3 ) δ 153.0, 147.1, 144.3, 142.9, 140.6, 129.5, 128.8, 128.1, 127.8,



127.2, 126.7, 124.4, 124.2, 123.5, 122.5, 121.2, 115.8, 111.9, 86.1, 71.1, 63.6, 55.1, 40.4, 36.0, 32.6. HRMS (ESI-FT-ICR) m/z: [M + H]+ Calcd for C25 H23 N2 O3 399.1709; found 399.1702. 7'-fluoro-1'-(naphthalen-1-yl)-2',3',3a',4'-tetrahydro-1'H,3H-spiro[isobenzofuran-1, 5'-pyrrolo[1,2-a]quinoline] (10ma) (purified by column chromatography over silica gel treated with petroleum ether/EtOAc (150:1)): Yellowish solid; 44.7 mg, yield 53%; dr = 17.8:5.6:1; m.p. 79-81 o C. 1 H NMR (400 MHz, Chloroform-d) δ 8.04 (d, J = 8.3 Hz, 1.42H), 7.87 – 7.78 (m, 1.42H), 7.68 – 7.61 (m, 1.39H), 7.53 – 7.36 (m, 3.51H), 7.31 – 7.19 (m, 6.21H), 7.12 (d, J = 3.7 Hz, 0.90H), 6.96 (d, J = 7.2 Hz, 0.98H), 6.72 (dd, J = 9.7, 3.1 Hz, 0.36H), 6.47 (td, J = 8.6, 3.0 Hz, 1.06H), 6.40 (td, J = 8.6, 3.0 Hz, 0.36H), 6.26 (dd, J = 9.6, 3.1 Hz, 1H), 5.91 (dd, J = 9.0, 4.6 Hz, 1.03H), 5.80 (dd, J = 9.0, 4.6 Hz, 0.33H), 5.47 (dd, J = 8.1, 5.7 Hz, 1.04H), 5.39 (d, J = 9.3 Hz, 0.36H), 5.30 – 5.05 (m, 2.81H), 4.30 (dtd, J = 13.0, 6.9, 3.3 Hz, 1.02H), 4.24 (s, 0.06H), 3.93 (tt, J = 11.0, 4.1 Hz, 0.32H), 2.77 (dtd, J = 12.9, 8.0, 5.0 Hz, 1.03H), 2.61 – 2.47 (m, 0.40H), 2.40 – 2.28 (m, 0.74H), 2.27 – 2.14 (m, 2.11H), 1.98 – 1.79 (m, 2.86H), 1.69 (dq, J = 11.7, 7.9 Hz, 1.53H);

13

C NMR (101 MHz, CDCl3 ) δ 155.5, 153.2, 148.7, 144.2, 140.6, 140.1, 138.9,

138.3, 137.9, 134.5, 130.7, 129.4, 129.3, 128.2, 128.0, 127.8, 127.7, 127.6, 127.4, 126.22, 126.18, 126.1, 125.8, 125.7, 124.1, 124.0, 123.6, 123.40, 123.35, 123.2, 122.6, 122.5, 121.3, 116.2, 116.0, 115.5, 115.2, 115.1, 114.9, 113.4, 113.3, 86.9, 86.2, 71.9, 71.2, 61.7,


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58.5, 56.8, 54.5, 40.8, 40.7, 34.5, 33.6, 32.1, 30.6. HRMS (ESI-FT-ICR) m/z: [M + H]+ Calcd for C29 H25FNO 422.1920; found: 422.1923. 7'-fluoro-1'-(thiophen-2-yl)-2',3',3a',4'-tetrahydro-1'H,3H-spiro[isobenzofuran-1,5'pyrrolo[1,2-a]quinoline] (10na) (purified by column chromatography over silica gel treated with petroleum ether/EtOAc (150:1)): Brown solid; 47.5 mg, yield 63%; dr = 14.7:2.5:1; m.p. 69.6-71.0o C. 1 H NMR (400 MHz, Chloroform-d) δ 7.33 – 7.15 (m, 4.04H), 7.09 – 7.00 (m, 1.33H), 6.99 – 6.89 (m, 1.36H), 6.89 – 6.81 (m, 2.34H), 6.74 – 6.53 (m, 1.58H), 6.33 (dd, J = 9.0, 4.7 Hz, 1.08H), 6.22 (td, J = 9.6, 3.7 Hz, 1.09H), 5.28 – 5.06 (m, 2.59H), 5.02 – 4.85 (m, 1.27H), 4.19 – 4.10 (m, 1H), 4.10 – 4.02 (m, 0.07H), 3.84 – 3.71 (m, 0.17H), 2.57 – 2.42 (m, 1.11H), 2.37 – 2.23 (m, 1.3H), 2.23 – 2.08 (m, 1.48H), 2.02 – 1.83 (m, 1.64H), 1.79 (t, J = 12.9 Hz, 1.11H), 1.68 – 1.55 (m, 1.16H); 13 C NMR (101 MHz, CDCl3 ) δ 155.8, 153.5, 150.2, 149.7, 148.6, 144.3, 140.6, 140.2, 138.3, 128.2, 128.0, 127.8, 127.6, 127.1, 127.0, 124.53, 124.48, 124.0, 123.42, 123.36, 123.3, 122.6, 122.4, 121.3, 116.2, 116.0, 115.3, 115.1, 113.4, 113.3, 100.2, 86.7, 86.1, 71.9, 71.2, 60.7, 57.9, 56.4, 53.8, 40.6, 40.5, 35.9, 35.3, 31.8, 31.5, 30.5. HRMS (ESI-FT-ICR) m/z: [M + H] + Calcd for C23 H21 FNOS 378.1328; found 378.1325. 2',3',3a',4'-tetrahydro-1'H,3H-spiro[isobenzofuran-1,5'-pyrrolo[1,2-a]quinoline] (10oa) (purified by column chromatography over silica gel treated with petroleum ether/EtOAc(150:1)): Yellowish solid; 30.1 mg, yield 54%; dr = 3:1; m.p. 58-60 o C. 1 H NMR (400 MHz, Chloroform-d) δ 7.33 – 7.15 (m, 4.05H), 7.15 – 6.99 (m, 2.17H), 6.93



(d, J = 7.4 Hz, 0.98H), 6.54 – 6.34 (m, 3.44H), 5.24 (q, J = 12.3 Hz, 0.63H), 5.17 – 5.02 (m, 2H), 3.76 – 3.57 (m, 1.31H), 3.43 – 3.20 (m, 2.63H), 2.28 – 2.15 (m, 1.33H), 2.09 (ddt, J = 20.6, 14.9, 5.9 Hz, 2.56H), 1.91 (tdd, J = 11.2, 8.4, 4.1 Hz, 1.48H), 1.74 (t, J = 12.7 Hz, 1.16H), 1.55 (d, J = 11.3 Hz, 2.13H); 13 C NMR (101 MHz, CDCl3 ) δ 145.1, 144.8, 140.6, 129.7, 129.1, 128.8, 127.9, 127.8, 127.6, 127.5, 126.7, 123.3, 123.1, 122.5, 121.2, 121.1, 115.6, 115.2, 111.1, 110.5, 86.6, 71.9, 70.9, 54.8, 53.9, 47.6, 46.9, 41.0, 39.0, 33.6, 33.1, 24.6, 23.8. HRMS (ESI-FT-ICR) m/z: [M + H]+ Calcd for C19 H20 NO 278.1545; found 278.1546. (E)-6-methoxy-1'-styryl-2',3',3a',4'-tetrahydro-1'H,3H-spiro[isobenzofuran-1,5'-pyr rolo[1,2-a]quinoline] (10pb) (purified by column chromatography over silica gel treated with petroleum ether/EtOAc (100:1)): Yellow solid; 52.4 mg, yield 64%; dr = 2.5:1; m.p. 84-86 o C. 1 H NMR (400 MHz, Chloroform-d) δ 7.34 – 7.25 (m, 3.06H), 7.24 – 7.17 (m, 3.15H), 7.17 – 7.05 (m, 3.25H), 7.02 – 6.88 (m, 1.67H), 6.81 (dt, J = 8.4, 2.2 Hz, 1.14H), 6.74 (p, J = 2.5 Hz, 0.61H), 6.62 (d, J = 8.2 Hz, 1.23H), 6.58 – 6.41 (m, 4.39H), 6.37 (t, J = 7.5 Hz, 1.06H), 6.27 – 6.08 (m, 1.49H), 5.26 – 4.95 (m, 2.94H), 4.40 (q, J = 6.9 Hz, 1H), 4.36 – 4.26 (m, 0.42H), 4.01 (ddq, J = 12.5, 7.0, 3.1 Hz, 1.2H), 3.81 – 3.70 (m, 0.37H), 3.66 (d, J = 1.9 Hz, 4.24H), 2.42 – 2.25 (m, 1.39H), 2.25 – 2.01 (m, 3.06H), 1.90 – 1.73 (m, 2.92H), 1.59 – 1.48 (m, 1.68H); 13 C NMR (101 MHz, CDCl3 ) δ 159.9, 159.6, 146.5, 144.1, 143.3, 137.1, 132.9, 132.6, 132.1, 129.9, 129.6, 129.3, 128.9, 128.8, 128.7, 128.7, 128.6, 127.6, 127.5, 126.6, 126.5, 126.5, 125.6, 122.9, 121.9, 121.8, 121.8, 116.3,


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116.0, 115.3, 114.8, 113.3, 113.0, 112.5, 112.3, 111.5, 109.6, 109.0, 107.2, 86.3, 71.7, 71.4, 70.7, 62.3, 62.1, 59.3, 56.4, 55.8, 55.72, 55.68, 53.7, 50.2, 41.0, 40.5, 38.5, 33.7, 32.9, 32.6, 32.3, 31.8, 30.8. HRMS (ESI-FT-ICR) m/z: [M + H]+ Calcd for C28 H28NO2 410.2120; found 410.2121. 7'-chloro-1'-(4-methoxyphenyl)-6-methyl-2',3',3a',4'-tetrahydro-1'H,3H-s piro[isobe nzofuran-1,5'-pyrrolo[1,2-a]quinoline] (10jc) (purified by column chromatography over silica gel treated with petroleum ether/EtOAc (40:1)): White solid; 68.0 mg, yield 79%; dr = 3.3:1; m.p. 85-87 o C. 1 H NMR (400 MHz, Chloroform-d) δ 7.26 – 7.12 (m, 5.26H), 7.09 – 7.00 (m,0.72H), 6.95 – 6.81 (m, 5.31H), 6.57 (d, J = 2.5 Hz, 1.04H), 6.17 (d, J = 8.8 Hz, 0.97H), 6.09 (d, J = 8.8 Hz, 0.23H), 5.36 – 5.12 (m, 2.74H), 4.87 – 4.69 (m, 1.32H), 4.28 (dddd, J = 12.4, 9.1, 5.8, 3.5 Hz, 1H), 4.00 – 3.93 (m, 0.29H), 3.82 (d, J = 1.8 Hz, 4.09H), 2.61 (dtd, J = 12.7, 7.5, 3.4 Hz, 1.1H), 2.38 (d, J = 12.0 Hz, 4.27H), 2.33 – 2.23 (m, 2.3H), 1.99 – 1.84 (m, 2.81H), 1.68 (dddd, J = 11.9, 10.4, 9.0, 7.4 Hz, 1.52H);

13

C NMR (101 MHz, CDCl3 ) δ 158.7, 158.6, 148.8, 144.2, 142.2, 141.4, 137.8,

137.6, 137.4, 136.5, 135.9, 135.4, 129.2, 129.2, 128.8, 128.4, 128.4, 128.3, 127.4, 127.2, 126.8, 124.7, 124.0, 122.9, 121.0, 121.0, 119.7, 114.5, 114.4, 114.2, 113.8, 113.4, 86.4, 85.9, 71.7, 71.1, 63.7, 61.3, 56.2, 55.5, 54.9, 40.7, 40.3, 36.4, 35.0, 32.4, 30.1, 21.6. HRMS (ESI-FT-ICR) m/z: [M + H]+ Calcd for C27 H27ClNO 2 432.1730; found 432.1728. 7'-chloro-5-fluoro-1'-(4-methoxyphenyl)-2',3',3a',4'-tetrahydro-1'H,3H-spiro[isoben zofuran-1,5'-pyrrolo[1,2-a]quinoline] (10jd) (purified by column chromatography over



silica gel treated with petroleum ether/EtOAc(40:1)): White solid; 67.3 mg, yield 77%; m.p. 93-95 o C. 1 H NMR (400 MHz, Chloroform-d) δ 7.30 – 7.17 (m, 3.29H), 7.12 – 6.95 (m, 5.12H), 6.93 – 6.81 (m, 3.85H), 6.63 (d, J = 2.5 Hz, 0.16H), 6.55 (d, J = 2.5 Hz, 0.76H), 6.23 – 6.14 (m, 1.08H), 6.09 (d, J = 8.8 Hz, 0.21H), 5.37 – 5.14 (m, 2.71H), 4.84 – 4.70 (m, 1.29H), 4.69 – 4.61 (m, 0.16H), 4.38 – 4.23 (m, 1H), 4.17 (ddd, J = 22.2, 10.0, 5.3 Hz, 0.2H), 3.88 – 3.80 (m, 4.38H), 2.63 (dtd, J = 12.7, 7.4, 3.1 Hz, 1.12H), 2.53 – 2.37 (m, 0.85H), 2.30 (ddd, J = 15.2, 9.1, 5.1 Hz, 2.08H), 2.05 (d, J = 12.5 Hz, 0.48H), 1.96 – 1.83 (m, 2.8H), 1.81 – 1.63 (m, 1.97H); 13 C NMR (101 MHz, CDCl3 ) δ 164.4, 161.9, 158.7, 158.7, 142.8, 142.7, 142.2, 139.6, 136.4, 129.3, 128.6, 128.2, 128.1, 127.3, 127.1, 126.8, 126.6, 124.6, 123.8, 123.7, 119.7, 115.5, 115.2, 114.6, 114.5, 114.4, 114.4, 114.3, 114.2, 114.0, 113.5, 108.7, 108.6, 108.4, 86.2, 85.7, 71.4, 70.7, 70.7, 63.6, 61.4, 61.3, 56.5, 56.2, 55.5, 54.9, 40.6, 40.2, 36.5, 35.0, 32.4, 30.0, 27.2. HRMS (ESI-FT-ICR) m/z: [M + H]+ Calcd for C26 H24ClFNO 2 436.1480; found 436.1484. (7) The characterization of products 11 4-methyl-2-phenyl-3a,4,9,9a-tetrahydro-1H-4,9-epoxybenzo[f]isoindole-1,3(2H)-dion e (endo) (11aa) (purified by column chromatography over silica gel treated with petroleum ether/EtOAc(10:1)): White solid; 57.7 mg, dr = 1.6:1; total yield 77%; m.p. 189-190 o C. 1 H NMR (400 MHz, Chloroform-d) δ 7.42 (dd, J = 8.4, 6.8 Hz, 2H), 7.37 – 7.29 (m, 2H), 7.27 – 7.17 (m, 5H), 5.66 (s, 1H), 3.14 (d, J = 6.7 Hz, 1H), 2.84 (d, J = 6.7 Hz, 1H), 1.93 (s, 3H);

13

C NMR (101 MHz, CDCl3 ) δ 175.6, 174.3, 147.2, 144.3, 131.9,


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129.4, 129.1, 128.1, 127.9, 126.8, 120.1, 119.0, 88.3, 80.9, 77.6, 77.3, 76.9, 52.2, 51.2, 15.0. HRMS m/z: [M + H]+ (ESI-FT-ICR) Calcd for C19 H16 NO3 306.1130; found 306.1141. 4,6-dimethyl-2-phenyl-3a,4,9,9a-tetrahydro-1H-4,9-epoxybenzo[f]isoindole-1,3(2H)dione (11ca) (purified by column chromatography over silica gel treated with petroleum ether/EtOAc(10:1)): Yellowish solid; 57.8 mg, dr = 1.4:1 total yield 78%; m.p. 170-172 o

C. 1 H NMR (400 MHz, Chloroform-d) δ 7.25 (p, J = 4.1, 3.6 Hz, 3H), 7.20 (d, J = 7.4

Hz, 1H), 7.12 – 7.05 (m, 2H), 6.44 – 6.35 (m, 2H), 5.67 (d, J = 5.9 Hz, 1H), 3.98 (dd, J = 8.3, 5.9 Hz, 1H), 3.46 (d, J = 8.3 Hz, 1H), 2.36 (s, 3H), 2.05 (s, 3H); 13 C NMR (101 MHz, CDCl3 ) δ 173.8, 173.7, 143.7, 139.1, 138.4, 131.2, 129.1, 128.8, 128.7, 126.5, 121.0, 120.9, 88.8, 79.5, 53.0, 51.0, 21.6, 17.7. HRMS (ESI-FT-ICR) m/z: [M + H]+ Calcd for C20 H18NO3 320.1287; found 320.1293. 7-fluoro-4-methyl-2-phenyl-3a,4,9,9a-tetrahydro-1H-4,9-epoxybenzo[f]isoindole-1,3( 2H)-dione (11da) (purified by column chromatography over silica gel treated with petroleum ether/EtOAc (5:1)): Yellowish solid; 58.1 mg, dr = 1.7:1, total yield 71%; m.p. 178-180 o C. 1 H NMR (400 MHz, Chloroform-d) δ 7.32 – 7.26 (m, 3H), 7.20 (dd, J = 8.1, 4.5 Hz, 1H), 7.07 (dd, J = 7.5, 2.3 Hz, 1H), 7.00 (ddd, J = 9.4, 8.1, 2.3 Hz, 1H), 6.52 – 6.45 (m, 2H), 5.69 (d, J = 5.9 Hz, 1H), 4.02 (dd, J = 8.4, 6.0 Hz, 1H), 3.50 (d, J = 8.4 Hz, 1H), 2.06 (s, 3H);

13

C NMR (101 MHz, CDCl3 ) δ 173.5, 173.4, 163.9, 161.5, 144.2,

144.1, 139.31, 139.28, 131.0, 129.3, 129.0, 126.3, 121.7, 121.6, 115.0, 114.8, 109.7,



109.4, 88.6, 79.36, 79.34, 53.0, 50.7, 17.8. HRMS (ESI-FT-ICR) m/z: [M + H]+ Calcd for C19 H15FNO3 324.1036; found 324.1041. 11-methyl-9-phenyl-10a,11-dihydro-7H-7,11-epoxynaphtho[1,2-f]isoindole-8,10(7aH ,9H)-dione (11ea) (purified by column chromatography over silica gel treated with petroleum ether/EtOAc (10:1)): White solid; 68.8 mg, dr = 1.5:1, total yield 81%; m.p. 185-186 o C. 1 H NMR (400 MHz, Chloroform-d) δ 8.16 (d, J = 8.4 Hz, 1H), 7.95 (d, J = 8.1 Hz, 1H), 7.83 (d, J = 8.1 Hz, 1H), 7.62 – 7.48 (m, 5H), 7.43 (t, J = 7.6 Hz, 1H), 7.39 – 7.32 (m, 2H), 5.86 (s, 1H), 3.21 (d, J = 6.6 Hz, 1H), 3.01 (d, J = 6.6 Hz, 1H), 2.38 (s, 3H);

13

C NMR (101 MHz, CDCl3) δ 175.6, 174.3, 143.4, 142.3, 134.0, 132.0, 129.7,

129.5, 129.1, 127.5, 126.8, 126.1, 122.8, 118.1, 90.0, 81.0, 53.0, 51.3, 18.6. HRMS (ESI-FT-ICR) m/z: [M + H - H2 O]+ Calcd for C23 H16 NO 2 338.1181; found 338.1175. 4,9-dimethyl-2-phenyl-3a,4,9,9a-tetrahydro-1H-4,9-epoxybenzo[f]isoindole-1,3(2H)dione (11fa) (purified by column chromatography over silica gel treated with petroleum ether/EtOAc (10:1)): White solid; 63.2 mg, dr = 1.7:1, total yield 79%; m.p. 183-184 o C. 1

H NMR (400 MHz, Chloroform-d) δ 7.29 – 7.20 (m, 2H), 7.15 (t, J = 5.7 Hz, 5H), 6.40

– 6.22 (m, 2H), 3.48 (s, 2H), 1.96 (s, 6H). 13 C NMR (101 MHz, CDCl3 ) δ 173.7, 144.1, 131.2, 129.0, 128.7, 128.2, 126.4, 120.0, 87.4, 55.1, 17.8. HRMS (ESI-FT-ICR) m/z: [M + H]+ Calcd for C20 H18NO3 320.1287; found: 320.1280. 2-(4-methoxyphenyl)-4,9-dimethyl-3a,4,9,9a-tetrahydro-1H-4,9-epoxybenzo[f]isoind ole-1,3(2H)-dione (11fb) (purified by column chromatography over silica gel treated


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with petroleum ether/EtOAc (5:1)): White solid, 75 mg, dr = 2.3:1, total yield 77%; m.p. 170-172 o C. 1 H NMR (400 MHz, Chloroform-d) δ 7.36 – 7.29 (m, 2H), 7.28 – 7.20 (m, 2H), 6.75 (dd, J = 8.7, 1.7 Hz, 2H), 6.34 – 6.25 (m, 2H), 3.73 (d, J = 1.5 Hz, 3H), 3.59 (d, J = 1.5 Hz, 2H), 2.05 (d, J = 1.5 Hz, 6H); 13 C NMR (101 MHz, CDCl3 ) δ 174.0, 159.7, 144.2, 128.2, 127.7, 123.8, 120.1, 114.4, 87.5, 55.6, 55.2, 17.9. HRMS (ESI-FT-ICR) m/z: [M + H] + Calcd for C21 H20 NO4 350.1392; found: 350.1391. 2-benzyl-4,9-dimethyl-3a,4,9,9a-tetrahydro-1H-4,9-epoxybenzo[f]isoindole-1,3(2H)dione (11fc) (purified by column chromatography over silica gel treated with petroleum ether/EtOAc (10:1)): White solid; 73.4 mg, dr > 30:1, total yield 55%; m.p. 177-179 o C. 1

H NMR (400 MHz, Chloroform-d) δ 7.08 (q, J = 6.7, 5.9 Hz, 3H), 6.96 (dt, J = 7.0, 3.7

Hz, 2H), 6.85 (ddd, J = 13.0, 6.5, 2.6 Hz, 4H), 3.88 (s, 2H), 3.35 (s, 2H), 1.89 (s, 6H); 13C NMR (101 MHz, CDCl3 ) δ 174.3, 143.5, 135.2, 129.2, 128.5, 127.9, 127.8, 119.4, 87.0, 77.6, 77.3, 76.9, 55.1, 42.0, 17.8. HRMS (ESI-FT-ICR) m/z: [M + H]+ Calcd for C21 H20NO3 334.1443; found: 334.1442. 2,4,9-trimethyl-3a,4,9,9a-tetrahydro-1H-4,9-epoxybenzo[f]isoindole-1,3(2H)-dione (11fd) (purified by column chromatography over silica gel treated with petroleum ether/EtOAc (5:1)): White solid; 71.3 mg, dr > 30:1, total yield 69%; m.p. 150-152 o C. 1

H NMR (400 MHz, Chloroform-d) δ 7.14 (dt, J = 7.3, 3.6 Hz, 2H), 7.07 (dd, J = 5.4, 3.0

Hz, 2H), 3.35 (s, 2H), 2.15 (s, 3H), 1.92 (s, 6H); 13 C NMR (101 MHz, CDCl3 ) δ 174.8,



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143.6, 128.0, 119.7, 87.2, 55.2, 23.9, 17.7. HRMS (ESI-FT-ICR) m/z: [M + H]+ Calcd for C15 H16NO3 258.1130; found: 258.1137. 9,10-dimethyl-4a,9,9a,10-tetrahydro-9,10-epoxyanthracene-1,4-dione (11fe) (purified by column chromatography over silica gel treated with petroleum ether/EtOAc (10:1)): White solid; 62.8 mg, dr > 30:1, total yield 62%; m.p. 164-166 o C. 1 H NMR (400 MHz, Chloroform-d) δ 7.09 (dt, J = 7.8, 4.0 Hz, 2H), 6.95 (dd, J = 5.3, 3.0 Hz, 2H), 5.83 (s, 2H), 3.18 (s, 2H), 1.91 (s, 6H); 13 C NMR (101 MHz, CDCl3 ) δ 196.1, 144.6, 139.3, 128.0, 119.8, 88.6, 56.0, 17.1. HRMS (ESI-FT-ICR) m/z: [M + H]+ Calcd for C 16 H15 O3 258.1021; Found 255.1016. 5,12-dimethyl-5,5a,11a,12-tetrahydro-5,12-epoxytetracene-6,11-dione (endo) (11ff) (purified by column chromatography over silica gel treated with petroleum ether/EtOAc (10:1)): Yellowish solid; 89.2 mg, dr > 30:1, total yield 73%; m.p. 206-208 o C. 1 H NMR (400 MHz, Chloroform-d) δ 7.56 (dd, J = 5.8, 3.4 Hz, 2H), 7.35 (dd, J = 5.9, 3.3 Hz, 2H), 6.80 (dd, J = 5.4, 3.1 Hz, 2H), 6.73 (dd, J = 5.4, 3.0 Hz, 2H), 3.43 (s, 2H), 1.98 (s, 6H); 13

C NMR (101 MHz, CDCl3 ) δ 194.5, 144.5, 134.4, 133.9, 127.5, 126.4, 119.8, 89.0, 77.6,

77.3, 76.9, 57.1, 17.3. HRMS (ESI-FT-ICR) m/z: [M+H-H2 O]+ Calcd for C20 H15 O2 287.1072; found 287.1072. 4,9-dimethyl-3a,4,9,9a-tetrahydro-4,9-epoxynaphtho[2,3-c]furan-1,3-dione

(endo)

(11fg) (purified by column chromatography over silica gel treated with petroleum ether/EtOAc (10:1)): White solid; 43.7 mg, dr = 1.7:1, total yield 71%; m.p. 159-160 o C.


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1

H NMR (400 MHz, Chloroform-d) δ 7.26 (dt, J = 7.0, 3.5 Hz, 2H), 7.20 – 7.15 (m, 2H),

3.65 (s, 2H), 1.94 (s, 6H); 13 C NMR (101 MHz, CDCl3 ) δ 168.3, 143.2, 129.0, 120.2, 88.0, 56.4, 17.5. HRMS (ESI-FT-ICR) m/z: [M + H] + Calcd for C14 H13O4 245.0814; found 245.0822. diethyl

1,4-dimethyl-1,4-dihydro-1,4-epoxynaphthalene-2,3-dicarboxylate

(11fh)

(purified by column chromatography over silica gel treated with petroleum ether/EtOAc (10:1)): Yellow liquid, 63.2 mg, yield 50%, 1 H NMR (400 MHz, Chloroform-d) δ 7.19 (dd, J = 5.2, 3.0 Hz, 2H), 6.99 (dd, J = 5.1, 3.0 Hz, 2H), 4.14 (q, J = 7.1 Hz, 4H), 1.89 (s, 6H), 1.20 (t, J = 7.1 Hz, 6H). 13 C NMR (101 MHz, CDCl3 ) δ 163.7, 152.9, 150.3, 126.0, 119.7, 89.8, 61.4, 14.3, 14.2. HRMS (ESI-FT-ICR) m/z: [M + H]+ Calcd for C18 H21 O5 317.1389; found 317.1388. 4-(buta-2,3-dien-2-yl)-9-methyl-2-phenyl-3a,4,9,9a-tetrahydro-1H-4,9-epoxybenzo[f] isoindole-1,3(2H)-dione (endo) (11ga) (purified by column chromatography over silica gel treated with petroleum ether/EtOAc (10:1)): White solid; 45.9 mg, dr = 2:1, total yield 48%; m.p. 195-197 o C. 1 H NMR (400 MHz, Chloroform-d) δ 7.26 (dt, J = 5.4, 3.5 Hz, 2H), 7.21 (ddd, J = 5.5, 4.4, 2.9 Hz, 2H), 7.18 – 7.11 (m, 3H), 6.36 – 6.28 (m, 2H), 5.14 – 5.06 (m, 1H), 5.05 – 4.97 (m, 1H), 3.97 (d, J = 8.4 Hz, 1H), 3.53 (d, J = 8.4 Hz, 1H), 2.00 (s, 3H), 1.83 (t, J = 3.1 Hz, 3H); 13 C NMR (101 MHz, CDCl3 ) δ 209.20, 173.62, 173.09, 144.21, 142.47, 131.28, 129.02, 128.72, 128.39, 128.27, 126.51, 121.45, 120.31,



95.22, 90.75, 87.36, 78.44, 54.97, 52.81, 17.78, 15.47. HRMS (ESI-FT-ICR) m/z: [M + H]+ Calcd for C23 H20NO3 358.1443; found: 358.1454. (8) The characterization of products 12 4,9-dimethyl-2-phenyl-1H-benzo[f]isoindole-1,3(2H)-dione (12fa) (purified by column chromatography over silica gel treated with petroleum ether/EtOAc (20:1)): White solid; 54.7 mg, yield 91%; m.p. 233-235 o C. 1 H NMR (400 MHz, Chloroform-d) δ 8.35 – 8.18 (m, 2H), 7.82 – 7.68 (m, 2H), 7.49 (ddd, J = 23.9, 15.7, 7.5 Hz, 5H), 3.11 (s, 6H); 13 C NMR (101 MHz, CDCl3 ) δ 173.7, 144.1, 131.2, 129.0, 128.7, 128.2, 126.4, 120.0, 87.4, 55.1, 17.8. HRMS (ESI-FT-ICR) m/z: [M + H]+ Calcd for C20 H15 NO2 302.1181; found: 302.1179. 2-benzyl-4,9-dimethyl-1H-benzo[f]isoindole-1,3(2H)-dione (12fc) (purified by column chromatography over silica gel treated with petroleum ether/EtOAc (20:1)): White solid; 54.3 mg, yield 86%; m.p.190-192 o C. 1 H NMR (400 MHz, Chloroform-d) δ 8.18 – 8.05 (m, 2H), 7.65 – 7.55 (m, 2H), 7.40 (d, J = 7.4 Hz, 2H), 7.25 (t, J = 7.5 Hz, 2H), 7.21 – 7.13 (m, 1H), 4.78 (s, 2H), 2.95 (s, 6H); 13 C NMR (101 MHz, CDCl3 ) δ 168.8, 137.0, 135.62, 135.56, 128.91, 128.87, 128.8, 127.9, 126.4, 123.9, 41.7, 13.2. HRMS (ESI-FT-ICR) m/z: [M + H]+ Calcd for C21 H18 NO2 316.1338; found 316.1341. 6,11-dimethyltetracene-5,12-dione (12ff) (purified by column chromatography over silica gel treated with petroleum ether/EtOAc (20:1)): Yellow solid; 51.2 mg, yield 89%; m.p. 222-224 o C. 1 H NMR (400 MHz, Chloroform-d) δ 8.35 (dd, J = 6.5, 3.3 Hz, 2H),


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8.15 (dd, J = 5.7, 3.3 Hz, 2H), 7.70 (ddd, J = 13.8, 6.2, 3.3 Hz, 4H), 3.10 (s, 6H); 13 C NMR (101 MHz, CDCl3 ) δ 187.5, 139.4, 136.1, 135.3, 133.5, 129.7, 128.9, 126.9, 126.6, 77.6, 77.3, 76.9, 17.5. HRMS (ESI-FT-ICR) m/z: [M + H]+ Calcd for C20 H15 O2 287.1072; found 287.1072.

SUPPORTING INFORMATION The NMR

spectra of all spiroisobenzofuran-b-pyrroloquinolines or brigded-

isobenzofuran polycycles as well as the X-ray data of compound endo-11ga are all provided in supporting information. This material is available free of charge via the Internet at http://pubs.acs.org.

ACKNOWLEDGEMENT We are grateful for financial support from the National Key Research and Development Program of China (2017YFD0201404) for this work and Natural Science Foundation of Tianjin City (17JCZDJC37300). And we also thank the support from the Collaborative Innovation Center of Chemical Science and Engineering (Tianjin).

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Co mplexes to Tandem Catalysis with Gold and other Carbophilic Lewis Acids. Synlett. 2013, 24, 1757-1771. (c) Zeni, G.; Larock, R. C. Synthesis of Heterocycles via Palladiu m π-Olefin and π-Alkyne Chemistry. Chem. Rev. 2004, 104, 2285-2309. (d) Patil, N. T.; Singh, V. A lkyne Hydroamination Triggered Cyclizat ions: A Powerfu l Tool fo r the Construction of Biologically Important Structural Motifs. J. Organomet. Chem. 2011, 696, 419-432. (2) (a) Zeng, X. Recent Advances in Catalytic Sequential React ions Involving Hydroelement Addition to Carbon-Carbon Multiple Bonds. Chem. Rev. 2013, 113, 6864-6900. (b) A lcaide, B.; Almendros, P.; Alonso, J. M. Go ld-Cataly zed Cyclizations of A lkynol-Based Co mpounds: Synthesis of Natural Products and Derivatives. Molecules. 2011, 16, 7815-7843. (c) A lcaide, B.; Almendros, P.; A lonsoa, J. M. Gold catalyzed Oxycyclizations of Alkynols and Alkyndiols. Org. Biomol. Chem. 2011, 9, 4405-4416. (3) (a) Li, D. Y.; Shi, K. J.; Mao, X. F.; Zhao, Z. L.; Wu, X. Y.; Liu, P. N. Selective Cyclization of Alkynols and Alkynylamines Cataly zed by Potassium tert-Buto xide. Tetrahedron. 2014, 70, 7022-7031. (b) Praveen, C.; Iyyappan, C.; Peru mal, P. T. Regioselective Synthesis of Phthalans via Cu(OTf)2 -catalyzed 5-exo-dig Intramo lecular Hydroalko xylat ion of 2-(Ethynyl)benzyl Alcohols. Tetrahedron Lett. 2010, 51, 4767-4771. (c) Praveen, C.; Iyyappan, C.; Girija, K.; Ku mar, K. S.; Peru mal, P. T. Regioselective Synthesis and Evaluation of 3-Alkylidene-1,3-dihydroisobenzofurans as Potential Antidepressant Agents. J. Chem. Sci. 2012, 124, 451-462. (4) (a) Zhu, C.; Ma, S. Sc(OTf)3 -Cataly zed Bicyclization of o-Alkynylanilines with Aldehydes: Ring‐ Fused 1,2‐ Dihydroquinolines. Angew. Chem. Int. Ed. 2014, 53, 13532-13535. (b) Han, Z. Y.;


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The Divergent Cascade Reactions of Arylalkynols ... - ACS Publications

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