Access to 3a-Benzoylmethyl Pyrrolidino[2,3-b]indolines via CuII

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Access to 3a-Benzoylmethyl Pyrrolidino[2,3-b]indolines via CuIICatalyzed Radical Annulation/C3-Functionalization Sequence Xiaofeng Chen, Jinbao Fan, Guangyao Zeng, Jinjin Ma, Chenxi Wang, Yajing Wang, Yingjun Zhou, and Xu Deng J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01017 • Publication Date (Web): 21 Jun 2018 Downloaded from http://pubs.acs.org on June 21, 2018

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The Journal of Organic Chemistry

Access to 3a-Benzoylmethyl Pyrrolidino[2,3-b]indolines via CuII-Catalyzed Radical Annulation/C3-Functionalization Sequence Xiaofeng Chen,†,‡ Jinbao Fan,†,‡ Guangyao Zeng,† Jinjin Ma,† Chenxi Wang,† Yajing Wang,ǁ Yingjun Zhou,*,† Xu Deng*,† † Xiangya School of Pharmaceutical Science, Central South University, Changsha 410013, Hunan, China ǁ Hunan University of Chinese Medicine, Changsha, 410028, Hunan, China. Email: [email protected], [email protected]

Table of Content

ABSTRACT: A CuII-catalyzed radical annulation/C3-functionalization cascade of tryptamine derivatives with aryl ethylene is reported. The mild catalytic conditions enables the facile construction of 3a-benzoylmethylpyrrolidino[2,3-b]indolines with excellent chemo- and regio-selectivities. Remarkably, this novel method utilizes earth-abundant and inexpensive cupric salt as the catalyst and air as the co-oxidant, rendering the process highly environmentally friendly and atom-economic. Presumably, the reaction

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proceeds through CuII-initiated formation of pyrrolidino[2,3-b]indolines radical intermediate I, which is successively trapped by aryl ethylene and O2 to form the product. And

18

O2-labelling experiment and several control experiments were

designed to support the mechanistic proposal.


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INTRODUCTION Pyrrolidino[2,3-b]indoline

alkaloids

with

a

3a-quaternary

carbon

center,

exemplified by (-)-physostigmine, (-)-vincorine and scholarisine F, represent a fascinating family of alkaloid natural products and have also been well documented to elicit

a

wide

array

of

promising

activities1.

3a-All-carbon

substituted

pyrrolidino[2,3-b]indolines can not only serve as key intermediates in total synthesis of complex natural products2, but also can be employed as biological probes3 and small

catalysts4.

molecular

Consequently,

3a-all-carbon-substituted

pyrrolidino[2,3-b]indolines have received wide interests among the synthetic chemistry communities. A diverse set of notable synthetic methods have been developed

for

the

efficient

assembly

of


pyrrolidino[2,3-b]indolines (Scheme 1),5 including the carbon-based electrophilic addition/intramolecular cyclization sequence of tryptamine precursors (eq 1)6, the formal [3+2] cycloaddition of 3a-substituted indole precursors with 1,3 dipolar intermediates (eq 2),7 and a Pd-catalyzed intramolecular Heck reaction to access C3-substituted

oxindole

followed

by

functional

manipulations

to

furnish

pyrrolidino[2,3-b]indolines (eq 3)8. However, the established approaches toward this structural motif either took advantage of prefunctionalized reagents as the starting material, or were based on multi-step sequence. In addition, it would be ideal to directly build 3a-all-carbon-substituted pyrrolidino[2,3-b]indolines by earth-abundant and inexpensive catalysts in view of green and sustainable chemistry.



Scheme

1.

Strategies

towards

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3a-All-carbon

Substituted

Pyrrolidino[2,3-b]indolines Recently, we disclosed unique CuII-catalyzed radical annulations of tryptamine derivatives via the common intermediate I (Scheme 1, eq 4), which was consecutively trapped

by

O2

or

another

tryptamine

derivatives,

thus

furnishing

3a-hydroxy-pyrrolidino[2,3-b]indolines9 and 3a,3a’-bispyrrolidino[2,3-b] indolines10 in a step-economy manner. Given that these reactions shared the common radical intermediate I (Scheme 1), we postulated that other radical scavengers should also be capable to trap this reactive species. Inspired by the proceeding reports on alkene as the radical trap11, we embarked on exploration of the possibilities regarding radical annulation involving selective incorporation of alkenes into 3a position of tryptamine


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derivatives

to

construct

pyrrolidino[2,3-b]indolines.

To

the this

challenging end,

the


reaction

must

show

high

chemoselectivity in the presence of other radical trap (such as O2 and another tryptamine derivative), site selectivity for indoles with regard to N1, C3 and the side chain nucleophiles (X), regioselectivity toward branched and linear (C1’ vs C2’) product. Additionally, given the electron-rich nature of the indole core, the control of the reaction pathways to prevent the oxidative cleavage of a C2-C3 double bond12 has also proven to be problematic. Herein, we present the successful execution of these ideas

and

describe

an

operationally

trivial

CuII-catalyzed

radical

annulation/C3-functionalization sequence of tryptamine derivatives that allows the formation of a diverse range of 3a-benzoylmethyl pyrrolidino[2,3-b]indolines with excellent chemo- and regio-selectivity. We expect this new catalysis method should be broadly applicable to natural product and medicinal agent synthesis. RESULTS AND DISCUSSIONS Given the hypothesis that the catalysts should play a key role in the reaction, our initial endeavors have been focused on the identification of an optimal oxidant to facilitate the annulations of tryptamine derivative 1a with styrene 2a as the model substrates (Table 1). Treatment of the substrates with various oxidants in the presence of co-oxidants in CH3CN provided significant varied results. As illustrated in table 1, when H2O2 was employed as the co-oxidant, FeCl3 and Cu(OAc)2 were found to be inefficient for the reaction (Table 1, entries 1 and 3). Gratifyingly, switching the oxidant to Fe2(SO4)3, Cu(OTf)2, Cu(BF4)2 and Cu(NO3)2 furnished the desired



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3a-benzoylmethyl pyrrolidino[2,3-b]indoline 3a (Table 1, entries 2 and 4-6), albeit with poor conversions and yields, wherein Cu(NO3)2 is optimal, indicating that both metal center and counter anions exerted a significant effect on the reaction outcomes. The structure of 3a was unambiguously characterized by NMR and X-ray analysis, which illustrates that both styrene and co-oxidant are appended onto the periphery of the pyrrolidino[2,3-b]indoline core. An in-depth survey of the side products revealed that the reaction demonstrated excellent chemo- and regio-selectivities, wherein no 3a-hydroxy-pyrrolidino[2,3-b]indolines, N1-alkyl

3a,3a’-bispyrrolidino[2,3-b]indolines,

pyrrolidino[2,3-b]indolines,

3a-branch-substituted

pyrrolidino[2,3-b]indolines or other intermediates were detected but C2-C3 oxidative cleavage is the main side reaction12. We envisaged that mild co-oxidant might be beneficial for this reaction. Accordingly, subsequent optimizations were conducted in an open flask, which led to a minor improvement in yields but with poor conversions. Further examinations of solvent effects revealed that polar protic solvents were more favorable (entries 7-11 and Table SI-1, entries 1-5). A full conversion was accomplished by using TFE as the solvent, albeit with remarkable decomposition of the starting material (entry 11). Fortunately, acidic additives (eg. HCOOH or PhCOOH) turned out to be beneficial (entries 14 and 15), while strong acids would significantly accelerate the degradation of the starting material, leading to low yield of the desired product (data not shown). Interestingly, basic additives (eg. TEA or K3PO4) significantly inhibited the reaction (entries 12, 13). Upon extensive screening, it’s found that a combination of polar solvent (TFE) and nonpolar solvents (DCM and


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CHCl3) gave 3a in optimal results (entries 16 and 17). Besides, the catalyst loading can be lowered to 5 mol% without affecting the yield significantly, albeit with prolonged reaction time. Table 1. Reaction Development and Optimizationa

HN R

O MX, Additive, Air

+ N 7 H

N Solvent 8

N H H 9

PG 9a

R entry MX co-oxidant additive solvent convb yieldc d Ts 1 FeCl3 H2O2 --CH3CN NR --Ts 2 13 11 Fe2(SO4)3 H2O2 --CH3CN d 3 NR --Ts Cu(OAc)2 H2O2 --CH3CN 4 25 20 Ts Cu(OTf)2 H2O2 --CH3CN 5 45 30 Ts Cu(BF4)2 H2O2 --CH3CN 6 52 32 Ts Cu(NO3)2 H2O2 --CH3CN 7 40 37 Ts Cu(NO3)2 air --CH3CN 8 25 20 Ts Cu(NO3)2 air --DCM 9 20 17 Ts Cu(NO3)2 air --THF 10 15 13 Ts Cu(NO3)2 air --EtOH 11 100 16 Ts Cu(NO3)2 air --TFE --12 NRd Ts Cu(NO3)2 air K3PO4 TFE d --13 NR Ts Cu(NO3)2 air TEA TFE 14 33 Ts Cu(NO3)2 air HCOOH TFE 100 15 51 Ts Cu(NO3)2 air PhCOOH TFE 100 16 71 Ns Cu(NO3)2 air PhCOOH TFE/DCM 100 17 84 Ns Cu(NO3)2 air PhCOOH TFE/CHCl3 100 a All the reactions were conducted with 1 (0.1 mmol) and styrene 2a (0.2 mmol, 2 equiv) in the presence of oxidant (0.01 mmol, 0.1 equiv), co-oxidant (0.2 mmol, 2 equiv for H2O2, or in air) and additive (0.1 mmol, 1 equiv) in specific solvent at room temperature for 24 hours unless otherwise noted; bthe reaction was quenched after 24 hours if it is in-complete by TLC; cthe isolated yields after chromatography; d no reaction; DCM = dichloromethane, THF = tetrahydrofuran, TFE = trifluoroethanol, TEA = triethyl amine;

Having established the optimized reaction conditions, we next turned to investigate the substrate scope and limitations of this novel CuII-catalyzed radical annulation/3a-benzoylmethylation sequence by variation of two reaction components, respectively (Scheme 2 and Scheme 3). As shown in Scheme 2, a range of



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tryptamine/tryptophol derivatives reacted smoothly to provide the corresponding pyrrolidino[2,3-b]indolines inmoderate to good yields. Exploration of the substituents on the pendant Nb revealed that electron-withdrawing substituents (eg. Ms, Ts, Ns, Bz, Boc, entries 1-5) are generally compatible with this transformation, whereas electron-donating ones (eg., Bn, Me) are not(data not shown),

which might be

attributed to the tight binding between the CuII promoter and the electron-rich amine, thereby inhibiting the C-N bond-forming step. It is noteworthy that the alcohol 3db was detected when Nb-benzoyl-protected tryptamine 1d was subjected to the catalytic system (entry 4). We hypothesized that 3db might be the precursor for its ketone congener 3da. Besides, substituents with varying electronic and steric properties on the indole core also exerted a significant effect on the reaction outcomes. For instance, both N1-unprotected and N1-alkyl tryptamine derivatives were well tolerated (entries 1 and 6), whereas N1-electron-withdrawing (e.g., Boc, Ts) group-masked substrates were inert under the reaction conditions (data not shown). Substrates with electron-donating substituents on C2 and C5 positions of the indole core also provided the desired products in good yields (entries 7 and 8). In addition, the pend ant enolate, alcohol and acid could also be served as capable nucleophiles to effect the transformation (entries 9, 10, 12), thereby affording a diverse set of fused-indolines in moderate to good yields. Notably, we were delighted to find that this mechanism can be translated to the formation of six-membered pyrano[2,3-b]indolines in good yields via 6-exo-trig cyclization using 3-indol propanol as the substrate (entry 11). Taken together, these results suggest that a variety of alkaloids pharmacophores might be


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readily generated using this new strategy. And in view of mechanism, these results also illustrated that the reaction is originated from N1 of indole core and the generation of radical is the rate-determining step in this transformation9, which is thus highly dependent on the electronic nature of the indole core and the oxidation potential of the catalysts. As such, electron-donating substituents on the indole core would be beneficial to the reactivity, whereas the electron-withdrawing ones would be detrimental.



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2 X R

R3

O

Cu(NO3)2 PhCOOH, air

n R1

+

TFE/CHCl3

N 4 1 R

n X

R3

N R1 3 R4

2a

1

3

2 O

4

O N

O N

Ts

N H H 3a, 70%b

N H H 3b, 84%b

N H H 3c, 58%b

N N H H 3e, 53%b

N H Me 3f, 44%b

O

N Me H 3g, 64%b

Me N

Ns

N H H 3h, 60%b

Ns

12

11 O

O

Bz

8

N

Ns

10

9

N H H 3d, 74%b

O N

Boc

N

Ms

7 O

O

O N

Ns

6

5

R2

O

O

O O N H H 3i, 68%b

a

O N H H 3j, 68%b

O N H H 3k, 71%b

COOMe N H COOMe H 3l, 52%b

All the reactions were conducted with 1 (0.1 mmol) and 2a (0.2 mmol, 2 equiv) in

the presence of Cu(NO3)2 (0.01 mmol, 0.1 equiv) and PhCOOH (0.1 mmol, 1 equiv) in TFE/CHCl3 (1:1, 0.1 M) at 0 ℃ unless otherwise noted; bthe isolated yields after chromatography; Scheme 2. Scope of Tryptamine Componenta


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We also explored the scope of this transformation with respect to the aryl ethylene counterpart (Scheme 3). For tryptamine derivatives, examinations of the substituent patterns on the aryl part revealed that this protocol is amenable to both

XH R1

R2

O

Cu(NO3)2

+ 1 1

PhCOOH, air

R2

X TFE/CHCl3

N H

2

Me

3

O

N

Ns

N H H 3m, 52%b

O

O

O N

N R H 3n, 56%b

N Ns

R1

4 F

3 Br

2

N H H

N H H 3o, 68%b

N

Ns

N H H 3p, 52%b

Ns

5 6

Cl

7

O

O N

N H H

8

Br Me N

Ns

N R H 3r, 42%b

3q, 64%b

Ns

O

O N

N H H 3s, 68%b

Ns

N N H H 3t, 58%b

Ns

Me 10

9 O

O N H H 3u, 46%b

Me

O

O N H H 3v, 43%b

a

All the reactions were conducted with 1 (0.1 mmol) and 2 (0.2 mmol, 2 equiv) in the presence of Cu(NO3)2 (0.01 mmol, 0.1 equiv) and PhCOOH (0.1 mmol, 1 equiv) in TFE/CHCl3 (1:1, 0.1 M) at 0 ℃ unless otherwise noted; bthe isolated yields after chromatography;

Scheme 3. Scope of Alkene Componenta



electron-donating and electron–withdrawing substituents in the para- (entries 1-4), meta- (entries 5-6), or ortho- (entry 7) positions. Additionally, 1-naphthyl ethylene also provided the corresponding product 3t in good yields (entry 8). For 3-indol propanol, substituents on the aryl part exerted a negligible effect on the reaction outcome (entries 9 and 10). However, the reaction seemed to be sensitive to the substituents on the alkene part. Alkyl ethylene went with poor conversions and yields, which might be attributed to the relatively poorer radical-trapping reactivity than that of aryl ethylene. And it did not proceed at all when 1,1-disubstituted alkenes, 1,2-disubstituted alkenes were used as the substrates. Next, the selectivity behavior of this reaction was examined. As illustrated in Scheme 4, the chemo-selectivity of this transformation was defined. When the substrate 4 with two competent nucleophilic functionalities on the side chain was applied to the catalytic systems, it provided 6-exo-trig cyclization product 5 exclusively (eq 5). Moreover,

the

reaction also demonstrated interesting

diastereoselectivities. When tryptophan derivatives 6 with different Nb protecting groups were subjected to the catalytic systems, the reaction provided both the exo product 7 and the endo product 8 with varied ratios (eq 6). The tosyl group (endo/exo = 1:3) gave better diastereoselectivity than that of p-nitrobenzenesulfonyl group (endo/exo = 1:2). It’s rationale that the nucleophilicity of the side chain and the stability of the radical intermediate are the governing factors that attribute to the diastereoselectivities.


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HN OH O

2a Cu(NO3)2 PhCOOH, air o

TFE/CHCl3, 0 C 65%

N H 4

COOMe NHR N H 6

2a Cu(NO3)2 PhCOOH, air

TFE/CHCl3, 0 oC

O

O O

O

NH O N H H 5

(5)

N

OH N H H not detected

O

O

COOMe

COOMe N

+

N

R

N H N H H H 7 8 R = Ns: 61% yield; 7a:8a (1:2) R = Ts: 46% yield; 7b:8b(1:3)

R

(6)

Scheme 4. Investigations of Selectivity Behavior To gain insight into the reaction mechanism, several experiments were also performed. Control experiments revealed that the reaction would not occur in the absence of air and cupric salts, indicating their key role in this transformation (Scheme SI-1, eq 2 and eq 3). Radical trapping experiment revealed that TEMPO completely inhibited the reaction (Scheme 5a, eq 7). And

18

O-labelling experiment

demonstrated that the oxygen in the product was derived from O2 in the air, but not from the acid or H2O (Scheme 5a, eq 8). To our surprise, when the alcohol 3db was applied to the catalytic system, no reaction occurred (Scheme 5a, eq 9), which suggests that 3db is not a precursor for 3da. On the other hand, when 3-methyl indole 10 was utilized as the starting material, the reaction ran smoothly to furnish the 3-benzoylmethyl-2-indolone 11 as the sole product (Scheme 5a, eq 10). On the basis of results mentioned above as well as previous reports9-10, a plausible mechanism was proposed (Scheme 5b). Initially, CuII-initiated oxidation of



tryptamine

Schemes 5. Mechanistic Studies and Proposed Mechanism. (a) Mechanistic Experiments. (b) Proposed Mechanism. derivative to generate the radical intermediate I, followed by Markovnikov-type radical addition to the aryl ethylene and being consecutively trapped by O2 to give radical intermediate II and III, respectively. Subsequently, peroxide intermediate III


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may evolve with significant varied pathways. On one hand, III may involve in homolytic fragmentation to provide the ketone product IV (path a)

13

. Since the

reaction is sensitive to the substituents on the alkene part (eg. di-, tri-substituent alkene), we speculate that heterolytic fragmentation is also possible (path b). On the other hand, III can also be reduced by CuI species generated in the catalytic cycle, thereby delivering the alcohol product IV (path c). Given that acid additives are beneficial to the reaction outcome, we speculate that the reaction might favor the later one and the acid plays a role in facilitating the heterolytic fragmentation. Further evidence is still required to clarify this mechanism. CONCLUSION In conclusion, we have developed a novel CuII-catalyzed oxidative annulation/ C3-functionalization sequence that allows the rapid construction of 3a-benzoylmethyl pyrrolidino[2,3-b]indolines with high chemo- and regio-selectivity from readily available tryptamine derivatives and aryl ethylene. Remarkably, this innovative methodology utilizes air as the co-oxidant, rendering the process highly environment-friendly and atom-economic. Presumably, the reaction proceeds through CuII-initiated formation of pyrrolidino[2,3-b]indolines radical intermediate I, which is successively trapped by aryl ethylene and O2 to form the product. Further applications of this method in total synthesis of complex pyrrolidino[2,3-b]indoline alkaloids are underway.

EXPERIMENTAL SECTION



General information. All reactions were performed under air atmosphere using flame-dried glassware unless otherwise noted.

All reagents were commercially

available and used without further purification unless indicated otherwise. Thin layer chromatographies were carried out on GF254 plates (0.25 mm layer thickness). Flash chromatography was performed with 300–400 mesh silica gels. Visualization of the developed chromatogram was performed by fluorescence quenching or by ceric ammonium molybdate, or KMnO4 stain. Yields reported were for isolated, spectroscopically pure compounds. 1

H and

13

C–NMR experiments were performed on a Bruker AM-400 and

DRX-600 NMR spectrometer at ambient temperature. The residual solvent protons (1H) or the solvent carbons (13C) were used as internal standards. 1H-NMR data are presented as follows: chemical shift in ppm downfield from tetramethylsilane (multiplicity, coupling constant, integration). The following abbreviations are used in reporting NMR data: s, singlet; br s, broad singlet; d, doublet; t, triplet; q, quartet; qt, quartet of triplets; dd, doublet of doublets; dt, doublet of triplets; AB, AB quartet; m, multiplet. ESIMS and HRESIMS were taken on API STAR Pulsar. X-ray diffraction was obtained by APEX DUO. General procedure for compounds 3a-3v, 5, 7a, 8a, 8b, 9, 11. To a stirred solution of compound 1 (0.1 mmol, 1.0 equiv) in TFE/CHCl3 (1:1, 1 mL) were added PhCOOH (0.1 mmol, 1.0 eq.) and aryl ethylene 2 (0.2 mmol, 2.0 eq.) successively at 0℃. Then Cu(NO3)2 (0.01 mmol, 0.1 eq.) was added. The mixture was stirred at 0℃ for 2-12 hours until no starting material was detected by TLC. The reaction was quenched with aqueous NaOH solution (2N) and was extracted with EtOAc for three times (20 mL). The combined organic layer was washed with brine (20 mL) and was dried over Na2SO4, filtered, and concentrated in vacuum. The residue was purified by flash column chromatography (PE/EA=6:1). 1-Toluenesulfonyl-3a-benzoylmethyl-3,3a,8,8a-tetrahydropyrrol[2,3-b]indoline (Compound 3a). White solid ( 30.3 mg from 0.1 mmol starting material, 70%), 1

H-NMR (500 MHz, CDCl3) δ 7.86-7.73 (m, 4H), 7.55 (t, J = 7.4 Hz, 1H), 7.42 (t, J

= 7.8 Hz, 2H), 7.34 (d, J = 8.1 Hz, 2H), 7.28 (s, 1H), 7.17 (d, J = 7.4 Hz, 1H), ACS Paragon Plus Environment

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7.13-7.07 (m, 1H), 6.75 (t, J = 7.4 Hz, 1H), 6.68 (d, J = 7.8 Hz, 1H), 5.35 (s, 1H), 3.51 – 3.39 (m, 2H), 3.19 (ddd, J = 29.5, 16.8, 11.7 Hz, 2H), 2.51-2.47 (m, 1H), 2.46 (s, 3H), 2.12 (ddd, J = 12.6, 10.3, 8.4 Hz, 1H); 13C-NMR (126 MHz, CDCl3) δ 197.3, 148.6, 143.5, 137.1, 135.8, 133.3, 131.2, 129.8, 128.8, 128.6, 128.0, 127.2, 123.8, 119.5, 110.1, 83.2, 55.6, 47.6, 44.2, 35.0, 21.6; HR-ESI-MS (m/z): calcd. For C25H25N2O3S [M+H]+ 433.1580, found 433.1575. 1-p-Nitrophenylsulfonyl-3a-benzoylmethyl-3,3a,8,8a-tetrahydropyrrol[2,3-b]indo line (Compound 3b). Yellow solid ( 38.9 mg from 0.1 mmol starting material, 84%), 1

H-NMR (400 MHz, CDCl3) δ 8.37 (dd, J = 8.7, 2.0 Hz, 2H), 8.16 (dd, J = 8.7, 2.0

Hz, 2H), 7.81 (d, J = 8.0 Hz, 2H), 7.59-7.52 (m, 1H), 7.43 (t, J = 6.9 Hz, 2H), 7.12 (d, J = 7.4 Hz, 1H), 7.01 (s, 1H), 6.72-6.64 (m, 1H), 6.61 (d, J = 7.8 Hz, 1H), 5.57 (s, 1H), 3.53 (s, 1H), 3.47 (dd, J = 17.5, 1.7 Hz, 1H), 3.28 (d, J = 1.7 Hz, 1H), 3.11-2.99 (m, 1H), 2.38 (s, 1H), 2.29-2.16 (m, 1H); 13C-NMR (101 MHz, CDCl3) δ 197.1, 149.6, 148.6, 144.6, 136.6, 133.1, 130.8, 128.5, 128.4, 128.3, 127.6, 124.0, 123.1, 118.7, 109.2, 82.4, 55.5, 47.0, 43.8, 35.0; HR-ESI-MS (m/z): calcd. for C24H21N3O5S Na [M+Na]+, 486.1094 , found 486.1094. 1-Methylsulfonyl-3a-benzoylmethyl-3,3a,8,8a-tetrahydropyrrol[2,3-b]indoline (Compound 3c). White solid ( 20.7 mg from 0.1 mmol starting material, 58%), 1

H-NMR (500 MHz, CDCl3) δ 7.89 (d, J = 7.5 Hz, 2H), 7.58 (t, J = 7.4 Hz, 1H), 7.45

(t, J = 7.7 Hz, 2H), 7.18 (d, J = 7.4 Hz, 1H), 7.13 (t, J = 7.5 Hz, 1H), 6.81 (t, J = 7.4 Hz, 1H), 6.70 (d, J = 7.8 Hz, 1H), 5.54 (s, 1H), 3.64 (t, J = 8.8 Hz, 1H), 3.57 (d, J = 18.0 Hz, 1H), 3.38 (d, J = 18.0 Hz, 1H), 3.21 (td, J = 10.6, 6.1 Hz, 1H), 3.06 (s, 3H), 2.62-2.51 (m, 1H), 2.43 (dd, J = 12.4, 5.6 Hz, 1H). 13C-NMR (126 MHz, CDCl3) δ 197.7, 148.8, 136.9, 133.5, 131.7, 128.9, 128.7, 127.9, 123.4, 119.7, 110.1, 82.0, 55.7, 47.3, 44.4, 37.3, 35.5. HR-ESI-MS (m/z): calcd. for C19H21N2O3S[M+H]+, 357.1267, found 357.1261. 1-Benzoyl-3a-benzoylmethyl-3,3a,8,8a-tetrahydropyrrol[2,3-b]indoline (Compound 3da). White solid ( 28.3 mg from 0.1 mmol starting material, 74% for the combined yield of compounds 3da and 3db, the ratio is 3da:3db = 1.89:1 by 1

H-NMR ), 1H-NMR (400 MHz, CDCl3) δ 7.92 -7.89 (m, 2H), 7.59-7.54 (m, 1H), ACS Paragon Plus Environment


7.53-7.36 (m, 7H), 7.33-7.29 (m, 1H), 7.13 (td, J = 7.7, 1.2 Hz, 1H), 6.76 (td, J = 7.5, 0.8 Hz, 1H), 6.70 (d, J = 7.8 Hz, 1H), 5.70 (s, 1H), 3.72-3.60 (m, 2H), 3.39 (td, J = 11.1, 6.0 Hz, 1H), 3.30 (d, J = 17.2 Hz, 1H), 2.72 (dd, J = 12.7, 5.9 Hz, 1H), 2.48-2.38 (m, 1H). 13C-NMR (101 MHz, CDCl3) δ 197.7, 170.0, 149.3, 137.2, 136.0, 133.2, 130.8, 130.2, 128.8, 128.6, 128.2, 128.0, 127.2, 124.6, 119.1, 109.6, 81.2, 53.7, 49.4, 44.4, 34.8. HR-ESI-MS (m/z): calcd. for C25H22N2O2 Na [M+Na]+, 405.1573 , found 405.1575. 1-Benzoyl-3a-(2-phenyl-2-hydroxyl-ethyl)-3,3a,8,8a-tetrahydropyrrol[2,3-b]indol ine (Compound 3db). Colorless film ( 28.3 mg from 0.1 mmol starting material, 74% for the combined yield of compounds 3da and 3db, the ratio is 3da:3db = 1.89:1 by 1

H-NMR ), 1H-NMR (500 MHz, CDCl3) δ 7.71-7.62 (m, 2H), 7.50 (t, J = 7.4 Hz,

1H), 7.42 (t, J = 7.6 Hz, 2H), 7.36-7.26 (m, 4H), 7.18 (t, J = 7.8 Hz, 2H), 6.89 (t, J = 7.4 Hz, 1H), 6.74 (d, J = 7.7 Hz, 1H), 6.37 (s, 1H), 5.66 (s, 1H), 4.76 (dd, J = 11.1, 4.4 Hz, 1H), 3.56 (dq, J = 12.7, 6.3 Hz, 1H), 3.29 (td, J = 13.7, 6.3 Hz, 1H), 2.61 (dd, J = 12.1, 4.4 Hz, 1H), 2.31 (dt, J = 12.5, 6.2 Hz, 1H), 2.23 (dt, J = 14.0, 7.2 Hz, 1H), 2.17 – 2.09 (m, 1H).13C-NMR (126 MHz, CDCl3) δ 167.1, 149.9, 140.7, 134.3, 131.4, 131.1, 128.8, 128.5, 128.4, 127.7, 126.8, 125.8, 123.6, 119.8, 109.3, 97.6, 80.4, 57.9, 49.6, 37.6, 37.1. HR-ESI-MS (m/z): calcd. for C25H23N2O2 [M-H]-, 383.1760, found 383.1765. 1-t-Butoxycarbonyl-3a-benzoylmethyl-3,3a,8,8a-tetrahydropyrrol[2,3-b]indoline (Compound 3e). White solid ( 20 mg from 0.1 mmol starting material, 53%), 1

H-NMR (400 MHz, CDCl3) δ 7.89 (d, J = 7.9 Hz, 4H), 7.59-7.51 (m, 2H), 7.43 (dd,

J = 10.4, 4.9 Hz, 4H), 7.24 (t, J = 7.8 Hz, 2H), 7.08 (td, J = 7.7, 1.1 Hz, 2H), 6.74 (dt, J = 15.2, 7.6 Hz, 2H), 6.65 (dd, J = 7.6, 5.4 Hz, 2H), 5.32 (s, 1H), 5.29 (s, 1H), 3.80 – 3.71 (m, 1H), 3.69 – 3.53 (m, 3H), 3.26 (dd, J = 20.7, 17.1 Hz, 2H), 3.07 (tt, J = 12.0, 6.2 Hz, 2H), 2.62 (dd, J = 12.6, 6.2 Hz, 1H), 2.54 (dd, J = 12.5, 6.0 Hz, 1H), 2.39 (ddd, J = 22.2, 12.8, 7.9 Hz, 2H), 1.55 (s, 6H), 1.47 (s, 6H), 1.28 (s, 6H); 13C-NMR (101 MHz, CDCl3) δ 197.8, 197.7, 154.5, 153.5, 149.2, 148.8, 137.3, 133.1, 131.5, 131.4, 128.6, 128.5, 128.0, 128.0, 124.4, 124.1, 119.3, 118.9, 109.7, 109.5, 80.8, 80.3,


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80.2, 79.8, 77.2, 55.3, 54.4, 46.1, 45.6, 44.3, 34.0, 28.6, 28.5; HR-ESI-MS (m/z): calcd. for C23H27N2O3[M+H]+, 379.2016, found 379.2019. 1-p-Nitrophenylsulfonyl-8-methyl-3a-benzoylmethyl-3,3a,8,8a-tetrahydropyrrol [2,3-b]indoline (Compound 3f). Yellow solid ( 42 mg from 0.2 mmol starting material, 44%), 1H-NMR (400 MHz, CDCl3) δ 8.41-8.36 (m, 2H), 8.20-8.14 (m, 2H), 7.84-7.77 (m, 2H), 7.58 (t, J = 7.4 Hz, 1H), 7.44 (t, J = 7.7 Hz, 2H), 7.16 (td, J = 7.7, 1.0 Hz, 1H), 7.07 (d, J = 6.8 Hz, 1H), 6.70 (t, J = 7.4 Hz, 1H), 6.47 (d, J = 7.8 Hz, 1H), 5.65 (s, 1H), 3.60 (dd, J = 11.8, 7.0 Hz, 1H), 3.35 (d, J = 17.3 Hz, 1H), 3.21 (d, J = 17.2 Hz, 1H), 3.11 (dd, J = 11.8, 5.2 Hz, 1H), 3.07 (s, 3H), 2.20 (dd, J = 12.3, 4.9 Hz, 1H), 1.92 (td, J = 12.0, 7.4 Hz, 1H); 13C-NMR (101 MHz, CDCl3) δ 197.0, 150.2, 150.0, 145.3, 136.6, 133.6, 131.1, 129.2, 128.8, 128.7, 127.9, 124.3, 122.7, 118.2, 106.6, 88.4, 55.1, 48.1, 43.9, 36.2, 32.1; HR-ESI-MS (m/z): calcd. for C25H24N3O5S[M+H]+, 478.1431, found 478.1429. 1-p-Nitrophenylsulfonyl-3a-benzoylmethyl-8a-methyl-3,3a,8,8a-tetrahydropyrrol [2,3-b]indoline (Compound 3g). Yellow solid ( 30.5 mg from 0.1 mmol starting material, 64%), 1H-NMR (500 MHz, CDCl3) δ 8.18 (d, J = 8.5 Hz, 2H), 7.79 (d, J = 8.5 Hz, 2H), 7.71 (d, J = 8.0 Hz, 2H), 7.51 (t, J = 7.0 Hz, 1H), 7.37 (t, J = 7.6 Hz, 2H), 7.11 (d, J = 7.5 Hz, 1H), 6.92 (t, J = 7.6 Hz, 1H), 6.57 (t, J = 7.5 Hz, 1H), 6.44 (d, J = 7.8 Hz, 1H), 3.59 (t, J = 8.5 Hz, 1H), 3.44 (d, J = 16.0 Hz, 1H), 3.08 (dd, J = 13.2, 6.7 Hz, 1H), 2.93-2.79 (m, 2H), 2.30-2.22 (m, 1H), 1.89 (s, 3H). 13C-NMR (126 MHz, CDCl3) δ 197.5, 149.6, 146.7, 145.1, 137.3, 133.2, 130.4, 128.5, 128.5, 128.1, 128.0, 125.3, 124.0, 119.8, 109.5, 93.7, 57.3, 47.5, 42.3, 31.7, 22.7. HR-ESI-MS (m/z): calcd. for C25H24N3O5S [M+H]+, 478.1431 , found 478.1429. 1-p-Nitrophenylsulfonyl-5-methyl-3a-benzoylmethyl-3,3a,8,8a-tetrahydropyrrol [2,3-b] indoline (Compound 3h). Yellow solid ( 28.6 mg from 0.1 mmol starting material, 60%), 1H-NMR (500 MHz, CDCl3) δ 8.49-8.37 (m, 2H), 8.20-8.09 (m, 2H), 7.81 (d, J = 8.1 Hz, 2H), 7.57 (t, J = 7.4 Hz, 1H), 7.44 (t, J = 7.7 Hz, 2H), 6.94 (d, J = 8.3 Hz, 2H), 6.60 (d, J = 7.7 Hz, 1H), 5.51 (s, 1H), 3.53 (t, J = 9.1 Hz, 1H), 3.45 (d, J = 17.6 Hz, 1H), 3.29-3.14 (m, 2H), 2.41-2.28 (m, 2H), 2.26 (s, 3H); 13C-NMR (126 MHz, CDCl3) δ 197.2, 150.1, 145.9, 144.8, 136.8, 133.5, 131.5, 129.5, 129.3, 128.7, ACS Paragon Plus Environment


Page 20 of 31

128.6, 127.9, 124.4, 124.0, 110.1, 82.8, 55.8, 47.6, 43.7, 34.6, 20.9; HR-ESI-MS (m/z): calcd. for C25H23N3O5SNa [M+Na]+, 500.1251, found 500.1250 . 3a-Benzoylmethyl-3,3a,8,8a-tetrahydrofuranyl

[2,3-b]

indoline-2-one

(Compound 3i). White solid ( 20.0 mg from 0.1 mmol starting material, 68%), 1

H-NMR (500 MHz, DMSO-d6) δ 7.94 (d, J = 7.7 Hz, 2H), 7.63 (t, J = 7.3 Hz, 1H),

7.50 (t, J = 7.5 Hz, 2H), 7.46 (s, 1H), 7.30 (d, J = 7.4 Hz, 1H), 7.06 (t, J = 7.5 Hz, 1H), 6.69 (t, J = 7.4 Hz, 1H), 6.63 (d, J = 7.7 Hz, 1H), 5.99 (s, 1H), 3.68 (d, J = 18.1 Hz, 1H), 3.53 (d, J = 18.2 Hz, 1H), 3.16 (d, J = 17.7 Hz, 1H), 2.99 (d, J = 17.9 Hz, 1H); 13

C-NMR (126 MHz, DMSO) δ 198.3, 175.8, 148.0, 137.1, 133.9, 132.5, 129.3,

129.1, 128.4, 125.3, 119.2, 109.4, 99.4, 51.0, 44.0; HR-ESI-MS (m/z): calcd. For C18H14NO3 [M-H]-, 292.0979, found 292.0977. 3a-Benzoylmethyl-3,3a,8,8a-tetrahydrofuranyl[2,3-b]indoline

(Compound 3j).

White solid ( 38 mg from 0.2 mmol starting material, 68%), 1H-NMR(500 MHz, CDCl3) δ 7.91 (d, J = 7.8 Hz, 2H), 7.56 (t, J = 7.3 Hz, 1H), 7.45 (t, J = 7.5 Hz, 2H), 7.21 (d, J = 7.4 Hz, 1H), 7.07 (t, J = 7.6 Hz, 1H), 6.73 (t, J = 7.4 Hz, 1H), 6.65 (d, J = 7.8 Hz, 1H), 5.64 (s, 1H), 4.04 (t, J = 8.0 Hz, 1H), 3.65 – 3.58 (m, 1H), 3.55 (s, 2H), 2.48 (dd, J = 12.0, 4.9 Hz, 1H), 2.34 (td, J = 11.6, 7.6 Hz, 1H)；13C-NMR (126 MHz, CDCl3) δ 197.7, 149.4, 137.2, 133.2, 132.1, 128.6, 128.4, 128.0, 124.1, 119.2, 108.8, 98.2, 67.0, 55.4, 45.5, 39.7; HR-ESI-MS (m/z): calcd. For C18H17NO2Na [M+Na]+, 302.1152, found 302.1150. 4a-Benzoylmethyl-4,4a,9,9a-hexahydropyranyl[2,3-b]indoline (Compound 3k). White solid ( 35 mg from 0.2 mmol starting material, 71%), 1H-NMR(500 MHz, CDCl3) δ 7.80 (d, J = 7.8 Hz, 2H), 7.51 (t, J = 7.3 Hz, 1H), 7.38 (t, J = 7.5 Hz, 2H), 7.14 (d, J = 7.3 Hz, 1H), 7.10 (t, J = 7.6 Hz, 1H), 6.77 (dd, J = 15.6, 7.7 Hz, 2H), 5.13 (s, 1H), 3.75 (d, J = 11.1 Hz, 1H), 3.60-3.52 (m, 1H), 3.30 (d, J = 16.2 Hz, 1H), 3.00 (d, J = 16.2 Hz, 1H), 2.49 (d, J = 13.9 Hz, 1H), 2.25-2.14 (m, 1H), 1.59-1.50 (m, 2H). 13

C-NMR (126 MHz, CDCl3) δ 198.6, 148.9, 137.7, 132.9, 132.0, 128.4, 128.1, 123.3,

119.6, 110.3, 92.7,63.0, 46.8, 45.6, 27.5, 21.8. HR-ESI-MS (m/z): calcd. For C19H19NO2 Na [M+Na]+, 316.1308, found 316.1311.


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1,1-dimethoxylcarbonyl-3a-Benzoylmethyl-3,3a,8,8a-tetrahydrocyclopentyl[2,3-b ]indoline (Compound 3l.) Colorless oil ( 20.4 mg from 0.1 mmol starting material, 52%), 1H-NMR (500 MHz, DMSO-d6) δ 7.91 (d, J = 7.5 Hz, 2H), 7.61 (t, J = 7.3 Hz, 1H), 7.49 (t, J = 7.7 Hz, 2H), 7.01 (d, J = 7.3 Hz, 1H), 6.83 (t, J = 7.5 Hz, 1H), 6.46 – 6.35 (m, 2H), 5.97 (d, J = 4.9 Hz, 1H), 4.82 (d, J = 4.9 Hz, 1H), 3.91 (d, J = 17.5 Hz, 1H), 3.68 (d, J = 3.1 Hz, 6H), 3.38 (d, J = 17.5 Hz, 1H), 2.11 – 2.03 (m, 1H), 2.03 – 1.93 (m, 2H), 1.78 (td, J = 12.2, 7.5 Hz, 1H). 13C-NMR (126 MHz, DMSO-d6) δ 198.7, 171.7, 169.2, 152.2, 137.7, 134.8, 133.5, 129.1, 128.3, 127.8, 123.1, 117.5, 108.7, 71.3, 67.7, 55.6, 53.1, 52.7, 47.8, 39.3, 30.8; HR-ESI-MS (m/z): calcd. For C23H24NO5 [M+H]+, 394.1649, found 394.1654. 1-p-Nitrophenylsulfonyl-3a-(p-methyl-benzoylmethyl)-3,3a,8,8a-tetrahydro pyrrol[2,3-b]indoline (Compound 3m). Yellow solid ( 25.0 mg from 0.1 mmol starting material, 52%), 1H-NMR (500 MHz, CDCl3) δ 8.41 (d, J = 8.5 Hz, 2H), 8.13 (d, J = 8.5 Hz, 2H), 7.70 (d, J = 7.9 Hz, 2H), 7.23 (d, J = 7.9 Hz, 2H), 7.15 (dd, J = 7.5, 4.0 Hz, 2H), 6.81 (t, J = 7.4 Hz, 1H), 6.69 (d, J = 7.8 Hz, 1H), 5.53 (s, 1H), 3.52 (s, 1H), 3.43 (d, J = 17.5 Hz, 1H), 3.24 (d, J = 6.3 Hz, 1H), 3.20 (d, J = 17.4 Hz, 1H), 2.41 (s, 3H), 2.36 – 2.32 (m, 2H); 13C-NMR (126 MHz, CDCl3) δ 196.8, 150.1, 148.2, 144.7, 144.5, 134.3, 131.3, 129.4, 129.1, 128.5, 128.0, 124.4, 123.3, 119.9, 110.1, 82.5, 55.8, 47.6, 43.5, 34.7, 21.7; HR-ESI-MS (m/z): calcd. for C25H23N3O5SNa [M+Na]+, 500.1251, found 500.1250. 1-p-Nitrophenylsulfonyl-3a-(p-isopropyl-benzoylmethyl)-3,3a,8,8a-tetrahydropyr rol[2,3-b]indoline (Compound 3n). Yellow solid ( 28.0 mg from 0.1 mmol starting material, 56%), 1H-NMR (400 MHz, CDCl3) δ 8.53-8.31 (m, 2H), 8.22-8.09 (m, 2H), 7.74 (d, J = 8.4 Hz, 2H), 7.29 (t, J = 4.1 Hz, 2H), 7.17-7.09 (m, 2H), 6.81 (td, J = 7.5, 0.8 Hz, 1H), 6.70 (d, J = 7.7 Hz, 1H), 5.53 (s, 1H), 3.52 (td, J = 8.1, 4.1 Hz, 1H), 3.44 (d, J = 17.6 Hz, 1H), 3.31 – 3.23 (m, 1H), 3.20 (d, J = 17.6 Hz, 1H), 3.01-2.92 (m, 1H), 2.32 (ddd, J = 18.6, 8.5, 4.9 Hz, 2H), 1.28 (s, 6H); 13C-NMR (101 MHz, CDCl3) δ 196.8, 155.2, 150.1, 148.2, 144.7, 134.7, 131.3, 129.1, 128.6, 128.2, 126.8, 124.4, 123.3, 119.9, 110.1, 82.5, 55.8, 47.7, 43.5, 34.7, 34.3, 23.6; HR-ESI-MS (m/z): calcd. For C27H27N3O5SNa [M+Na]+, 528.1564, found 528.1568. ACS Paragon Plus Environment


1-p-Nitrophenylsulfonyl-3a-(p-bromo-benzoylmethyl)-3,3a,8,8a-tetrahydropyrrol [2,3-b]indoline (Compound 3o). Yellow solid ( 36.8 mg from 0.1 mmol starting material, 68%), 1H-NMR (400 MHz, CDCl3) δ 8.47-8.38 (m, 2H), 8.14 (d, J = 8.9 Hz, 2H), 7.69-7.63 (m, 2H), 7.57 (d, J = 8.6 Hz, 2H), 7.14 (ddd, J = 7.0, 4.0, 2.8 Hz, 2H), 6.81 (td, J = 7.5, 0.6 Hz, 1H), 6.69 (d, J = 7.8 Hz, 1H), 5.50 (s, 1H), 3.53 (ddd, J = 9.8, 8.1, 1.4 Hz, 1H), 3.43 (d, J = 17.8 Hz, 1H), 3.27-3.16 (m, 2H), 2.42-2.35 (m, 1H), 2.32-2.23 (m, 1H); 13C-NMR (126 MHz, CDCl3) δ 196.2, 150.2, 148.2, 144.8, 135.4, 132.0, 131.6, 130.9, 129.4, 129.2, 128.5, 124.4, 123.4, 119.9, 110.2, 82.5, 55.6, 47.6, 43.7, 34.7; HR-ESI-MS (m/z): calcd. forC24H20BrN3O5SNa [M+Na]+, 564.0199, found 564.0200. 1-p-Nitrophenylsulfonyl-3a-(p-fluoro-benzoylmethyl)-3,3a,8,8a-tetrahydropyrrol [2,3-b]indoline (Compound 3p). Yellow solid ( 25.0 mg from 0.1 mmol starting material, 52%), 1H-NMR (500 MHz, CDCl3) δ 8.40 (t, J = 10.6 Hz, 2H), 8.14 (t, J = 9.4 Hz, 2H), 7.83 (dd, J = 8.7, 5.4 Hz, 2H), 7.16-7.07 (m, 4H), 6.80 (t, J = 7.4 Hz, 1H), 6.69 (d, J = 7.9 Hz, 1H), 5.52 (s, 1H), 3.54 (t, J = 8.7 Hz, 1H), 3.44 (d, J = 17.6 Hz, 1H), 3.26-3.17 (m, 2H), 2.38 (dd, J = 12.2, 5.7 Hz, 1H), 2.33-2.25 (m, 1H); 13

C-NMR (126 MHz, CDCl3) δ 195.6, 166.9, 164.9, 150.1, 148.2, 144.8, 133.2, 133.2,

131.0, 130.6, 130.6, 129.2, 128.5, 124.4, 123.4, 119.9, 115.9, 115.7, 110.2, 82.5, 55.7, 47.6, 43.7, 34.7; HR-ESI-MS (m/z): calcd. for C24H20FN3O5SNa [M+Na]+, 504.1000, found 504.1002. 1-p-Nitrophenylsulfonyl-3a-(m-chloro-benzoylmethyl)-3,3a,8,8a-tetrahydropyrro l[2,3-b]indoline (Compound 3q). Yellow solid ( 32 mg from 0.1 mmol starting material, 64%), 1H-NMR (400 MHz, CDCl3) δ 8.49-8.39 (m, 2H), 8.16-8.07 (m, 2H), 7.84-7.73 (m, 1H), 7.70-7.66 (m, 1H), 7.58-7.48 (m, 1H), 7.43-7.34 (m, 1H), 7.13 (ddd, J = 15.7, 8.6, 7.3 Hz, 2H), 6.86-6.76 (m, 1H), 6.69 (d, J = 7.7 Hz, 1H), 5.51 (s, 1H), 3.54 (ddd, J = 9.9, 8.2, 1.5 Hz, 1H), 3.44 (d, J = 17.8 Hz, 1H), 3.29 – 3.14 (m, 2H), 2.44 – 2.36 (m, 1H), 2.33 – 2.24 (m, 1H); 13C-NMR (101 MHz, CDCl3) δ 196.0, 150.2, 148.2, 144.8, 138.2, 135.1, 133.4, 130.8, 130.0, 129.2, 128.5, 128.0, 126.0, 124.4, 123.4, 120.0, 110.2, 82.5, 55.6, 47.6, 44.0, 34.7; HR-ESI-MS (m/z): calcd. for C24H20ClN3O5S Na [M+Na]+, 520.0704, found 520.0706. ACS Paragon Plus Environment

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1-p-Nitrophenylsulfonyl-3a-(m-bromo-benzoylmethyl)-3,3a,8,8a-tetrahydro pyrrol[2,3-b]indoline (Compound 3r). Yellow solid ( 23 mg from 0.1 mmol starting material, 42%), 1H-NMR (500 MHz, CDCl3) δ 8.42 (d, J = 8.7 Hz, 2H), 8.13 (d, J = 8.7 Hz, 2H), 7.92 (s, 1H), 7.70 (dd, J = 16.2, 7.9 Hz, 2H), 7.35-7.26 (m, 1H), 7.18 – 7.11 (m, 2H), 6.81 (t, J = 7.4 Hz, 1H), 6.69 (d, J = 7.8 Hz, 1H), 5.50 (s, 1H), 3.53 (t, J = 8.9 Hz, 1H), 3.44 (d, J = 17.8 Hz, 1H), 3.29 – 3.14 (m, 2H), 2.40 (dd, J = 12.4, 5.7 Hz, 1H), 2.31 – 2.23 (m, 1H); 13C-NMR (126 MHz, CDCl3) δ 195.9, 150.2, 148.2, 144.8, 138.4, 136.4, 131.0, 130.8, 130.3, 129.2, 128.5, 126.4, 124.4, 123.4, 123.0, 120.0, 110.2, 82.5, 55.6, 47.6, 44.0, 34.7; HR-ESI-MS (m/z): calcd. for C24H20BrN3O5SNa [M+Na]+, 564.0199, found 564.0196. 1-p-Nitrophenylsulfonyl-3a-(o-methyl-benzoylmethyl)-3,3a,8,8a-tetrahydro pyrrol[2,3-b]indoline (Compound 3s). Yellow solid ( 32 mg from 0.1 mmol starting material, 68%), 1H-NMR (500 MHz, CDCl3) δ 8.45-8.38 (m, 2H), 8.16 (dd, J = 12.7, 5.7 Hz, 2H), 7.48 (d, J = 7.7 Hz, 1H), 7.37 (t, J = 7.0 Hz, 1H), 7.21 (t, J = 7.8 Hz, 2H), 7.13 (t, J = 7.8 Hz, 2H), 6.79 (t, J = 7.4 Hz, 1H), 6.69 (d, J = 7.7 Hz, 1H), 5.55 (s, 1H), 3.57 (ddd, J = 9.9, 8.2, 1.4 Hz, 1H), 3.37 (d, J = 17.6 Hz, 1H), 3.24 (td, J = 10.6, 6.2 Hz, 1H), 3.18 (d, J = 17.6 Hz, 1H), 2.37 (dd, J = 12.6, 5.0 Hz, 1H), 2.31 (d, J = 5.9 Hz, 3H), 2.30-2.24 (m, 1H);

13

C-NMR (126 MHz, CDCl3) δ 201.2, 150.1, 148.3, 144.8,

138.3, 137.4, 132.2, 131.8, 131.1, 129.1, 128.6, 128.4, 125.8, 124.4, 123.3, 119.9, 110.1, 82.3, 56.0, 47.6, 46.4, 35.1, 21.3; HR-ESI-MS (m/z): calcd. for C25H23N3O5SNa [M+Na]+, 500.1251, found 500.1250. 1-p-Nitrophenylsulfonyl-3a-(1-naphthoylmethyl)-3,3a,8,8a-tetrahydro pyrrol[2,3-b]indoline (Compound 3t). Yellow solid ( 30 mg from 0.1 mmol starting material, 58%), 1H-NMR (500 MHz, CDCl3) δ 8.42 (d, J = 7.9 Hz, 2H), 8.31 (s, 1H), 8.14 (d, J = 7.9 Hz, 2H), 7.96-7.83 (m, 4H), 7.63 (t, J = 7.4 Hz, 1H), 7.58 (t, J = 7.4 Hz, 1H), 7.20 (d, J = 7.5 Hz, 1H), 7.16 (t, J = 7.7 Hz, 1H), 6.83 (t, J = 7.4 Hz, 1H), 6.72 (d, J = 7.8 Hz, 1H), 5.57 (s, 1H), 3.60 (d, J = 17.5 Hz, 1H), 3.55 (t, J = 9.1 Hz, 1H), 3.37 (d, J = 17.5 Hz, 1H), 3.28 (dt, J = 16.7, 8.3 Hz, 1H), 2.37 (dd, J = 17.6, 8.1 Hz, 2H); 13C-NMR (126 MHz, CDCl3) δ 197.1, 150.2, 148.2, 144.7, 135.7, 134.0, 132.3, 131.3, 129.8, 129.6, 129.2, 128.8, 128.6, 128.5, 127.8, 127.0, 124.4, 123.4, ACS Paragon Plus Environment


123.3, 119.9, 110.2, 82.5, 55.8, 47.7, 43.7, 34.6; HR-ESI-MS (m/z): calcd. for C28H23N3O5S Na [M+Na]+, 536.1251, found 536.1252. 4a-(p-methyl-benzoylmethyl)-4,4a,9,9a-hexahydropyranyl[2,3-b]indoline (Compound 3u). White solid ( 14 mg from 0.1 mmol starting material, 46%), 1

H-NMR (400 MHz, CDCl3) δ 7.71 (d, J = 8.2 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 7.14

(d, J = 7.3 Hz, 1H), 7.13-7.08 (m, 1H), 6.83-6.68 (m, 2H), 5.13 (s, 1H), 3.75 (ddd, J = 11.1, 5.2, 3.5 Hz, 1H), 3.61-3.50 (m, 1H), 3.25 (d, J = 16.1 Hz, 1H), 2.98 (d, J = 16.1 Hz, 1H), 2.47 (dd, J = 13.8, 1.5 Hz, 1H), 2.42 (s, 3H), 2.26-2.15 (m, 1H), 1.60-1.49 (m, 2H); 13C-NMR (101 MHz, CDCl3) δ 198.3, 149.1, 143.7, 135.3, 132.1, 129.1, 128.2, 128.0, 123.3, 119.4, 110.2, 92.6, 63.0, 46.8, 45.5, 27.4, 21.9, 21.6; HR-ESI-MS (m/z): calcd. for C20H21NO2Na [M+Na]+, 330.1465, found 330.1464. 4a-(o-methyl-benzoylmethyl)-4,4a,9,9a-hexahydropyranyl[2,3-b]indoline (Compound 3v). White solid ( 13 mg from 0.1 mmol starting material, 43%), 1

H-NMR (400 MHz, CDCl3) δ 7.35 (dd, J = 7.8, 4.5 Hz, 1H), 7.33 – 7.27 (m, 1H),

7.20 (d, J = 7.6 Hz, 1H), 7.15 (d, J = 8.4 Hz, 1H), 7.12 (d, J = 2.6 Hz, 1H), 7.09 (dd, J = 7.6, 1.2 Hz, 1H), 6.78 (td, J = 7.5, 0.8 Hz, 1H), 6.74 (d, J = 7.7 Hz, 1H), 5.14 (s, 1H), 3.81 – 3.69 (m, 1H), 3.66 – 3.50 (m, 1H), 3.18 (d, J = 16.3 Hz, 1H), 2.96 (d, J = 16.3 Hz, 1H), 2.55 – 2.48 (m, 1H), 2.45 (s, 3H), 2.24 – 2.13 (m, 1H), 1.59 – 1.50 (m, 2H); 13C-NMR (101 MHz, CDCl3) δ 203.1, 149.1, 139.0, 137.6, 131.9, 131.8, 131.0, 128.3, 128.0, 125.5, 123.3, 119.4, 110.1, 92.5, 62.8, 48.7, 47.0, 27.7, 21.8, 21.1; HR-ESI-MS (m/z): calcd. for C20H21NO2Na [M+Na]+, 330.1465, found 330.1468. 4a-Benzoylmethyl-4,4a,9,9a-(1,2)-(2H)-hexahydroxazinyl[2,3-b]indoline (Compound 5). White solid ( 20 mg from 0.1 mmol starting material, 65%),1H-NMR (400 MHz, DMSO) δ 9.69 (s, 1H), 7.95 (d, J = 7.3 Hz, 2H), 7.62 (d, J = 7.4 Hz, 1H), 7.51 (t, J = 7.7 Hz, 2H), 7.25 (d, J = 7.2 Hz, 1H), 7.02 (td, J = 7.7, 1.0 Hz, 1H), 6.75 (s, 1H), 6.64 (t, J = 7.2 Hz, 1H), 6.58 (d, J = 7.7 Hz, 1H), 5.18 (d, J = 1.4 Hz, 1H), 3.66 (d, J = 18.3 Hz, 1H), 3.43 (d, J = 18.3 Hz, 1H), 2.80 (d, J = 16.7 Hz, 1H), 2.62 (d, J = 16.7 Hz, 1H); 13C-NMR (101 MHz, DMSO) δ 198.6, 167.0, 148.9, 137.2, 134.7, 133.8, 129.1, 128.9, 128.4, 124.6,118.6, 110.0, 80.6, 45.8, 44.9; HR-ESI-MS (m/z): calcd. For C18H17N2O3[M+H]+, 309.1233, found 309.1227. ACS Paragon Plus Environment

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(2S,3aS,8aR)-1-p-Nitrophenylsulfonyl-2-methoxycarboyl-3a-benzoylmethyl-3,3a, 8,8a-tetrahydropyrrol[2,3-b]indoline (Compound 7a). Yellow solid ( 10 mg from 0.1 mmol starting material, 20%), 1H-NMR (400 MHz, CDCl3) δ 8.49-8.43 (m, 2H), 8.20-8.15 (m, 2H), 7.79-7.74 (m, 2H), 7.57 (t, J = 7.4 Hz, 1H), 7.43 (t, J = 7.7 Hz, 2H), 7.14 (td, J = 7.8, 1.1 Hz, 1H), 7.09 (d, J = 7.4 Hz, 1H), 6.79 (d, J = 7.4 Hz, 1H), 6.73 (d, J = 7.8 Hz, 1H), 5.53 (s, 1H), 4.47 (d, J = 8.1 Hz, 1H), 3.49-3.39 (m, 1H), 3.24 (s, 3H), 3.15 (d, J = 18.0 Hz, 1H), 2.76 (d, J = 12.6 Hz, 1H), 2.70-2.63 (m, 1H); 13

C-NMR (101 MHz, CDCl3) δ 196.9, 171.1, 148.7, 136.5, 133.7, 130.2, 129.5, 128.7,

128.6, 127.8, 124.5, 123.8, 119.7, 110.2, 82.9, 61.5, 55.0, 52.5, 42.9, 38.6; HR-ESI-MS (m/z): calcd. For C26H24N3O7S[M+H]+, 522.1329, found 522.1327. (2S,3aR,8aS)-1-p-Nitrophenylsulfonyl-2-methoxycarboyl-3a-benzoylmethyl-3,3a, 8,8a-tetrahydropyrrol[2,3-b]indoline (Compound 8a) Yellow solid ( 21 mg from 0.1 mmol starting material,41 %), 1H-NMR (400 MHz, CDCl3) δ 8.28 (d, J = 8.8 Hz, 2H), 8.04 (d, J = 8.8 Hz, 2H), 7.83 (t, J = 7.0 Hz, 2H), 7.54 (t, J = 7.4 Hz, 1H), 7.40 (t, J = 7.7 Hz, 2H), 7.18 (d, J = 7.4 Hz, 1H), 7.01 (t, J = 7.3 Hz, 1H), 6.71 (t, J = 7.5 Hz, 1H), 6.48 (d, J = 7.8 Hz, 1H), 5.72 (s, 1H), 4.18 (t, J = 7.7 Hz, 1H), 3.74 (d, J = 5.0 Hz, 3H), 3.56 – 3.49 (m, 1H), 3.36 (d, J = 17.6 Hz, 1H), 2.91 (dd, J = 13.0, 7.2 Hz, 1H), 2.59 (dd, J = 13.0, 8.2 Hz, 1H); 13C-NMR (101 MHz, CDCl3) δ 196.9, 172.0, 149.8, 147.4, 146.3, 136.8, 133.5, 131.2, 129.1, 128.7, 128.4, 128.0, 124.0, 120.1, 109.8, 84.6, 61.2, 55.0, 52.8, 44.4, 40.4; HR-ESI-MS (m/z): calcd. for C26H23N3O7SNa [M+Na]+, 544.1149, found 544.1147. (2S,3aS,8aR)-1-toluenylsulfonyl-2-methoxycarboyl-3a-benzoylmethyl-3,3a,8,8a-t etrahydropyrrol[2,3-b]indoline (Compound 8b). White solid ( 23 mg from 0.1 mmol starting material, 46%), 1H-NMR (500 MHz, CDCl3) δ 7.87-7.83 (m, 2H), 7.72 (d, J = 8.3 Hz, 2H), 7.54 (t, J = 7.4 Hz, 1H), 7.42 (t, J = 7.8 Hz, 2H), 7.26 (d, J = 8.1 Hz, 2H), 7.21 (d, J = 7.4 Hz, 1H), 7.01 (td, J = 7.7, 1.0 Hz, 1H), 6.69 (t, J = 7.3 Hz, 1H), 6.49 (d, J = 7.8 Hz, 1H), 5.63 (s, 1H), 4.17 – 4.12 (m, 1H), 3.71 (s, 3H), 3.58 (d, J = 17.4 Hz, 1H), 3.39 (d, J = 17.4 Hz, 1H), 2.97 (dd, J = 13.2, 7.5 Hz, 1H), 2.59 – 2.54 (m, 1H), 2.42 (d, J = 4.9 Hz, 3H); 13C-NMR (126 MHz, CDCl3) δ 197.1, 172.6, 147.7, 143.5, 137.0, 133.3, 131.3, 130.0, 129.5, 128.8, 128.6, 128.0, 127.3, 124.3, ACS Paragon Plus Environment


119.5, 109.6, 84.8, 60.9, 54.9, 52.6, 44.7, 40.5, 21.5; HR-ESI-MS (m/z): calcd. for C27H26N2O5S Na [M+Na]+, 513.1455, found 513.1457. 1-p-Nitrophenylsulfonyl-3a-([18O]-benzoylmethyl)-3,3a,8,8a-tetrahydropyrrol [2,3-b]indoline (Compound 9). Yellow solid ( 28 mg from 0.1 mmol starting material, 60%), 1H-NMR (400 MHz, DMSO) δ 8.31 (d, J = 8.8 Hz, 2H), 8.12 (d, J = 8.9 Hz, 2H), 7.84 – 7.71 (m, 2H), 7.51 (t, J = 7.4 Hz, 1H), 7.38 (t, J = 7.7 Hz, 2H), 7.06 (d, J = 7.4 Hz, 1H), 6.89 (dd, J = 11.0, 4.3 Hz, 1H), 6.53 (dd, J = 17.1, 7.7 Hz, 2H), 5.53 (d, J = 1.4 Hz, 1H), 3.53-3.36 (m, 2H), 3.24 (d, J = 17.5 Hz, 1H), 2.91 (td, J = 10.5, 5.9 Hz, 1H), 2.31 (dd, J = 12.3, 5.5 Hz, 1H), 2.11 (td, J = 11.7, 8.0 Hz, 1H); 13

C-NMR (101 MHz, DMSO) δ 197.4, 149.9, 149.3, 144.9, 137.0, 133.4, 131.2,

129.0, 128.7, 128.6, 128.0, 124.3, 123.5, 118.6, 109.2, 82.9, 55.7, 47.3, 44.3, 35.6; HR-ESI-MS (m/z): calcd. for C24H22N3O418OS [M+H]+, 466.1317 , found 466.1320. 3-Methyl-3-benzoylmethyl-indol-2(1H)-one (Compound 11). White solid ( 20 mg from 0.1 mmol starting material, 75%), 1H-NMR (400 MHz, CDCl3) δ 8.51 (s, 1H), 7.91 (dd, J = 5.2, 3.3 Hz, 2H), 7.70 (t, J = 5.8 Hz, 1H), 7.61 – 7.56 (m, 1H), 7.47 (t, J = 7.7 Hz, 2H), 7.42 (d, J = 7.9 Hz, 1H), 7.38 (dd, J = 7.6, 1.2 Hz, 1H), 7.32 – 7.25 (m, 1H), 3.60 (d, J = 17.2 Hz, 1H), 3.16 (d, J = 17.2 Hz, 1H), 1.51 (d, J = 13.8 Hz, 3H); 13

C-NMR (101 MHz, CDCl3) δ 197.1, 178.0, 154.4, 143.5, 136.8, 133.5, 128.7, 128.1,

128.1, 126.3, 121.7, 121.5, 55.0, 43.8, 19.6. HR-ESI-MS (m/z): calcd. for C17H16NO2 [M+H]+, 266.1176, found 266.1182.

ASSOCIATED CONTENT SUPPORTING INFORMATION This material is available free of charge via the Internet at http://pubs.acs.org. Additional results, spectra for all new compounds and X-ray crystal structure for compound 3a. Accession Codes


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CCDC 1820346 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

AUTHOR INFORMATION Corresponding Author *Email: [email protected], [email protected]. Author Contributions ‡X.-F. Chen and J.-B. Fan contributed equally to this work. ORCID Xu Deng: 0000-0001-7683-1626. Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT The authors are grateful for the financial support by National Natural Science Foundation of China (21302193 and 81573314), Nature Science of Hunan Province (2018JJ3707), Changsha Science and Technology Projects (kq1701088), Foundation of Hunan Educational committee (16C1214), and the Start-up funds of Central South University (Xu Deng).



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Deng, X.; Liang, K.; Tong, X.; Ding, M.; Li, D.; Xia, C. Copper-Catalyzed

Radical Cyclization To Access 3-Hydroxypyrroloindoline: Biomimetic Synthesis of Protubonine A. Org. Lett. 2014, 16, 3276-3279. (10) (a) Liang, K.; Deng, X.; Tong, X.; Li, D.; Ding, M.; Zhou, A.; Xia, C. Copper-Mediated

Dimerization

to

Access

3a,3a ′ -Bispyrrolidinoindoline:

Diastereoselective Synthesis of (+)-WIN 64821 and (−)-Ditryptophenaline. Org. Lett. 2015, 17, 206-209; (b) Ding, M.; Liang, K.; Pan, R.; Zhang, H.; Xia, C. Total Synthesis of (+)-Chimonanthine, (+)-Folicanthine, and (−)-Calycanthine. J. Org. Chem. 2015, 80, 10309-10316. (11) (a) Bruncko, M.; Crich, D., J. Org. Chem. 1994, 59 (15), 4239-4249; (b) Duan, X.-Y.; Yang, X.-L.; Fang, R.; Peng, X.-X.; Yu, W.; Han, B. Hydrazone Radical Promoted Vicinal Difunctionalization of Alkenes and Trifunctionalization of Allyls: Synthesis of Pyrazolines and Tetrahydropyridazines. J. Org. Chem. 2013, 78, ACS Paragon Plus Environment

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10692-10704. (12) (a) Nakagawa, M.; Yokoyama, Y.; Kato, S.; Hino, T. Dye-sensitized photo-oxygenation of tryptophan. Tetrahedron 1985, 41, 2125-2132; (b) Yukimasa, H.; Sawai, H.; Takizawa, T. Oxidative cleavage of indoles using copper-pyridine complex. Chem. Pharm. Bull. 1979, 27, 551-553. (13) (a) for reviews on benzylic oxidation, see: Sheldon, R. A.; Kochi, J. K. MetalCatalyzed Oxidations of Organic Compounds; Academic: New York, 1981. (b) Punniyamurthy, T.; Velusamy, S.; Iqbal, J., Recent Advances in Transition Metal Catalyzed Oxidation of Organic Substrates with Molecular Oxygen. Chem. Rev. 2005, 105 (6), 2329-2364; for selected examples on benzylic oxidation, see: (c) Fisher, T. J.; Dussault,

P.

H.,

Fragmentation

of

chloroperoxides:

hypochlorite-mediated

dehydration of hydroperoxyacetals to esters. Tetrahedron Lett. 2010, 51, 5615-5617. (d) Hanson, S. K.; Wu, R.; Silks, L. A. P., Mild and Selective Vanadium-Catalyzed Oxidation of Benzylic, Allylic, and Propargylic Alcohols Using Air. Org. Lett. 2011, 13 (8), 1908-1911; (e) Han, X.; Zhou, Z.; Wan, C.; Xiao, Y.; Qin, Z., Co(acac)2-Catalyzed Allylic and Benzylic Oxidation by tert-Butyl Hydroperoxide. Synthesis 2013, 45 (05), 615-620;


Access to 3a-Benzoylmethyl Pyrrolidino[2,3-b]indolines via CuII

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