Rh(III)-Catalyzed Oxidative Annulation of Isoquinolones with

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Rh(III)-Catalyzed Oxidative Annulation of Isoquinolones with Diazoketoesters Featuring an in situ Deacylation: Synthesis of Isoindoloisoquinolones and Their Transformation to Rosettacin’s Analogues Shenghai Guo, Lincong Sun, Fang Wang, Xinying Zhang, and Xuesen Fan J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01982 • Publication Date (Web): 29 Aug 2018 Downloaded from http://pubs.acs.org on August 30, 2018

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The Journal of Organic Chemistry

Rh(III)-Catalyzed Oxidative Annulation of Isoquinolones with Diazoketoesters Featuring an in situ Deacylation: Synthesis of Isoindoloisoquinolones and Their Transformation to Rosettacin’s Analogues Shenghai Guo,* Lincong Sun, Fang Wang, Xinying Zhang, and Xuesen Fan* Henan Key Laboratory of Organic Functional Molecules and Drug Innovation, Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, Key Laboratory of Green Chemical Media and Reactions, Ministry of Education, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, Henan 453007, P. R. China. E-mail: [email protected]; [email protected]

Abstract:

A

novel

and

practical

procedure

for

the

preparation

of

isoindolo[2,1-b]isoquinoline-7-carboxylate derivatives through a Rh(III)-catalyzed oxidative [4+1] cycloaddition of isoquinolones with diazoketoesters followed by an in situ deacylation reaction is disclosed. Intriguingly, the title compounds could be easily converted into isoindolo[2,1-b]isoquinolin-5(7H)-ones via deesterification, which are rosettacin’s analogues and frequently found in various natural alkaloids and synthetic drug molecules.

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Introduction Over the past few years, transition metal-catalyzed direct functionalization of inert C(sp2)-H bonds has become an attractive and reliable strategy for the synthesis of complex organic molecules and natural products in a step- and atom-economic manner since it avoids tedious prefunctionalization and minimizes the production of toxic wastes.1 In most cases, the heteroatom-containing coordinating moieties have been often introduced as directing groups to increase the reactivity and selectivity of challenging arene C(sp2)-H bonds.2 Among them, NH isoquinolone moiety proved to be a good functionalizable directing group, which not only facilitates a ortho C(sp2)-H bond activation but also participates in a subsequent intramolecular cyclization. For example, NH isoquinolone-directed oxidative annulation reactions with different coupling partners, such as alkynes,3 activated olefins,4 carbon monoxide,5 and benzoquinones,6 have been well established for the construction of isoquinolone-containing tetracyclic skeletons, especially for the synthesis of spirocyclic products, in the presence of Ru, Rh, Pd, or Ir catalyst. Therefore, it is still in high demand to develop novel transition metal-catalyzed oxidative annulations of NH isoquinolone substrates with other coupling partners with the aim to develop novel approaches toward new isoquinolone polycyclic products. Recently, rhodium-catalyzed oxidative annulation reactions of various arenes with diazo compounds as smart coupling partners turned out to be a powerful tool for the synthesis of a number of more complex carbocyclic and heterocyclic compounds from simple starting materials via C-H activation/carbenoid insertion/intramolecular annulation strategy.7 Among them, Rh-catalyzed formal [4+1] cycloaddition reactions with the use of diazo reagents as a C1 synthon have been widely studied and could be successfully applied for the construction


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of various five-membered carbocyclic and heterocyclic frameworks (Scheme 1, Eq. a).8 Meanwhile, Rh-catalyzed [4+1] cycloadditions involving an in situ deacylation are rare. In this regard, only a few examples have been reported independently for the synthesis of indole-3-carboxylate derivatives by Li, Chen, and Liu (Scheme 1, Eq. b).9 As a continuation of our recent studies on rhodium-catalyzed carbenoid insertion/annulation reactions with α-diazo carbonyl compounds as powerful carbene precursors,10 we herein report a new Rh-catalyzed oxidative [4+1] cycloaddition of isoquinolones with diazoketoesters involving a C(acyl)-C(N2) bond cleavage (Scheme 1, Eq. c) to provide isoindoloisoquinolones, which are present in various natural alkaloids and synthetic drug molecules (Figure 1).11 Scheme 1. Rh(III)-Catalyzed Construction of Five-Membered Cycles via Two Different [4+1] Annulation Versions

Figure 1. Representative compounds with an isoindoloisoquinolone scaffold.



Results and Discussion We commenced our studies by screening the reaction conditions of the oxidative annulation of 3,4-diphenylisoquinolin-1(2H)-one (1a) with ethyl 2-diazo-3-oxo-3-phenylpropanoate (2a), including catalysts, oxidants, solvents, and temperature. As demonstrated in Table 1, when 1a (0.2 mmol) and 2a (0.3 mmol) were treated with [Cp*RhCl2]2 (2.5 mol%), Ag2CO3 (0.4 mmol) in 1,4-dioxane (2 mL) at 120 oC for 16 h, the desired oxidative [4+1] cycloaddition and deacylation proceeded smoothly to deliver ethyl 5-oxo-12-phenyl-5,7-dihydroisoindolo [2,1-b]isoquinoline-7-carboxylate (3a) as the target product in 52% yield (entry 1). To improve the efficiency, other oxidants including AgOTf, AgSbF6, AgOTFA, AgOAc, Cu(OAc)2, and K2S2O8 were examined (entries 2-7). Among them, AgOAc provided the best result (75%). With Pd(OAc)2 as catalyst, this reaction could only give rise to 3a in 16% yield (entry 8). When [Cp*Co(CO)I2] and [Cp*IrCl2]2 were employed as catalysts, the reactions did not occur at all (entries 9-10). Then, with [Cp*RhCl2]2 as the catalyst and AgOAc as the oxidant, we also tested the effect of other solvents including CH3OH, DCE, DME, PhCl, toluene, and DMF (entries 11-16), and 1,4-dioxane was proved to be the best reaction medium (entry 5 vs. 11-16). In addition, control experimental results revealed that both AgOAc and [Cp*RhCl2]2 are essential for the formation of 3a (entries 17-18). In following studies, we also found that reaction temperature affects the efficiency of this oxidative annulation reaction significantly (entries 5, 19-20). When the reaction was run at 140 oC for 10 h, 3a was obtained in the highest yield of 90% (entry 20). Meanwhile, benzoic acid was detected in the reaction mixture by GC-MS analysis (see the Supporting Information). Next, the amount of diazo compound (2a) was also investigated, and it was observed that reducing or increasing the amount of 2a from 1.5 equiv failed to improve the yield of 3a (entries


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21-22). Finally, under nitrogen atmosphere, the reaction could also proceed smoothly to afford 3a in 87% yield (entry 23). Table 1. Optimization of Reaction Conditions for the Synthesis of 3aa

entry

catalyst

oxidant

solvent

yield (%)b

1

[Cp*RhCl2]2

Ag2CO3

1,4-dioxane

52

2

[Cp*RhCl2]2

AgOTf

1,4-dioxane

0

3

[Cp*RhCl2]2

AgSbF6

1,4-dioxane

0

4

[Cp*RhCl2]2

AgOTFA

1,4-dioxane

0

5

[Cp*RhCl2]2

AgOAc

1,4-dioxane

75

6

[Cp*RhCl2]2

Cu(OAc)2

1,4-dioxane

0

7

[Cp*RhCl2]2

K2S2O8

1,4-dioxane

0

8

Pd(OAc)2

AgOAc

1,4-dioxane

16

9

[Cp*Co(CO)I2]

AgOAc

1,4-dioxane

0

10

[Cp*IrCl2]2

AgOAc

1,4-dioxane

0

11

[Cp*RhCl2]2

AgOAc

CH3OH

32

12

[Cp*RhCl2]2

AgOAc

DCE

55

13

[Cp*RhCl2]2

AgOAc

DME

22

14

[Cp*RhCl2]2

AgOAc

PhCl

61

15

[Cp*RhCl2]2

AgOAc

toluene

60

16

[Cp*RhCl2]2

AgOAc

DMF

23

17

[Cp*RhCl2]2

-

1,4-dioxane

0

18

-

AgOAc

1,4-dioxane

0

c

[Cp*RhCl2]2

AgOAc

1,4-dioxane

39

d

[Cp*RhCl2]2

AgOAc

1,4-dioxane

90

e

[Cp*RhCl2]2

AgOAc

1,4-dioxane

50

f

[Cp*RhCl2]2

AgOAc

1,4-dioxane

81

19 20

21

22

g

23 [Cp*RhCl2]2 AgOAc 1,4-dioxane 87 The reactions were run with: 1a (0.2 mmol), 2a (0.3 mmol), catalyst (0.005 mmol), oxidant (0.4 mmol), solvent (2 mL), 120 oC, 16 h. bIsolated yield. cThe reaction was run at 100 oC. dThe reaction was run at 140 o C for 10 h. e1a:2a = 1:1.2, at 140 oC. f1a:2a = 1:2.0, at 140 oC. gUnder N2, at 140 oC. a



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With the optimized reaction conditions (Table 1, entry 20) in hand, we next explored the scope and limitation of this interesting transformation, and the representative results are shown in Table 2. With 2a as a model substrate, the scope of diversely substituted isoquinolones (1) was firstly tested. It was observed that various isoquinolones (1) with either electron-donating groups (e.g. CH3 and CH3O) or electron-withdrawing groups (e.g. F, Cl, CF3, and NO2) at the 6-position reacted with 2a very well to deliver the corresponding tetracyclic products 3a-3g in 65%-93% yields. Different R1 substituents (e.g. CH3, Br, Cl, and F) attached on 7- and 8-positions of isoquinolones (1) were also compatible with the optimized conditions to yield the expected products 3h-3l in good yields. In addition, we also found that other fused pyridones 1m-1o underwent this Rh(III)-catalyzed oxidative [4+1] annulation reaction smoothly to provide the corresponding polycyclic products 3m-3o. For example, the oxidative annulation of naphtho-fused pyridone 1m with 2a afforded the desired pentacyclic product 3m in 75% yield. With thieno- and furo-fused pyridones as reactants, this reaction also proceeded very well to give the expected products 3n and 3o in 76% and 68% yields, respectively. When methyl-substituted pyridone was employed, product 3p was obtained in 70% yield. Next, we investigated the effect of R2 groups on this reaction. Both electron-donating and electron-withdrawing R2 substituents attached on the para-position of 3-phenyl ring of isoquinolones (1) were tolerated with the reaction conditions to afford products

3q-3s

in

64%-86%

yields.

Furthermore,

when

3,4-di(thiophen-2-yl)isoquinolin-1(2H)-one (1t) was used, 3t was obtained in 67% yield. To further extend the isoquinolone’s scope, the Rh(III)-catalyzed oxidative annulation of 4-methyl substituted and 4-unsubstituted isoquinolones with 2a were also performed, and it turned out that 4-methyl substituted isoquinolone 1u worked well to give 3u in 49% yield


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Table 2. Substrate Scope of Isoquinolones (1)a,b O R

O N

1

H

H

R3 1

3a, R = H, 93%/90%c 3b, R = CH3, 87% 3c, R = CH3O, 73% 3d, R = F, 67% 3e, R = Cl, 90% 3f, R = CF3, 86% 3g, R = NO2, 65%

O + R2

O

Ph

[Cp*RhCl2]2 (2.5 mol %), AgOAc (2.0 eq) OEt

1,4-dioxane, 140 oC, 10 h

N2

R2

R3 3

2a

3h, 82%

R

CO2Et N

1

3i, 83%

3j, 88% O

CO2Et N

Ph

3k, 79%

3l, 86%

3m, 75%

3n, 76%

3o, 68%

3p, 70%

3q, 75%

3r, 64%

3s, 86%

3t, 67%

3u, 49%

O

CO2Et N

Br

3v, 74% a Reaction conditions: 1 (0.4 mmol), 2a (0.6 mmol), [Cp*RhCl2]2 (0.01 mmol), AgOAc (0.8 mmol), 1,4-dioxane (4 mL), 140 oC. bIsolated yields. c1a (1.19 g, 4 mmol ) was used.

whereas 4-unsubstituted one failed to yield the expected product. When 4-bromo substituted isoquinolone (1v) was employed, the expected product (3v) was obtained in 74% yield. Finally, to test the practicability of the present protocol, a gram-scale reaction using 1a (1.19 g) was run, and it gave 3a (1.37 g) in 90% yield. Next, we investigated the oxidative annulation reaction of different α-diazo carbonyl compounds (2) with 1a in details. As shown in Scheme 2, ethyl 2-diazo-3-oxobutanoate (2b) could took park in this reaction to deliver 3a in 56% yield, and we found that methyl-substituted diazo compound 2b is less effective than the phenyl-substituted one 2a.



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When ethyl 2-diazo-4,4-dimethyl-3-oxopentanoate (2c) was subjected to the standard conditions, 3a was not obtained. With diazoketoester 2d, this oxidative annulation reaction proceeded smoothly to give 3w in 87% yield. The structure of 3w was unambiguously confirmed by X-ray single craystal diffraction (see the Supporting Information). In addition, the reactions of acyclic diazodiketones 2e and 2f with 1a were also examined. With 3-diazopentane-2,4-dione (2e), it provided the corresponding product 3x in 78% yield by increasing

the

reaction

time

to

20

h.

In

sharp

contrast,

the

reaction

of

2-diazo-1,3-diphenylpropane-1,3-dione (2f) with 1a did not occur and the formation of 3y was not observed. In addition, cyclic diazo compounds 2g-2i as carbene precursors were also tested. Unfortunately, compounds 2g-2i could not react with 1a to provide the desired products 3z-3ab. Scheme 2. Substrate Scope of α-diazo compounds (2)

As

shown

in

Scheme

3,

when

diazodiester

(2j)

and

methyl

2-diazo-2-(phenylsulfonyl)acetate (2k) were subjected to the standard conditions, the Rh(III)-catalyzed reactions did not afford cyclic products 3, but yielded acyclic alkylated products

4a

and

4b

in

79%

and

86%

yields,

respectively.

With

methyl

2-diazo-2-(diethoxyphosphoryl)acetate (2l) as carbene precursor, the reaction could not provide any cyclic or acyclic product.


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Scheme 3. Alkylation of 1a with α-diazo esters 2j-2l

To showcase the synthetic application of this reaction, we attempted to study the deesterification of compounds 3, thus leading to isoindolo[2,1-b]isoquinolin-5(7H)-ones (5), which are the key structural motifs encountered in various natural alkaloids and synthetic drug molecules, such as rosettacin, camptothecin, and novel topoisomerase I inhibitors.11 After several attempts, we were delighted to find that treatment of 3a with NaOH followed by AcOH could give rise to the desired rosettacin’s analogue 5a in a total yield of 85% (Table 3). Next, we also investigated the scope of this deesterification reaction. When four other compounds (3) were subjected to the above deesterification conditions, the corresponding rosettacin’s analogues 5b-5e were obtained in good to excellent yields. Table 3. Synthesis of Rosettacin’s Analogues 5a,b

O N

Ph

5e, 90% 5d, 77% 5c, 71% 5a, 85% 5b, 90% Reaction conditions: 1) 3 (0.2 mmol), NaOH (6.6 equiv, 3 M), MeOH (3 mL), reflux, 10 h; 2) AcOH (5 mL), reflux, 16 h. bIsolated yields. a



To explore the reaction mechanism for the Rh(III)-catalyzed oxidative annulation of 1 with 2, several experiments were carried out and the results are outlined in Scheme 4. First, a competitive reaction with the use of an equimolar amount of 1q and 1s was run for 5 h under the standard conditions, and it turned out that 3q and 3s were obtained in a ratio of 1:2.37, indicating that the aromatic C(sp2)-H bond activation might go through a concerted metalation-deprotonation (CMD) mechanism (Scheme 4a). Second, treatment of 1a (0.2 mmol) and 1a-d10 (0.2 mmol) with 2a (0.2 mmol) under the standard conditions for 10 h delivered a mixture of 3a and 3a-d9 (0.72:0.28) by 1H NMR analysis. In addition, parallel reactions of 1a (0.2 mmol) and 1a-d10 (0.2 mmol) with 2a (0.3 mmol) under the standard conditions for 15 min were also carried out, and 3a and 3a-d9 were obtained in a ratio of 0.79:0.21. Based on the above observations, the intermolecular and parallel KIE values are 2.57 and 3.76, respectively, suggesting that the aromatic C(sp2)-H cleavage might be involved in the turnover-limiting step (Scheme 4b). Third, when the Rh(III)-catalyzed oxidative annulation reaction of 1a with 2a was performed in anhydrous 1,4-dioxane for 40 min, compound 6 was isolated in 89% yield. Subsequently, treatment of 6 with or without HOAc in 1,4-dioxane at 140 oC for 5 h or 10 h could provide 3a in 95% or 73% yield (Scheme 4c). Meanwhile, GC-MS analysis revealed that benzoic acid was formed in the deacylation reaction of 6 in the presence/absence of HOAc. On the basis of the above observations and previous reports,8,9 a possible mechanism for the formation of 3a is depicted in Scheme 5. First, an active Rh(III)-catalyzed N-H/C-H bond cleavage of 1a affords a five-membered rhodacycle A, which then reacts with 2a to deliver a rhodium carbene intermediate B with the release of N2. Subsequent 1,1-migratory insertion generates a six-membered rhodacycle C. And then, intermediate C undergoes a reductive


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elimination to afford intermediate 6 and a Rh(I)-species which is reoxidized to the active Rh(III) catalyst by AgOAc. Finally, a nucleophilic attack of H2O from solvent on the carbonyl group of benzoyl unit of 6 with the promotion of acid gives rise to 3a and benzoic acid. Scheme 4. Mechanistic Studies

Scheme 5. Possible Reaction Mechanism



Conclusion In summary, we have successfully developed an efficient synthetic route to 7-carboxylate substituted isoindolo[2,1-b]isoquinolines via a Rh-catalyzed oxidative annulation of isoquinolones with diazoketoesters involving a C(acyl)-C(N2) bond cleavage. The preliminary mechanistic studies suggested that this reaction undergoes a C-H activation/carbenoid insertion/reductive elimination/deacylation cascade and the aryl C-H cleavage might be the rate-determining step. In addition, the title compounds could undergo a deesterification reaction to afford rosettacin’s analogues, isoindolo[2,1-b]isoquinolin-5(7H)-ones, in good yields. Further development of NH isoquinolone’s reactivities via C-H bond activation is in progress. Experimental Section General Methods. Isoquinolones (1),12 diazo compounds (2),13 and [Cp*RhCl2]214 were prepared according to the reported procedures. Unless noted, other commercial reagents and solvents were used without further purification. Melting points were recorded with a micro melting point apparatus and uncorrected. The 1H NMR spectra were recorded at 400 or 600 MHz. The 13C NMR spectra were recorded at 100 or 150 MHz. High-resolution mass spectra (HRMS) were collected in ESI mode by using a MicrOTOF mass spectrometer. All reactions were monitored by thin-layer chromatography (TLC) using silica gel plates (silica gel 60 F254 0.25 mm), and components were visualized by observation under UV light (254 and 365 nm). General Procedure for the Preparation of Isoindolo[2,1-b]isoquinoline-7-carboxylate Derivatives 3. To a sealed tube (15 mL) containing a mixture of NH isoquinolone 1 (0.4 mmol), [Cp*RhCl2]2 (0.01 mmol), AgOAc (0.8 mmol) in 1,4-dioxane (4 mL) was added


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diazo compound 2 (0.6 mmol). Then, the resulting mixture was stirred at 140 oC for 10 h until isoquinolone 1 was consumed completely. Next, 1,4-dioxane was removed under reduced pressure, and the residue was added H2O and extracted with dichloromethane. The extract was washed with brine and then dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by silica gel chromatography using petroleum ether/ethyl acetate (2:1) as eluent to afford the corresponding product 3. Ethyl

5-oxo-12-phenyl-5,7-dihydroisoindolo[2,1-b]isoquinoline-7-carboxylate

(3a):

Yellow solid (142 mg, 93%), mp 204-205 oC; IR (KBr) ν 3059, 2969, 1752, 1660, 1195, 1187, 1025, 758 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.34 (t, J = 7.2 Hz, 3H), 4.29-4.37 (m, 2H), 6.06 (s, 1H), 6.44 (d, J = 8.0 Hz, 1H), 7.15 (t, J = 7.6 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 7.34-7.38 (m, 2H), 7.48-7.53 (m, 2H), 7.58-7.65 (m, 5H), 8.55 (d, J = 8.0 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 14.2, 62.2, 64.5, 114.9, 122.9, 124.2, 124.7, 125.5, 126.6, 127.6, 128.6, 129.2, 129.46, 129.52, 129.6, 130.9, 131.2, 132.4, 134.5, 134.9, 136.2, 137.7, 139.0, 160.4, 167.3. HRMS (ESI) calcd for C25H20NO3 [M + H]+ 382.1438, found 382.1438. Ethyl

2-methyl-5-oxo-12-phenyl-5,7-dihydroisoindolo[2,1-b]isoquinoline-7-carboxylate

(3b): Yellow solid (138 mg, 87%), mp 233-234 oC; IR (KBr) ν 2983, 1751, 1654, 1195, 1155, 764, 747, 732, 711 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.33 (t, J = 7.2 Hz, 3H), 2.38 (s, 3H), 4.29-4.35 (m, 2H), 6.04 (s, 1H), 6.39 (d, J = 8.0 Hz, 1H), 6.99 (s, 1H), 7.13 (t, J = 8.0 Hz, 1H), 7.32-7.38 (m, 3H), 7.48-7.49 (m, 1H), 7.59-7.63 (m, 4H), 8.43 (d, J = 8.4 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 14.2, 22.0, 62.2, 64.4, 114.8, 122.5, 122.8, 124.2, 125.2, 127.6, 128.2, 128.5, 129.1, 129.41, 129.44, 129.5, 131.0, 131.2, 134.6, 135.0, 136.3, 137.7, 139.1, 143.0, 160.4, 167.4. HRMS (ESI) calcd for C26H22NO3 [M + H]+ 396.1594, found 396.1604.



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Ethyl 2-methoxy-5-oxo-12-phenyl-5,7-dihydroisoindolo[2,1-b]isoquinoline-7-carboxylate (3c): Yellow solid (120 mg, 73%), mp 202-203 oC; IR (KBr) ν 3056, 2940, 1749, 1652, 1202, 1109, 1031, 763, 730 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.33 (t, J = 7.2 Hz, 3H), 3.73 (s, 3H), 4.29-4.37 (m, 2H), 6.02 (s, 1H), 6.41 (d, J = 8.0 Hz, 1H), 6.59 (d, J = 2.4 Hz, 1H), 7.08 (dd, J = 2.4, 8.8 Hz, 1H ), 7.14 (t, J = 7.6 Hz, 1H), 7.33-7.38 (m, 2H), 7.48 (d, J = 7.2 Hz, 1H), 7.58-7.64 (m, 4H), 8.47 (d, J = 8.8 Hz, 1H); 13C NMR (CDCl3, 150 MHz) δ 14.2, 55.3, 62.2, 64.3, 107.5, 114.5, 115.1, 118.7, 122.8, 124.3, 128.6, 129.1, 129.50, 129.53, 129.6, 129.7, 130.9, 131.2, 134.5, 134.9, 136.4, 138.3, 141.2, 160.1, 162.9, 167.4. HRMS (ESI) calcd for C26H22NO4 [M + H]+ 412.1543, found 412.1547. Ethyl

2-fluoro-5-oxo-12-phenyl-5,7-dihydroisoindolo[2,1-b]isoquinoline-7-carboxylate

(3d): Yellow solid (107 mg, 67%), mp 180-181 oC; IR (KBr) ν 2987, 1748, 1659, 1613, 1465, 1196, 761, 700 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.34 (t, J = 7.6 Hz, 3H), 4.30-4.37 (m, 2H), 6.04 (s, 1H), 6.45 (d, J = 8.4 Hz, 1H), 6.85 (dd, J = 2.4, 10.4 Hz, 1H), 7.14-7.22 (m, 2H), 7.35-7.40 (m, 2H), 7.47-7.48 (m, 1H), 7.60-7.65 (m, 4H), 8.53-8.57 (m, 1H);

13

C NMR

(CDCl3, 100 MHz) δ 14.2, 62.3, 64.5, 110.6 (d, J = 23.3 Hz, 1C), 114.2 (d, J = 3.7 Hz, 1C), 115.1 (d, J = 23.2 Hz, 1C), 121.3, 122.9, 124.4, 128.8, 129.3, 129.6, 129.7, 129.9, 130.7 (d, J = 10.2 Hz, 1C), 130.8, 131.1, 134.2, 134.3, 136.4, 139.0, 141.6 (d, J = 10.2 Hz, 1C), 159.7, 165.5 (d, J = 251.0 Hz, 1C), 167.1. HRMS (ESI) calcd for C25H19FNO3 [M + H]+ 400.1343, found 400.1349. Ethyl

2-chloro-5-oxo-12-phenyl-5,7-dihydroisoindolo[2,1-b]isoquinoline-7-carboxylate

(3e): Yellow solid (149 mg, 90%), mp 226-227 oC; IR (KBr) ν 2983, 1749, 1655, 1594, 1461, 1202, 763, 723 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.34 (t, J = 7.2 Hz, 3H), 4.29-4.37 (m, 2H), 6.04 (s, 1H), 6.41 (d, J = 8.0 Hz, 1H), 7.14-7.18 (m, 2H), 7.35-7.40 (m, 2H), 7.43-7.48


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(m, 2H), 7.61-7.65 (m, 4H), 8.46 (d, J = 8.4 Hz, 1H); 13C NMR (CDCl3, 150 MHz) δ 14.2, 62.3, 64.5, 113.9, 122.9, 123.0, 124.5, 124.8, 127.0, 128.9, 129.3, 129.4, 129.69, 129.75, 129.9, 130.9, 131.1, 134.11, 134.14, 136.4, 139.1, 139.2, 140.4, 159.8, 167.1. HRMS (ESI) calcd for C25H19ClNO3 [M + H]+ 416.1048, found 416.1049. Ethyl

5-oxo-12-phenyl-2-(trifluoromethyl)-5,7-dihydroisoindolo[2,1-b]isoquinoline-7-

carboxylate (3f): Yellow solid (154 mg, 86%), mp 184-185 oC; IR (KBr) ν 2978, 1750, 1662, 1342, 1313, 789, 722, 709, 688 cm-1; 1H NMR (CDCl3, 600 MHz) δ 1.36 (t, J = 7.2 Hz, 3H), 4.33-4.39 (m, 2H), 6.09 (s, 1H), 6.46 (d, J = 8.4 Hz, 1H), 7.19 (t, J = 7.8 Hz, 1H), 7.39-7.43 (m, 2H), 7.51-7.52 (m, 2H), 7.64-7.68 (m, 4H), 7.72 (dd, J = 1.2, 8.4 Hz, 1H), 8.68 (d, J = 8.4 Hz, 1H); 13C NMR (CDCl3, 150 MHz) δ 14.2, 62.4, 64.6, 114.4, 122.5 (q, J = 3.3 Hz, 1C), 122.6, 122.9, 123.7 (q, J = 271.2 Hz, 1C), 124.6, 126.6, 128.7, 129.1, 129.4, 129.8, 129.9, 130.1, 130.8, 131.1, 133.8, 134.0, 134.3 (q, J = 32.9 Hz, 1C), 136.3, 139.1, 139.3, 159.6, 166.9. HRMS (ESI) calcd for C26H19F3NO3 [M + H]+ 450.1312, found 450.1311. Ethyl

2-nitro-5-oxo-12-phenyl-5,7-dihydroisoindolo[2,1-b]isoquinoline-7-carboxylate

(3g): Yellow solid (110 mg, 65%), mp 217-218 oC; IR (KBr) ν 2987, 1744, 1663, 1523, 1283, 1206, 769, 745 cm-1; 1H NMR (CDCl3, 600 MHz) δ 1.35 (t, J = 7.2 Hz, 3H), 4.32-4.38 (m, 2H), 6.08 (s, 1H), 6.46 (d, J = 7.8 Hz, 1H), 7.19 (t, J = 7.8 Hz, 1H), 7.39 (s, 1H), 7.42 (t, J = 7.2 Hz, 1H), 7.49-7.50 (m, 1H), 7.65-7.68 (m, 4H), 8.09 (s, 1H), 8.24 (d, J = 9.0 Hz, 1H), 8.69 (d, J = 8.4 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 14.2, 62.6, 64.7, 114.4, 120.1, 120.9, 123.0, 124.7, 128.0, 129.4, 129.5, 129.7, 129.97, 130.04, 130.5, 130.8, 131.1, 133.3, 133.7, 136.3, 139.9, 140.1, 150.5, 159.2, 166.7. HRMS (ESI) calcd for C25H19N2O5 [M + H]+ 427.1288, found 427.1287.



Ethyl


(3h): Yellow solid (130 mg, 82%), mp 169-170 oC; IR (KBr) ν 3062, 2978, 1750, 1714, 1595, 1232, 1169, 766, 704 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.33 (t, J = 7.2 Hz, 3H), 2.50 (s, 3H), 4.29-4.36 (m, 2H), 6.05 (s, 1H), 6.43 (d, J = 8.0 Hz, 1H), 7.12-7.15 (m, 2H), 7.32-7.38 (m, 2H), 7.41 (d, J = 8.4 Hz, 1H), 7.48 (d, J = 6.4 Hz, 1H), 7.58-7.64 (m, 4H), 8.35 (s, 1H); 13

C NMR (CDCl3, 150 MHz) δ 14.2, 21.4, 62.2, 64.5, 114.9, 122.8, 124.1, 124.6, 125.5, 127.3,

128.5, 129.1, 129.3, 129.4, 129.5, 130.9, 131.2, 133.8, 134.6, 135.0, 136.1, 136.7, 136.8, 160.4, 167.4 (one 13C signal was not observed). HRMS (ESI) calcd for C26H22NO3 [M + H]+ 396.1594, found 396.1600. Ethyl


(3i): Yellow solid (131 mg, 83%), mp 189-190 oC; IR (KBr) ν 3061, 2974, 1745, 1658, 1199, 1184, 1153, 766, 715 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.33 (t, J = 7.6 Hz, 3H), 3.02 (s, 3H), 4.25-4.40 (m, 2H), 6.01 (s, 1H), 6.36 (d, J = 8.0 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H), 7.13 (t, J = 7.6 Hz, 1H), 7.24-7.26 (m, 1H), 7.32-7.36 (m, 2H), 7.40 (t, J = 7.6 Hz, 1H), 7.46 (d, J = 6.8 Hz, 1H), 7.57-7.63 (m, 4H);

13

C NMR (CDCl3, 100 MHz) δ 14.2, 23.9, 62.1, 64.7,

114.8, 122.8, 123.1, 123.9, 124.2, 128.4, 129.1, 129.4, 129.45, 129.51, 129.8, 131.0, 131.3, 131.5, 134.6, 135.6, 136.3, 137.5, 140.7, 142.0, 161.2, 167.6. HRMS (ESI) calcd for C26H22NO3 [M + H]+ 396.1594, found 396.1595. Ethyl

3-bromo-5-oxo-12-phenyl-5,7-dihydroisoindolo[2,1-b]isoquinoline-7-carboxylate

(3j): Yellow solid (162 mg, 88%), mp 212-213 oC; IR (KBr) ν 2989, 1739, 1657, 1469, 1266, 1028, 767, 708 cm-1; 1H NMR (CDCl3, 600 MHz) δ 1.36 (t, J = 7.2 Hz, 3H), 4.32-4.38 (m, 2H), 6.06 (s, 1H), 6.45 (d, J = 8.4 Hz, 1H), 7.12 (d, J = 8.4 Hz, 1H), 7.17 (t, J = 7.8 Hz, 1H), 7.36-7.41 (m, 2H), 7.48-7.50 (m, 1H), 7.61-7.68 (m, 5H), 8.69 (d, J = 2.4 Hz, 1H); 13C NMR


Page 16 of 32

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(CDCl3, 150 MHz) δ 14.2, 62.4, 64.5, 114.4, 120.7, 122.9, 124.3, 126.0, 127.2, 128.8, 129.3, 129.6, 129.7, 129.8, 130.2, 130.9, 131.1, 134.2, 134.3, 135.5, 136.2, 137.7, 138.2, 159.2, 167.0. HRMS (ESI) calcd for C25H18BrNNaO3 [M + Na]+ 482.0362, found 482.0363. Ethyl

4-chloro-5-oxo-12-phenyl-5,7-dihydroisoindolo[2,1-b]isoquinoline-7-carboxylate

(3k): Yellow solid (131 mg, 79%), mp 222-223 oC; IR (KBr) ν 2984, 1746, 1655, 1626, 1196, 1152, 769, 708, 698 cm-1; 1H NMR (CDCl3, 600 MHz) δ 1.35 (t, J = 7.2 Hz, 3H), 4.31-4.40 (m, 2H), 6.05 (s, 1H), 6.37 (d, J = 7.8 Hz, 1H), 7.14-7.18 (m, 2H), 7.36-7.44 (m, 3H), 7.47-7.52 (m, 2H), 7.61-7.66 (m, 4H); 13C NMR (CDCl3, 150 MHz) δ 14.2, 62.3, 64.8, 114.0, 121.1, 122.8, 124.5, 124.8, 128.8, 129.2, 129.6, 129.7, 129.8, 129.9, 131.0, 131.2, 131.8, 134.1, 134.9, 135.8, 136.5, 138.6, 142.2, 158.7, 167.1. HRMS (ESI) calcd for C25H18ClNNaO3 [M + Na]+ 438.0867, found 438.0867. Ethyl

2-chloro-4-fluoro-5-oxo-12-phenyl-5,7-dihydroisoindolo[2,1-b]isoquinoline-7-

carboxylate (3l): Yellow solid (149 mg, 86%), mp 244-245 oC; IR (KBr) ν 3058, 2983, 1749, 1661, 1597, 1209, 1195, 725, 707 cm-1; 1H NMR (CDCl3, 600 MHz) δ 1.36 (t, J = 7.2 Hz, 3H), 4.32-4.38 (m, 2H), 6.03 (s, 1H), 6.38 (d, J = 8.4 Hz, 1H), 6.97 (s, 1H), 7.15-7.19 (m, 2H), 7.35-7.37 (m, 1H), 7.41 (t, J = 7.2 Hz, 1H), 7.46-7.48 (m, 1H), 7.62-7.66 (m, 4H); 13C NMR (CDCl3, 100 MHz) δ 14.2, 62.4, 64.5, 112.3 (d, J = 5.9 Hz, 1C), 113.1 (d, J = 2.9 Hz, 1C), 114.3 (d, J = 24.7 Hz, 1C), 121.0 (d, J = 4.4 Hz, 1C), 122.9, 124.7, 129.1, 129.4, 129.8, 129.9, 130.3, 130.9, 131.1, 133.8, 134.0, 136.5, 138.9 (d, J = 11.7 Hz, 1C), 140.1, 142.7, 157.1 (d, J = 3.7 Hz, 1C), 162.8 (d, J = 266.2 Hz, 1C), 166.9. HRMS (ESI) calcd for C25H18ClFNO3 [M + H]+ 434.0954, found 434.0955. Ethyl

7-oxo-14-phenyl-5,7-dihydrobenzo[g]isoindolo[2,1-b]isoquinoline-5-carboxylate

(3m): Yellow solid (130 mg, 75%), mp 228-229 oC; IR (KBr) ν 3054, 2982, 1747, 1660, 1626,



Page 18 of 32

1191, 770, 716 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.33 (t, J = 7.2 Hz, 3H), 4.29-4.38 (m, 2H), 6.06 (s, 1H), 6.41 (d, J = 8.0 Hz, 1H), 7.13 (t, J = 7.2 Hz, 1H), 7.33 (t, J = 7.6 Hz, 1H), 7.43-7.55 (m, 4H), 7.61-7.67 (m, 5H), 7.76 (d, J = 8.0 Hz, 1H), 8.04 (d, J = 8.0 Hz, 1H), 9.12 (s, 1H); 13C NMR (CDCl3, 150 MHz) δ 14.3, 62.2, 64.3, 114.9, 122.9, 123.3, 124.3, 124.4, 126.2, 128.0, 128.1, 128.6, 128.9, 129.2, 129.4, 129.5, 129.57, 129.62, 131.1, 131.3, 131.5, 134.6, 135.2, 135.29, 135.31, 136.2, 136.6, 161.0, 167.6. HRMS (ESI) calcd for C29H21NNaO3 [M + Na]+ 454.1414, found 454.1414. Ethyl 11-oxo-4-phenyl-9,11-dihydrothieno[3',2':4,5]pyrido[2,1-a]isoindole-9-carboxylate (3n): Yellow solid (118 mg, 76%), mp 220-221 oC; IR (KBr) ν 2999, 2942, 1732, 1651, 1590, 1254, 1028, 769 cm-1; 1H NMR (CDCl3, 600 MHz) δ 1.36 (t, J = 7.2 Hz, 3H), 4.33-4.37 (m, 2H), 6.05 (s, 1H), 6.72 (d, J = 8.4 Hz, 1H), 6.95 (d, J = 5.4 Hz, 1H), 7.19 (t, J = 7.2 Hz, 1H), 7.38-7.40 (m, 1H), 7.44-7.46 (m, 1H), 7.55-7.60 (m, 4H), 7.66-7.68 (m, 2H);

13

C NMR

(CDCl3, 150 MHz) δ 14.2, 62.3, 64.3, 113.8, 122.9, 123.8, 124.5, 127.9, 128.6, 129.2, 129.29, 129.34, 129.5, 130.3, 130.5, 133.2, 134.3, 135.1, 136.2, 139.5, 148.2, 156.5, 167.1. HRMS (ESI) calcd for C23H18NO3S [M + H]+ 388.1002, found 388.1002. Ethyl

11-oxo-4-phenyl-9,11-dihydrofuro[3',2':4,5]pyrido[2,1-a]isoindole-9-carboxylate

(3o): Pink solid (101 mg, 68%), mp 126-127 oC; IR (KBr) ν 2983, 1752, 1673, 1591, 1465, 1190, 1155, 773, 720, 701 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.33 (t, J = 7.2 Hz, 3H), 4.28-4.37 (m, 2H), 6.03 (s, 1H), 6.47 (d, J = 2.0 Hz, 1H), 6.90 (d, J = 8.0 Hz, 1H), 7.18 (t, J = 7.6 Hz, 1H), 7.36 (t, J = 7.2 Hz, 1H), 7.44-7.46 (m, 1H), 7.54-7.55 (m, 4H), 7.65 (d, J = 7.6 Hz, 1H), 7.75 (d, J = 2.0 Hz, 1H); 13C NMR (CDCl3, 150 MHz) δ 14.2, 62.4, 64.4, 107.3, 111.2, 123.0, 123.4, 128.6, 129.1, 129.2, 129.26, 129.29, 130.0, 130.3, 134.1, 134.4, 136.52,


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136.55, 138.6, 141.7, 148.6, 151.3, 167.0. HRMS (ESI) calcd for C23H18NO4 [M + H]+ 372.1230, found 372.1242. Ethyl

3-methyl-4-oxo-1-phenyl-4,6-dihydropyrido[2,1-a]isoindole-6-carboxylate

(3p):

Brown solid (96 mg, 70%), mp 166-167 oC; IR (KBr) ν 3055, 2982, 1751, 1651, 1608, 1597, 1189, 1149, 758, 706 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.34 (t, J = 7.2 Hz, 3H), 2.27 (d, J = 0.4 Hz, 3H), 4.29-4.36 (m, 2H), 5.94 (s, 1H), 7.01 (d, J = 8.0 Hz, 1H), 7.19 (t, J = 7.6 Hz, 1H), 7.34-7.51 (m, 7H), 7.63 (d, J = 7.6 Hz, 1H); 13C NMR (CDCl3, 150 MHz) δ 14.2, 16.4, 62.3, 65.0, 116.9, 122.9, 123.5, 127.4, 128.2, 128.9, 129.1, 129.6, 129.7, 134.3, 136.3, 136.9, 140.8, 141.4, 160.8, 166.8. HRMS (ESI) calcd for C22H20NO3 [M + H]+ 346.1438, found 346.1438. Ethyl 9-methyl-5-oxo-12-(p-tolyl)-5,7-dihydroisoindolo[2,1-b]isoquinoline-7-carboxylate (3q): Yellow solid (122 mg, 75%), mp 242-243 oC; IR (KBr) ν 2978, 1751, 1658, 1197, 1163, 1142, 772, 693 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.33 (t, J = 7.2 Hz, 3H), 2.37 (s, 3H), 2.52 (s, 3H), 4.31-4.34 (m, 2H), 5.99 (s, 1H), 6.39 (d, J = 8.0 Hz, 1H), 6.97 (d, J = 8.0 Hz, 1H), 7.24-7.26 (m, 2H), 7.34-7.40 (m, 3H), 7.42 (s, 1H), 7.47 (t, J = 7.6 Hz, 1H), 7.54-7.58 (m, 1H), 8.52 (d, J = 8.0 Hz, 1H); 13C NMR (CDCl3, 150 MHz) δ 14.2, 21.5, 21.6, 62.2, 64.4, 114.1, 123.2, 124.1, 124.5, 125.4, 126.3, 127.6, 130.1, 130.15, 130.18, 130.8, 131.1, 131.9, 132.0, 132.3, 136.4, 137.9, 138.2, 139.3, 140.1, 160.5, 167.5. HRMS (ESI) calcd for C27H24NO3 [M + H]+ 410.1751, found 410.1759. Ethyl

9-fluoro-12-(4-fluorophenyl)-5-oxo-5,7-dihydroisoindolo[2,1-b]isoquinoline-7-

carboxylate (3r): Yellow solid (106 mg, 64%), mp 210-211 oC; IR (KBr) ν 2982, 1739, 1652, 1253, 1236, 1221, 1019, 781, 708, 697 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.35 (t, J = 7.2 Hz, 3H), 4.34 (q, J = 6.8 Hz, 2H), 6.02 (s, 1H), 6.41-6.45 (m, 1H), 6.90 (dt, J = 2.0, 8.8 Hz,



1H), 7.19 (d, J = 8.4 Hz, 1H), 7.28-7.37 (m, 4H), 7.44-7.48 (m, 1H), 7.51 (t, J = 7.6 Hz, 1H), 7.60 (t, J = 7.6 Hz, 1H), 8.53 (d, J = 7.6 Hz, 1H); 13C NMR (CDCl3, 150 MHz) δ 14.2, 62.6, 64.2 (d, J = 2.1 Hz, 1C), 110.5 (d, J = 24.2 Hz, 1C), 113.2, 116.7 (d, J = 5.6 Hz, 1C), 116.8 (d, J = 4.4 Hz, 1C), 117.0 (d, J = 23.0 Hz, 1C), 124.5, 125.2, 125.8 (d, J = 8.7 Hz, 1C), 126.8, 127.7, 130.4 (d, J = 3.3 Hz, 1C), 130.5 (d, J = 3.3 Hz, 1C), 132.6, 132.7 (d, J = 7.7 Hz, 1C), 133.0 (d, J = 7.7 Hz, 1C), 137.1, 138.4 (d, J = 9.8 Hz, 1C), 138.9, 160.3, 163.0 (d, J = 247.2 Hz, 1C), 163.4 (d, J = 249.3 Hz, 1C), 166.7. HRMS (ESI) calcd for C25H17F2NNaO3 [M + Na]+ 440.1069, found 440.1067. Ethyl

9-chloro-12-(4-chlorophenyl)-5-oxo-5,7-dihydroisoindolo[2,1-b]isoquinoline-7-

carboxylate (3s): Yellow solid (155 mg, 86%), mp 203-204 oC; IR (KBr) ν 3065, 2981, 1760, 1654, 1202, 1167, 839, 825, 773, 696 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.36 (t, J = 7.2 Hz, 3H), 4.34 (q, J = 7.2 Hz, 2H), 6.00 (s, 1H), 6.43 (d, J = 8.4 Hz, 1H), 7.17-7.20 (m, 2H), 7.31-7.34 (m, 1H), 7.41-7.44 (m, 1H), 7.50-7.53 (m, 1H), 7.57-7.62 (m, 4H), 8.51-8.53 (m, 1H); 13C NMR (CDCl3, 150 MHz) δ 14.2, 62.6, 64.1, 113.7, 123.4, 124.7, 125.0, 125.2, 127.0, 127.8, 129.8, 129.9, 130.0, 132.3, 132.59, 132.64, 132.7, 133.0, 134.9, 135.9, 136.9, 137.8, 138.5, 160.2, 166.6. HRMS (ESI) calcd for C25H17Cl2NNaO3 [M + Na]+ 472.0478, found 472.0478. Ethyl 6-oxo-11-(thiophen-2-yl)-4,6-dihydrothieno[2',3':3,4]pyrrolo[1,2-b]isoquinoline-4carboxylate (3t): Brown solid (105 mg, 67%), mp 172-173 oC; IR (KBr) ν 3077, 2907, 1756, 1662, 1625, 1193, 1119, 773, 729, 720 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.33 (t, J = 7.2 Hz, 3H), 4.28-4.37 (m, 2H), 5.98 (s, 1H), 7.13 (d, J = 4.8 Hz, 1H), 7.20 (brs, 1H), 7.26-7.29 (m, 1H), 7.40 (d, J = 4.8 Hz, 1H), 7.48-7.52 (m, 2H), 7.60-7.66 (m, 2H), 8.51 (dd, J = 1.2, 8.4 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 14.2, 62.4, 63.1, 104.2, 120.5, 124.3, 125.0, 126.5,


Page 20 of 32

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127.78, 127.80, 127.9, 129.7, 132.8, 133.7, 134.8, 136.4, 138.1, 138.8, 142.3, 160.3, 166.2. HRMS (ESI) calcd for C21H16NO3S2 [M + H]+ 394.0566, found 394.0563. Ethyl

12-methyl-5-oxo-5,7-dihydroisoindolo[2,1-b]isoquinoline-7-carboxylate

(3u):

Yellow solid (63 mg, 49%), mp 132-133 oC; IR (KBr) ν 2975, 1743, 1656, 1619, 1193, 760, 713 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.30 (t, J = 7.2 Hz, 3H), 2.73 (s, 3H), 4.25-4.33 (m, 2H), 6.00 (s, 1H), 7.47 (t, J = 7.2 Hz, 1H), 7.51-7.55 (m, 2H), 7.70 (d, J = 7.6 Hz, 1H), 7.74-7.78 (m, 1H), 7.87 (d, J = 8.4 Hz, 1H), 8.05 (d, J = 7.6 Hz, 1H), 8.53 (dd, J = 0.8, 7.6 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 12.4, 14.2, 62.1, 64.4, 108.6, 123.2, 123.4, 124.6, 124.9, 126.5, 128.0, 129.2, 129.5, 132.4, 135.3, 136.3, 137.4, 138.8, 160.2, 167.5. HRMS (ESI) calcd for C20H17NNaO3 [M + Na]+ 342.1101, found 342.1103. Ethyl

12-bromo-5-oxo-5,7-dihydroisoindolo[2,1-b]isoquinoline-7-carboxylate

(3v):

Petroleum ether/ethyl acetate (1:1) as eluent; white solid (114 mg, 74%), mp 147-148 oC; IR (KBr) ν 2978, 1744, 1660, 1189, 1165, 759, 723, 713, 682 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.30 (t, J = 7.2 Hz, 3H), 4.25-4.34 (m, 2H), 6.00 (s, 1H), 7.53-7.61 (m, 3H), 7.70 (dd, J = 1.2, 7.2 Hz, 1H), 7.79-7.83 (m, 1H), 8.11 (d, J = 8.4 Hz, 1H), 8.48 (dd, J = 1.2, 8.0 Hz, 1H), 8.74-8.76 (m, 1H); 13C NMR (CDCl3, 150 MHz) δ 14.2, 62.4, 64.9, 96.4, 123.0, 125.0, 125.9, 126.3, 127.6, 127.9, 129.4, 130.6, 133.3, 134.3, 136.8, 137.0, 138.5, 159.8, 166.9. HRMS (ESI) calcd for C19H15BrNO3 [M + H]+ 384.0230, found 384.0228. Methyl

5-oxo-12-phenyl-5,7-dihydroisoindolo[2,1-b]isoquinoline-7-carboxylate

(3w):

Yellow solid (127 mg, 87%), mp 170-171 oC; IR (KBr) ν 2949, 1740, 1657, 1623, 1250, 759, 713, 706 cm-1; 1H NMR (CDCl3, 400 MHz) δ 3.85 (s, 3H), 6.08 (s, 1H), 6.44 (d, J = 7.6 Hz, 1H), 7.15 (t, J = 7.6 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H), 7.34-7.38 (m, 2H), 7.48-7.53 (m, 2H), 7.58-7.65 (m, 5H), 8.55 (d, J = 8.0 Hz, 1H); 13C NMR (CDCl3, 150 MHz) δ 53.2, 64.4, 115.0,



123.0, 124.3, 124.6, 125.5, 126.7, 127.6, 128.6, 129.3, 129.48, 129.53, 129.6, 130.9, 131.2, 132.4, 134.5, 134.8, 136.1, 137.6, 139.0, 160.5, 167.9. HRMS (ESI) calcd for C24H17NNaO3 [M + Na]+ 390.1101, found 390.1110. 7-Acetyl-12-phenylisoindolo[2,1-b]isoquinolin-5(7H)-one (3x): Yellow solid (109 mg, 78%), mp 230-231 oC; IR (KBr) ν 2924, 1718, 1656, 1625, 764, 706, 696 cm-1; 1H NMR (CDCl3, 600 MHz) δ 2.13 (s, 3H), 6.01 (s, 1H), 6.49 (d, J = 7.8 Hz, 1H), 7.18 (t, J = 7.8 Hz, 1H), 7.29 (d, J = 7.8 Hz, 1H), 7.38-7.43 (m, 2H), 7.50-7.52 (m, 1H), 7.55-7.58 (m, 2H), 7.62-7.66 (m, 4H), 8.58 (dd, J = 0.6, 7.8 Hz, 1H); 13C NMR (CDCl3, 150 MHz) δ 25.0, 71.4, 115.1, 123.0, 124.36, 124.39, 125.6, 126.8, 127.6, 128.7, 129.3, 129.57, 129.60, 129.8, 130.9, 131.1, 132.6, 134.5, 134.7, 135.6, 137.7, 139.0, 160.6, 201.9. HRMS (ESI) calcd for C24H18NO2 [M + H]+ 352.1332, found 352.1335. Ethyl 2-(2-(1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl)phenyl)acetate (4a): Petroleum ether/ethyl acetate (1:1) as eluent; white solid (121 mg, 79%), mp 193-194 oC; IR (KBr) ν 2923, 1720, 1638, 1149, 785, 762, 705 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.22 (t, J = 7.2 Hz, 3H), 3.51 (d, J = 16.0 Hz, 1H), 3.64 (d, J = 15.6 Hz, 1H), 4.13 (q, J = 7.2 Hz, 2H), 7.01-7.29 (m, 9H), 7.34 (d, J = 8.0 Hz, 1H), 7.48-7.52 (m, 1H), 7.56-7.60 (m, 1H), 8.49 (dd, J = 0.8, 8.0 Hz, 1H), 9.48 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ 14.1, 39.0, 61.7, 118.0, 125.58, 125.64, 126.8, 127.2, 127.3, 127.7, 128.1, 128.4, 129.4, 130.2, 130.8, 131.4, 131.8, 132.7, 132.9, 134.8, 135.3, 136.5, 138.3, 162.0, 172.0. HRMS (ESI) calcd for C25H21NNaO3 [M + Na]+ 406.1414, found 406.1417. Methyl 2-(2-(1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl)phenyl)-2-(phenylsulfonyl)acetate (4b): Petroleum ether/ethyl acetate (1:1) as eluent; white solid (174 mg, 86%), mp 226-227 oC; IR


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(KBr) ν 3054, 2941, 1737, 1657, 1341, 1316, 1167, 755, 754, 705 cm-1; 1H NMR (CDCl3, 400 MHz) δ 3.64 (s, 3H), 5.29 (s, 1H), 6.90 (d, J = 7.6 Hz, 1H), 7.09 (t, J = 7.6 Hz, 1H), 7.16-7.20 (m, 3H), 7.26-7.39 (m, 4H), 7.55-7.63 (m, 4H), 7.68-7.72 (m, 1H), 7.85-7.90 (m, 3H), 8.57 (dd, J = 1.2, 7.6 Hz, 1H), 9.07 (brs, 1H);

13

C NMR (CDCl3, 150 MHz) δ 53.1, 70.7, 119.0,

125.8, 125.9, 127.2, 127.4, 127.8, 128.1, 128.2, 129.4, 129.5, 129.6, 129.7, 130.6, 130.9, 131.7, 131.8, 132.8, 134.7, 134.8, 134.9, 136.5, 137.3, 138.1, 161.6, 164.4 (one

13

C signal

was not observed). IR (KBr) ν 1737, 1657, 1341, 1316, 1167, 1134, 755, 754, 705, 686 cm-1; HRMS (ESI) calcd for C30H23NNaO5S [M + Na]+ 532.1189, found 532.1181. General Procedure for the Preparation of Rosettacin’s Analogues 5. To a mixture of 3 (0.2 mmol) in MeOH (3 mL) was added aqueous NaOH solution (3 M, 0.44 mL) and then the reaction was heated to reflux for 10 h. After the removal of MeOH under reduced pressure, AcOH (5 mL) was added into the reaction system and the resulting mixture was stirred at reflux for another 16 h. Next, the reaction was quenched with H2O and extracted with dichloromethane. The combined organic phase was washed with saturated NaHCO3 and brine and then dried over anhydrous Na2SO4. Finally, dichloromethane was removed under reduced pressure and the residue was purified by silica gel chromatography using petroleum ether/ethyl acetate (1:1) as eluent to afford the corresponding product 5. 12-Phenylisoindolo[2,1-b]isoquinolin-5(7H)-one (5a):11d White solid (53 mg, 85%), mp 257-258 oC; IR (KBr) ν 2922, 1650, 1620, 1602, 1470, 758, 719 cm-1; 1H NMR (CDCl3, 400 MHz) δ 5.30 (s, 2H), 6.48 (d, J = 8.0 Hz, 1H), 7.14 (t, J = 7.2 Hz, 1H), 7.25-7.28 (m, 1H), 7.37-7.45 (m, 3H), 7.51-7.65 (m, 6H), 8.61 (dd, J = 1.2, 7.6 Hz, 1H); 13C NMR (CDCl3, 150 MHz) δ 51.8, 114.5, 123.1, 124.1, 124.2, 125.2, 126.3, 127.3, 127.9, 128.5, 129.3, 129.5, 131.1, 132.0, 134.5, 135.3, 138.1, 138.5, 138.8, 160.8. MS (ESI) m/z 310 [M + H]+.



2-Methyl-12-phenylisoindolo[2,1-b]isoquinolin-5(7H)-one (5b):11d Yellow solid (58 mg, 90%), mp 273-274 oC; IR (KBr) ν 3054, 1657, 1609, 1598, 1467, 760, 703 cm-1; 1H NMR (CDCl3, 400 MHz) δ 2.37 (s, 3H), 5.22 (s, 2H), 6.39 (d, J = 8.0 Hz, 1H), 6.99 (s, 1H), 7.09 (t, J = 7.6 Hz, 1H), 7.29-7.35 (m, 2H), 7.38-7.41 (m, 2H), 7.51 (d, J = 7.6 Hz, 1H), 7.58-7.62 (m, 3H), 8.45 (d, J = 8.4 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 22.0, 51.7, 114.4, 122.1, 123.1, 124.0, 124.9, 127.3, 127.89, 127.94, 128.4, 129.1, 129.5, 131.2, 134.5, 135.4, 138.2, 138.5, 138.9, 142.6, 160.7. MS (ESI) m/z 324 [M + H]+. 2-Chloro-12-phenylisoindolo[2,1-b]isoquinolin-5(7H)-one (5c):11d White solid (49 mg, 71%), mp 284-285 oC; IR (KBr) ν 3056, 1646, 1594, 1462, 769, 722, 699 cm-1; 1H NMR (CDCl3, 400 MHz) δ 5.22 (s, 2H), 6.42 (d, J = 8.0 Hz, 1H), 7.11 (t, J = 7.6 Hz, 1H), 7.18 (d, J = 2.0 Hz, 1H), 7.36-7.42 (m, 4H), 7.53 (d, J = 7.6 Hz, 1H), 7.59-7.63 (m, 3H), 8.47 (d, J = 8.4 Hz, 1H); 13C NMR (CDCl3, 150 MHz) δ 51.9, 113.6, 122.5, 123.1, 124.3, 124.5, 126.7, 128.1, 128.8, 129.1, 129.65, 129.69, 131.1, 134.1, 134.5, 138.3, 138.8, 139.8, 140.2, 160.2. MS (ESI) m/z 344 [M + H]+. 4-Methyl-12-phenylisoindolo[2,1-b]isoquinolin-5(7H)-one (5d):11d Yellow solid (50 mg, 77%), mp >300 oC; IR (KBr) ν 3052, 2924, 1656, 1623, 1596, 1471, 762, 723, 711 cm-1; 1H NMR (CDCl3, 400 MHz) δ 3.06 (s, 3H), 5.20 (s, 2H), 6.36 (d, J = 8.0 Hz, 1H), 7.06-7.11 (m, 2H), 7.24 (d, J = 7.2 Hz, 1H), 7.33-7.41 (m, 4H), 7.52-7.61 (m, 4H); 13C NMR (CDCl3, 100 MHz) δ 24.0, 52.0, 114.4, 122.7, 123.1, 123.7, 124.0, 127.9, 128.3, 129.1, 129.49, 129.50, 131.1, 131.2, 134.5, 136.0, 138.2, 138.3, 140.6, 141.6, 161.7. MS (ESI) m/z 324 [M + H]+. 9-Methyl-12-(p-tolyl)isoindolo[2,1-b]isoquinolin-5(7H)-one (5e): White solid (61 mg, 90%), mp 280-281 oC; IR (KBr) ν 3054, 2922, 1651, 1625, 1603, 1476, 722, 696 cm-1; 1H NMR (CDCl3, 400 MHz) δ 2.38 (s, 3H), 2.54 (s, 3H), 5.21 (s, 2H), 6.42 (d, J = 8.0 Hz, 1H), 6.95 (d,


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J = 8.0 Hz, 1H), 7.25-7.29 (m, 3H), 7.35 (s, 1H), 7.40 (d, J = 7.6 Hz, 2H), 7.46-7.50 (m, 1H), 7.54-7.58 (m, 1H), 8.57 (dd, J = 0.8, 7.6 Hz, 1H); 13C NMR (CDCl3, 150 MHz) δ 21.5, 21.6, 51.7, 113.8, 123.5, 123.9, 124.1, 125.1, 125.9, 127.3, 129.0, 130.1, 131.0, 131.89, 131.91, 132.3, 138.1, 138.4, 138.6, 139.1, 139.7, 160.8. HRMS (ESI) calcd for C24H19NNaO [M + Na]+ 360.1359, found 360.1366. Ethyl 7-benzoyl-5-oxo-12-phenyl-5,7-dihydroisoindolo[2,1-b]isoquinoline-7-carboxylate (6): Petroleum ether/ethyl acetate (2:1) as eluent; white solid (173 mg, 89%), mp 194-195 oC; IR (KBr) ν 2983, 1741, 1656, 1282, 1261, 1222, 760, 697 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.24 (t, J = 7.2 Hz, 3H), 4.28 (q, J = 7.2 Hz, 2H), 6.48 (d, J = 8.0 Hz, 1H), 7.15-7.21 (m, 4H), 7.30-7.45 (m, 6H), 7.50-7.65 (m, 5H), 7.74 (d, J = 7.6 Hz, 1H), 8.39 (dd, J = 0.8, 8.0 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 13.9, 62.9, 80.8, 116.1, 124.3, 124.5, 125.1, 125.5, 126.9, 127.9, 128.0, 128.1, 128.8, 129.6, 129.7, 129.9, 130.0, 130.9, 131.1, 132.1, 132.6, 134.2, 134.6, 136.5, 136.9, 137.5, 138.7, 160.3, 164.9, 191.6. HRMS (ESI) calcd for C32H24NO4 [M + H]+ 486.1700, found 486.1700. Supporting Information GC-MS analysis for the reaction mixture (Table 1, entry 20), X-ray crystal structure and data of 3w, mechanistic studies, and 1H and 13C NMR spectra of 3a-3x, 4a-4b, 5a-5e, and 6. This material is available free of charge via the Internet at ............ Acknowledgments We thank the National Natural Science Foundation of China (Grants 21202040 and 21572047), Project Funded by China Postdoctoral Science Foundation (2014M552007 and 2015T80771), and the Program for Innovative Research Team in Science and Technology in University of Henan Province (15IRTSTHN003) for financial support.



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with Diazo Compounds Leading to Substituted Naphtho[1,8-bc]pyrans by Sequential C-H Functionalization. Adv. Synth. Catal. 2018, 360, 2272-2279. (e) Gao, M.; Yang, Y.; Chen, H.; Zhou, B. Rhodium-Catalyzed C-H Functionalization of Indoles with Diazo Compounds: Synthesis of Structurally Diverse 2,3-Fused Indoles. Adv. Synth. Catal. 2018, 360, 100-105. (f) Li, Y.; Wang, Q.; Yang, X.; Xie, F.; Li, X. Divergent Access to 1-Naphthols and Isocoumarins via Rh(III)-Catalyzed C−H Activation Assisted by Phosphonium Ylide. Org. Lett. 2017, 19, 3410-3413. (g) Shi, P.; Wang, L.; Guo, S.; Chen, K.; Wang, J.; Zhu, J. A C−H Activation-Based Strategy for N‑Amino Azaheterocycle Synthesis. Org. Lett. 2017, 19, 4359-4362. (h) Cui, S.; Zhang, Y.; Wang, D.; Wu, Q. Rh(III)-Catalyzed C–H Activation/[4+3] Cycloaddition of Benzamides and Vinylcarbenoids: Facile Synthesis of Azepinones. Chem. Sci. 2013, 4, 3912-3916. (8) (a) Hyster, T. K.; Ruhl, K. E.; Rovis, T. A Coupling of Benzamides and Donor/Acceptor Diazo Compounds to Form γ‑Lactams via Rh(III)-Catalyzed C−H Activation. J. Am. Chem. Soc. 2013, 135, 5364-5367. (b) Ye, B.; Cramer, N. Asymmetric Synthesis of Isoindolones by Chiral Cyclopentadienyl Rhodium(III)-Catalyzed C-H Functionalizations. Angew. Chem., Int. Ed. 2014, 53, 7896-7899. (c) Yu, S.; Liu, S.; Lan, Y.; Wan, B.; Li, X. Rhodium-Catalyzed C−H Activation of Phenacyl Ammonium Salts Assisted by an Oxidizing C−N Bond: A Combination of Experimental and Theoretical Studies. J. Am. Chem. Soc. 2015, 137, 1623-1631. (d) Yang, Y.; Wang, X.; Li, Y.; Zhou, B. A [4+1] Cyclative Capture Approach to 3H-Indole-N-oxides at Room Temperature by Rhodium(III)-Catalyzed C-H Activation. Angew. Chem., Int. Ed. 2015, 54, 15400-15404. (e) Li, Y.; Qi, Z.; Wang, H.; Yang, X.; Li, X. Ruthenium(II)-Catalyzed C-H Activation of Imidamides and Divergent Couplings with Diazo



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(11) For selected examples, see: (a) Cinelli, M. A.; Morrell, A.; Dexheimer, T. S.; Scher, E. S.; Pommier, Y.; Cushman, M. Design, Synthesis, and Biological Evaluation of 14-Substituted Aromathecins as Topoisomerase I Inhibitors. J. Med. Chem. 2008, 51, 4609-4619. (b) Li, K.; Ou, J.; Gao, S. Total Synthesis of Camptothecin and Related Natural Products by a Flexible Strategy. Angew. Chem., Int. Ed. 2016, 55, 14778-14783. (c) Reddy, C. R.; Mallesh, K. Rh(III)-Catalyzed Cascade Annulations to Access Isoindolo[2,1-b]isoquinolin-5(7H)‑ones via C−H Activation: Synthesis of Rosettacin. Org. Lett. 2018, 20, 150-153. (d) Song, L.; Tian, G.; He, Y.; Van der Eycken, E. V. Rhodium(III)-Catalyzed Intramolecular Annulation through C–H Activation: Concise Synthesis of Rosettacin and Oxypalmatime. Chem. Commun. 2017, 53, 12394-12397. (e) Thomas, C. J.; Rahier, N. J.; Hecht, S. M. Camptothecin: Current Perspectives. Bioorg. Med. Chem. 2004, 12, 1585-1604. (f) Van, H. T. M.;

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to

Isoindolo[2,1-b]isoquinolinones for the Development of Novel Topoisomerase 1 Inhibitors with Molecular Docking Study. Bioorg. Med. Chem. Lett. 2009, 19, 2551-2554. (g) Xu, X.; Liu, Y.; Park, C.-M. Rhodium(III)-Catalyzed Intramolecular Annulation through C-H Activation: Total Synthesis of (±)-Antofine, (±)-Septicine, (±)-Tylophorine, and Rosettacin. Angew. Chem., Int. Ed. 2012, 51, 9372-9376. (12) (a) Guimond, N.; Gouliaras, C.; Fagnou, K. Rhodium(III)-Catalyzed Isoquinolone Synthesis: The N-O Bond as a Handle for C-N Bond Formation and Catalyst Turnover. J. Am. Chem. Soc. 2010, 132, 6908-6909. (b) Guimond, N.; Gorelsky, S. I.; Fagnou, K. Rhodium(III)-Catalyzed Heterocycle Synthesis Using an Internal Oxidant: Improved Reactivity and Mechanistic Studies. J. Am. Chem. Soc. 2011, 133, 6449-6457.



(13) Jiang, Y.; Khong, V. Z. Y.; Lourdusamy, E.; Park, C.-M. Synthesis of 2-Aminofurans and 2-Unsubstituted Furans via Carbenoid-Mediated [3+2] Cycloaddition. Chem. Commun. 2012, 48, 3133-3135. (14) Fujita, K.-i.; Takahashi, Y.; Owaki, M.; Yamamoto, K.; Yamaguchi, R. Synthesis of Five-, Six-, and Seven-Membered Ring Lactams by Cp*Rh Complex-Catalyzed Oxidative N-Heterocyclization of Amino Alcohols. Org. Lett. 2004, 6, 2785-2788.


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Rh(III)-Catalyzed Oxidative Annulation of Isoquinolones with

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