Gold-catalyzed Rapid Construction of Nitrogen-containing Heterocyclic Compound Library with Scaffold Diversity and Molecular Complexity

Title: Gold-catalyzed Rapid Construction of Nitrogen-containing

Heterocyclic Compound Library with Scaffold Diversity and

Molecular Complexity

Authors: Jin Qiao, Xiuwen Jia, Pinyi Li, Xiaoyan Liu, Jingwei Zhao, Yu

Zhou, Jiang Wang, Hong Liu, and Fei Zhao

This manuscript has been accepted after peer review and appears as an

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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201801494

Link to VoR: http://dx.doi.org/10.1002/adsc.201801494

10.1002/adsc.201801494

Advanced Synthesis & Catalysis

UPDATE

DOI: 10.1002/adsc.201((will be filled in by the editorial staff))

Gold-catalyzed Rapid Construction of Nitrogen-containing

Heterocyclic Compound Library with Scaffold Diversity and

Molecular Complexity

Jin Qiao,^a‡ Xiuwen Jia,^a‡ Pinyi Li,^aXiaoyan Liu,^aJingwei Zhao,^aYu Zhou,^b,cJiang

Wang,^b,cHong Liu^b,c* and Fei Zhao^a*

a

Antibiotics Research and Re-evaluation Key Laboratory of Sichuan Province, Sichuan Industrial Institute of

Antibiotics, Chengdu University, 168 Hua Guan Road, Chengdu 610052, P. R. China. E-mail: zhaofei@cdu.edu.cn

State Key Laboratory of Drug Research and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia

b

Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, P. R. China. E-mail:

hliu@simm.ac.cn

University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, P. R. China.

c

‡

These authors contributed equally to this work.

Received: ((will be filled in by the editorial staff))

Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please

delete if not appropriate))

Abstract. 1,3-unsubstituted 2-(1H-indol-2-yl)ethanamines constructed rapidly using various amine nucleophiles (ANs)

were employed for the first time to react with alkynoic acids and diverse AAs as the building blocks. This general

(AAs) to achieve gold-catalyzed highly selective cascade protocol features excellent selectivity, extraordinarily broad

reactions to furnish novel indole-fused skeletons. substrate scope, readily available inputs, good to high

Furthermore, with this powerful gold catalytic system, a yields, high bond-forming efficiency, and step economy,

library

of thus providing a facile and efficient access to a variety of

indole/pyrrole/thiophene/benzene/naphthalene/pyridine-

valuable nitrogen-containing heterocycles.

based nitrogen-containing heterocyclic compounds (NCHCs) Keywords: Alkynes; Amines; Cascade reaction;

with scaffold diversity and molecular complexity was

Compound library; Gold; Scaffold diversity.

Introduction

Gold catalysts have attracted considerable attention^[1]

in cascade reactions because of their outstanding

performance in activating alkynes,^[2]alkenes,^[3]

allenes,^[4]etc. Remarkably, alkynoic acids (AAs) are

widely employed as building blocks in gold-catalyzed

cascade reactions to construct nitrogen-containing

heterocyclic compounds (NCHCs) since Dixon’s

pioneering work (Scheme 1a).^[5]They revealed that

linear aliphatic AAs underwent a cascade reaction

smoothly with amine nucleophiles (ANs) carrying a

nucleophilic C atom to provide indole- or pyrrole-

fused heterocycles under the catalysis of

AuPPh₃Cl/AgOTf. Soon afterwards, the group of

Patil further broadened the substrate scope of this

cascade reaction using a similar catalytic system

(Scheme 1b).^[6]They proved cyclic aromatic AA,

namely 2-ethynylbenzoic acid, and ANs carrying a

nucleophilic N atom were also suitable substrates. In

our ongoing efforts to develop facile approaches for

the construction of nitrogen-containing heterocyclic

scaffolds via gold catalysis,^[7]we herein extensively

study the cascade reaction between diverse AAs and

ANs, and develop a much more general and efficient

Scheme 1. Cascade reactions between AAs and ANs.

1

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Advanced Synthesis & Catalysis

catalytic system, which tolerates a much more

broader substrate scope of AAs and ANs, and

therefore allows the rapid construction of NCHC

library with scaffold diversity and molecular

complexity (Scheme 1c). We found the combination

of Au(PPh₃)Cl, which acts as a Lewis acid catalyst to

activate the carbon-carbon triple bonds of AAs, and a

Brønsted acid, namely CF₃CO₂H, allows diverse

linear aliphatic AAs as well as various cyclic

aromatic AAs react well with a broader ANs carrying

materials through a one-pot cascade process still

represents a significant synthetic challenge. As part

of our interests in the synthesis of indole-fused

heterocycles,^[13]here we aim to develop a highly

selective cascade reaction between 1,3-unsubstituted

2-(1H-indol-2-yl)ethanamines and AAs to assemble

novel indole-fused skeletons. As shown in Scheme 2,

we expected that AAs could undergo intramolecular

cyclization motivated by proper metal catalysts to

give the enol lactone A (path a) or B (path b) due to

the C1/C2 regioselectivity of the AAs,^[5]and the

following aminolysis of A or B by 1,3-unsubstituted

2-(1H-indol-2-yl)ethanamines could produce A' or B'.

Then A' or B' would undergo an iminium ion

formation/nucleophilic cyclization sequence to

provide four possible scaffolds A1 (path a1), A2

(path a2), B1 (path b1), and B2 (path b2) owing to the

C3/N1 site selectivity of the indole ring. The main

challenge of this method is to achieve high levels of

chemoselectivity including C1/C2 regioselectivity

and C3/N1 site selectivity to generate a single

skeleton in high efficiency. In this paper, we report

the highly selective and efficient construction of the

novel A1 scaffold through gold catalysis. To the best

of our knowledge, 1,3-unsubstituted 2-(1H-indol-2-

yl)ethanamines are employed for the first time to

react with AAs to achieve highly selective tandem

reactions, thus affording the novel indole-fused

framework A1. More importantly, the gold catalytic

system was proved to be compatible with various

ANs and diverse AAs, and was successfully

employed for the rapid construction of an

indole/pyrrole/thiophene/benzene/naphthalene/pyridi

ne-based nitrogen-containing heterocyclic compound

(NCHC) library with scaffold diversity and molecular

complexity.

a

nucleophilic C/N/O atom to assemble

indole/pyrrole/thiophene/benzene/naphthalene/pyridi

ne-based NCHCs with a large diverse scaffolds. The

extraordinarily broad substrate scope of this catalytic

system significantly widens the application of the

cascade reactions between AAs and ANs in the

assembly of nitrogen-containing heterocycles.

On the other hand, indole-fused skeletons are

highly valuable scaffolds because they are widely

found in bioactive natural products^[8]and

pharmaceutical agents^[9]. Hence, they are considered

as one of the most prominent privileged structures^[10]

in drug development. As a result, methods for the

generation of indole-fused frameworks have captured

wide attention, and tremendous efforts have been

made^[11,12]to develop efficient protocols to assemble

these frameworks to provide potentially useful

scaffolds for drug screening. Apparently, one-pot

cascade reactions featuring simple operation and

multiple bond formation in a single one chemical

process are much more efficient and convenient for

the furnishment of these complex scaffolds as

compared with multistep synthesis. Despite the

remarkable achievements made, the construction of

indole-fused heterocyclic multi-ring architectures in

high selectivity and efficiency from simple starting

The hit rates of most of current combinatorial

libraries in high-throughput screening (HTS) are far

from satisfactory. This is because the scaffold

diversity of these libraries, which contain similar

molecular skeletons decorated with different

substituents, is too limited to possess a wide chemical

space. In recent years, skeletal diversity of a

compound library is well recognized to be much

more important than the appendices in HTS. Since

compound libraries featuring a high degree of

scaffold diversity can effectively improve the

occupation of chemical space to increase the hit rates

for various biological targets.^[14]Apart from scaffold

diversity, drug-like properties are equally important,

as a library created with little consideration of drug-

like properties may suffer from more absorption,

distribution, metabolism, excretion, and toxicity

(ADMET) problems during the drug development

process.^[15]Therefore, a high-quality and valuable

compound library should display scaffold diversity as

well as good drug-like properties. Undoubtfully,

privileged-substructure-based

diversity-oriented

synthesis (pDOS) offers a powerful strategy to

construct high-quality compound libraries because

privileged structures exhibit inherent affinity for

diverse biological targets and ubiquitously exist in

Scheme 2. Possible reaction pathways.

2

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Advanced Synthesis & Catalysis

Table 1. Optimization of the reaction conditions.^[a]

Entry

Catalyst

Solvent

Yield of 3a (%)^[b]3a/3a¹/3a²/3a^3[c]

1

2

3

4

5

6

7

8

Pd(OAc)₂

Cu(OAc)₂

AgSbF₆

AgOTf

Ni(OTf)₂

NiCl₂

Co(acac)₂

Co(OAc)₂

PtCl₂

PtCl₄

AuCl

Toluene

THF

15

22

53

44

18

15

47

36

10

12

85

79

88

90

77

82

85

78

96

84

75

55

41

0/0^[h]

0

—

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

90:10:0:0

92:8:0:0

>99:1:0:0

84:16:0:0

>99:1:0:0

80:20:0:0

>99:1:0:0

—

AuCl₃

Au(PPh₃)OTf^[d]

Au(PPh₃)Cl

Au catalyst X^[e]

Au catalyst Y^[f]

Au catalyst Z^[g]

Au(PPh₃)Cl

HOAc

DCE

1,4-dioxane

CH₃CN

DMF

CH₃OH

DCE

—

TFA

HOTf

—

^[a]Reaction conditions: 1a (0.25 mmol), 2a (0.3 mmol), catalyst (0.0125 mmol), solvent (2.0 ml), 120 C, 24 h. ^[b]Isolated

o

yield of 3a. ^[c]The ratio was determined by HPLC. ^[d]Au(PPh₃)OTf was prepared in situ by the reaction of Au(PPh₃)Cl and

[e]

[f]

AgOTf.

Chloro[(1,1′-biphenyl-2-yl)di-tert-butylphosphine]gold(I);

butylphosphine]gold(I) hexafluoroantimonate; ^[h]0.25 mmol acid was used.

Au catalyst X = Chloro[1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]gold(I);

Au catalyst Y =

[g]

Au catalyst

Z

=

(Acetonitrile)[(2-biphenyl)di-tert-

natural and pharmaceutical products.^[16]However, the

development of robust processes to generate diverse

scaffolds embedded with privileged structures

remains a challenge and is highly demanding for drug

screening. We herein introduce an efficient protocol,

which allows the rapid access to the pDOS library of

NCHCs encompassing molecular complexity,

scaffold diversity, and drug-like properties. More

importantly, two potent compounds with good

antiproliferative activities were identified from this

library.

catalysts were screened in toluene in a sealed tube at

o

120 C for 24 h at first, and it turned out that AuCl

was more effective than other metal species such as

Pd, Cu, Ag, Ni, Co, and Pt catalysts (entries 1-11). A

high yield of 3a (85%) with excellent C1/C2

regioselectivity and high C3/N1 site selectivity

(90:10) were obtained with AuCl. Then a series of Au

catalysts were explored (entries 12-17). Isomers 3a²

and 3a³, which derive from the 6-endo ring closure

intermediate of 2a, were not observed in these cases.

Among them, Au(PPh₃)Cl showed the highest

catalytic performance and C3/N1 site selectivity

(>99:1) (entry 14). Subsequently, a further screening

of solvents (entries 18-23) revealed the

transformation was strongly influenced by the

solvents used, and DCE turned out to be the best

choice for this reaction resulting in almost

quantitative yield (96%) with excellent C1/C2

regioselectivity and C3/N1 site selectivity (>99:1)

(entry 19). In addition, Brønsted acids such as HOAc,

Results and Discussion

Initial screening experiments were carried out with 2-

(1H-indol-2-yl)ethanamine (1a) and 4-pentynoic acid

(2a) as model substrates to optimize the reaction

conditions including catalysts and solvents (Table 1).

A variety of metal complexes (5 mol%) as Lewis acid

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Advanced Synthesis & Catalysis

TFA and HOTf were also tested as the catalysts

(entries 24-26), but none of them could catalyze this

transformation. They also could not promote this

reaction even when a stoichiometric amount (1

equivalent) of them was used. By contrast, control

experiments showed that Au(PPh₃)Cl played a crucial

and indispensable role in this cascade reaction (entry

27). In this way, the optimum results were obtained

when 2-(1H-indol-2-yl)ethanamine (0.25 mmol) and

4-pentynoic acid (0.3 mmol) were treated with 5

mol% of Au(PPh₃)Cl in DCE in a sealed tube at 120

^oC for 24 h.

indol-2-yl)ethanamines 1 with 4-pentynoic acid 2a.

As shown in Scheme 3, the reactions of 2-(1H-indol-

2-yl)ethanamines bearing electron-donating (5-OMe,

5-Me) or electron-withdrawing group (5-F) appeared

to be reactive and afforded the corresponding

products 3b-3d in high yields. It should be noted that

the reaction of 2-(5-fluoro-1H-indol-2-yl)ethanamine

with 2a was sluggish under standard conditions

because the C3 nucleophilicity was weakened by the

fluorine. An improved two-step one-pot procedure, in

which a Brønsted acid, namely CF₃CO₂H, was added

to accelerate the formation of iminium ion, well

addressed this issue. Similar results were also

observed when the reactions were carried out with

other AAs such as 5-hexynoic acid, 2-ethynylbenzoic

acid, 2-(2-ethynylphenyl)acetic acid and 2-hexyl-4-

pentynoic acid, and this may be attributed to the

relatively lower reactivities of these AAs.

Nevertheless, these AAs underwent the tandem

reactions smoothly to produce the desired products

3e-3k in 70-96% yields under improved conditions.

In addition to terminal AAs, internal AAs were also

tested as the reaction substrates. However, we found

the reaction between 5-phenylpent-4-ynoic acid and

2-(1H-indol-2-yl)ethanamine 1a was not active, and

the desired product 3l was obtained in a low yield

(15%). This may be ascribed to the lower reactivities

of internal carbon-carbon triple bonds caused by

steric hindrance as compared with terminal ones. We

hypothesized the addition of silver salts, which can

increase the catalytic activity of Au(PPh₃)Cl,^[1o]

would be able to activate the internal carbon-carbon

triple bonds of terminally substituted AAs to solve

this problem. Therefore, several silver complexes

such as AgBF₄, AgOTf, and AgSbF₆were added and

screened. Pleasingly, AgBF₄was found to be the most

efficient silver additive, with which product 3l was

produced in a good yield (67%) at a higher

temperature. Similarly, other internal AAs such as 6-

phenylhex-5-ynoic acid, 2-(phenylethynyl)benzoic

acid, 2-(2-(phenylethynyl)phenyl)acetic acid or 2-

(hex-1-yn-1-yl)benzoic acid also reacted well with 2-

(1H-indol-2-yl)ethanamine 1a under the catalysis of

Au(PPh₃)Cl/AgBF₄/CF₃CO₂H to afford the desired

products 3m-3p in moderate to good yields. We also

made our efforts to achieve the synthesis of 3q from

2-(2-(hex-1-yn-1-yl)phenyl)acetic acid. Unfortunately,

a complex reaction mixture was obtained and only a

trace amount of 3q was detected by LC-MS. Notably,

excellent C1/C2 regioselectivity of AAs and C3/N1

site selectivity of the indole ring were observed in all

examples, providing the corresponding novel indole-

fused scaffolds presented by 3a-3p with high

efficiency. The excellent C3/N1 site selectivity of the

indole ring may be attributed to the stronger

nucleophilicity of C3 than that of N1, whose

nucleophilicity is reduced by the aromatic ring.^[17,18]

As a result, indole C3 instead of indole N1 attacked

the iminium ion intermediate in priority to give the

C3-cyclization products selectively.

With the optimal conditions established, we then

investigated the scope of this method. Firstly, we

examined the reactions of various substituted 2-(1H-

Scheme 3. Substrate scope of 2-(1H-indol-2-

yl)ethanamines and AAs. ^[a]Unless noted, reactions were

performed through a two-step one-pot process: (i) 1 (0.25

mmol), 2 (0.3 mmol), Au(PPh₃)Cl (0.0125 mmol), DCE

o

(2.0 ml), 120 C, 20 h; (ii) after the first step, CF₃CO₂H

o

[b]

(0.25 mmol) was added, and then 120 C, 4 h; 1 (0.25

mmol), 2 (0.3 mmol), Au(PPh₃)Cl (0.0125 mmol), DCE

o

[c]

(2.0 ml), 120 C, 24 h; (i) 1 (0.25 mmol), 2 (0.3 mmol),

Au(PPh₃)Cl (0.0125 mmol), AgBF₄(0.0125 mmol), DCE

o

(2.0 ml), 140 C, 20 h; (ii) after the first step, CF₃CO₂H

o

[d]

(0.25 mmol) was added, and then 140 C, 4 h;

AgOTf

[e]

Further experiments under the standard or

improved reaction conditions demonstrated that the

was used as the silver additive; AgSbF₆was used as the

silver additive.

4

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Advanced Synthesis & Catalysis

substrates, their reactions with various AAs worked

well to afford the corresponding products 5aj-5ax in

46-92% yields. To our delight, 3-(1H-indol-1-

yl)propan-1-amines were well tolerated and

converted into the polycyclic products embedded

with a seven-membered ring in good yields (5ay-5ba).

This further highlights the efficiency of this approach

because the generation of seven-membered ring

analogues is less favored on energetics and dynamics

in cascade reactions. Gratifyingly, this process could

also be applicable to 2-(1H-indol-1-yl)anilines, which

underwent this transformation successfully to give

more rigid compounds 5bb-5bd in 62-89% yields. It

should be noticed that the indole-fused polycyclic

scaffolds presented by 3a-3q and 5aa-5bd are

considered as valuable heterocycles in view of their

frequent occurrence in biologically active natural

products and drugs.^[19]

Pleasingly, other 2-aryl-ethanamines such as 2-

(1H-pyrrol-2-yl)ethanamine,

2-(1H-pyrrol-1-

yl)ethanamine,

2-(thiophen-3-yl)ethanamine,

2-

(thiophen-2-yl)ethanamine

and

2-(3,4-

dimethoxyphenyl)ethanamine also turned out to be

suitable substrates for this cascade process. They

reacted well with AAs to afford the desired NCHCs

[a]

Scheme 4. Substrate scope of ANs and AAs.

Unless

noted, reactions were performed through a two-step one-

pot process: (i) 4 (0.25 mmol), 2 (0.3 mmol), Au(PPh₃)Cl

o

(0.0125 mmol), DCE (2.0 ml), 120 C, 20 h; (ii) after the

first step, CF₃CO₂H (0.25 mmol) was added, and then 120

[b]

^oC, 4 h;

4 (0.25 mmol), 2 (0.3 mmol), Au(PPh₃)Cl

(0.0125 mmol), DCE (2.0 ml), 120 ^oC, 24 h.

protocol could be extended to the reactions of various

AAs with diverse ANs containing an indole moiety,

such as 2-(1H-indol-3-yl)ethanamines, 2-(1H-indol-

1-yl)ethanamines, 3-(1H-indol-1-yl)propan-1-amines

and 2-(1H-indol-1-yl)anilines, to generate a variety of

indole-fused scaffolds. In general, all the

corresponding NCHCs embedded with an indole

motif were obtained in moderate to high yields

(Scheme

4).

Specifically,

2-(1H-indol-3-

[a]

yl)ethanamines reacted smoothly with anyone of 4-

pentynoic acid, 5-hexynoic acid, 2-ethynylbenzoic

acid, 2-(2-ethynylphenyl)acetic acid and 2-hexyl-4-

pentynoic acid, providing the desired products 5aa-

5ai in 61-94% yields. Similarly, 2-(1H-indol-1-

yl)ethanamines were also found to be suitable

Scheme 5. Substrate scope of ANs and AAs. Reactions

were performed through a two-step one-pot process: (i) 6

(0.25 mmol), 2 (0.3 mmol), Au(PPh₃)Cl (0.0125 mmol),

DCE (2.0 ml), 140 ^oC, 20 h; (ii) after the first step,

o

CF₃CO₂H (0.25 mmol) was added, and then 140 C, 4 h.

ND = Not detected.

5

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Advanced Synthesis & Catalysis

with high selectivity and moderate to high yields

(Scheme 5). For example, the reaction of 2-(1H-

pyrrol-2-yl)ethanamine with 2-ethynylbenzoic acid

took place smoothly and selectively, producing the

C3 ring closure product 7a instead of N1 ring closure

product 7a'. Likewise, 2-(thiophen-3-yl)ethanamine

underwent this transformation with various AAs in a

highly selective manner, providing the C2 ring

closure products rather than C4 closure ones (7c-7e).

Similarly, the ring closure site occurred at the less-

hindered position selectively in the reactions between

cyclization step, the stronger and less-hindered

nucleophilic site tends to attack the iminium ion with

strict priority to afford the corresponding ring closure

products in this cascade process.

The applicability of this cascade reaction in ANs 8

bearing another nucleophilic heteroatom (O, N) was

also well studied and established. As shown in

Scheme 6, the reactions of 2-aminobenzoic acid/3-

amino-2-naphthoic/2-aminonicotinic

acid

with

diverse AAs worked smoothly to give the desired

products 9a-9g in 35-94% yields. Even (2-

2-(3,4-dimethoxyphenyl)ethanamine and AAs (7h-7j). aminophenyl)methanol could react with AAs to

Based on these results, we could conclude that, when

two or more nucleophilic sites exist in the final

provide the products 9h-9i, albeit with lower yields.

It is worth noting that the aniline N played as the

nucleophile which attacked the enol lactone

intermediate, and the amide N played as the

nucleophile which attacked the iminium ion when 2-

aminobenzamide was employed as the bisnucleophile

to react with 4-pentynoic acid, thus leading to the

formation of 9j selectively instead of 9j'. Similar

results have been observed in the reactions of 2-

aminobenzamide with other AAs such as 2-hexyl-4-

pentynoic acid, 5-hexynoic acid, 2-ethynylbenzoic

acid, and 2-(2-ethynylphenyl)acetic acid, affording

the single kind of products with high selectivity (9k-

9n). To our delight, positive results were also

observed when 2-amino-N-methylbenzamide and

AAs were subjected to the reaction conditions, and

the corresponding products 9o-9r were obtained in

38-91% yields. Despite the lower yields, benzene-

1,2-diamine was also found to be a suitable substrate,

which could be converted into the desired products

9s-9t. Interestingly, in the reaction of 2-

(aminomethyl)aniline with 4-pentynoic acid, the

more nucleophilic amine N rather than the aniline N

displayed as the nucleophile to attack the enol lactone

intermediate in the first step. As a result, the aniline

N could only display as the nucleophile to attack the

iminium ion in the final cyclization step, thus

affording 9u selectively instead of 9u'. Similarly, 9v

was obtained as the only product in 43% yield when

2-(aminomethyl)aniline and 2-ethynylbenzoic acid

were used as the starting materials. From the above

results, we could come to a conclusion that the more

nucleophilic N is generally involved in the first ring-

opening of enol lactone intermediate, while the less

nucleophilic N is normally involved in the final

cyclization step when bisnucleophiles carrying two

nitrogen atoms are employed as the substrates.

Briefly, these findings further broadened the substrate

scope of the methodology.

Thus, the cascade reactions between various ANs

and diverse AAs rapidly created a library of

indole/pyrrole/thiophene/benzene/naphthalene/pyridi

ne-based NCHCs with scaffold diversity and

molecular complexity. It should be noted that two

rings and three new bonds were formed efficiently in

a single one step to give the NCHCs bearing a

quaternary carbon center. It is also worth noting that

lots of the scaffolds in this paper are reported for the

first time and turn out to be novel nitrogen-containing

heterocyclic frameworks. Such a divergent synthesis

[a]

Scheme 6. Substrate scope of ANs and AAs.

Unless

noted, reactions were performed through the two-step one-

pot process with the following conditions: (i) 8 (0.25

mmol), 2 (0.3 mmol), Au(PPh₃)Cl (0.0125 mmol), DCE

o

(2.0 ml), 120 C, 20 h; (ii) after the first step, CF₃CO₂H

o

[b]

(0.25 mmol) was added, and then 120 C, 4 h.

The

reaction was performed at 140 ^oC. ND = Not detected.

6

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Advanced Synthesis & Catalysis

Scheme 7. Gram-scale cascade reaction and derivatization.

of heterocycles is evidently appealing and promising

in diversity oriented synthesis because it provides a

platform to assemble thousands of NCHCs with

scaffold diversity in an efficient manner.

To further illustrate the practicality of this

methodology, the cascade reaction between 1a and 2a

was carried out on a gram scale under optimal

conditions. Impressively, the desired product 3a was

obtained in 90% yield (Scheme 7a). In addition, the

reported potent α_1A-adrenoceptor antagonists^[7g]5ag-1,

5ah-1, 5ai-1 were prepared easily via a simple

reduction of the corresponding precursors in our

library (Scheme 7b). Besides, a pharmacological

screening of these NCHCs in this library to evaluate

their inhibitory activities against human cancer cell

lines A549 and HL60 resulted in the identification of

two potent compounds 3g and 9k, which exhibited

moderate to good inhibition activities as compared

with the positive control Adriamycin (Table 2). These

aspects further highlight the advantages and potential

applications of our approach.

Scheme 8. Mechanistic study experiments.

acid 2g was isolated in 52% yield, and the treatment

of 3m-1 with TFA in DCE at 140 ^oC for 4 h provided

the target product 3m in a high yield (Scheme 8c).

These results suggest that the enol lactone species is

likely to be involved in this cascade reaction. Besides,

the reaction of 1a with the commercially available

enol lactone C could afford the desired product 3a

with or without Au(PPh₃)Cl, and a higher yield was

obtained in the presence of Au(PPh₃)Cl as compared

with catalyst-free conditions (Scheme 8d). This

indicates that the gold catalyst may not only catalyze

the formation of enol lactone intermediate, but also

promote the iminium ion formation.

Based on the above mechanistic study results, we

proposed a plausible catalytic cycle (Scheme 9). The

complexation of the Au catalyst to the alkyne moiety

of AAs gives intermediate D1, which undergoes

intramolecular exo cyclization to afford the vinylgold

intermediate D2. Then the protodemetalation of D2

occurs to provide the key enol lactone intermediate

D3 with the release of the Au catalyst. The

subsequent aminolysis of D3 by ANs produces

intermediate D4. Then the coordination of the Au

catalyst to the carbonyl of D4 takes place to generate

intermediate D5, which undergoes a sequential

nucleophilic addition and iminium ion formation to

yield intermediate D7. The final nucleophilic

cyclization of D7 provides the products and

regenerates the Au catalyst. In brief, two catalytic

cycles were involved in the proposed reaction

mechanism. The Au catalyst could catalyze the

Table 2. Antiproliferative activities of 3g and 9k against

human cancer cell lines A549 and HL60.

Inhibition rate (%)

Concentration

Compound

(μM)

A549

HL60

10

67.8

62.6

92.1

72.7

-

87.2

3g

9k

Adriamycin

Furthermore, mechanistic studies were performed

to probe the reaction mechanism. When 2-

ethynylbenzoic acid (2c) or 2-(2-ethynylphenyl)acetic

acid (2d) was subjected to the standard conditions

without ANs, the corresponding enol lactone 2c-1 or

1

2d-1, whose structure was confirmed by HNMR,

¹³CNMR and HRMS, was isolated as the product

(Scheme 8a and 8b). In addition, the aminolysis

product 3m-1 of the enol lactone derived from 6-

phenylhex-5-ynoic acid 2g in the reaction of 2-(1H-

indol-2-yl)ethanamine 1a and 6-phenylhex-5-ynoic

7

10.1002/adsc.201801494

Advanced Synthesis & Catalysis

studies of this library are currently in progress in our

laboratory, and we expect these valuable nitrogen-

containing heterocycles embedded with privileged

structures may find more pharmaceutical applications.

Experimental Section

General information

Unless noted, the reagents were purchased from

commercial suppliers and used without further purification.

Analytical thin-layer chromatography (TLC) was

performed on HSGF 254 (0.15-0.2 mm thickness),

visualized by irradiation with UV light (254 nm). Column

chromatography was performed using silica gel FCP 200-

300. Melting points were measured with a micro melting

point apparatus. Nuclear magnetic resonance spectra were

recorded on a Brucker instrument. Chemical shifts were

reported in parts per million (ppm, δ) downfield from

tetramethylsilane. Proton coupling patterns were described

as singlet (s), doublet (d), triplet (t), quartet (q), multiplet

(m), and broad (br). Low- and high-resolution mass spectra

(LRMS and HRMS) were measured on a spectrometer.

Preparation procedure of Au(PPh₃)OTf

Au(PPh₃)OTf was prepared in situ by the reaction of

Au(PPh₃)Cl and AgOTf according to the literature

process.^[20]A mixture of Au(PPh₃)Cl (24.7 mg, 0.05 mmol)

and AgOTf (12.8 mg, 0.05 mmol) in dry toluene (2.0 ml)

was stirred at room temperature for 16 h. Then

Au(PPh₃)OTf was obtained quantitatively in toluene (0.025

mol/L), while AgCl was deposited at the bottom as white

solids.

Scheme 9. Proposed catalytic cycle.

formation of enol lactone intermediate as well as the

iminium ion intermediate. Besides, CF₃CO₂H could

accelerate the formation of iminium ion intermediate

to promote this cascade reaction.

Preparation and characterization data of the terminally

substituted alkynoic acids 2f-2k

5-phenylpent-4-ynoic acid (2f): SOCl₂(5.8 ml, 80.0

mmol) was added dropwise to a solution of 4-pentynoic

acid (981.0 mg, 10.0 mmol) in methanol (20.0 ml) at 0 ^oC,

and the mixture was heated to reflux for 4 h. Then the

reaction mixture was concentrated, and the residue

obtained was dissolved in ethyl acetate (30.0 ml), the

resulting mixture was washed with saturated NaHCO₃

aqueous solution, water and brine, dried over Na₂SO₄, and

concentrated to give crude methyl pent-4-ynoate (1.0 g,

89%). To a solution of pent-4-ynoate (1.0 g, 8.92 mmol) in

DMF (5.0 ml) and Et₃N (5.0 ml) was added PdCl₂(PPh₃)₂

(313.0 mg, 445.92 μmol), CuI (169.85 mg, 891.85 μmol),

and iodobenzene (999.7 μl, 8.92 mmol), and the resulting

mixture was stirred under nitrogen atmosphere at room

temperature for 8 hours. Then water (100.0 ml) was added

and the reaction mixture was extracted with ethyl acetate

(30.0 ml x 3). The combined organic extracts were washed

with brine, dried over Na₂SO₄, and concentrated. The

residue obtained was purified to give methyl 5-phenylpent-

4-ynoate (1.43 g, 85%). To a solution of methyl 5-

phenylpent-4-ynoate (1.43 g, 7.6 mmol) in MeOH (5.0 ml)

was added 1 mol/L NaOH aqueous solution (15.2 ml) at

room temperature. Two hours later, the reaction mixture

was acidified with 1 mol/L HCl aqueous solution (25.0 ml),

and the resulting mixture was extracted with ethyl acetate

(20.0 ml x 3). The combined organic extracts were washed

with saturated NaHCO₃aqueous solution, water and brine,

dried over Na₂SO₄, and concentrated. The residue obtained

was purified to give 5-phenylpent-4-ynoic acid as a white

Conclusion

In summary, we empolyed 1,3-unsubstituted 2-(1H-

indol-2-yl)ethanamines for the first time to react with

AAs to achieve gold-catalyzed highly selective

cascade reaction to furnish novel indole-fused

skeletons. More importantly, this gold catalytic

system has been successfully used for the rapid

construction

of

an

indole/pyrrole/thiophene/benzene/naphthalene/pyridi

ne-based NCHCs library with scaffold diversity and

molecular complexity by employing various ANs and

diverse AAs as the scaffold-building reagents. This

synthetic protocol exhibits valuable features of

readily available inputs, operational simplicity,

extraordinarily broad substrate scope, good to high

yields, excellent selectivity, high bond-forming

efficiency, and step economy. In addition, two potent

compounds with good antiproliferative activities were

identified from this library, highlighting the potential

and value of this strategy. Considering the large

presence of NCHCs in natural and pharmaceutical

products, the approach presented here is very

promising as it could provide a rapid and powerful

tool to construct a library of thousands of NCHCs

with a large diverse scaffolds. Further bioactivity

o

1

solid (1.25 g, 94%). Mp 95-96 C, H NMR (400 MHz,

DMSO-d₆) δ 12.32 (s, 1H), 7.51-7.20 (m, 5H), 2.67-2.60

(m, 2H), 2.57-2.51 (m, 2H); ¹³C NMR (101 MHz, DMSO-

d₆) δ 172.96, 131.27, 128.60, 128.07, 123.03, 89.56, 80.53,

33.07, 14.77; LRMS (ESI) m/z: 173 [M-H]^-; HRMS (ESI)

m/z calculated for C₁₁H₉O₂[M-H]^-173.0608, found:

173.0604.

8

10.1002/adsc.201801494

Advanced Synthesis & Catalysis

6-phenylhex-5-ynoic acid (2g): 6-phenylhex-5-ynoic acid

7.26-7.20 (m, 1H), 3.70 (s, 2H), 2.43 (t, J = 6.8 Hz, 2H),

1.57-1.49 (m, 2H), 1.48-1.38 (m, 2H), 0.91 (t, J = 7.2 Hz,

3H); ¹³C NMR (101 MHz, DMSO-d₆) δ 172.10, 136.93,

131.37, 130.21, 127.74, 126.85, 123.72, 94.81, 78.79,

39.37, 30.27, 21.40, 18.46, 13.50; LRMS (ESI) m/z: 217

was prepared following the similar procedure carried out

1

for 5-phenylpent-4-ynoic acid. Yellow oil, H NMR (400

MHz, DMSO-d₆) δ 12.15 (s, 1H), 7.53-7.18 (m, 5H), 2.46

(t, J = 7.1 Hz, 2H), 2.38 (t, J = 7.3 Hz, 2H), 1.81-1.72 (m,

J = 7.2 Hz, 2H); ¹³C NMR (101 MHz, DMSO-d₆) δ 174.06, [M+H]⁺; HRMS (ESI) m/z calculated for C₁₄H₁₆O₂+H⁺

131.28, 128.58, 127.99, 123.15, 89.86, 80.98, 32.61, 23.70,

18.12; LRMS (ESI) m/z: 189 [M+H]⁺; HRMS (ESI) m/z

calculated for C₁₂H₁₂O₂+H⁺189.0910, found: 189.0909.

217.1223, found: 217.1223.

General procedure for the synthesis of compounds 3a-

3c, 5aa, 5ac

2-(phenylethynyl)benzoic acid (2h): SOCl₂(2.9 ml, 40.0

mmol) was added dropwise to a solution of 2-iodobenzoic

A 25 mL Schlenk tube equipped with a magnetic stir bar

was charged with amine nucleophiles (0.25 mmol),

alkynoic acids (0.3 mmol), Au(PPh₃)Cl (0.0125 mmol),

DCE (2.0 ml), and then capped with a septa. After that, the

o

acid (1.24 g, 5.0 mmol) in methanol (20.0 ml) at 0 C, and

the mixture was heated to reflux for 4 h. Then the reaction

mixture was concentrated, and the residue obtained was

dissolved in ethyl acetate (30 ml), the resulting mixture

was washed with saturated NaHCO₃aqueous solution,

water and brine, dried over Na₂SO₄, and concentrated. The

residue obtained was purified to give methyl 2-

iodobenzoate (1.18 g, 90%). To a solution of methyl 2-

iodobenzoate (1.18 g, 4.5 mmol) in DMF (5.0 ml) and

Et₃N (5.0 ml) was added PdCl₂(PPh₃)₂(158.03 mg, 225.15

μmol), CuI (85.76 mg, 450.31 μmol), and ethynylbenzene

(494.53 μl, 4.5 mmol), and the resulting mixture was

stirred under nitrogen atmosphere at room temperature for

8 hours. Then water (100.0 ml) was added and the reaction

mixture was extracted with ethyl acetate (30.0 ml x 3). The

combined organic extracts were washed with brine, dried

over Na₂SO₄, and concentrated. The residue obtained was

purified to give methyl 2-(phenylethynyl)benzoate (870.2

o

tube was kept in the preheated oil bath at 120 C for 24 h.

Then the reaction was cooled to ambient temperature, and

saturated Na₂CO₃solution (25 ml) was added. The mixture

obtained was extracted with ethyl acetate (3 × 15 ml). The

combined organic phase was washed brine, dried with

Na₂SO₄and concentrated. The residue was purified by

flash chromatography on silica gel to give the desired

products.

General procedure for the synthesis of compounds 3d-

3k, 5ab, 5ad-5bd, 7a-7j, 9a-9v

A 25 mL Schlenk tube equipped with a magnetic stir bar

was charged with amine nucleophiles (0.25 mmol),

alkynoic acids (0.3 mmol), Au(PPh₃)Cl (0.0125 mmol),

DCE (2.0 ml), and then capped with a septa. After that, the

tube was kept in the preheated oil bath at the temperature

indicated for 20 h. After the reaction was cooled,

CF₃CO₂H (0.25 mmol) was added into the reaction mixture,

and the resulting mixture was stirred at the temperature

indicated for another 4 h. Then the reaction was cooled to

ambient temperature, and saturated Na₂CO₃solution (25

ml) was added. The mixture obtained was extracted with

ethyl acetate (3 × 15 ml). The combined organic phase was

washed brine, dried with Na₂SO₄and concentrated. The

mg,

82%).

To

a

solution

of

methyl

2-

(phenylethynyl)benzoate (870.2 mg, 3.68 mmol) in MeOH

(5.0 ml) was added 1 mol/L NaOH aqueous solution (7.36

ml) at room temperature. Two hours later, the reaction

mixture was acidified with 1 mol/L HCl aqueous solution

(15.0 ml), and the resulting mixture was extracted with

ethyl acetate (20.0 ml x 3). The combined organic extracts

were washed with saturated NaHCO₃aqueous solution,

water and brine, dried over Na₂SO₄, and concentrated. The

residue

obtained

was

purified

to

give

2-

(phenylethynyl)benzoic acid as a pale yellow solid (778.8

mg, 95%). Mp 119-120 ^oC, ¹H NMR (400 MHz, DMSO-d₆) residue was purified by flash chromatography on silica gel

δ 13.18 (s, 1H), 7.92 (dd, J = 7.8, 1.0 Hz, 1H), 7.71-7.65

(m, 1H), 7.63-7.58 (m, 1H), 7.57-7.48 (m, 3H), 7.48-7.40

(m, 3H); ¹³C NMR (151 MHz, DMSO-d₆) δ 167.18, 133.58,

133.22, 131.77, 131.34, 130.13, 128.92, 128.79, 128.60,

122.68, 122.20, 93.56, 88.62; LRMS (ESI) m/z: 223

[M+H]⁺; HRMS (ESI) m/z calculated for C₁₅H₁₀O₂+H⁺

223.0754, found: 223.0751.

to give the desired products.

General procedure for the synthesis of compounds 3l-

3q

A 25 mL Schlenk tube equipped with a magnetic stir bar

was charged with amine nucleophiles (0.25 mmol),

alkynoic acids (0.3 mmol), Au(PPh₃)Cl (0.0125 mmol),

AgBF₄(0.0125 mmol), DCE (2.0 ml), and then capped

with a septa. After that, the tube was kept in the preheated

2-(2-(phenylethynyl)phenyl)acetic acid (2i): 2-(2-

(phenylethynyl)phenyl)acetic acid was prepared following

o

the

similar

procedure

carried

out

for

2-

oil bath at 140 C for 20 h. After the reaction was cooled,

o

(phenylethynyl)benzoic acid. White solid, mp 117-118 C,

¹H NMR (400 MHz, DMSO-d₆) δ 12.42 (s, 1H), 7.62-7.51

(m, 3H), 7.49-7.37 (m, 5H), 7.36-7.30 (m, 1H), 3.83 (s,

2H); ¹³C NMR (126 MHz, DMSO-d₆) δ 172.11, 137.41,

131.45, 131.28, 130.51, 128.85, 128.76, 127.10, 122.71,

122.38, 93.45, 87.67, 39.76; LRMS (ESI) m/z: 237 [M+H]⁺;

HRMS (ESI) m/z calculated for C₁₆H₁₂O₂+H⁺237.0910,

found: 237.0912.

CF₃CO₂H (0.25 mmol) was added into the reaction mixture,

o

and the resulting mixture was stirred at 140 C for another

4 h. Then the reaction was cooled to ambient temperature,

and saturated Na₂CO₃solution (25 ml) was added. The

mixture obtained was extracted with ethyl acetate (3 × 15

ml). The combined organic phase was washed brine, dried

with Na₂SO₄and concentrated. The residue was purified

by flash chromatography on silica gel to give the desired

products.

2-(hex-1-yn-1-yl)benzoic acid (2j): 2-(hex-1-yn-1-

yl)benzoic acid was prepared following the similar

procedure carried out for 2-(phenylethynyl)benzoic acid.

Pale yellow oil, ¹H NMR (400 MHz, DMSO-d₆) δ 12.94 (s,

1H), 7.79 (d, J = 7.6 Hz, 1H), 7.58-7.44 (m, 2H), 7.44-7.34

(m, 1H), 2.44 (t, J = 6.5 Hz, 2H), 1.58-1.40 (m, 4H), 0.91

(t, J = 7.0 Hz, 3H); ¹³C NMR (101 MHz, DMSO-d₆) δ

167.47, 133.61, 133.42, 131.35, 129.61, 127.58, 123.08,

95.33, 79.42, 30.17, 21.32, 18.71, 13.55; LRMS (ESI) m/z:

203 [M+H]⁺; HRMS (ESI) m/z calculated for C₁₃H₁₄O₂+H⁺

203.1067, found: 203.1065.

11c-methyl-5,6,7,11c-tetrahydro-1H-indolizino[7,8-

b]indol-3(2H)-one (3a): yellow solid (57.6 mg, yield 96%),

o

mp 96-97 C. ¹H NMR (500 MHz, DMSO-d₆) δ 10.90 (s,

1H), 7.47 (d, J = 7.8 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H),

7.08-7.00 (m, 1H), 7.00-6.92 (m, 1H), 4.27-4.18 (m, 1H),

3.16-3.04 (m, 1H), 2.81-2.67 (m, 2H), 2.65-2.54 (m, 1H),

2.54-2.47 (m, 1H), 2.27-2.17 (m, 1H), 2.02-1.92 (m, 1H),

1.54 (s, 3H); ¹³C NMR (101 MHz, DMSO-d₆) δ 171.54,

135.89, 130.53, 123.91, 120.53, 118.64, 117.92, 115.29,

111.11, 59.20, 33.23, 33.21, 30.15, 25.02, 22.77; LRMS

(ESI) m/z: 241 [M+H]⁺; HRMS (ESI) m/z calculated for

C₁₅H₁₆N₂O+H⁺241.1335, found: 241.1332.

2-(2-(hex-1-yn-1-yl)phenyl)acetic acid (2k): 2-(2-(hex-1-

yn-1-yl)phenyl)acetic acid was prepared following the

similar procedure carried out for 2-(phenylethynyl)benzoic

10-methoxy-11c-methyl-5,6,7,11c-tetrahydro-1H-

indolizino[7,8-b]indol-3(2H)-one (3b): pale yellow solid

1

acid. Pale yellow oil, H NMR (400 MHz, DMSO-d₆) δ

12.29 (s, 1H), 7.35 (d, J = 7.8 Hz, 1H), 7.31-7.26 (m, 2H),

9

10.1002/adsc.201801494

Advanced Synthesis & Catalysis

(61.9 mg, yield 92%), mp 193-194 ^oC. ¹H NMR (500 MHz, HRMS (ESI) m/z calculated for C₂₀H₁₈N₂O+H⁺303.1492,

DMSO-d₆) δ 10.72 (s, 1H), 7.19 (d, J = 8.7 Hz, 1H), 6.93

(d, J = 2.3 Hz, 1H), 6.69 (dd, J = 8.7, 2.4 Hz, 1H), 4.25-

4.15 (m, 1H), 3.77 (s, 3H), 3.14-3.03 (m, 1H), 2.79-2.65

(m, 2H), 2.64-2.52 (m, 2H), 2.27-2.18 (m, 1H), 2.01-1.91

(m, 1H), 1.54 (s, 3H); ¹³C NMR (101 MHz, DMSO-d₆) δ

171.54, 153.06, 131.26, 131.00, 124.22, 115.11, 111.66,

109.84, 100.59, 59.17, 55.47, 33.19, 33.01, 30.11, 24.76,

22.86; LRMS (ESI) m/z: 271 [M+H]⁺; HRMS (ESI) m/z

calculated for C₁₆H₁₈N₂O₂+H⁺271.1441, found: 271.1437.

found: 303.1486.

2-hexyl-11c-methyl-5,6,7,11c-tetrahydro-1H-

indolizino[7,8-b]indol-3(2H)-one (3h): pale yellow oil

[74.7 mg, yield 92% (dr = 5:1)], and the two diastereomers

were separable by chromatography. The major

1

diastereomer: H NMR (400 MHz, DMSO-d₆) δ 10.89 (s,

1H), 7.52-7.44 (m, 1H), 7.29 (d, J = 7.9 Hz, 1H), 7.08-6.91

(m, 2H), 4.28-4.14 (m, 1H), 3.22-3.01 (m, 1H), 2.88-2.53

(m, 4H), 1.82-1.66 (m, 1H), 1.58-1.48 (m, 3H), 1.39-1.08

(m, 10H), 0.90-0.75 (m, 3H); ¹³C NMR (101 MHz,

DMSO-d₆) δ 172.75, 135.90, 130.33, 123.92, 120.54,

118.62, 117.99, 115.59, 111.10, 57.22, 40.71, 40.51, 33.18,

31.20, 30.60, 28.73, 26.60, 24.68, 22.93, 22.06, 13.96;

LRMS (ESI) m/z: 325 [M+H]⁺; HRMS (ESI) m/z

calculated for C₂₁H₂₈N₂O+H⁺325.2274, found: 325.2268.

10,11c-dimethyl-5,6,7,11c-tetrahydro-1H-

indolizino[7,8-b]indol-3(2H)-one (3c): pale yellow oil

1

(57.8 mg, yield 91%). H NMR (500 MHz, DMSO-d₆) δ

10.75 (s, 1H), 7.25 (s, 1H), 7.18 (d, J = 8.2 Hz, 1H), 6.86

(dd, J = 8.2, 1.0 Hz, 1H), 4.26-4.15 (m, 1H), 3.15-3.03 (m,

1H), 2.80-2.65 (m, 2H), 2.64-2.54 (m, 1H), 2.50-2.46 (m,

1H), 2.38 (s, 3H), 2.29-2.17 (m, 1H), 2.02-1.91 (m, 1H),

1.53 (s, 3H); ¹³C NMR (126 MHz, DMSO-d₆) δ 171.54,

134.24, 130.53, 127.05, 124.15, 122.04, 117.65, 114.84,

110.83, 59.24, 33.27, 33.24, 30.17, 25.00, 22.82, 21.31;

LRMS (ESI) m/z: 255 [M+H]⁺; HRMS (ESI) m/z

calculated for C₁₆H₁₈N₂O+H⁺255.1492, found: 255.1489.

2-hexyl-10-methoxy-11c-methyl-5,6,7,11c-tetrahydro-

1H-indolizino[7,8-b]indol-3(2H)-one (3i): pale yellow oil

[84.8 mg, yield 96% (dr = 3.3:1)], and the two

diastereomers were inseparable by chromatography. ¹H

NMR (400 MHz, DMSO-d₆) δ 10.70 (s, 1H), 7.22-7.14 (m,

1H), 6.99-6.91 (m, 1H), 6.72-6.65 (m, 1H), 4.27-4.12 (m,

1H), 3.77 (s, 3H), 3.24-3.02 (m, 1H), 2.87-2.53 (m, 4H),

1.81-1.67 (m, 1H), 1.57-1.48 (m, 3H), 1.43-1.10 (m, 10H),

10-fluoro-11c-methyl-5,6,7,11c-tetrahydro-1H-

indolizino[7,8-b]indol-3(2H)-one (3d): pale yellow solid

(53.8 mg, yield 83%), mp 104-105 ^oC. ¹H NMR (400 MHz, 0.91-0.79 (m, 3H); ¹³C NMR (101 MHz, DMSO-d₆) δ

DMSO-d₆) δ 11.00 (s, 1H), 7.34-7.21 (m, 2H), 6.93-6.82

(m, 1H), 4.28-4.15 (m, 1H), 3.16-3.01 (m, 1H), 2.83-2.67

(m, 2H), 2.64-2.51 (m, 2H), 2.28-2.16 (m, 1H), 1.99-1.87

(m, 1H), 1.52 (s, 3H); ¹³C NMR (101 MHz, DMSO-d₆) δ

171.54, 156.70 (d, J_C-F= 231.1 Hz), 132.88, 132.51,

124.00 (d, J_C-F= 10.1 Hz), 115.69 (d, J_C-F= 4.5 Hz),

111.91 (d, J_C-F= 9.9 Hz), 108.33 (d, J_C-F= 25.8 Hz),

102.88 (d, J_C-F= 23.4 Hz), 59.03, 33.09, 32.93, 30.11,

24.76, 22.85; LRMS (ESI) m/z: 259 [M+H]⁺; HRMS (ESI)

m/z calculated for C₁₅H₁₅FN₂O+H⁺259.1241, found:

259.1238.

172.77, 153.09, 131.07, 131.03, 124.26, 115.44, 111.65,

109.85, 100.68, 57.22, 55.51, 40.52, 40.50, 33.18, 31.20,

30.60, 28.76, 26.61, 24.36, 23.04, 22.08, 13.95; LRMS

(ESI) m/z: 355 [M+H]⁺; HRMS (ESI) m/z calculated for

C₂₂H₃₀N₂O₂+H⁺355.2380, found: 355.2378.

2-hexyl-10,11c-dimethyl-5,6,7,11c-tetrahydro-1H-

indolizino[7,8-b]indol-3(2H)-one (3j): pale yellow oil

[69.1 mg, yield 82% (dr = 3:1)], and the two diastereomers

1

were inseparable by chromatography. H NMR (400 MHz,

DMSO-d₆) δ 10.73 (s, 1H), 7.26 (s, 1H), 7.20-7.14 (m, 1H),

6.85 (d, J = 8.2 Hz, 1H), 4.27-4.12 (m, 1H), 3.24-3.03 (m,

1H), 2.86-2.54 (m, 4H), 2.37 (s, 3H), 1.83-1.67 (m, 1H),

1.58-1.48 (m, 3H), 1.42-1.08 (m, 10H), 0.90-0.78 (m, 3H);

¹³C NMR (101 MHz, DMSO-d₆) δ 172.73, 134.25, 130.30,

127.03, 124.15, 122.03, 117.68, 115.15, 110.80, 57.23,

40.76, 40.51, 33.19, 31.21, 30.60, 28.75, 26.60, 24.61,

22.96, 22.07, 21.29, 13.95; LRMS (ESI) m/z: 339 [M+H]⁺;

HRMS (ESI) m/z calculated for C₂₂H₃₀N₂O+H⁺339.2431,

found: 339.2428.

12c-methyl-1,2,3,6,7,12c-hexahydroindolo[3,2-

a]quinolizin-4(8H)-one (3e): white solid (47.9 mg, yield

o

1

75%), mp 132-133 C. H NMR (400 MHz, DMSO-d₆) δ

10.91 (s, 1H), 7.51 (d, J = 7.8 Hz, 1H), 7.29 (d, J = 8.0 Hz,

1H), 7.07-6.99 (m, 1H), 6.99-6.90 (m, 1H), 4.92-4.80 (m,

1H), 3.01-2.89 (m, 1H), 2.78-2.60 (m, 3H), 2.43-2.32 (m,

1H), 2.32-2.19 (m, 1H), 2.01-1.85 (m, 1H), 1.77-1.65 (m,

2H), 1.63 (s, 3H); ¹³C NMR (126 MHz, DMSO-d₆) δ

168.08, 136.10, 131.92, 123.96, 120.25, 118.63, 118.49,

115.68, 111.09, 57.04, 35.59, 34.68, 31.94, 25.11, 23.26,

16.53; LRMS (ESI) m/z: 255 [M+H]⁺; HRMS (ESI) m/z

calculated for C₁₆H₁₈N₂O+H⁺255.1492, found: 255.1488.

10-fluoro-2-hexyl-11c-methyl-5,6,7,11c-tetrahydro-1H-

indolizino[7,8-b]indol-3(2H)-one (3k): yellow oil [60.1

mg, yield 70% (dr = 2.6:1)], and the two diastereomers

1

were inseparable by chromatography. H NMR (400 MHz,

13b-methyl-6,7-dihydro-5H-benzo[1,2]indolizino[7,8-

b]indol-9(13bH)-one (3f): pale yellow solid (64.8 mg,

DMSO-d₆) δ 11.00 (s, 1H), 7.34-7.21 (m, 2H), 6.92-6.80

(m, 1H), 4.28-4.11 (m, 1H), 3.24-3.03 (m, 1H), 2.89-2.51

(m, 4H), 1.82-1.67 (m, 1H), 1.55-1.45 (m, 3H), 1.44-1.03

(m, 10H), 0.91-0.76 (m, 3H); ¹³C NMR (101 MHz,

DMSO-d₆) δ 172.77, 156.70 (d, J_C-F= 231.0 Hz), 132.66,

132.50, 124.00 (d, J_C-F= 10.0 Hz), 115.98 (d, J_C-F= 4.6

Hz), 111.88 (d, J_C-F= 9.8 Hz), 108.33 (d, J_C-F= 25.8 Hz),

102.95 (d, J_C-F= 23.5 Hz), 57.05, 40.48, 40.38, 33.05,

31.19, 30.57, 28.71, 26.58, 24.41, 22.98, 22.04, 13.94;

LRMS (ESI) m/z: 343 [M+H]⁺; HRMS (ESI) m/z

calculated for C₂₁H₂₇FN₂O+H⁺343.2180, found: 343.2178.

o

1

yield 90%), mp 235-236 C. H NMR (500 MHz, DMSO-

d₆) δ 11.10 (s, 1H), 8.27 (d, J = 7.8 Hz, 1H), 8.12-8.03 (m,

1H), 7.71 (d, J = 7.5 Hz, 1H), 7.69-7.64 (m, 1H), 7.52-7.44

(m, 1H), 7.34-7.26 (m, 1H), 7.12-7.03 (m, 2H), 4.56-4.46

(m, 1H), 3.45-3.37 (m, 1H), 2.91-2.80 (m, 1H), 2.80-2.70

(m, 1H), 1.90 (s, 3H); ¹³C NMR (126 MHz, DMSO-d₆) δ

167.33, 151.36, 135.88, 132.31, 131.99, 130.21, 128.08,

124.33, 123.19, 123.06, 120.71, 119.04, 119.01, 111.64,

111.26, 63.56, 34.65, 25.75, 23.42; LRMS (ESI) m/z: 289

[M+H]⁺; HRMS (ESI) m/z calculated for C₁₉H₁₆N₂O+H⁺

289.1335, found: 289.1330.

11c-benzyl-5,6,7,11c-tetrahydro-1H-indolizino[7,8-

b]indol-3(2H)-one (3l): pale yellow oil (52.8 mg, yield

67%). ¹H NMR (500 MHz, CDCl₃) δ 8.33 (s, 1H), 7.52 (d,

J = 7.6 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.26-7.23 (m,

3H), 7.22-7.13 (m, 2H), 7.12-7.06 (m, 2H), 4.50 (dd, J =

12.9, 6.4 Hz, 1H), 3.30 (d, J = 13.9 Hz, 1H), 3.21 (d, J =

13.9 Hz, 1H), 3.08-2.98 (m, 1H), 2.97-2.85 (m, 1H), 2.72-

2.60 (m, 2H), 2.22-2.09 (m, 2H), 1.78-1.65 (m, 1H); ¹³C

NMR (126 MHz, CDCl₃) δ 174.27, 136.70, 136.20, 130.55,

130.24, 128.51, 127.05, 124.36, 121.82, 119.90, 118.48,

115.89, 111.33, 63.79, 44.61, 34.29, 31.64, 30.97, 23.13;

LRMS (ESI) m/z: 317 [M+H]⁺; HRMS (ESI) m/z

calculated for C₂₁H₂₀N₂O+H⁺317.1648, found: 317.1651.

14c-methyl-8,9,10,14c-

tetrahydroindolo[3',2':3,4]pyrido[2,1-a]isoquinolin-

6(5H)-one (3g): yellow solid (70.1 mg, yield 93%), mp

o

1

250-251 C. H NMR (400 MHz, DMSO-d₆) δ 11.26 (s,

1H), 7.59 (d, J = 7.6 Hz, 1H), 7.44-7.38 (m, 2H), 7.30-7.19

(m, 2H), 7.15-7.04 (m, 3H), 4.95-4.86 (m, 1H), 4.10 (d, J =

19.2 Hz, 1H), 3.62 (d, J = 19.4 Hz, 1H), 3.02-2.89 (m, 1H),

2.84-2.73 (m, 1H), 2.72-2.60 (m, 1H), 1.89 (s, 3H); ¹³C

NMR (101 MHz, DMSO-d₆) δ 169.32, 141.44, 136.03,

134.55, 132.37, 127.67, 127.15, 126.20, 126.05, 124.74,

120.52, 120.23, 119.18, 111.52, 111.24, 61.51, 38.20,

36.86, 25.69, 23.26; LRMS (ESI) m/z: 303 [M+H]⁺;

10

10.1002/adsc.201801494

Advanced Synthesis & Catalysis

12c-benzyl-1,2,3,6,7,12c-hexahydroindolo[3,2-

mg, yield 87% (dr = 1.1:1)], and the two diastereomers

were separable by chromatography. Diastereomer 1: white

a]quinolizin-4(8H)-one (3m): pale yellow oil (42.1 mg,

1

o

1

yield 51%). H NMR (400 MHz, DMSO-d₆) δ 10.95 (s,

solid, mp 207-209 C. H NMR (400 MHz, DMSO-d₆) δ

11.02 (s, 1H), 7.39-7.25 (m, 2H), 7.10-7.00 (m, 1H), 7.00-

6.90 (m, 1H), 4.21-4.09 (m, 1H), 3.24-3.11 (m, 1H), 2.74-

2.54 (m, 3H), 2.30-2.17 (m, 1H), 1.91-1.81 (m, 1H), 1.79-

1.68 (m, 1H), 1.59 (s, 3H), 1.44-1.19 (m, 9H), 0.86 (t, J =

6.6 Hz, 3H); ¹³C NMR (101 MHz, DMSO-d₆) δ 176.32,

138.66, 135.84, 126.41, 121.01, 118.56, 117.85, 111.13,

105.33, 58.18, 41.11, 37.53, 35.21, 31.59, 31.20, 28.57,

28.52, 26.86, 22.06, 20.13, 13.97; LRMS (ESI) m/z: 325

[M+H]⁺; HRMS (ESI) m/z calculated for C₂₁H₂₈N₂O+H⁺

325.2274, found: 325.2271. Diastereomer 2: white solid,

1H), 7.33 (d, J = 7.9 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H),

7.23-7.14 (m, 3H), 7.06-6.96 (m, 3H), 6.94-6.86 (m, 1H),

4.85-4.74 (m, 1H), 3.41 (d, J = 13.5 Hz, 1H), 3.24 (d, J =

13.6 Hz, 1H), 2.81-2.64 (m, 3H), 2.61-2.53 (m, 1H), 2.24-

2.05 (m, 2H), 1.90-1.78 (m, 1H), 1.68-1.54 (m, 1H), 1.52-

1.41 (m, 1H); ¹³C NMR (151 MHz, DMSO-d₆) δ 169.23,

137.82, 136.01, 132.97, 130.35, 127.91, 126.43, 124.32,

120.25, 118.98, 118.50, 114.22, 111.10, 60.85, 44.27,

35.01, 33.86, 31.69, 22.95, 16.34; LRMS (ESI) m/z: 331

[M+H]⁺; HRMS (ESI) m/z calculated for C₂₂H₂₂N₂O +H⁺

331.1805, found: 331.1812.

1

mp 250-252 ^oC. H NMR (600 MHz, DMSO-d₆) δ 11.05 (s,

1H), 7.37 (d, J = 7.8 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H),

7.09-7.02 (m, 1H), 7.00-6.93 (m, 1H), 4.24-4.17 (m, 1H),

3.09-3.01 (m, 1H), 2.78-2.61 (m, 2H), 2.61-2.50 (m, 2H),

1.76-1.68 (m, 1H), 1.65-1.56 (m, 1H), 1.53 (s, 3H), 1.35-

1.08 (m, 9H), 0.83 (t, J = 7.0 Hz, 3H); ¹³C NMR (151 MHz,

DMSO-d₆) δ 173.06, 139.19, 135.93, 126.26, 121.01,

118.60, 118.01, 111.12, 104.38, 56.94, 40.41, 39.84, 34.21,

31.19, 30.40, 28.65, 26.52, 24.53, 22.03, 21.06, 13.96;

LRMS (ESI) m/z: 325 [M+H]⁺; HRMS (ESI) m/z

calculated for C₂₁H₂₈N₂O+H⁺325.2274, found: 325.2272.

13b-benzyl-6,7-dihydro-5H-benzo[1,2]indolizino[7,8-

b]indol-9(13bH)-one (3n): white solid (64.8 mg, yield

o

1

71%), mp 281-282 C. H NMR (500 MHz, DMSO-d₆) δ

11.14 (s, 1H), 8.43 (d, J = 7.8 Hz, 1H), 8.32 (d, J = 7.8 Hz,

1H), 7.66-7.58 (m, 1H), 7.46 (d, J = 7.4 Hz, 1H), 7.39-7.30

(m, 2H), 7.20-7.08 (m, 2H), 7.08-6.98 (m, 3H), 6.95-6.87

(m, 2H), 4.53 (dd, J = 13.0, 5.6 Hz, 1H), 3.85 (d, J = 13.9

Hz, 1H), 3.57 (d, J = 13.8 Hz, 1H), 3.49-3.38 (m, 1H),

2.91-2.72 (m, 2H); ¹³C NMR (126 MHz, DMSO-d₆) δ

167.69, 148.85, 135.93, 135.74, 132.77, 131.36, 130.99,

129.98, 127.83, 127.25, 126.17, 124.40, 123.87, 122.58,

120.74, 119.39, 119.12, 111.31, 111.13, 67.12, 42.72,

34.78, 23.45; LRMS (ESI) m/z: 365 [M+H]⁺; HRMS (ESI)

m/z calculated for C₂₅H₂₀N₂O+H⁺365.1648, found:

365.1649.

8-methoxy-11b-methyl-5,6,11,11b-tetrahydro-1H-

indolizino[8,7-b]indol-3(2H)-one (5ac): yellow oil (63.7

mg, yield 94%). ¹H NMR (500 MHz, DMSO-d₆) δ 10.88 (s,

1H), 7.20 (d, J = 8.7 Hz, 1H), 6.89 (d, J = 2.3 Hz, 1H),

6.70 (dd, J = 8.7, 2.4 Hz, 1H), 4.24-4.15 (m, 1H), 3.74 (s,

3H), 3.10-2.98 (m, 1H), 2.73-2.64 (m, 1H), 2.64-2.52 (m,

2H), 2.31-2.20 (m, 2H), 2.07-1.97 (m, 1H), 1.53 (s, 3H);

¹³C NMR (126 MHz, DMSO-d₆) δ 171.86, 153.20, 139.67,

130.94, 126.60, 111.75, 110.78, 104.55, 100.18, 58.93,

55.38, 34.30, 32.63, 30.09, 24.99, 21.01; LRMS (ESI) m/z:

271 [M+H]⁺; HRMS (ESI) m/z calculated for

C₁₆H₁₈N₂O₂+H⁺271.1441, found: 271.1437.

14c-benzyl-8,9,10,14c-

tetrahydroindolo[3',2':3,4]pyrido[2,1-a]isoquinolin-

1

6(5H)-one (3o): pale yellow oil (45.2 mg, yield 48%). H

NMR (500 MHz, CDCl₃) δ 8.36 (s, 1H), 7.96-7.88 (m, 1H),

7.66 (d, J = 7.9 Hz, 1H), 7.50-7.42 (m, 1H), 7.33-7.28 (m,

2H), 7.28-7.20 (m, 2H), 7.16-7.08 (m, 2H), 7.08-7.00 (m,

2H), 6.80-6.71 (m, 2H), 4.79 (dd, J = 12.7, 4.3 Hz, 1H),

3.96-3.76 (m, 3H), 3.40 (d, J = 13.8 Hz, 1H), 2.67-2.56 (m,

1H), 2.48-2.38 (m, 1H), 1.84-1.73 (m, 1H); ¹³C NMR (126

MHz, CDCl₃) δ 170.65, 140.98, 136.36, 136.08, 135.68,

132.27, 130.37, 128.23, 128.00, 127.71, 127.31, 126.87,

126.75, 125.97, 121.64, 121.40, 120.53, 111.66, 109.94,

66.48, 44.96, 39.14, 38.75, 23.34; LRMS (ESI) m/z: 379

[M+H]⁺; HRMS (ESI) m/z calculated for C₂₆H₂₂N₂O+H⁺

379.1805, found: 379.1815.

2-hexyl-8-methoxy-11b-methyl-5,6,11,11b-tetrahydro-

1H-indolizino[8,7-b]indol-3(2H)-one (5ad): white solid

[53.8 mg, yield 61% (dr = 1.2:1)], and the two

diastereomers were separable by chromatography.

Diastereomer 1: white solid, mp 200-202 ^oC. ¹H NMR (400

MHz, DMSO-d₆) δ 10.85 (s, 1H), 7.19 (d, J = 8.7 Hz, 1H),

6.85 (d, J = 2.3 Hz, 1H), 6.69 (dd, J = 8.7, 2.4 Hz, 1H),

4.22-4.07 (m, 1H), 3.73 (s, 3H), 3.24-3.10 (m, 1H), 2.71-

2.53 (m, 3H), 2.29-2.16 (m, 1H), 1.90-1.79 (m, 1H), 1.78-

1.67 (m, 1H), 1.59 (s, 3H), 1.47-1.17 (m, 9H), 0.87 (t, J =

6.6 Hz, 3H); ¹³C NMR (101 MHz, DMSO-d₆) δ 176.29,

153.20, 139.37, 130.87, 126.74, 111.73, 110.80, 105.21,

100.06, 58.21, 55.38, 41.10, 37.56, 35.23, 31.58, 31.20,

28.57, 28.55, 26.86, 22.06, 20.21, 13.96; LRMS (ESI) m/z:

355 [M+H]⁺; HRMS (ESI) m/z calculated for

C₂₂H₃₀N₂O₂+H⁺355.2380, found: 355.2377. Diastereomer

13b-pentyl-6,7-dihydro-5H-benzo[1,2]indolizino[7,8-

b]indol-9(13bH)-one (3p): pale yellow oil (44.6 mg, yield

52%). ¹H NMR (400 MHz, CDCl₃) δ 8.23 (s, 1H), 8.06 (d,

J = 7.7 Hz, 1H), 7.99 (d, J = 7.7 Hz, 1H), 7.85 (d, J = 7.5

Hz, 1H), 7.62-7.54 (m, 1H), 7.45-7.38 (m, 1H), 7.31 (d, J

= 7.8 Hz, 1H), 7.23-7.12 (m, 2H), 4.77 (dd, J = 13.1, 6.1

Hz, 1H), 3.38-3.24 (m, 1H), 3.13-2.98 (m, 1H), 2.76-2.58

(m, 2H), 2.24-2.10 (m, 1H), 1.20-1.02 (m, 5H), 0.89-0.83

(m, 1H), 0.77 (t, J = 6.7 Hz, 3H); ¹³C NMR (151 MHz,

CDCl₃) δ 169.42, 149.58, 136.09, 132.02, 131.85, 131.81,

128.13, 124.85, 123.91, 122.90, 121.75, 119.99, 119.43,

113.53, 111.43, 67.44, 38.22, 35.27, 31.80, 24.14, 23.15,

22.52, 14.09; LRMS (ESI) m/z: 345 [M+H]⁺; HRMS (ESI)

m/z calculated for C₂₃H₂₄N₂O+H⁺345.1961, found:

345.1966.

1

2: white solid, mp 184-185 ^oC. H NMR (400 MHz,

DMSO-d₆) δ 10.86 (s, 1H), 7.20 (d, J = 8.7 Hz, 1H), 6.88

(d, J = 2.4 Hz, 1H), 6.70 (dd, J = 8.7, 2.5 Hz, 1H), 4.26-

4.14 (m, 1H), 3.74 (s, 3H), 3.10-2.97 (m, 1H), 2.75-2.60

(m, 2H), 2.61-2.53 (m, 1H), 2.50-2.45 (m, 1H), 1.79-1.67

(m, 1H), 1.65-1.56 (m, 1H), 1.52 (s, 3H), 1.33-1.11 (m,

9H), 0.84 (t, J = 6.7 Hz, 3H); ¹³C NMR (101 MHz,

DMSO-d₆) δ 173.05, 153.22, 139.91, 130.95, 126.60,

111.71, 110.76, 104.28, 100.22, 56.97, 55.39, 40.40, 39.88,

34.23, 31.17, 30.40, 28.64, 26.50, 24.56, 22.01, 21.14,

13.94; LRMS (ESI) m/z: 355 [M+H]⁺; HRMS (ESI) m/z

calculated for C₂₂H₃₀N₂O₂+H⁺355.2380, found: 355.2379.

11b-methyl-5,6,11,11b-tetrahydro-1H-indolizino[8,7-

b]indol-3(2H)-one (5aa): white solid (53.8 mg, yield 90%),

mp 260-261 ^oC. ¹H NMR (500 MHz, DMSO-d₆) δ 11.06 (s,

1H), 7.39 (d, J = 7.8 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H),

7.10-7.02 (m, 1H), 7.01-6.94 (m, 1H), 4.25-4.16 (m, 1H),

3.11-3.00 (m, 1H), 2.75-2.67 (m, 1H), 2.66-2.55 (m, 2H),

2.32-2.20 (m, 2H), 2.07-1.99 (m, 1H), 1.54 (s, 3H); ¹³C

NMR (101 MHz, DMSO-d₆) δ 171.88, 138.95, 135.93,

126.27, 120.99, 118.58, 117.98, 111.13, 104.66, 58.88,

34.26, 32.58, 30.08, 24.95, 20.90; LRMS (ESI) m/z: 241

[M+H]⁺; HRMS (ESI) m/z calculated for C₁₅H₁₆N₂O+H⁺

241.1335, found: 241.1331.

12b-methyl-1,2,3,6,7,12b-hexahydroindolo[2,3-

a]quinolizin-4(12H)-one (5ae): white solid (45.4 mg,

o

1

yield 71%), mp 255-256 C. H NMR (500 MHz, DMSO-

d₆) δ 10.92 (s, 1H), 7.39 (d, J = 7.8 Hz, 1H), 7.32 (d, J =

8.0 Hz, 1H), 7.10-7.02 (m, 1H), 7.00-6.93 (m, 1H), 4.90-

4.81 (m, 1H), 2.99-2.87 (m, 1H), 2.69-2.62 (m, 1H), 2.61-

2.53 (m, 1H), 2.45-2.32 (m, 2H), 2.32-2.21 (m, 1H), 1.97-

1.86 (m, 1H), 1.80-1.68 (m, 2H), 1.60 (s, 3H); ¹³C NMR

(126 MHz, DMSO-d₆) δ 167.92, 139.68, 135.95, 126.19,

120.94, 118.53, 117.86, 111.05, 105.79, 56.37, 35.55,

34.77, 31.78, 25.32, 21.02, 16.30; LRMS (ESI) m/z: 255

2-hexyl-11b-methyl-5,6,11,11b-tetrahydro-1H-

indolizino[8,7-b]indol-3(2H)-one (5ab): white solid [70.9

11

10.1002/adsc.201801494

Advanced Synthesis & Catalysis

[M+H]⁺; HRMS (ESI) m/z calculated for C₁₆H₁₈N₂O+H⁺

1H), 6.91-6.85 (m, 1H), 6.80 (d, J = 7.1 Hz, 1H), 6.32 (s,

1H), 4.78-4.68 (m, 1H), 4.25-4.17 (m, 1H), 4.16-4.06 (m,

1H), 3.44-3.36 (m, 1H), 2.68 (s, 3H), 2.62-2.53 (m, 1H),

2.44-2.35 (m, 1H), 2.29-2.15 (m, 2H), 1.58 (s, 3H); ¹³C

NMR (126 MHz, DMSO-d₆) δ 171.94, 142.25, 134.40,

128.28, 123.66, 121.20, 119.69, 118.03, 96.39, 58.53,

43.98, 34.71, 34.01, 29.63, 27.27, 19.81; LRMS (ESI) m/z:

255 [M+H]⁺; HRMS (ESI) m/z calculated for

C₁₆H₁₈N₂O+H⁺255.1492, found: 255.1487.

255.1492, found: 255.1488.

9-methoxy-12b-methyl-1,2,3,6,7,12b-

hexahydroindolo[2,3-a]quinolizin-4(12H)-one (5af): pale

o

1

yellow solid (55.9 mg, yield 79%), mp 190-191 C. H

NMR (400 MHz, DMSO-d₆) δ 10.73 (s, 1H), 7.20 (d, J =

8.7 Hz, 1H), 6.89 (d, J = 2.4 Hz, 1H), 6.70 (dd, J = 8.7, 2.4

Hz, 1H), 4.90-4.79 (m, 1H), 3.74 (s, 3H), 2.99-2.86 (m,

1H), 2.66-2.51 (m, 2H), 2.42-2.21 (m, 3H), 1.97-1.84 (m,

1H), 1.79-1.66 (m, 2H), 1.59 (s, 3H); ¹³C NMR (126 MHz,

DMSO-d₆) δ 167.90, 153.18, 140.39, 130.97, 126.50,

111.67, 110.73, 105.69, 100.05, 56.41, 55.38, 35.59, 34.79,

31.77, 25.39, 21.10, 16.33; LRMS (ESI) m/z: 285 [M+H]⁺;

HRMS (ESI) m/z calculated for C₁₇H₂₀N₂O₂+H⁺285.1598,

found: 285.1593.

8-ethyl-12b-methyl-1,5,6,12b-

tetrahydropyrrolo[2',1':3,4]pyrazino[1,2-a]indol-3(2H)-

1

one (5al): colorless oil (56.4 mg, yield 84%). H NMR

(300 MHz, CDCl₃) δ 7.43 (dd, J = 7.7, 1.1 Hz, 1H), 7.09-

7.02 (m, 1H), 7.01-6.95 (m, 1H), 6.32 (s, 1H), 4.65-4.55

(m, 1H), 4.51-4.40 (m, 1H), 4.25-4.10 (m, 1H), 3.49-3.34

(m, 1H), 3.16-2.98 (m, 2H), 2.71-2.55 (m, 1H), 2.52-2.31

(m, 3H), 1.65 (s, 3H), 1.36 (t, J = 7.5 Hz, 3H); ¹³C NMR

(101 MHz, CDCl₃) δ 173.01, 142.05, 134.38, 129.05,

127.83, 122.98, 120.56, 118.51, 97.62, 59.34, 44.39, 35.16,

34.77, 30.25, 27.78, 26.06, 16.51; LRMS (ESI) m/z: 269

[M+H]⁺; HRMS (ESI) m/z calculated for C₁₇H₂₀N₂O+H⁺

269.1648, found: 269.1644.

13b-methyl-7,8,13,13b-tetrahydro-5H-

benzo[1,2]indolizino[8,7-b]indol-5-one (5ag): white solid

(63.6 mg, yield 88%), mp 283-284 ^oC. ¹H NMR (400 MHz,

DMSO-d₆) δ 11.35 (s, 1H), 8.32 (d, J = 7.9 Hz, 1H), 7.79-

7.68 (m, 2H), 7.58-7.49 (m, 1H), 7.44-7.34 (m, 2H), 7.15-

7.05 (m, 1H), 7.03-6.93 (m, 1H), 4.59-4.47 (m, 1H), 3.47-

3.36 (m, 1H), 2.85-2.75 (m, 1H), 2.75-2.63 (m, 1H), 1.86

(s, 3H); ¹³C NMR (101 MHz, DMSO-d₆) δ 167.19, 149.33,

136.17, 135.17, 132.22, 130.25, 128.61, 125.97, 123.17,

122.77, 121.60, 118.88, 118.32, 111.21, 106.34, 62.01,

35.42, 25.89, 21.45; LRMS (ESI) m/z: 289 [M+H]⁺;

HRMS (ESI) m/z calculated for C₁₉H₁₆N₂O+H⁺289.1335,

found: 289.1330.

10-methoxy-12b-methyl-1,5,6,12b-

tetrahydropyrrolo[2',1':3,4]pyrazino[1,2-a]indol-3(2H)-

one (5am): pale yellow oil (62.4 mg, yield 92%). ¹H NMR

(300 MHz, CDCl₃) δ 7.15 (d, J = 8.8 Hz, 1H), 7.06-7.01

(m, 1H), 6.85 (dd, J = 8.8, 2.2 Hz, 1H), 6.20 (s, 1H), 4.50

(dd, J = 13.6, 4.9 Hz, 1H), 4.15 (dd, J = 11.6, 4.6 Hz, 1H),

3.90-3.82 (m, 4H), 3.43-3.31 (m, 1H), 2.69-2.56 (m, 1H),

2.51-2.32 (m, 3H), 1.62 (s, 3H); ¹³C NMR (126 MHz,

CDCl₃) δ 173.31, 154.75, 142.22, 130.98, 128.47, 111.61,

109.85, 102.43, 95.87, 59.49, 55.99, 41.23, 34.77, 34.20,

30.26, 27.65; LRMS (ESI) m/z: 271 [M+H]⁺; HRMS (ESI)

m/z calculated for C₁₆H₁₈N₂O₂+H⁺271.1441, found:

271.1436.

10-methoxy-13b-methyl-7,8,13,13b-tetrahydro-5H-

benzo[1,2]indolizino[8,7-b]indol-5-one (5ah): white solid

(70.2 mg, yield 88%), mp 164-165 ^oC. ¹H NMR (400 MHz,

DMSO-d₆) δ 11.18 (s, 1H), 8.29 (d, J = 7.9 Hz, 1H), 7.77-

7.67 (m, 2H), 7.58-7.47 (m, 1H), 7.26 (d, J = 8.7 Hz, 1H),

6.89 (d, J = 2.1 Hz, 1H), 6.73 (dd, J = 8.7, 2.1 Hz, 1H),

4.57-4.45 (m, 1H), 3.73 (s, 3H), 3.45-3.35 (m, 1H), 2.81-

2.73 (m, 1H), 2.72-2.60 (m, 1H), 1.84 (s, 3H); ¹³C NMR

(126 MHz, DMSO-d₆) δ 167.15, 153.34, 149.37, 135.78,

132.21, 131.18, 130.24, 128.59, 126.32, 123.15, 122.76,

111.89, 111.54, 106.18, 100.29, 62.04, 55.36, 35.45, 25.96,

21.55; LRMS (ESI) m/z: 319 [M+H]⁺; HRMS (ESI) m/z

calculated for C₂₀H₁₈N₂O₂+H⁺319.1441, found: 319.1435.

12b-methyl-3-oxo-1,2,3,5,6,12b-

hexahydropyrrolo[2',1':3,4]pyrazino[1,2-a]indole-10-

carbonitrile (5an): yellow solid (54.3 mg, yield 82%), mp

182-183 ^oC. ¹H NMR (500 MHz, DMSO-d₆) δ 8.07 (s, 1H),

7.59 (d, J = 8.5 Hz, 1H), 7.49 (d, J = 8.5 Hz, 1H), 6.54 (s,

1H), 4.45-4.36 (m, 1H), 4.33-4.24 (m, 1H), 3.89-3.77 (m,

1H), 3.50-3.39 (m, 1H), 2.66-2.54 (m, 1H), 2.48-2.40 (m,

1H), 2.32-2.17 (m, 2H), 1.60 (s, 3H); ¹³C NMR (101 MHz,

DMSO-d₆) δ 172.10, 144.85, 136.80, 127.37, 125.40,

123.57, 120.62, 111.12, 101.83, 96.60, 58.59, 41.28, 34.21,

33.33, 29.57, 27.06; LRMS (ESI) m/z: 266 [M+H]⁺;

HRMS (ESI) m/z calculated for C₁₆H₁₅N₃O+H⁺266.1288,

found: 266.1285.

14b-methyl-8,9,14,14b-

tetrahydroindolo[2',3':3,4]pyrido[2,1-a]isoquinolin-

6(5H)-one (5ai): pale yellow solid (65.0 mg, yield 86%),

mp 137-138 ^oC. ¹H NMR (400 MHz, DMSO-d₆) δ 11.56 (s,

1H), 7.52-7.43 (m, 3H), 7.31-7.24 (m, 2H), 7.24-7.18 (m,

1H), 7.18-7.12 (m, 1H), 7.08-6.98 (m, 1H), 4.96-4.85 (m,

1H), 4.08 (d, J = 19.2 Hz, 1H), 3.63 (d, J = 19.4 Hz, 1H),

2.96-2.86 (m, 1H), 2.86-2.75 (m, 1H), 2.50-2.41 (m, 1H),

1.84 (s, 3H); ¹³C NMR (101 MHz, DMSO-d₆) δ 168.96,

139.88, 136.11, 135.07, 132.26, 127.79, 127.45, 126.35,

125.97, 124.13, 121.43, 118.81, 118.18, 111.30, 109.24,

60.89, 37.99, 37.89, 26.20, 21.05; LRMS (ESI) m/z: 303

[M+H]⁺; HRMS (ESI) m/z calculated for C₂₀H₁₈N₂O+H⁺

303.1492, found: 303.1487.

12b-methyl-10-nitro-1,5,6,12b-

tetrahydropyrrolo[2',1':3,4]pyrazino[1,2-a]indol-3(2H)-

one (5ao): yellow oil (32.9 mg, yield 46%). ¹H NMR (300

MHz, CDCl₃) δ 8.48 (d, J = 2.2 Hz, 1H), 8.07 (dd, J = 9.0,

2.2 Hz, 1H), 7.28 (d, J = 9.1 Hz, 1H), 6.46 (s, 1H), 4.57

(dd, J = 13.8, 4.5 Hz, 1H), 4.27 (dd, J = 12.0, 3.9 Hz, 1H),

4.02-3.90 (m, 1H), 3.48-3.36 (m, 1H), 2.69-2.58 (m, 1H),

2.53-2.35 (m, 3H), 1.66 (s, 3H); ¹³C NMR (101 MHz,

CDCl₃) δ 173.04, 145.02, 142.25, 138.45, 127.30, 117.54,

117.23, 109.10, 98.66, 59.28, 41.72, 34.78, 33.82, 30.11,

27.63; LRMS (ESI) m/z: 286 [M+H]⁺; HRMS (ESI) m/z

calculated for C₁₅H₁₅N₃O₃+H⁺286.1186, found: 286.1182.

12b-methyl-1,5,6,12b-

tetrahydropyrrolo[2',1':3,4]pyrazino[1,2-a]indol-3(2H)-

one (5aj): white solid (55.3 mg, yield 92%), mp 121-122

1

^oC. H NMR (400 MHz, DMSO-d₆) δ 7.51 (d, J = 7.7 Hz,

1H), 7.38 (d, J = 8.1 Hz, 1H), 7.15-7.09 (m, 1H), 7.08-7.01

(m, 1H), 6.34 (s, 1H), 4.34-4.22 (m, 2H), 3.81-3.68 (m,

1H), 3.49-3.38 (m, 1H), 2.65-2.53 (m, 1H), 2.47-2.36 (m,

1H), 2.33-2.17 (m, 2H), 1.59 (s, 3H); ¹³C NMR (126 MHz,

DMSO-d₆) δ 172.10, 142.15, 135.22, 127.61, 120.73,

119.90, 119.78, 109.62, 95.46, 58.63, 40.85, 34.33, 33.57,

29.65, 27.25; LRMS (ESI) m/z: 241 [M+H]⁺; HRMS (ESI)

m/z calculated for C₁₅H₁₆N₂O+H⁺241.1335, found:

241.1330.

10-fluoro-12b-methyl-1,5,6,12b-

tetrahydropyrrolo[2',1':3,4]pyrazino[1,2-a]indol-3(2H)-

1

one (5ap): colorless oil (95.1 mg, yield 74%). H NMR

(300 MHz, CDCl₃) δ 7.24-7.12 (m, 2H), 6.99-6.88 (m, 1H),

6.25 (s, 1H), 4.57-4.46 (m, 1H), 4.22-4.12 (m, 1H), 3.94-

3.80 (m, 1H), 3.46-3.31 (m, 1H), 2.68-2.54 (m, 1H), 2.51-

2.31 (m, 3H), 1.63 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ

173.10, 158.34 (d, J_C-F= 235.0 Hz), 143.30, 132.31,

128.33 (d, J_C-F= 10.3 Hz), 109.86 (d, J_C-F= 17.5 Hz),

109.68, 105.36 (d, J_C-F= 23.6 Hz), 96.28 (d, J_C-F= 4.5 Hz),

59.35, 41.32, 34.75, 34.05, 30.22, 27.62; LRMS (ESI) m/z:

259 [M+H]⁺; HRMS (ESI) m/z calculated for

C₁₅H₁₅FN₂O+H⁺259.1241, found: 259.1239.

8,12b-dimethyl-1,5,6,12b-

tetrahydropyrrolo[2',1':3,4]pyrazino[1,2-a]indol-3(2H)-

one (5ak): yellow solid (57.7 mg, yield 91%), mp 159-161

1

^oC. H NMR (500 MHz, DMSO-d₆) δ 7.31 (d, J = 7.7 Hz,

12

10.1002/adsc.201801494

Advanced Synthesis & Catalysis

10-bromo-12b-methyl-1,5,6,12b-

10-fluoro-13b-methyl-2,3,6,7-tetrahydro-1H-

tetrahydropyrrolo[2',1':3,4]pyrazino[1,2-a]indol-3(2H)-

one (5aq): pale yellow solid (67.6 mg, yield 85%), mp

119-120 ^oC. ¹H NMR (400 MHz, DMSO-d₆) δ 7.77 (d, J =

1.8 Hz, 1H), 7.44 (d, J = 8.7 Hz, 1H), 7.30 (dd, J = 8.6, 1.9

Hz, 1H), 6.42 (s, 1H), 4.41-4.30 (m, 2H), 3.89-3.76 (m,

1H), 3.56-3.44 (m, 1H), 2.72-2.60 (m, 1H), 2.52-2.43 (m,

1H), 2.37-2.23 (m, 2H), 1.64 (s, 3H); ¹³C NMR (101 MHz,

DMSO-d₆) δ 172.06, 143.69, 133.97, 129.41, 123.17,

122.09, 112.30, 111.72, 95.27, 58.55, 41.03, 34.23, 33.41,

29.60, 27.10; LRMS (ESI) m/z: 321 ([M+H]⁺, Br⁸¹), 319

([M+H]⁺, Br⁷⁹); HRMS (ESI) m/z calculated for

C₁₅H₁₅BrN₂O+H⁺319.0441, found: 319.0439.

pyrido[2',1':3,4]pyrazino[1,2-a]indol-4(13bH)-one (5av):

pale yellow oil (39.7 mg, yield 58%). ¹H NMR (400 MHz,

CDCl₃) δ 7.46 (dd, J = 8.6, 5.3 Hz, 1H), 6.98-6.83 (m, 2H),

6.22 (s, 1H), 5.15 (ddd, J = 13.8, 4.6, 1.2 Hz, 1H), 4.08

(ddd, J = 11.6, 4.3, 1.3 Hz, 1H), 3.94-3.82 (m, 1H), 3.38-

3.24 (m, 1H), 2.61-2.49 (m, 1H), 2.48-2.38 (m, 1H), 2.36-

2.29 (m, 1H), 2.21-2.09 (m, 1H), 2.03-1.93 (m, 1H), 1.93-

1.83 (m, 1H), 1.70 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ

169.46, 159.51 (d, J_C-F= 237.8 Hz), 142.49 (d, J_C-F= 3.6

Hz), 135.55 (d, J_C-F= 11.9 Hz), 124.46, 121.10 (d, J_C-F

9.9 Hz), 108.93 (d, J_C-F= 24.4 Hz), 95.75, 95.58 (d, J_C-F

26.4 Hz), 57.35, 41.72, 37.37, 35.16, 32.15, 28.85, 17.35;

LRMS (ESI) m/z: 273 [M+H]⁺; HRMS (ESI) m/z

calculated for C₁₆H₁₇FN₂O+H⁺273.1398, found: 273.1393.

=

2-hexyl-12b-methyl-1,5,6,12b-

tetrahydropyrrolo[2',1':3,4]pyrazino[1,2-a]indol-3(2H)-

one (5ar): pale yellow oil [46.1 mg, yield 57% (dr =

1.7:1)], and the two diastereomers were inseparable by

13b-methyl-6,7-dihydroisoindolo[1',2':3,4]pyrazino[1,2-

a]indol-9(13bH)-one (5aw): pale yellow solid (52.5 mg,

1

o

1

chromatography. H NMR (600 MHz, CDCl₃) δ 7.60-7.56

yield 73%), mp 149-150 C. H NMR (400 MHz, DMSO-

d₆) δ 8.24 (d, J = 7.6 Hz, 1H), 7.80-7.69 (m, 2H), 7.59-7.48

(m, 2H), 7.38 (d, J = 8.1 Hz, 1H), 7.17-7.09 (m, 1H), 7.08-

7.00 (m, 1H), 6.84 (s, 1H), 4.68-4.57 (m, 1H), 4.45-4.31

(m, 1H), 3.90-3.75 (m, 2H), 1.91 (s, 3H); ¹³C NMR (101

MHz, DMSO-d₆) δ 166.58, 150.30, 137.82, 135.25, 132.78,

129.85, 128.71, 127.29, 123.08, 121.17, 120.01, 119.95,

109.91, 97.80, 61.38, 41.06, 34.25, 28.19; LRMS (ESI) m/z:

289 [M+H]⁺; HRMS (ESI) m/z calculated for

C₁₉H₁₆N₂O+H⁺289.1335, found: 289.1332.

(m, 0.88H), 7.30-7.24 (m, 1.14H), 7.23-7.18 (m, 0.91H),

7.16-7.11 (m, 0.87H), 6.30 (s, 0.52H), 6.29 (s, 0.31H),

4.58-4.46 (m, 0.89H), 4.29-4.20 (m, 0.33H), 4.17-4.07 (m,

0.54H), 3.98-3.91 (m, 0.53H), 3.90-3.83 (m, 0.34H), 3.56-

3.45 (m, 0.53H), 3.42-3.32 (m, 0.30H), 2.81-2.74 (m,

0.53H), 2.70-2.62 (m, 0.68H), 2.47-2.37 (m, 0.58H), 2.09-

2.00 (m, 0.60H), 2.01-1.90 (m, 1.35H), 1.69 (s, 1.71H),

1.62 (s, 1.04H), 1.55-1.14 (m, 9.70H), 0.93-0.82 (m,

3.12H); ¹³C NMR (151 MHz, CDCl₃) δ 177.20, 174.63,

142.18, 141.52, 136.21, 135.51, 128.18, 127.90, 121.62,

121.55, 120.48, 120.46, 109.19, 109.15, 96.36, 96.11,

58.44, 57.51, 42.32, 41.85, 41.53, 41.11, 40.53, 40.47,

34.55, 34.17, 31.96, 31.82, 31.77, 30.86, 30.59, 29.25,

27.52, 27.30, 27.25, 22.72, 22.68, 14.20; LRMS (ESI) m/z:

325[M+H]⁺; HRMS (ESI) m/z calculated for

C₂₁H₂₈N₂O+H⁺325.2274, found: 325.2273.

15b-methyl-8,9-dihydro-5H-

indolo[2',1':3,4]pyrazino[2,1-a]isoquinolin-6(15bH)-one

o

(5ax): yellow solid (41.3 mg, yield 55%), mp 235-236 C.

¹H NMR (400 MHz, DMSO-d₆) δ 7.67 (d, J = 7.7 Hz, 1H),

7.44-7.38 (m, 2H), 7.33-7.25 (m, 2H), 7.23-7.15 (m, 2H),

7.15-7.08 (m, 1H), 6.83 (s, 1H), 4.99-4.90 (m, 1H), 4.40-

4.31 (m, 1H), 4.10 (d, J = 19.4 Hz, 1H), 3.81-3.72 (m, 1H),

3.68 (d, J = 19.5 Hz, 1H), 3.20-3.08 (m, 1H), 1.89 (s, 3H);

13b-methyl-2,3,6,7-tetrahydro-1H-

pyrido[2',1':3,4]pyrazino[1,2-a]indol-4(13bH)-one (5as): ¹³C NMR (126 MHz, DMSO-d₆) δ 168.25, 138.64, 136.90,

o

1

white solid (42.2 mg, yield 66%), mp 113-114 C. H

NMR (500 MHz, DMSO-d₆) δ 7.50 (d, J = 7.8 Hz, 1H),

7.37 (d, J = 8.1 Hz, 1H), 7.14-7.07 (m, 1H), 7.06-7.01 (m,

1H), 6.34 (s, 1H), 4.95-4.85 (m, 1H), 4.33-4.24 (m, 1H),

3.81-3.70 (m, 1H), 3.40-3.25 (m, 1H), 2.42-2.26 (m, 3H),

2.07-1.99 (m, 1H), 1.98-1.88 (m, 1H), 1.78-1.69 (m, 1H),

1.67 (s, 3H); ¹³C NMR (126 MHz, DMSO-d₆) δ 168.11,

142.39, 135.06, 127.66, 120.55, 119.85, 119.70, 109.41,

95.16, 56.72, 41.23, 36.60, 34.53, 31.66, 28.24, 16.87;

LRMS (ESI) m/z: 255 [M+H]⁺; HRMS (ESI) m/z

calculated for C₁₆H₁₈N₂O+H⁺255.1492, found: 255.1488.

136.55, 132.07, 128.00, 127.65, 127.20, 126.45, 124.22,

121.37, 120.31, 119.92, 109.74, 101.43, 61.84, 42.84,

37.73, 37.40, 28.57; LRMS (ESI) m/z: 303 [M+H]⁺;

HRMS (ESI) m/z calculated for C₂₀H₁₈N₂O+H⁺303.1492,

found: 303.1487.

13b-methyl-5,6,7,13b-tetrahydro-1H-

pyrrolo[2',1':3,4][1,4]diazepino[1,2-a]indol-3(2H)-one

1

(5ay): colorless oil (46.2 mg, yield 73%). H NMR (400

MHz, CDCl₃) δ 7.57 (d, J = 7.8 Hz, 1H), 7.30 (d, J = 8.3

Hz, 1H), 7.24-7.19 (m, 1H), 7.13-7.06 (m, 1H), 6.45 (s,

1H), 4.56-4.33 (m, 2H), 4.20 (ddd, J = 14.8, 9.1, 2.5 Hz,

1H), 3.17-3.04 (m, 1H), 2.80-2.70 (m, 1H), 2.53-2.42 (m,

2H), 2.14-1.88 (m, 3H), 1.72 (s, 3H); ¹³C NMR (101 MHz,

CDCl₃) δ 174.15, 142.53, 137.66, 126.93, 122.01, 120.69,

11-methoxy-13b-methyl-2,3,6,7-tetrahydro-1H-

pyrido[2',1':3,4]pyrazino[1,2-a]indol-4(13bH)-one (5at):

pale yellow oil (56.7 mg, yield 80%). ¹H NMR (300 MHz,

CDCl₃) δ 7.17 (d, J = 8.8 Hz, 1H), 7.04 (d, J = 2.3 Hz, 1H), 119.87, 109.04, 99.59, 62.41, 43.37, 38.51, 34.96, 30.47,

6.85 (dd, J = 8.8, 2.4 Hz, 1H), 6.17 (s, 1H), 5.15 (dd, J =

13.7, 3.6 Hz, 1H), 4.13 (dd, J = 11.7, 3.2 Hz, 1H), 3.97-

3.78 (m, 4H), 3.39-3.22 (m, 1H), 2.63-2.28 (m, 3H), 2.21-

1.83 (m, 3H), 1.70 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ

169.49, 154.73, 142.60, 130.91, 128.50, 111.50, 109.74,

102.38, 95.41, 57.36, 56.06, 41.67, 37.37, 35.30, 32.18,

28.77, 17.38; LRMS (ESI) m/z: 285 [M+H]⁺; HRMS (ESI)

m/z calculated for C₁₇H₂₀N₂O₂+H⁺285.1598, found:

285.1594.

28.05, 26.37; LRMS (ESI) m/z: 255 [M+H]⁺; HRMS (ESI)

m/z calculated for C₁₆H₁₈N₂O+H⁺255.1492, found:

255.1489.

9-ethyl-13b-methyl-5,6,7,13b-tetrahydro-1H-

pyrrolo[2',1':3,4][1,4]diazepino[1,2-a]indol-3(2H)-one

(5az): pale yellow oil (54.7 mg, yield 77%). ¹H NMR (400

MHz, CDCl₃) δ 7.41 (dd, J = 7.4, 1.6 Hz, 1H), 7.06-6.96

(m, 2H), 6.48 (s, 1H), 4.68-4.58 (m, 1H), 4.49 (ddd, J =

15.1, 7.0, 2.9 Hz, 1H), 4.29 (ddd, J = 14.1, 5.8, 2.8 Hz, 1H),

3.16-2.96 (m, 3H), 2.73-2.61 (m, 1H), 2.56-2.43 (m, 2H),

9-ethyl-13b-methyl-2,3,6,7-tetrahydro-1H-

pyrido[2',1':3,4]pyrazino[1,2-a]indol-4(13bH)-one (5au): 2.15-1.93 (m, 3H), 1.73 (s, 3H), 1.37 (t, J = 7.5 Hz, 3H);

pale yellow oil (51.1 mg, yield 72%). ¹H NMR (300 MHz,

CDCl₃) δ 7.45-7.37 (m, 1H), 7.09-7.01 (m, 1H), 7.00-6.93

(m, 1H), 6.28 (s, 1H), 5.13-5.01 (m, 1H), 4.62-4.50 (m,

1H), 4.33-4.18 (m, 1H), 3.39-3.21 (m, 1H), 3.14-3.00 (m,

2H), 2.65-2.22 (m, 3H), 2.19-1.83 (m, 3H), 1.74 (s, 3H),

1.36 (t, J = 7.5 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ

169.23, 142.35, 134.20, 129.06, 127.79, 122.62, 120.42,

118.38, 97.12, 57.49, 44.90, 37.67, 35.99, 31.89, 28.63,

25.79, 17.37, 16.59; LRMS (ESI) m/z: 283 [M+H]⁺;

HRMS (ESI) m/z calculated for C₁₈H₂₂N₂O+H⁺283.1805,

found: 283.1801.

¹³C NMR (126 MHz, CDCl₃) δ 174.15, 142.62, 135.62,

128.17, 127.02, 124.35, 120.09, 118.96, 101.49, 62.71,

44.41, 37.80, 35.57, 30.42, 28.09, 27.20, 26.23, 15.89;

LRMS (ESI) m/z: 283 [M+H]⁺; HRMS (ESI) m/z

calculated for C₁₈H₂₂N₂O+H⁺283.1805, found: 283.1802.

10-fluoro-13b-methyl-5,6,7,13b-tetrahydro-1H-

pyrrolo[2',1':3,4][1,4]diazepino[1,2-a]indol-3(2H)-one

(5ba): pale yellow oil (42.9 mg, yield 63%). ¹H NMR (300

MHz, CDCl₃) δ 7.45 (dd, J = 8.6, 5.5 Hz, 1H), 6.96 (dd, J

= 10.3, 2.0 Hz, 1H), 6.89-6.80 (m, 1H), 6.40 (s, 1H), 4.43-

4.27 (m, 2H), 4.20-4.06 (m, 1H), 3.16-3.02 (m, 1H), 2.78-

13

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Advanced Synthesis & Catalysis

2.64 (m, 1H), 2.51-2.40 (m, 2H), 2.12-1.87 (m, 3H), 1.70

(s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 174.02, 159.98 (d,

J_C-F= 237.7 Hz), 142.96 (d, J_C-F= 3.6 Hz), 137.75 (d, J_C-F

= 11.8 Hz), 123.15, 121.36 (d, J_C-F= 10.1 Hz), 108.48 (d,

J_C-F= 24.4 Hz), 99.51, 95.70 (d, J_C-F= 26.8 Hz), 62.20,

43.81, 38.45, 34.74, 30.40, 28.00, 26.29; LRMS (ESI) m/z:

273 [M+H]⁺; HRMS (ESI) m/z calculated for

C₁₆H₁₇FN₂O+H⁺273.1398, found: 273.1392.

NMR (500 MHz, DMSO-d₆) δ 7.40 (d, J = 5.0 Hz, 1H),

6.80 (d, J = 5.1 Hz, 1H), 4.11 (dd, J = 13.3, 6.2 Hz, 1H),

3.07-2.96 (m, 1H), 2.72-2.63 (m, 1H), 2.61-2.51 (m, 2H),

2.32-2.19 (m, 2H), 2.03-1.92 (m, 1H), 1.50 (s, 3H); ¹³C

NMR (101 MHz, DMSO-d₆) δ 171.66, 141.84, 132.28,

127.06, 123.48, 60.38, 35.08, 33.58, 30.20, 27.88, 25.10;

LRMS (ESI) m/z: 208 [M+H]⁺; HRMS (ESI) m/z

calculated for C₁₁H₁₃NOS+H⁺208.0791, found: 208.0788.

14b-methyl-1,14b-dihydroindolo[1,2-a]pyrrolo[2,1-

11b-methyl-4,5-dihydrothieno[2',3':3,4]pyrido[2,1-

c]quinoxalin-3(2H)-one (5bb): pale yellow solid (64.3 mg, a]isoindol-7(11bH)-one (7d): pale yellow solid (59.2 mg,

o

1

o

yield 89%), mp 179-180 C. H NMR (400 MHz, DMSO-

d₆) δ 8.16 (d, J = 8.1 Hz, 1H), 8.13-8.04 (m, 2H), 7.67 (d, J

= 7.7 Hz, 1H), 7.46-7.39 (m, 1H), 7.35-7.26 (m, 2H), 7.25-

7.17 (m, 1H), 6.64 (s, 1H), 2.95-2.81 (m, 1H), 2.69-2.55

(m, 2H), 2.55-2.45 (m, 1H), 1.39 (s, 3H); ¹³C NMR (101

yield 93%), mp 137-138 C. ¹H NMR (500 MHz, DMSO-

d₆) δ 7.97-7.90 (m, 1H), 7.76-7.67 (m, 2H), 7.57-7.49 (m,

1H), 7.45 (d, J = 5.1 Hz, 1H), 6.82 (d, J = 5.1 Hz, 1H),

4.43 (dd, J = 13.5, 6.2 Hz, 1H), 3.40 (ddd, J = 13.4, 12.0,

4.7 Hz, 1H), 2.76 (dd, J = 16.2, 4.5 Hz, 1H), 2.62 (ddd, J =

MHz, DMSO-d₆) δ 172.18, 142.66, 133.14, 129.30, 128.79, 16.2, 11.7, 6.5 Hz, 1H), 1.82 (s, 3H); ¹³C NMR (101 MHz,

125.81, 125.74, 124.08, 122.97, 122.70, 121.39, 121.16,

117.24, 111.80, 97.57, 59.35, 31.19, 30.04, 25.92; LRMS

(ESI) m/z: 289 [M+H]⁺; HRMS (ESI) m/z calculated for

C₁₉H₁₆N₂O+H⁺289.1335, found: 289.1331.

DMSO-d₆) δ 166.55, 150.20, 137.99, 133.42, 132.47,

130.02, 128.68, 127.07, 124.45, 123.13, 122.41, 63.14,

34.35, 28.78, 25.59; LRMS (ESI) m/z: 256 [M+H]⁺;

HRMS (ESI) m/z calculated for C₁₅H₁₃NOS+H⁺256.0791,

found: 256.0789.

15b-methyl-2,3-dihydro-1H-indolo[1,2-a]pyrido[2,1-

c]quinoxalin-4(15bH)-one (5bc): pale yellow oil (50.3 mg, 12b-methyl-8,12b-dihydro-4H-

1

yield 67%). H NMR (400 MHz, DMSO-d₆) δ 8.08-8.01

(m, 2H), 7.71-7.64 (m, 2H), 7.47-7.40 (m, 1H), 7.33-7.24

(m, 2H), 7.23-7.17 (m, 1H), 6.60 (s, 1H), 2.71-2.56 (m,

2H), 2.42-2.28 (m, 2H), 1.97-1.75 (m, 2H), 1.29 (s, 3H);

¹³C NMR (101 MHz, DMSO-d₆) δ 168.17, 142.52, 133.20,

130.55, 129.10, 128.41, 127.78, 126.59, 123.42, 122.80,

121.25, 121.18, 116.89, 111.53, 96.76, 57.29, 33.27, 32.89,

27.70, 17.12; LRMS (ESI) m/z: 303 [M+H]⁺; HRMS (ESI)

m/z calculated for C₂₀H₁₈N₂O+H⁺303.1492, found:

303.1486.

thieno[2',3':3,4]pyrido[2,1-a]isoquinolin-7(5H)-one (7e):

pale yellow solid (38.6 mg, yield 57%), mp 155-156 ^oC. ¹H

NMR (500 MHz, DMSO-d₆) δ 7.77-7.71 (m, 1H), 7.55 (d,

J = 5.1 Hz, 1H), 7.32-7.22 (m, 3H), 6.91 (d, J = 5.1 Hz,

1H), 4.90-4.79 (m, 1H), 3.97 (d, J = 20.2 Hz, 1H), 3.64 (d,

J = 20.3 Hz, 1H), 3.10-2.99 (m, 1H), 2.76-2.68 (m, 1H),

2.50-2.44 (m, 1H), 1.87 (s, 3H); ¹³C NMR (101 MHz,

DMSO-d₆) δ 167.85, 139.01, 138.79, 136.38, 131.27,

127.97, 127.59, 127.45, 126.50, 124.84, 124.55, 62.60,

37.03, 36.71, 31.74, 25.20; LRMS (ESI) m/z: 270 [M+H]⁺;

HRMS (ESI) m/z calculated for C₁₆H₁₅NOS+H⁺270.0947,

found: 270.0942.

15b-methylindolo[1,2-a]isoindolo[1,2-c]quinoxalin-

11(15bH)-one (5bd): white solid (52.3 mg, yield 62%),

mp 149-150 ^oC. ¹H NMR (400 MHz, DMSO-d₆) δ 8.35 (d,

J = 7.6 Hz, 1H), 8.31-8.26 (m, 1H), 8.15 (d, J = 8.4 Hz,

1H), 8.04 (dd, J = 7.9, 1.5 Hz, 1H), 7.96-7.87 (m, 2H),

7.76-7.68 (m, 1H), 7.65 (d, J = 7.5 Hz, 1H), 7.57-7.51 (m,

1H), 7.47-7.40 (m, 1H), 7.35-7.29 (m, 1H), 7.24-7.18 (m,

1H), 6.77 (s, 1H), 1.65 (s, 3H); ¹³C NMR (101 MHz,

DMSO-d₆) δ 164.12, 146.45, 137.13, 133.86, 133.53,

129.71, 129.49, 129.32, 128.95, 126.54, 124.60, 124.42,

124.03, 123.85, 123.67, 123.46, 121.63, 121.33, 117.52,

9a-methyl-4,5,9,9a-tetrahydrothieno[2,3-g]indolizin-

7(8H)-one (7f): pale yellow solid (39.5 mg, yield 76%),

mp 128-129 ^oC. ¹H NMR (400 MHz, DMSO-d₆) δ 7.37 (d,

J = 5.1 Hz, 1H), 6.99 (d, J = 5.2 Hz, 1H), 4.15 (dd, J =

13.2, 5.6 Hz, 1H), 3.09-2.98 (m, 1H), 2.85-2.76 (m, 1H),

2.74-2.62 (m, 1H), 2.61-2.52 (m, 1H), 2.31-2.15 (m, 2H),

1.90-1.79 (m, 1H), 1.42 (s, 3H); ¹³C NMR (101 MHz,

DMSO-d₆) δ 171.57, 141.76, 131.34, 124.18, 124.06,

60.37, 33.69, 33.40, 30.06, 25.75, 24.31; LRMS (ESI) m/z:

111.94, 99.28, 61.21, 26.30; LRMS (ESI) m/z: 337 [M+H]⁺; 208 [M+H]⁺; HRMS (ESI) m/z calculated for

HRMS (ESI) m/z calculated for C₂₃H₁₆N₂O+H⁺337.1335,

C₁₁H₁₃NOS+H⁺208.0791, found: 208.0788.

found: 337.1329.

11b-methyl-4,5-dihydrothieno[3',2':3,4]pyrido[2,1-

11b-methyl-4,5-dihydro-3H-

a]isoindol-7(11bH)-one (7g): yellow solid (58.6 mg, yield

o

1

pyrrolo[3',2':3,4]pyrido[2,1-a]isoindol-7(11bH)-one (7a): 92%), mp 199-200 C. H NMR (400 MHz, DMSO-d₆) δ

pale yellow solid (41.1 mg, yield 69%), mp 237-238 ^oC. ¹H

NMR (500 MHz, DMSO-d₆) δ 10.56 (s, 1H), 7.97 (d, J =

7.6 Hz, 1H), 7.68-7.60 (m, 2H), 7.49-7.42 (m, 1H), 6.62-

6.55 (m, 1H), 6.31-6.26 (m, 1H), 4.48-4.37 (m, 1H), 3.41-

3.27 (m, 1H), 2.66-2.54 (m, 2H), 1.66 (s, 3H); ¹³C NMR

(101 MHz, DMSO-d₆) δ 166.84, 152.18, 131.93, 129.95,

127.76, 122.75, 122.73, 122.34, 119.86, 116.84, 103.97,

62.26, 34.48, 27.71, 22.62; LRMS (ESI) m/z: 239 [M+H]⁺;

HRMS (ESI) m/z calculated for C₁₅H₁₄N₂O+H⁺239.1179,

found: 239.1175.

8.16 (d, J = 7.6 Hz, 1H), 7.74-7.63 (m, 2H), 7.56-7.48 (m,

2H), 7.39 (d, J = 5.3 Hz, 1H), 4.47 (dd, J = 13.4, 5.7 Hz,

1H), 3.46-3.38 (m, 1H), 2.93-2.84 (m, 1H), 2.82-2.71 (m,

1H), 1.75 (s, 3H); ¹³C NMR (101 MHz, DMSO-d₆) δ

166.78, 150.24, 137.84, 132.75, 132.30, 130.06, 128.41,

125.25, 124.03, 122.99, 122.98, 63.45, 34.70, 27.02, 24.81;

LRMS (ESI) m/z: 256 [M+H]⁺; HRMS (ESI) m/z

calculated for C₁₅H₁₃NOS+H⁺256.0791, found: 256.0785.

8,9-dimethoxy-10b-methyl-1,5,6,10b-

tetrahydropyrrolo[2,1-a]isoquinolin-3(2H)-one

(7h):

o

1

12b-methyl-5,6-dihydropyrrolo[2',1':3,4]pyrazino[2,1-

white solid (55.5 mg, yield 85%), mp 53-54 C. H NMR

(500 MHz, DMSO-d₆) δ 6.78 (s, 1H), 6.66 (s, 1H), 4.08-

4.00 (m, 1H), 3.75 (s, 3H), 3.71 (s, 3H), 3.05-2.96 (m, 1H),

2.70-2.62 (m, 2H), 2.59-2.47 (m, 1H), 2.45-2.37 (m, 1H),

2.25-2.15 (m, 1H), 1.93-1.82 (m, 1H), 1.45 (s, 3H); ¹³C

a]isoindol-8(12bH)-one (7b): pale yellow solid (50.6 mg,

o

1

yield 85%), mp 156-157 C. H NMR (500 MHz, DMSO-

d₆) δ 8.06 (d, J = 7.9 Hz, 1H), 7.75-7.65 (m, 2H), 7.55-7.47

(m, 1H), 6.67-6.60 (m, 1H), 6.39-6.31 (m, 1H), 6.06-5.98

(m, 1H), 4.45 (dd, J = 13.3, 4.2 Hz, 1H), 4.08 (dd, J = 12.0, NMR (101 MHz, DMSO-d₆) δ 171.27, 147.74, 147.38,

3.6 Hz, 1H), 3.78-3.70 (m, 1H), 3.69-3.60 (m, 1H), 1.76 (s,

3H); ¹³C NMR (101 MHz, DMSO-d₆) δ 166.82, 151.09,

132.61, 129.96, 129.64, 128.35, 122.95, 122.78, 119.44,

107.82, 104.20, 61.35, 43.80, 34.87, 28.51; LRMS (ESI)

m/z: 239 [M+H]⁺; HRMS (ESI) m/z calculated for

C₁₅H₁₄N₂O+H⁺239.1179, found: 239.1175.

134.89, 124.06, 111.90, 108.70, 60.31, 55.76, 55.47, 34.28,

33.43, 30.20, 27.72, 26.81; LRMS (ESI) m/z: 262 [M+H]⁺;

HRMS (ESI) m/z calculated for C₁₅H₁₉NO₃+H⁺262.1438,

found: 262.1434.

9,10-dimethoxy-11b-methyl-2,3,6,7-tetrahydro-1H-

pyrido[2,1-a]isoquinolin-4(11bH)-one (7i): white solid

o

1

9a-methyl-4,5,9,9a-tetrahydrothieno[3,2-g]indolizin-

7(8H)-one (7c): colorless oil (47.5 mg, yield 92%). H

(45.1 mg, yield 66%), mp 75-76 C. H NMR (400 MHz,

1

DMSO-d₆) δ 6.84 (s, 1H), 6.65 (s, 1H), 4.75-4.63 (m, 1H),

14

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Advanced Synthesis & Catalysis

3.74 (s, 3H), 3.71 (s, 3H), 2.87-2.75 (m, 1H), 2.68-2.53 (m,

2H), 2.49-2.41 (m, 1H), 2.37-2.16 (m, 2H), 1.96-1.81 (m,

1H), 1.75-1.64 (m, 1H), 1.64-1.57 (m, 1H), 1.55 (s, 3H);

¹³C NMR (101 MHz, DMSO-d₆) δ 167.68, 147.44, 147.17,

135.24, 125.45, 111.74, 109.31, 58.21, 55.84, 55.41, 36.66,

34.85, 31.54, 28.47, 27.26, 16.55; LRMS (ESI) m/z: 276

[M+H]⁺; HRMS (ESI) m/z calculated for C₁₆H₂₁NO₃+H⁺

276.1594, found: 276.1589.

36.27, 33.68, 27.68, 16.73; LRMS (ESI) m/z: 282 [M+H]⁺;

HRMS (ESI) m/z calculated for C₁₇H₁₅NO₃+H⁺282.1125,

found: 282.1117.

4b-methyl-4bH-naphtho[2',3':4,5][1,3]oxazino[2,3-

a]isoindole-6,14-dione (9f): white solid (71.1 mg, yield

90%), mp 210-212 ^oC. ¹H NMR (600 MHz, CDCl₃) δ 8.79

(s, 1H), 8.49 (s, 1H), 8.02-7.95 (m, 3H), 7.81-7.79 (m, 1H),

7.78-7.74 (m, 1H), 7.69-7.64 (m, 2H), 7.58-7.54 (m, 1H),

1.98 (s, 3H); ¹³C NMR (151 MHz, ) δ 164.68, 162.41,

144.04, 136.93, 133.93, 133.54, 131.07, 130.87, 130.41,

130.30, 130.03, 129.85, 128.00, 126.82, 124.78, 122.63,

119.39, 115.03, 92.73, 25.00; LRMS (ESI) m/z: 316

[M+H]⁺; HRMS (ESI) m/z calculated for C₂₀H₁₃NO₃+H⁺

316.0968, found: 316.0959.

2,3-dimethoxy-12b-methyl-5,6-dihydroisoindolo[1,2-

a]isoquinolin-8(12bH)-one (7j): white solid (66.7 mg,

o

1

yield 86%), mp 187-188 C. H NMR (500 MHz, DMSO-

d₆) δ 8.30 (d, J = 7.7 Hz, 1H), 7.72-7.65 (m, 2H), 7.53-7.47

(m, 1H), 7.39 (s, 1H), 6.69 (s, 1H), 4.39-4.31 (m, 1H), 3.83

(s, 3H), 3.69 (s, 3H), 3.42-3.34 (m, 1H), 2.83-2.67 (m, 2H),

1.82 (s, 3H); ¹³C NMR (126 MHz, DMSO-d₆) δ 166.48,

151.09, 147.75, 147.50, 132.16, 130.82, 130.34, 128.27,

125.26, 123.38, 122.80, 112.22, 110.23, 63.38, 56.07,

55.45, 34.63, 28.75, 28.19; LRMS (ESI) m/z: 310 [M+H]⁺;

HRMS (ESI) m/z calculated for C₁₉H₁₉NO₃+H⁺310.1438,

found: 310.1432.

6a-methyl-7,8-dihydro-5H-pyrido[2,3-d]pyrrolo[2,1-

b][1,3]oxazine-5,9(6aH)-dione (9g): colorless oil (19.0

mg, yield 35%). ¹H NMR (600 MHz, CDCl₃) δ 8.81 (dd, J

= 4.9, 1.9 Hz, 1H), 8.42 (dd, J = 7.7, 1.9 Hz, 1H), 7.36 (dd,

J = 7.7, 4.9 Hz, 1H), 2.86-2.69 (m, 2H), 2.68-2.60 (m, 1H),

2.52-2.41 (m, 1H), 1.72 (s, 3H); ¹³C NMR (151 MHz,

CDCl₃) δ 171.58, 161.32, 155.13, 149.05, 139.45, 121.98,

112.97, 96.08, 32.25, 29.76, 25.38; LRMS (ESI) m/z: 219

[M+H]⁺; HRMS (ESI) m/z calculated for C₁₁H₁₀N₂O₃+H⁺

219.0764, found: 219.0763.

3a-methyl-3,3a-dihydro-1H-benzo[d]pyrrolo[2,1-

b][1,3]oxazine-1,5(2H)-dione (9a): white solid (47.1 mg,

o

1

yield 87%), mp 114-115 C. H NMR (400 MHz, DMSO-

d₆) δ 8.08-7.92 (m, 2H), 7.83-7.76 (m, 1H), 7.44-7.36 (m,

1H), 2.82-2.71 (m, 1H), 2.68-2.59 (m, 1H), 2.48-2.41 (m,

2H), 1.63 (s, 3H); ¹³C NMR (126 MHz, DMSO-d₆) δ

171.74, 161.12, 136.08, 135.65, 129.86, 125.51, 120.47,

115.69, 95.42, 31.72, 29.06, 24.01; LRMS (ESI) m/z: 218

[M+H]⁺; HRMS (ESI) m/z calculated for C₁₂H₁₁NO₃+H⁺

218.0812, found: 218.0809.

3a-methyl-2,3,3a,5-tetrahydro-1H-benzo[d]pyrrolo[2,1-

b][1,3]oxazin-1-one (9h): pale yellow oil (18.3 mg, yield

1

36%). H NMR (500 MHz, DMSO-d₆) δ 8.20 (d, J = 8.1

Hz, 1H), 7.32-7.25 (m, 1H), 7.21-7.16 (m, 1H), 7.16-7.10

(m, 1H), 4.99 (d, J = 16.0 Hz, 1H), 4.88 (d, J = 16.0 Hz,

1H), 2.76-2.65 (m, 1H), 2.43 (ddd, J = 17.1, 10.0, 2.1 Hz,

1H), 2.29-2.19 (m, 1H), 2.07-1.97 (m, 1H), 1.45 (s, 3H);

¹³C NMR (126 MHz, DMSO-d₆) δ 170.92, 132.65, 127.14,

124.69, 123.67, 123.17, 119.21, 89.63, 61.98, 32.53, 29.65,

20.73; LRMS (ESI) m/z: 204 [M+H]⁺; HRMS (ESI) m/z

calculated for C₁₂H₁₃NO₂+H⁺204.1019, found: 204.1017.

4a-methyl-2,3,4,4a-tetrahydrobenzo[d]pyrido[2,1-

b][1,3]oxazine-1,6-dione (9b): colorless oil (37.6 mg,

1

yield 65%). H NMR (500 MHz, DMSO-d₆) δ 7.98-7.93

(m, 1H), 7.77-7.70 (m, 2H), 7.46-7.39 (m, 1H), 2.68-2.58

(m, 1H), 2.55-2.48 (m, 1H), 2.31-2.21 (m, 2H), 1.95-1.86

(m, 1H), 1.86-1.77 (m, 1H), 1.55 (s, 3H); ¹³C NMR (126

MHz, DMSO-d₆) δ 169.04, 161.83, 138.55, 134.13, 128.65,

126.10, 119.86, 92.69, 34.88, 32.91, 25.85, 16.12; LRMS

(ESI) m/z: 232 [M+H]⁺; HRMS (ESI) m/z calculated for

C₁₃H₁₃NO₃+H⁺232.0968, found: 232.0965.

6a-methyl-5H-benzo[4,5][1,3]oxazino[2,3-a]isoindol-

1

11(6aH)-one (9i): colorless oil (18.5 mg, yield 29%). H

NMR (600 MHz, CDCl₃) δ 8.25 (d, J = 8.2 Hz, 1H), 7.91

(d, J = 7.5 Hz, 1H), 7.68-7.60 (m, 2H), 7.59-7.54 (m, 1H),

7.40-7.35 (m, 1H), 7.19-7.15 (m, 1H), 7.14-7.10 (m, 1H),

5.20 (d, J = 15.3 Hz, 1H), 4.98 (d, J = 15.3 Hz, 1H), 1.74

(s, 3H); ¹³C NMR (151 MHz, CDCl₃) δ 165.22, 146.07,

133.09, 132.63, 131.24, 130.17, 127.86, 124.33, 124.32,

124.22, 122.96, 121.81, 121.50, 88.12, 63.26, 20.80;

LRMS (ESI) m/z: 252 [M+H]⁺; HRMS (ESI) m/z

calculated for C₁₆H₁₃NO₂+H⁺252.1019, found: 252.1018.

6a-methyl-5H-benzo[4,5][1,3]oxazino[2,3-a]isoindole-

5,11(6aH)-dione (9c): pale yellow solid (31.2 mg, yield

o

1

47%), mp 138-139 C. H NMR (400 MHz, DMSO-d₆) δ

8.08 (dd, J = 7.8, 1.2 Hz, 1H), 8.06-8.00 (m, 2H), 7.95 (d,

J = 7.5 Hz, 1H), 7.93-7.85 (m, 2H), 7.79-7.73 (m, 1H),

7.51-7.45 (m, 1H), 1.94 (s, 3H); ¹³C NMR (126 MHz,

DMSO-d₆) δ 164.06, 161.32, 143.85, 135.98, 135.68,

134.35, 131.28, 130.15, 129.42, 125.73, 124.22, 123.16,

121.19, 115.32, 92.53, 23.39; LRMS (ESI) m/z: 266

[M+H]⁺; HRMS (ESI) m/z calculated for C₁₆H₁₁NO₃+H⁺

266.0812, found: 266.0807.

3a-methyl-2,3,3a,4-tetrahydropyrrolo[1,2-

a]quinazoline-1,5-dione (9j): white solid (43.0 mg, yield

o

1

80%), mp 177-178 C. H NMR (500 MHz, DMSO-d₆) δ

8.94 (s, 1H), 8.07 (d, J = 8.0 Hz, 1H), 7.91 (dd, J = 7.7, 1.4

Hz, 1H), 7.65-7.57 (m, 1H), 7.32-7.25 (m, 1H), 2.78-2.68

(m, 1H), 2.56-2.49 (m, 1H), 2.30-2.19 (m, 2H), 1.42 (s,

3H); ¹³C NMR (101 MHz, DMSO-d₆) δ 171.88, 161.24,

135.69, 133.19, 127.72, 124.51, 119.89, 119.75, 74.00,

32.43, 29.62, 26.36; LRMS (ESI) m/z: 217 [M+H]⁺;

HRMS (ESI) m/z calculated for C₁₂H₁₂N₂O₂+H⁺217.0972,

found: 217.0969.

3a-methyl-3,3a-dihydro-1H-naphtho[2,3-d]pyrrolo[2,1-

b][1,3]oxazine-1,5(2H)-dione (9d): yellow solid (62.7 mg,

yield 94%), mp 228-230 ^oC. ¹H NMR (600 MHz, CDCl₃) δ

8.72 (s, 1H), 8.44 (s, 1H), 7.95 (d, J = 8.2 Hz, 1H), 7.91 (d,

J = 8.3 Hz, 1H), 7.67-7.62 (m, 1H), 7.56-7.51 (m, 1H),

2.84-2.77 (m, 1H), 2.76-2.68 (m, 1H), 2.68-2.61 (m, 1H),

2.50-2.42 (m, 1H), 1.72 (s, 3H); ¹³C NMR (151 MHz,

CDCl₃) δ 171.72, 162.30, 136.68, 133.20, 131.07, 130.48,

129.89, 129.74, 128.02, 126.89, 119.44, 115.70, 95.71,

32.32, 29.62, 25.66; LRMS (ESI) m/z: 268 [M+H]⁺;

HRMS (ESI) m/z calculated for C₁₆H₁₃NO₃+H⁺268.0968,

found: 268.0962.

2-hexyl-3a-methyl-2,3,3a,4-tetrahydropyrrolo[1,2-

a]quinazoline-1,5-dione (9k): white solid [60.7 mg, yield

81% (dr

=

5:1)], mp 100-101 ^oC, and the two

diastereomers were separable by chromatography. The

major diastereomer: ¹H NMR (400 MHz, DMSO-d₆) δ 8.95

(s, 1H), 8.12 (dd, J = 8.2, 0.6 Hz, 1H), 7.91 (dd, J = 7.8,

1.4 Hz, 1H), 7.61 (ddd, J = 8.2, 7.5, 1.6 Hz, 1H), 7.32-7.23

(m, 1H), 2.86-2.73 (m, 1H), 2.48-2.37 (m, 1H), 1.95-1.76

(m, 2H), 1.42 (s, 3H), 1.39-1.19 (m, 9H), 0.87 (t, J = 6.8

Hz, 3H); ¹³C NMR (101 MHz, DMSO-d₆) δ 173.29,

161.12, 135.62, 133.22, 127.76, 124.36, 119.52, 119.50,

72.13, 40.04, 39.45, 31.19, 29.84, 28.62, 26.35, 26.06,

22.07, 13.97; LRMS (ESI) m/z: 301 [M+H]⁺; HRMS (ESI)

m/z calculated for C₁₈H₂₄N₂O₂+H⁺301.1911, found:

301.1909.

4a-methyl-2,3,4,4a-tetrahydronaphtho[2,3-

d]pyrido[2,1-b][1,3]oxazine-1,6-dione (9e): pale yellow

1

oil (56.7 mg, yield 81%). H NMR (600 MHz, CDCl₃) δ

8.67 (s, 1H), 8.22 (s, 1H), 7.96 (d, J = 8.2 Hz, 1H), 7.90 (d,

J = 8.3 Hz, 1H), 7.66-7.61 (m, 1H), 7.57-7.53 (m, 1H),

2.74-2.61 (m, 2H), 2.52-2.46 (m, 1H), 2.22-2.12 (m, 2H),

1.94-1.87 (m, 1H), 1.64 (s, 3H); ¹³C NMR (151 MHz,

CDCl₃) δ 169.30, 163.29, 135.95, 133.05, 131.84, 130.78,

129.56, 129.49, 128.24, 127.11, 124.86, 119.21, 92.53,

15

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Advanced Synthesis & Catalysis

4a-methyl-3,4,4a,5-tetrahydro-1H-pyrido[1,2-

(d, J = 20.8 Hz, 1H), 3.90 (d, J = 21.0 Hz, 1H), 2.66 (s,

3H), 1.79 (s, 3H); ¹³C NMR (151 MHz, DMSO-d₆) δ

169.18, 162.15, 138.58, 131.88, 131.83, 130.62, 129.89,

128.94, 128.02, 127.66, 127.01, 126.93, 126.70, 125.24,

76.73, 36.24, 29.91, 25.70; LRMS (ESI) m/z: 293 [M+H]⁺;

HRMS (ESI) m/z calculated for C₁₈H₁₆N₂O₂+H⁺293.1285,

found: 293.1284.

a]quinazoline-1,6(2H)-dione (9l): white solid (36.8 mg,

o

1

yield 64%), mp 198-199 C. H NMR (500 MHz, DMSO-

d₆) δ 8.85 (s, 1H), 7.86 (dd, J = 7.7, 1.4 Hz, 1H), 7.66 (d, J

= 8.0 Hz, 1H), 7.60-7.52 (m, 1H), 7.36-7.28 (m, 1H), 2.62-

2.54 (m, 1H), 2.48-2.39 (m, 1H), 2.17-2.09 (m, 1H), 2.09-

2.02 (m, 1H), 1.90-1.74 (m, 2H), 1.35 (s, 3H); ¹³C NMR

(101 MHz, DMSO-d₆) δ 168.77, 162.31, 138.08, 131.76,

126.54, 126.22, 125.25, 123.70, 71.07, 34.68, 33.08, 28.29,

16.61; LRMS (ESI) m/z: 231 [M+H]⁺; HRMS (ESI) m/z

calculated for C₁₃H₁₄N₂O₂+H⁺231.1128, found: 231.1126.

3a-methyl-2,3,3a,4-tetrahydro-1H-benzo[d]pyrrolo[1,2-

a]imidazol-1-one (9s): colorless oil (26.2 mg, yield 56%).

¹H NMR (600 MHz, CDCl₃) δ 7.43 (dd, J = 7.6, 1.1 Hz,

1H), 6.98-6.93 (m, 1H), 6.84-6.79 (m, 1H), 6.68 (dd, J =

7.7, 0.7 Hz, 1H), 2.78 (ddd, J = 16.8, 11.7, 8.5 Hz, 1H),

2.54 (ddd, J = 16.8, 8.5, 1.6 Hz, 1H), 2.44-2.33 (m, 2H),

6a-methyl-6,6a-dihydroisoindolo[2,1-a]quinazoline-

5,11-dione (9m): white solid (51.5 mg, yield 78%), mp

219-220 ^oC. ¹H NMR (400 MHz, DMSO-d₆) δ 9.48 (s, 1H), 1.51 (s, 3H); ¹³C NMR (151 MHz, CDCl₃) δ 173.85,

8.04-7.98 (m, 2H), 7.95 (d, J = 7.6 Hz, 1H), 7.89 (d, J =

7.5 Hz, 1H), 7.85-7.78 (m, 1H), 7.77-7.71 (m, 1H), 7.70-

7.64 (m, 1H), 7.42-7.36 (m, 1H), 1.72 (s, 3H); ¹³C NMR

(101 MHz, DMSO-d₆) δ 164.44, 162.54, 145.97, 135.17,

133.68, 133.62, 130.09, 129.40, 127.96, 125.12, 124.00,

122.89, 121.24, 119.80, 74.17, 27.26; LRMS (ESI) m/z:

265 [M+H]⁺; HRMS (ESI) m/z calculated for

C₁₆H₁₂N₂O₂+H⁺265.0972, found: 265.0966.

142.81, 128.68, 125.36, 120.29, 115.54, 110.71, 85.71,

37.79, 33.74, 26.33; LRMS (ESI) m/z: 189 [M+H]⁺;

HRMS (ESI) m/z calculated for C₁₁H₁₂N₂O+H⁺189.1022,

found: 189.1023.

12a-methyl-12,12a-dihydrobenzo[4,5]imidazo[2,1-

a]isoquinolin-6(5H)-one (9t): colorless oil (24.4 mg, yield

1

39%). H NMR (600 MHz, CDCl₃) δ 8.02-7.98 (m, 1H),

7.41 (dd, J = 7.6, 0.9 Hz, 1H), 7.37-7.33 (m, 1H), 7.33-

7.30 (m, 1H), 7.24 (d, J = 7.5 Hz, 1H), 7.02-6.97 (m, 1H),

6.93-6.89 (m, 1H), 6.85 (dd, J = 7.6, 0.5 Hz, 1H), 4.48 (s,

1H), 3.88 (d, J = 19.0 Hz, 1H), 3.71 (d, J = 19.0 Hz, 1H),

1.69 (s, 3H); ¹³C NMR (151 MHz, CDCl₃) δ 165.54,

139.35, 139.12, 131.28, 129.84, 128.44, 127.95, 127.65,

125.02, 123.17, 121.58, 116.63, 111.97, 82.31, 38.67,

29.46; LRMS (ESI) m/z: 251 [M+H]⁺; HRMS (ESI) m/z

calculated for C₁₆H₁₄N₂O+H⁺251.1179, found: 251.1178.

4b-methyl-4bH-isoquinolino[2,1-a]quinazoline-

6,12(5H,13H)-dione (9n): yellow solid (57.6 mg, yield

o

1

83%), mp 225-226 C. H NMR (400 MHz, DMSO-d₆) δ

8.89 (s, 1H), 7.93 (dd, J = 7.7, 1.5 Hz, 1H), 7.82 (d, J = 7.8

Hz, 1H), 7.79-7.71 (m, 1H), 7.68-7.61 (m, 1H), 7.45-7.36

(m, 3H), 7.30-7.23 (m, 1H), 4.16 (d, J = 21.1 Hz, 1H), 3.84

(d, J = 21.2 Hz, 1H), 1.71 (s, 3H); ¹³C NMR (101 MHz,

DMSO-d₆) δ 165.54, 161.90, 137.55, 133.11, 132.15,

128.77, 128.64, 127.47, 127.22, 126.63, 126.18, 126.15,

125.66, 123.33, 73.91, 35.25, 30.55; LRMS (ESI) m/z: 279

[M+H]⁺; HRMS (ESI) m/z calculated for C₁₇H₁₄N₂O₂+H⁺

279.1128, found: 279.1122.

3a-methyl-2,3,3a,4-tetrahydropyrrolo[2,1-b]quinazolin-

1(9H)-one (9u): white solid (42.8 mg, yield 85%), mp

o

1

141-143 C. H NMR (600 MHz, DMSO-d₆) δ 7.02-6.93

(m, 2H), 6.64-6.57 (m, 1H), 6.53 (d, J = 8.0 Hz, 1H), 6.09

(s, 1H), 4.76 (d, J = 16.7 Hz, 1H), 4.09 (d, J = 16.7 Hz,

1H), 2.38-2.27 (m, 2H), 2.08-1.93 (m, 2H), 1.41 (s, 3H);

¹³C NMR (151 MHz, DMSO-d₆) δ 173.89, 143.01, 127.26,

126.60, 117.23, 116.24, 115.56, 71.08, 37.99, 31.78, 29.17,

25.00; LRMS (ESI) m/z: 203 [M+H]⁺; HRMS (ESI) m/z

calculated for C₁₂H₁₄N₂O+H⁺203.1179, found: 203.1178.

3a,4-dimethyl-2,3,3a,4-tetrahydropyrrolo[1,2-

a]quinazoline-1,5-dione (9o): white solid (52.4 mg, yield

91%), mp 105-107 ^oC. ¹H NMR (600 MHz, CDCl₃) δ 8.26

(dd, J = 8.2, 0.8 Hz, 1H), 8.08 (dd, J = 7.8, 1.6 Hz, 1H),

7.56-7.51 (m, 1H), 7.27-7.24 (m, 1H), 3.07 (s, 3H), 2.70-

2.63 (m, 2H), 2.48-2.39 (m, 1H), 2.30 (ddd, J = 12.0, 6.1,

4.0 Hz, 1H), 1.46 (s, 3H); ¹³C NMR (151 MHz, CDCl₃) δ

171.26, 162.10, 135.25, 133.40, 128.64, 124.98, 119.72,

119.39, 78.55, 32.43, 30.30, 27.78, 21.79; LRMS (ESI) m/z:

231 [M+H]⁺; HRMS (ESI) m/z calculated for

C₁₃H₁₄N₂O₂+H⁺231.1128, found: 231.1127.

4b-methyl-4b,5-dihydroisoindolo[1,2-b]quinazolin-

12(10H)-one (9v): pale yellow solid (26.8 mg, yield 43%),

o

1

mp 222-223 C. H NMR (600 MHz, DMSO-d₆) δ 7.87-

7.81 (m, 1H), 7.74-7.68 (m, 2H), 7.59-7.52 (m, 1H), 7.13

(d, J = 7.4 Hz, 1H), 7.05-6.98 (m, 1H), 6.76 (s, 1H), 6.71-

6.65 (m, 1H), 6.63 (d, J = 8.0 Hz, 1H), 5.07 (d, J = 17.0 Hz,

1H), 4.40 (d, J = 17.0 Hz, 1H), 1.62 (s, 3H); ¹³C NMR

(151 MHz, DMSO-d₆) δ 164.94, 148.44, 141.59, 132.19,

130.25, 129.12, 127.56, 126.83, 123.12, 121.92, 117.69,

116.15, 115.56, 70.66, 37.33, 23.43; LRMS (ESI) m/z: 251

[M+H]⁺; HRMS (ESI) m/z calculated for C₁₆H₁₄N₂O+H⁺

251.1179, found: 251.1178.

4a,5-dimethyl-3,4,4a,5-tetrahydro-1H-pyrido[1,2-

a]quinazoline-1,6(2H)-dione (9p): white solid (45.3 mg,

yield 74%), mp 138-139 ^oC. ¹H NMR (600 MHz, CDCl₃) δ

8.02 (dd, J = 7.8, 1.6 Hz, 1H), 7.62 (dd, J = 8.1, 0.9 Hz,

1H), 7.54-7.49 (m, 1H), 7.32-7.28 (m, 1H), 3.12 (s, 3H),

2.74-2.65 (m, 1H), 2.63-2.55 (m, 1H), 2.44-2.36 (m, 1H),

2.17-2.10 (m, 1H), 1.98-1.86 (m, 2H), 1.39 (s, 3H); ¹³C

NMR (151 MHz, CDCl₃) δ 169.34, 163.59, 137.36, 131.96,

127.79, 126.21, 125.97, 123.93, 75.47, 34.45, 33.72, 27.51,

24.59, 16.94; LRMS (ESI) m/z: 245 [M+H]⁺; HRMS (ESI)

m/z calculated for C₁₄H₁₆N₂O₂+H⁺245.1285, found:

245.1284.

General procedure of the preparation of 5ag-1, 5ah-1,

5ai-1

To a suspension of LiAlH₄(0.4 mmol) and AlCl₃(0.4

mmol) in anhydrous THF was added a THF solution of

o

6,6a-dimethyl-6,6a-dihydroisoindolo[2,1-a]quinazoline-

5,11-dione (9q): white solid (43.3 mg, yield 62%), mp

5ag/5ah/5ai (0.2 mmol) dropwise at 0 C. After addition,

the mixture was heated to reflux for 4 h. After the reaction

was cooled, dichloromethane (100 ml) was added to dilute

the reaction mixture, and water was added dropwise at 0 ^oC

to quench the reaction. Then, the solid which precipitated

out was removed by filtration, and the organic phase

obtained was dried with Na₂SO₄and concentrated. The

residue was purified to give 5ag-1/5ah-1/5ai-1.

o

1

182-184 C. H NMR (600 MHz, CDCl₃) δ 8.15 (dd, J =

8.1, 1.0 Hz, 1H), 8.05-7.99 (m, 2H), 7.76-7.70 (m, 2H),

7.67-7.63 (m, 2H), 7.37-7.32 (m, 1H), 3.25 (s, 3H), 1.72 (s,

3H); ¹³C NMR (151 MHz, CDCl₃) δ 165.02, 162.95,

143.29, 134.80, 133.51, 132.79, 131.39, 130.45, 128.90,

125.50, 125.18, 124.65, 121.82, 120.65, 78.09, 29.59,

23.25; LRMS (ESI) m/z: 279 [M+H]⁺; HRMS (ESI) m/z

calculated for C₁₇H₁₄N₂O₂+H⁺279.1128, found: 279.1127.

13b-methyl-7,8,13,13b-tetrahydro-5H-

benzo[1,2]indolizino[8,7-b]indole (5ag-1): pale yellow

solid (43.8 mg, yield 80%), mp 204-206 ^oC. ¹H NMR (400

MHz, CDCl₃) δ 7.93 (s, 1H), 7.85-7.74 (m, 2H), 7.31-7.22

(m, 2H), 7.21-7.13 (m, 2H), 7.13-7.03 (m, 2H), 4.27-4.18

(m, 2H), 3.54-3.38 (m, 2H), 3.28-3.13 (m, 1H), 2.62-2.53

(m, 1H), 1.95 (s, 3H); ¹³C NMR (126 MHz, DMSO-d₆) δ

4b,5-dimethyl-4bH-isoquinolino[2,1-a]quinazoline-

6,12(5H,13H)-dione (9r): yellow oil (27.7 mg, yield 38%).

¹H NMR (600 MHz, DMSO-d₆) δ 7.92 (dd, J = 7.6, 1.3 Hz,

1H), 7.88 (d, J = 7.6 Hz, 1H), 7.67-7.62 (m, 1H), 7.53-7.47

(m, 2H), 7.47-7.43 (m, 2H), 7.35 (d, J = 7.5 Hz, 1H), 4.08

16

10.1002/adsc.201801494

Advanced Synthesis & Catalysis

135.53, 131.75, 126.46, 126.38, 124.88, 122.76, 122.44,

120.16, 118.98, 118.29, 110.81, 52.72, 41.00, 26.19, 17.09;

LRMS (ESI) m/z: 275 [M+H]⁺; HRMS (ESI) m/z

calculated for C₁₉H₁₈N₂+H⁺275.1543, found: 275.1541.

Province (2018JY0345) and Chengdu University New Faculty

Start-up Funding (2081915037).

References

10-methoxy-13b-methyl-7,8,13,13b-tetrahydro-5H-

benzo[1,2]indolizino[8,7-b]indole (5ah-1): pale yellow oil

1

(47.6 mg, yield 78%). H NMR (400 MHz, CDCl₃) δ 7.60

[1] For selected reviews, see: a) A. S. K. Hashmi, Chem.

Rev. 2007, 107, 3180-3211; b) Z. Li, C. Brouwer, C.

He, Chem. Rev. 2008, 108, 3239-3265; c) A. Corma, A.

Leyva-Pérez, M. J. Sabater, Chem. Rev. 2011, 111,

1657-1712; d) N. Krause, C. Winter, Chem. Rev. 2011,

111, 1994-2009; e) H. Huang, Y. Zhou, H. Liu,

Beilstein J. Org. Chem. 2011, 7, 897-936; f) B. Alcaide,

P. Almendros, J. M. Alonso, Org. Biomol. Chem. 2011,

9, 4405-4416; g) W. Yang, A. S. K. Hashmi, Chem.

Soc. Rev. 2014, 43, 2941-2955; h) A. S. K. Hashmi,

Acc. Chem. Res. 2014, 47, 864-876; i) L. Zhang, Acc.

Chem. Res. 2014, 47, 877-888; j) C. Obradors, A. M.

Echavarren, Acc. Chem. Res. 2014, 47, 902-912; k) D.-

H. Zhang, X.-Y. Tang, M. Shi, Acc. Chem. Res. 2014,

47, 913-924; l) B. Alcaide, P. Almendros, Acc. Chem.

Res. 2014, 47, 939-952; m) L. Fensterbank, M.

Malacria, Acc. Chem. Res. 2014, 47, 953-965; n) Y.

Wang, M. E. Muratore, A. M. Echavarren, Chem. Eur.

J. 2015, 21, 7332-7339; o) R. Dorel, A. M. Echavarren,

Chem. Rev. 2015, 115, 9028-9072; p) Y. Zhu, W. Zhou,

E. M. Petryna, B. R. Rogers, C. S. Day, A. C. Jones,

ACS Catal. 2016, 6, 7357-7362; q) D. B. Huple, S.

Ghorpade, R.-S. Liu, Adv. Synth. Catal. 2016, 358,

1348-1367; r) F. Gao, Y. Zhou, H. Liu, Curr. Org.

Chem. 2017, 21, 1530-1566; s) A. Issaian, K. N. Tu, S.

A. Blum, Acc. Chem. Res. 2017, 50, 2598-2609.

(s, 1H), 7.45 (d, J = 7.4 Hz, 1H), 7.33-7.27 (m, 1H), 7.25-

7.18 (m, 2H), 7.15 (d, J = 8.7 Hz, 1H), 6.93 (d, J = 2.4 Hz,

1H), 6.78 (dd, J = 8.7, 2.5 Hz, 1H), 4.26-4.15 (m, 2H),

3.84 (s, 3H), 3.54-3.43 (m, 2H), 3.13 (ddd, J = 16.2, 11.1,

6.4 Hz, 1H), 2.60 (ddd, J = 15.8, 4.3, 1.4 Hz, 1H), 1.86 (s,

3H); ¹³C NMR (101 MHz, CDCl₃) δ 154.22, 144.86,

138.98, 137.76, 131.33, 127.74, 127.67, 127.38, 123.38,

121.14, 111.73, 111.66, 106.87, 100.87, 64.95, 56.13,

53.25, 41.68, 25.98, 16.43; LRMS (ESI) m/z: 305 [M+H]⁺;

HRMS (ESI) m/z calculated for C₂₀H₂₀N₂O+H⁺305.1648,

found: 305.1645.

14b-methyl-5,6,8,9,14,14b-

hexahydroindolo[2',3':3,4]pyrido[2,1-a]isoquinoline

1

(5ai-1): pale yellow oil (47.1 mg, yield 82%). H NMR

(400 MHz, CDCl₃) δ 7.87 (s, 1H), 7.65 (d, J = 7.8 Hz, 1H),

7.49 (d, J = 7.6 Hz, 1H), 7.37-7.31 (m, 1H), 7.31-7.27 (m,

1H), 7.25-7.20 (m, 1H), 7.19-7.05 (m, 3H), 3.76 (ddd, J =

13.9, 10.0, 5.8 Hz, 1H), 3.26 (ddd, J = 13.8, 6.1, 2.6 Hz,

1H), 3.19-3.15 (m, 1H), 3.14-3.07 (m, 1H), 3.07-2.91 (m,

2H), 2.85-2.66 (m, 2H), 1.95 (s, 3H); ¹³C NMR (101 MHz,

CDCl₃) δ 139.97, 137.45, 135.79, 134.53, 130.12, 127.71,

126.80, 126.55, 125.95, 121.81, 119.60, 118.46, 110.98,

105.93, 58.34, 46.83, 45.45, 30.39, 28.80, 17.87; LRMS

(ESI) m/z: 289 [M+H]⁺; HRMS (ESI) m/z calculated for

C₂₀H₂₀N₂+H⁺289.1699, found: 289.1695.

3-methyleneisobenzofuran-1(3H)-one (2c-1): colorless

1

oil (37.1 mg, yield 85%). H NMR (500 MHz, DMSO-d₆)

δ 8.08 (d, J = 7.8 Hz, 1H), 7.94 (d, J = 7.7 Hz, 1H), 7.91-

7.85 (m, 1H), 7.79-7.63 (m, 1H), 5.63 (d, J = 3.0 Hz, 1H),

5.33 (d, J = 3.0 Hz, 1H); ¹³C NMR (151 MHz, CDCl₃) δ

167.02, 151.94, 139.12, 134.61, 130.60, 125.42, 125.22,

120.73, 91.44; LRMS (ESI) m/z: 147 [M+H]⁺; HRMS (ESI)

m/z calculated for C₉H₆O₂+H⁺147.0441, found: 147.0438.

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1-methyleneisochroman-3-one (2d-1): pale yellow oil

(26.8 mg, yield 56%).¹H NMR (600 MHz, CDCl₃) δ 7.59

(d, J = 8.1 Hz, 1H), 7.39-7.35 (m, 1H), 7.35-7.31 (m, 1H),

7.18 (d, J = 7.5 Hz, 1H), 5.13 (d, J = 2.4 Hz, 1H), 5.03 (d,

J = 2.5 Hz, 1H), 3.84 (s, 2H); ¹³C NMR (151 MHz, CDCl₃)

δ 166.29, 153.76, 130.08, 128.62, 127.95, 127.44, 127.24,

124.81, 95.09, 34.94; LRMS (ESI) m/z: 161 [M+H]⁺;

HRMS (ESI) m/z calculated for C₁₀H₈O₂+H⁺161.0597,

found: 161.0593.

N-(2-(1H-indol-2-yl)ethyl)-5-oxo-6-phenylhexanamide

1

(3m-1): pale yellow oil (45.6 mg, yield 52%). H NMR

(500 MHz, DMSO-d₆) δ 10.92 (s, 1H), 7.93-7.86 (m, 1H),

7.40 (d, J = 7.8 Hz, 1H), 7.33-7.25 (m, 3H), 7.25-7.20 (m,

1H), 7.18-7.12 (m, 2H), 7.01-6.96 (m, 1H), 6.94-6.89 (m,

1H), 6.16 (s, 1H), 3.68 (s, 2H), 3.42-3.35 (m, 2H), 2.83 (t,

J = 7.2 Hz, 2H), 2.44 (t, J = 7.3 Hz, 2H), 2.03 (t, J = 7.3

Hz, 2H), 1.70-1.62 (m, 2H); ¹³C NMR (126 MHz, DMSO-

d₆) δ 207.66, 171.61, 137.50, 135.99, 134.87, 129.54,

128.28, 128.23, 126.44, 120.08, 119.11, 118.55, 110.62,

98.75, 48.71, 40.78, 38.24, 34.34, 28.02, 19.36; LRMS

(ESI) m/z: 349 [M+H]⁺; HRMS (ESI) m/z calculated for

C₂₂H₂₄N₂O₂+H⁺349.1911, found: 349.1910.

Acknowledgements

We gratefully acknowledge financial support from the National

Natural Science Foundation of China (21602022, 81620108027

and 21632008), the Major Project of Chinese National Programs

for Fundamental Research and Development (2015CB910304),

1000 Talents Program of Sichuan Province, Chengdu Talents

Program, Science and Technology Planning Program of Sichuan

17

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10.1002/adsc.201801494

Advanced Synthesis & Catalysis

UPDATE

Gold-catalyzed Rapid Construction of Nitrogen-

containing Heterocyclic Compound Library with

Scaffold Diversity and Molecular Complexity

Adv. Synth. Catal. Year, Volume, Page – Page

Jin Qiao,^a‡ Xiuwen Jia,^a‡ Pinyi Li,^aXiaoyan Liu,^a

Jingwei Zhao,^aYu Zhou,^b,cJiang Wang,^b,cHong

Liu^b,c* and Fei Zhao^a*

21

Article Doi

Gold-catalyzed Rapid Construction of Nitrogen-containing Heterocyclic Compound Library with Scaffold Diversity and Molecular Complexity

DOI: 10.1002/adsc.201801494

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Article abstract of DOI:10.1002/adsc.201801494

Full text of DOI:10.1002/adsc.201801494

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