Green and facile assembly of diverse fused N-heterocycles using gold-catalyzed cascade reactions in water

Article abstract of DOI:10.3390/molecules24050988

The present study describes an AuPPh₃Cl/AgSbF₆-catalyzed cascade reaction between amine nucleophiles and alkynoic acids in water. This process proceeds in high step economy with water as the sole coproduct, and leads to the generation of two rings, together with the formation of three new bonds in a single operation. This green cascade process exhibits valuable features such as low catalyst loading, good to excellent yields, high efficiency in bond formation, excellent selectivity, great tolerance of functional groups, and extraordinarily broad substrate scope. In addition, this is the first example of the generation of an indole/thiophene/pyrrole/pyridine/naphthalene/ benzene-fused N-heterocycle library through gold catalysis in water from readily available materials. Notably, the discovery of antibacterial molecules from this library demonstrates its high quality and potential for the identification of active pharmaceutical ingredients.

Full text of DOI:10.3390/molecules24050988

molecules
Article
Green and Facile Assembly of Diverse Fused
N-Heterocycles Using Gold-Catalyzed Cascade
Reactions in Water
Xiuwen Jia 1 , Pinyi Li 1, Xiaoyan Liu 1, Jiafu Lin 1,*, Yiwen Chu 1, Jinhai Yu 2, Jiang Wang 3,4
,
Hong Liu 3,4,* and Fei Zhao 1,
*
1
Antibiotics Research and Re-evaluation Key Laboratory of Sichuan Province, Sichuan Industrial Institute of
Antibiotics, Chengdu University, Chengdu 610052, China; jiaxiuwen2018@126.com (X.J.);
pinyiLi19950206@126.com (P.L.); 19940826097@163.com (X.L.); siiakyb@139.com (Y.C.)
School of Biological Science and Technology, University of Jinan, Jinan 250022, China; bio_yujh@ujn.edu.cn
State Key Laboratory of Drug Research and CAS Key Laboratory of Receptor Research, Shanghai Institute of
Materia Medical, Chinese Academy of Sciences, Shanghai 201203, China; jwang@simm.ac.cn
University of Chinese Academy of Sciences, Beijing 100049, China
2
3
4
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
Academic Editor: Gianfranco Favi
Received: 4 February 2019; Accepted: 4 March 2019; Published: 11 March 2019
ꢀꢁꢂꢃꢄꢅꢆ
Abstract: The present study describes an AuPPh3Cl/AgSbF6-catalyzed cascade reaction between
amine nucleophiles and alkynoic acids in water. This process proceeds in high step economy with
water as the sole coproduct, and leads to the generation of two rings, together with the formation
of three new bonds in a single operation. This green cascade process exhibits valuable features
such as low catalyst loading, good to excellent yields, high efficiency in bond formation, excellent
selectivity, great tolerance of functional groups, and extraordinarily broad substrate scope. In addition,
this is the first example of the generation of an indole/thiophene/pyrrole/pyridine/naphthalene/
benzene-fused N-heterocycle library through gold catalysis in water from readily available materials.
Notably, the discovery of antibacterial molecules from this library demonstrates its high quality and
potential for the identification of active pharmaceutical ingredients.
Keywords: amine nucleophiles; alkynoic acids; cascade reaction; gold catalysis; fused N-heterocycles
1. Introduction
Rapid advances in genomics and proteomics have resulted in the identification of an increasing
number of novel therapeutic targets [
the needs of drug screening. Therefore, it is highly demanding to develop robust synthetic methods
to construct new compound libraries for drug discovery aimed at these targets [ ]. Considering
1–5], and the existing compound libraries can no longer well meet
6–8
the structurally diverse targets in a wide “biological space”, high-throughput screening (HTS) of
skeletally diverse compounds, which occupy a broader “chemical space”, can apparently enhance the
hit rates [9,10]. In addition to skeletal diversity, drug-like properties of the compounds are equally
important for the generation of high-quality compound libraries [11–14], which can increase the
possibility of identifying drug-like hit compounds. As a result, privileged structures have received
wide attention in drug discovery because they are widely found in natural and pharmaceutical
products [15–19]
.
Although privileged substructure-based diversity-oriented synthesis (pDOS)
26], it is still challenging
provides a useful access to assemble compound libraries with high-quality [20
–
to develop efficient and practical approaches to generate a variety of molecular frameworks embedded
with privileged structures, especially in a green and sustainable manner. With our interests to develop
green and efficient protocols to synthesize valuable N-heterocycles [27–31], we herein construct a
library of privileged substructure-based N-heterocycles with diverse scaffolds using gold-catalyzed
Molecules 2019, 24, 988; doi:10.3390/molecules24050988
www.mdpi.com/journal/molecules

Molecules 2019, 24, 988
2 of 30
cascade reactions in water. To the best of our knowledge, this is the first example of the generation
of pDOS compound library encompassing skeletal diversity, molecular complexity, and drug-like
properties through gold catalysis in water.
Alkynoic acids are extensively used to react with amine nucleophiles to furnish heterocyclic
compounds because of the efficient cascade reaction developed by Dixon’s group [32], in which,
an activated cyclic enol lactone species, which derives from alkynoic acids, is involved as the key
intermediate (Scheme 1a). Dixon and co-workers disclosed linear aliphatic terminal alkynoic acids
reacted smoothly with amine nucleophiles bearing a nucleophilic carbon atom in toluene or xylene to
produce pyrrole- or indole-based heterocyclic frameworks catalyzed by AuPPh3Cl/AgOTf. It should be
noted that, based on Dixon’s pioneering work, the reactions of alkynoic acids with amine nucleophiles
in aprotic solvents such as toluene, xylene, 1,2-dichloroethane, dichloromethane, etc., have been well
studied by Patil’s group as well as our group [33
amine nucleophiles in the environmentally friendly, abundant, and cheap solvent—water—was seldom
explored [44 45], mainly because the ring opening reaction of the activated enol lactone intermediate
–43]. However, the reactivity of alkynoic acids and
,
in water at elevated temperature may lead to the failure of the cascade reaction. This reason prevented
researchers’ steps from investigating the nature of the cascade reaction in water. To date, only two
successful examples in water were reported by our group [44,45], although the alkynoic acids were
only limited to linear aliphatic terminal alkynoic acids, amine nucleophiles were only limited to
amine nucleophiles carrying a nucleophilic carbon atom, and complicated Au catalysts were required
(Scheme 1b). However, considering water often displays unique reactivity and selectivity which can’t
be obtained in common organic solvents [46–51] and it is an environmentally benign solvent, we aim
to develop a more general cascade process between various alkynoic acids and amine nucleophiles
in water with great interest. Despite the possibility of hydrolysis of enol lactone intermediate in
water at high temperature which may result in the failure of the cascade reaction, we hypothesize
that a more general cascade process could also be achieved in water but with a proper catalytic
system. In the present study, we develop a greener, and more general and efficient catalytic system
(AuPPh3Cl/AgSbF6/CF3CO2H) in water, which tolerates a broader substrate scope of alkynoic acids
as well as amine nucleophiles. As shown in Scheme 1c, not only linear aliphatic terminal and
internal alkynoic acids but also cyclic aromatic terminal and internal alkynoic acids are well tolerated.
In addition, extraordinarily broad amine nucleophiles bearing a nucleophilic carbon/nitrogen/oxygen
atom turned out to be suitable substrates. Besides, the reaction mechanism in water was carefully
checked and studied for the first time. Interestingly, when D2O was used as the reaction solvent, we
observed the highly deuterated products generated from the H–D exchange between the reaction
substrates/intermediates and D2O. Herein, we also present the library construction of skeletally
diverse N-heterocycles embedded with privileged structures employing different alkynoic acids and
various amine nucleophiles as the building blocks. To our delight, five antimicrobial compounds were
identified from this library after biological evaluation. The production of N-heterocycles with diverse
scaffolds and the discovery of active pharmaceutical ingredients (APIs) demonstrate the power of this
method in both organic synthesis and medicinal chemistry.

Molecules 2019, 24, 988
3 of 30
Scheme 1. Gold-catalyzed tandem reactions between alkynoic acids and amine nucleophiles.
(a). Dixon’s work. (b). Our previous work. (c). This work.
2. Results and Discussion
4-pentynoic acid (1a) and tryptamine (2a) were employed as the model substrates to optimize the
cascade reaction conditions (Table 1). Pleasingly, treatment of starting materials 1a and 2a in water
without any catalyst at 100 ◦C for 24 h gave the desired product SF1a, albeit with a low yield (entry
1). Then various metal catalysts were screened to improve the reaction yield. A screening of Pd, Cu,
Ni, and Mn complexes (entries 2–11), disclosed, at first, that Pd(II) sources, such as PdCl2(CH3CN)2
and Pd(PPh3)2Cl2, NiOAc and Mn(OAc)2, had little enhancement on the yield; while Pd(0) sources
such as Pd(PPh3)4 and Pd2(dba)3; copper catalysts, such as Cu(OAc)2 and Cu(OH)2, and CuCl; and
Ni(PPh3)2Cl inhibited this transformation. A subsequent survey of Ag, Ru, and Co catalysts (entries
12–16) revealed that Ag2CO3, AgOAc, [RuCl2(p-cym)]2, CoCl2, and Co(acac)2 could obviously increase
the yield, affording the product SF1a in moderate yields (38–57%). Notably, a good yield (70%) was
◦
achieved with AuPPh3Cl (entry 17), and increasing the temperature to 120 C was much more efficient
in improving the yield as compared with extending the reaction time to 48 h (entries 18 and 19).
Encouraged by this result, an investigation of other Au catalysts at 120 ◦C was carried out (entries
20–24). Among them, none displayed higher catalytic reactivity than AuPPh3Cl. To further improve
the yield of the product, a series of silver salts, which were proved to be able to increase the catalytic
reactivity of gold catalysts [52–57], were screened as the additives (entries 25–28). To our delight,
AgSbF6 was found to be the best choice, with which product SF1a was obtained in 91% yield (entry 28).
In addition, other typical organic solvents were also tested as the reaction solvents, and toluene, xylene,
and DCE also turned out to be suitable solvents, in which similar high isolated yields were observed
(See Supplementary Materials for details). However, considering water is more environmentally
benign, we then decided to use water as the solvent to explore the substrate scope of this method.

Molecules 2019, 24, 988
4 of 30
In this way, the optimal reaction conditions were identified using a catalytic system consisting of
AuPPh3Cl/AgSbF6 in water at 120 ◦C for 24 h.
Table 1. Reaction condition optimization for the tandem synthesis of compound SF1a a.
◦
Yield (%) b
Entry
Catalyst/Additive
Solvent
T ( C)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18 c
19
20
21
22
23
24
25
26
27
28
-
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
120
120
120
120
120
120
120
120
120
120
17
26
31
0
PdCl2(CH3CN)2
Pd(PPh3)2Cl2
Pd(PPh3)4
Pd2(dba)3
Cu(OAc)2
Cu(OH)2
CuCl
0
trace
5
trace
33
11
25
51
57
48
38
50
70
76
83
52
46
81
78
80
85
86
89
91
NiOAc
Ni(PPh3)2Cl
Mn(OAc)2
Ag2CO3
AgOAc
[RuCl2(p-cym)]2
CoCl2
Co(acac)2
AuPPh3Cl
AuPPh3Cl
AuPPh3Cl
AuBr3
AuI
Au1 catalyst d
Au2 catalyst e
Au3 catalyst f
AuPPh3Cl/Ag2CO3
AuPPh3Cl/AgOAc
AuPPh3Cl/AgOTf
AuPPh3Cl/AgSbF6
a
Reaction conditions: 4-pentynoic acid 1a (0.6 mmol), tryptamine 2a (0.5 mmol), catalyst/additive
b
c
(0.005 mmol), and solvent (4.0 mL).
Yield refers to isolated yield.
The reaction was performed
d
e
for 48 h.
Au1 catalyst = Chloro[(1,10-biphenyl-2-yl)di-tert-butylphosphine]gold(I).
Au2 catalyst =
Chloro[1,3-bis(2,6- diisopropylphenyl)imidazol-2-ylidene]gold(I). f Au3 catalyst = (Acetonitrile)[(2-biphenyl)di-tert-
butylphosphine]gold(I) hexafluoroantimonate.
After determining the optimal reaction conditions, we then began to construct a high-quality
library of privileged substructure-based N-heterocycles with diverse scaffolds. We first examined
the generality of the process with various amine nucleophiles
on a heteroaromatic or aromatic ring. In general, this process tolerated a variety of amine
nucleophiles and alkynoic acids , and 26 scaffolds embedded with privileged structures were
2 containing a nucleophilic carbon
2
1
furnished in good to high yields in water under optimal or modified reaction conditions (Scheme 2).
For example, tryptamines reacted smoothly with terminal alkynoic acids such as 4-pentynoic
acid under standard conditions to give products SF1a and SF1b in high yields. The reactions of
tryptamines with other terminal alkynoic acids, such as 5-hexynoic acid, 2-ethynylbenzoic acid, and
2-(2-ethynylphenyl)acetic acid, also afforded the corresponding products (SF2a, SF2b, SF3a, SF3b,
and SF4a) in good to high yields under a modified two-step one-pot process, in which CF3CO2H
(TFA) was added to promote the iminium ion formation. In addition, internal alkynoic acids,

Molecules 2019, 24, 988
5 of 30
such as 5-phenylpent-4-ynoic acid, 6-phenylhex-5-ynoic acid, 2-(phenylethynyl)benzoic acid, and
2-(2-(phenylethynyl)phenyl)acetic acid, were also tested as the substrates. Unfortunately, they all
failed to react with tryptamines to give the desired products (SF1c, SF2c, SF3c, and SF4b) even
under further improved conditions. Interestingly, 2-(1H-indol-2-yl)ethylamines could undergo this
transformation with terminal alkynoic acids as well as internal alkynoic acids to yield the desired
products SF5–SF8 in 35–96% yields. It should be noted that no N1 ring closure products were
observed when 2-(1H-indol-2-yl)ethylamines were used as the amine nucleophiles, suggesting excellent
selectivity of this cascade process. This may be because the C3 nucleophilicity is stronger than N1
nucleophilicity [58]. Likewise, the reactivity of 2-(1H-indol-1-yl)ethanamines in this cascade reaction
was very similar to that of tryptamines. They reacted well with terminal alkynoic acids while their
reactions with internal alkynoic acids failed to give the desired products (SF9
the protocol was also compatible with 3-(1H-indol-1-yl)propan-1-amines, which furnished products
SF13 carrying a seven-membered ring in 54–80% yields. Similarly, products SF14 SF16 were
–SF12). Interestingly,
–
obtained in 59–86% yields when 2-(1H-indol-1-yl)anilines and alkynoic acids were subjected to
the modified conditions. Notably, the indole-containing polycyclic frameworks, represented
by compounds SF1
presence in biologically active molecules [59
–
SF16, are regarded as valuable N-heterocycles considering their ubiquitous
63]. Subsequently, 2-(1H-pyrrol-2-yl)ethanamines,
–
2-(1H-pyrrol-1-yl)ethanamines, 2-(thiophen-2-yl)ethanamines, and 2-(thiophen-3-yl)ethanamines were
employed as amine nucleophiles. Their reactions with diverse alkynoic acids took place successfully
to provide pyrrole- or thiophene-fused compounds SF17–SF23 in moderate to high yields, despite the
fact that stronger conditions were required. In particular, 2-phenylethanamines with electron-donating
substituents on the benzene ring were also well tolerated, leading to the formation of benzene-fused
heterocyclic products SF24–SF26 in yields ranging from 47 to 88%. It is also worth noting that excellent
selectivity was achieved in the reactions of 2-(1H-pyrrol-2-yl)ethanamine, 2-(thiophen-3-yl)ethanamine
or 2-phenylethanamines, even though two potential cyclization sites existed in the final step. It should
be noted that compound SF26 is the analog of tetrahydroberberines, which were extracted from the
Chinese herb Corydalis ambigua and exhibited a broad range of biological activities [64,65].
To further broaden the substrate scope of this approach, amine nucleophiles
nucleophilic heteroatom (Z = amide/aniline N, acid/alcohol O) were tested as substrates. Overall,
this protocol was also applicable to diverse amine nucleophiles , and 17 scaffolds were constructed
with high efficiency (Scheme 3). For instance, the reactions of 2-aminobenzamides with various
alkynoic acids worked successfully, affording benzene-fused polycyclic products SF27 SF30 in
moderate to high yields. Gratifyingly, this approach was compatible with 2-(aminomethyl)anilines
and benzene-1,2-diamines, although the desired benzene-based heterocyclic products SF31 SF34
3 containing a
3
–
–
were obtained in lower yields. Remarkably, in the case of substrates such as 2-aminobenzamides
and 2-(aminomethyl)anilines, which contain two nitrogen atoms as the nucleophiles, the nitrogen
atom with stronger nucleophilicity tended to attack the enol lactone intermediate and therefore
the other nitrogen atom with weaker nucleophilicity attacked the iminium ion intermediate to
selectively provide the corresponding products, while not in the reverse way. Besides, 2-aminobenzoic
acids, 3-amino-2-naphthoic acids, or 2-aminonicotinic acids reacted with various alkynoic acids
smoothly, producing the corresponding benzene-, naphthalene-, or pyridine-fused heterocyclic
products SF35–SF41 in yields of 50–96%. Surprisingly, 2-aminobenzyl alcohols were also found
to be suitable substrates, which could undergo the cascade reaction with alkynoic acids to give the
desired benzene-fused polycyclic products SF42 and SF43, albeit with lower yields. In addition,
we also tried to synthesize the indole-fused compounds SF44–SF46 embedded with an eight- or
nine-membered ring; unfortunately, we failed. This may be attributed to the low reactivities of the
amine nucleophiles and the instability of the large rings in energetics.

Molecules 2019, 24, 988
6 of 30
a
Scheme 2. Generation of scaffold diversity. Reaction conditions: alkynoic acids 1 (0.6 mmol), amine
◦
nucleophiles 2
(0.5 mmol), AuPPh3Cl/AgSbF6 (0.005 mmol), H2O (4.0 mL), and 120 C, 24 h. b Reaction
conditions: (i) alkynoic acids ◦
1 (0.6 mmol), amine nucleophiles 2 (0.5 mmol), AuPPh3Cl/AgSbF6
◦
(0.01 mmol), H2O (4.0 mL), 120 C, 20 h; (ii) TFA (0.5 mmol) was added, and then 120 C, 4 h. c Reaction
conditions: (i) alkynoic acids
1 (0.6 mmol), amine nucleophiles 2 (0.5 mmol), AuPPh3Cl/AgSbF6
(0.015 mmol), H2O (4.0 mL), 140 ◦C, 20 h; (ii) TFA (0.5 mmol) was added, and then 140 ◦C, 4 h.
ND = Not detected.

Molecules 2019, 24, 988
7 of 30
a
Scheme 3. Generation of scaffold diversity. Reactions conditions: (i) Alkynoic acids
1 (0.6 mmol),
◦
amine nucleophiles
3
(0.5 mmol), AuPPh3Cl/AgSbF6 (0.01 mmol), H2O (4.0 mL), 120 C, 20 h; (ii) TFA
(0.5 mmol) was added, and then 120 ◦C, 4 h.
reaction was carried out with 5◦mol% AuPPh3Cl/AgSbF6. The reaction was performed with 5
mol% AuPPh3Cl/AgSbF6 at 140 C. ND = Not detected.
b
c
The reaction was carried out at 140 ◦C. The
d
The diversity of the library can be further expanded by the derivatization of the target compounds.
We herein introduce the derivatization of the target compounds based on the simple reduction of the
carbonyl group, and the selected results are shown in Scheme 4. Nine different scaffolds represented
by indole-, pyrrole-, or thiophene-based polycyclic compounds SF47–SF55 containing a tertiary
amine were produced conveniently through an easy reduction of the corresponding precursors with
LiAlH4/AlCl3. Notably, these scaffolds are very similar to those found in natural and pharmaceutical

Molecules 2019, 24, 988
8 of 30
agents [65]. We expect the screening of these compounds towards specific biological targets might lead
to the identification of bioactive molecules.
Scheme 4. Derivatization of the target compounds in the library.
Thus, using various amine nucleophiles and alkynoic acids as the building blocks, a library of
privileged substructure-based N-heterocycles with diverse scaffolds was constructed through gold
catalysis in a green and efficient manner. It is worth noting this cascade process constructs three new
bonds together with two rings in one chemical process, suggesting the high efficiency of this cascade
reaction in synthesizing nitrogen-containing heterocyclic compounds. Regarding the large occurrence
of nitrogen-containing heterocyclic compounds in APIs [66–68], the method presented in this paper is
prospective since it could provide an environmentally benign and useful platform for the preparation
of diverse nitrogen-containing heterocyclic compounds.
To verify our expectation that this approach could provide useful scaffolds with attractive
bioactivities, a bioactivity study of this library was carried out. An initial pharmacological study
of these nitrogen-containing heterocyclic compounds led to the discovery of five antimicrobial
compounds—SF9d
revealed that compound SF36 displayed the most potent antibacterial activity against S. aureus strain,
with a MIC90 value of 10–25 g/mL (Table 2) (Time-kill assays and colony-forming unit studies of
, SF29b, SF33, SF36, and SF41. The minimal inhibitory concentration (MIC) results
µ
compounds SF9d, SF29b, SF33, SF36 and SF41 could be found in Supplementary Materials).
Table 2. MIC90 of compounds SF9d, SF29b, SF33, SF36, and SF41 against the S. aureus strain.
Compound
MIC90 (µg/mL)
SF9d
SF29b
SF33
SF36
SF41
100–200
50
100–200
10–25
100
Mechanistic studies were carried out with deuterium-labeling experiments, and the hydrogens
of the products were assigned at first by the analysis of the 1H-NMR, 13C-NMR, HSQC, HMBC, and
1H-1H COSY spectrum to confirm the deuterated positions (See Supplementary Materials for details).
Interestingly, the reaction of 4-pentynoic acid 1a with tryptamine 2a in D2O under the standard
conditions afforded the deuterated product [D]n-SF1a, not only at the methyl position but also at

Molecules 2019, 24, 988
9 of 30
the
β-position of the carbonyl (Scheme 5a). Specifically, a 96% deuteration at the methyl position
and a similar deuteration (90%) of the two unequal hydrogens at the
β-position of the carbonyl were
observed. The reactions of 2-(1H-indol-2-yl)ethylamines with 4-pentynoic acid 1a in D2O gave the
similar results (Scheme 5b,c).
Scheme 5. Deuterium-labeling experiments.; (
1a and 2a in D2O; ( ) the deuterium-labeling experiment of substrates 1a and 2c in D2O; (
deuterium-labeling experiment of substrates 1a and 2d in D2O.
a
) the deuterium-labeling experiment of substrates
b
c) the
According to the results of deuterium-labeling experiments, we hypothesize two possible reaction
pathways (Schemes 6 and 7). The reaction of with 4-pentynoic acid 1a with tryptamine 2a in the
presence of Au catalyst in D2O is taken as the example to illustrate the reaction pathway. The first
hypothetic reaction pathway (Scheme 6) may involve the gold-catalyzed hydration of carbon–carbon
triple bond, which was observed in our previous work [69]. The H–D exchange between the carboxyl
group of 4-pentynoic acid 1a and D2O leads to the formation of intermediate A1. Gold-catalyzed
addition of D2O to the carbon–carbon triple bond of intermediate A1 produces intermediate A2
which undergoes two keto–enol tautomerizations to give intermediate A4. The subsequent H–D
exchange between the hydroxyl group of intermediate A4 and D2O affords intermediate A5, which
undergoes keto–enol tautomerization again to give intermediate A6. The two acidic protons at
,
the α-position of the carbonyl in intermediate A6 undergo H–D exchange with D2O via keto–enol
tautomerizations to yield intermediate A7. The following condensation between intermediate A7
and tryptamine 2a, the subsequent iminium ion formation, and the final cyclization achieve the
product [D]n-SF1a. The second hypothetic reaction pathway is shown in Scheme 7; the H–D exchange
between the carboxyl group of 4-pentynoic acid 1a and D2O produces intermediate A1. Gold-catalyzed
intramolecular cyclization of intermediate A1 produces enol lactone intermediate B1, which is attacked
by tryptamine 2a to give intermediate B2. The subsequent H–D exchange between the hydroxyl group
of intermediate B2 and D2O yields intermediate B3, which undergoes enol–keto tautomerization

Molecules 2019, 24, 988
10 of 30
to provide intermediate B4. Similarly, the three acidic protons at the
α
-position of the carbonyl in
intermediate B4 undergo H–D exchange with D2O via keto–enol tautomerizations to yield intermediate
C1, which is converted into the product [D]n-SF1a via an iminium ion formation/cyclization sequence.
Scheme 6. Hypothetic reaction pathway 1.
Scheme 7. Hypothetic reaction pathway 2.
To further verify the reaction mechanism, the reaction of 4-pentynoic acid 1a and tryptamine 2a
under gold catalysis in O18-labeled water was carried out first. This reaction in H2O18 was stopped
after 0.5 h to track the reaction intermediates. As shown in Scheme 8a, apart from the remaining starting
materials, intermediate 2a” and the product SF1a were obtained in 21% and 15% yield, respectively.
While the O18-labeled intermediate 2a0 was not observed. This result clearly indicates the hydration
of alkyne moiety, which is proposed in Scheme 6, is not involved. By contrast, the commercially
purchased enol lactone
D reacted smoothly with tryptamine 2a without the gold catalyst (Scheme 8b).

Molecules 2019, 24, 988
11 of 30
This result shows that the enol lactone species B1, which is proposed in Scheme 7, is likely to be the
key intermediate.
Scheme 8. Mechanistic study experiments. (a) the mechanistic experiment of substrates 1a and 2a in
H2O18; (b) the mechanistic experiment of substrates D and 2a without catalyst/additive.
On the basis of the above results of mechanistic experiments, a final proposed reaction mechanism
is outlined in Scheme 9. The proposed mechanism commences with the coordination of the gold
catalyst to the carbon–carbon triple bond of alkynoic acids to produce intermediate I1. The subsequent
intramolecular exo cyclization of I1 yields intermediate I2. The following protodemetalation of
intermediate I2 takes place to produce the enol lactone species I3 with the regeneration of the catalyst.
Then intermediate I3 undergoes aminolysis by amine nucleophiles to give intermediate I4, which
tautomerizes to produce intermediate I5. Intermediate I5 is converted into the iminium ion I8 under
the catalysis of the gold catalyst. The final nucleophilic cyclization of intermediate I8 affords the desired
products with the release of the gold catalyst. The stronger nucleophilicity of amine nucleophiles
compared to that of H2O results in the aminolysis of enol lactone I3 by amine nucleophiles instead
of hydrolysis by H2O. It should be noted that the reaction solvent H2O participates in this cascade
reaction via the H–H exchange with the carboxyl group of alkynoic acids, the hydroxyl group of
intermediate I4, and the
α hydrogen atoms of the carbonyl group of intermediate I5, as demonstrated
by deuterium-labeling experiments. Besides, TFA could promote this reaction by accelerating the
formation of iminium ion I8.

Molecules 2019, 24, 988
12 of 30
Scheme 9. A final proposed reaction mechanism.
3. Materials and Methods
3.1. General Information
If not otherwise specified, the starting materials were obtained from commercial sources and
used directly without purification. Analytical thin-layer chromatography (TLC): HSGF 254 (0.15–0.2
mm thickness). Detection under UV light at 254 nm. Column chromatography: Separations were
carried out on silica gel FCP 200–300. Yields refer to isolated compounds. Melting point apparatus: a
micro melting point apparatus, values are uncorrected. Nuclear magnetic resonance (NMR) apparatus:
a Brucker instrument. Chemical shifts (δ) are given in ppm. Proton coupling patterns were recorded
as singlet (s), doublet (d), triplet (t), quartet (q), and multiplet (m). LRMS (low-resolution mass)
and HRMS (high-resolution mass) were measured on a spectrometer with an electrospray ionization
(ESI) source.
3.2. General Procedure for the Preparation of Compounds SF1a, SF1b, SF5a, SF5b, and SF5c
A suspension of alkynoic acids
AuPPh3Cl/AgSbF6 (0.005 mmol) in H2O (4.0 mL) was stirred at 120 C for 24 h. At ambient
temperature, saturated Na2CO3 solution (25.0 mL) was added to the reaction mixture. The resulting
1
(0.6 mmol), amine nucleophiles
2
(0.5 mmol), and
◦
mixture was then extracted with ethyl acetate (3
with brine, and dried over Na2SO4. After filtration and removal of the solvents in vacuo, the crude
product was purified by flash chromatography on silica gel to provide the desired product.
×
15 mL). The combined organic layers were washed
11b-Methyl-5,6,11,11b-tetrahydro-1H-indolizino[8,7-b]indol-3(2H)-one (SF1a): white solid (109.7 mg, yield
91%), mp 260–261 ◦C. 1H-NMR (500 MHz, DMSO-d6)
δ 1.54 (s, 3H), 2.07–1.99 (m, 1H), 2.32–2.20 (m,
2H), 2.66–2.55 (m, 2H), 2.75–2.67 (m, 1H), 3.11–3.00 (m, 1H), 4.25–4.16 (m, 1H), 7.01–6.94 (m, 1H),
7.10-7.02 (m, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.39 (d, J = 7.8 Hz, 1H), 11.06 (s, 1H); 13C-NMR (100 MHz,
DMSO-d6)
δ 171.9 (CO), 139.0 (C, Ar), 135.9 (C, Ar), 126.3 (C, Ar), 121.0 (CH, Ar), 118.6 (CH, Ar), 118.0
(CH, Ar), 111.1 (CH, Ar), 104.7 (C, Ar), 58.9 (C), 34.3 (CH2), 32.6 (CH2), 30.1 (CH2), 25.0 (CH3), 20.9
(CH2); ESI-LRMS m/z: 241 [M + H]+; ESI-HRMS m/z calcd for M + H+ 241.1335, found: 241.1331.
The characterization data is in accordance with that reported in [32].

Molecules 2019, 24, 988
13 of 30
8-Methoxy-11b-methyl-5,6,11,11b-tetrahydro-1H-indolizino[8,7-b]indol-3(2H)-one (SF1b): yellow oil
(120.2 mg, yield 89%). 1H-NMR (500 MHz, DMSO-d6)
1.53 (s, 3H), 2.07–1.97 (m, 1H), 2.31–2.20
δ
(m, 2H), 2.64–2.52 (m, 2H), 2.73–2.64 (m, 1H), 3.10–2.98 (m, 1H), 3.74 (s, 3H), 4.24–4.15 (m, 1H), 6.70 (dd,
J = 8.7, 2.4 Hz, 1H), 6.89 (d, J = 2.3 Hz, 1H), 7.20 (d, J = 8.7 Hz, 1H), 10.88 (s, 1H); 13C-NMR (125 MHz,
DMSO-d6) δ 171.9 (CO), 153.2 (C, Ar), 139.7 (C, Ar), 130.9 (C, Ar), 126.6 (C, Ar), 111.7 (CH, Ar), 110.8
(CH, Ar), 104.6 (C, Ar), 100.2 (CH, Ar), 58.9 (C), 55.4 (OCH3), 34.3 (CH2), 32.6 (CH2), 30.1 (CH2), 25.0
(CH3), 21.0 (CH2); ESI-LRMS m/z: 271 [M + H]+; ESI-HRMS m/z calcd for M + H+ 271.1441, found:
271.1437. The characterization data is in accordance with that reported in [43].
11c-Methyl-5,6,7,◦11c-tetrahydro-1H-indolizino[7,8-b]indol-3(2H)-one (SF5a): yellow solid (114.2 mg, yield
δ 1.54 (s, 3H), 2.02–1.92 (m, 1H), 2.27–2.17 (m, 1H),
95%), mp 96–97 C. 1H-NMR (500 MHz, DMSO-d6)
2.54–2.47 (m, 1H), 2.65–2.54 (m, 1H), 2.81–2.67 (m, 2H), 3.16–3.04 (m, 1H), 4.27–4.18 (m, 1H), 7.00–6.92
(m, 1H), 7.08–7.00 (m, 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.47 (d, J = 7.8 Hz, 1H), 10.90 (s, 1H); 13C-NMR
(100 MHz, DMSO-d6)
δ 171.5 (CO), 135.9 (C, Ar), 130.5 (C, Ar), 123.9 (C, Ar), 120.5 (CH, Ar), 118.6 (CH,
Ar), 117.9 (CH, Ar), 115.3 (C, Ar), 111.1 (CH, Ar), 59.2 (C), 33.2 (CH2), 33.2 (CH2), 30.2 (CH2), 25.0
(CH3), 22.8 (CH2); ESI-LRMS m/z: 241 [M + H]+; ESI-HRMS m/z calcd for M + H+ 241.1335, found:
241.1332. The characterization data is in accordance with that reported in [43].
10-Methoxy-11c-methyl-5,6,7,11c-tetrahydro-1H-indolizino[7,8-b]indol-3(2H)-one (SF5b): pale yellow solid
(129.5 mg, yield 96%), mp 193–194 ◦C. 1H-NMR (500 MHz, DMSO-d6)
δ 1.54 (s, 3H), 2.01–1.91 (m, 1H),
2.27–2.18 (m, 1H), 2.64–2.52 (m, 2H), 2.79–2.65 (m, 2H), 3.14–3.03 (m, 1H), 3.77 (s, 3H), 4.25–4.15 (m, 1H),
6.69 (dd, J = 8.7, 2.4 Hz, 1H), 6.93 (d, J = 2.3 Hz, 1H), 7.19 (d, J = 8.7 Hz, 1H), 10.72 (s, 1H); 13C-NMR
(100 MHz, DMSO-d6)
δ 171.5 (CO), 153.1 (C, Ar), 131.3 (C, Ar), 131.0 (C, Ar), 124.2 (C, Ar), 115.1 (C, Ar),
111.7 (CH, Ar), 109.8 (CH, Ar), 100.6 (CH, Ar), 59.2 (C), 55.5 (OCH3), 33.2 (CH2), 33.0 (CH2), 30.1 (CH2),
24.8 (CH3), 22.9 (CH2); ESI-LRMS m/z: 271 [M + H]+; ESI-HRMS m/z calcd for M + H+ 271.1441, found:
271.1437. The characterization data is in accordance with that reported in [43].
10,11c-Dimethyl-5,6,7,11c-tetrahydro-1H-indolizino[7,8-b]indol-3(2H)-one (SF5c): pale yellow oil (118.4 mg,
1
yield 93%). H-NMR (500 MHz, DMSO-d6)
δ 1.53 (s, 3H), 2.02–1.91 (m, 1H), 2.29–2.17 (m, 1H), 2.38
(s, 3H), 2.50–2.46 (m, 1H), 2.64–2.54 (m, 1H), 2.80–2.65 (m, 2H), 3.15–3.03 (m, 1H), 4.26–4.15 (m, 1H),
6.86 (dd, J = 8.2, 1.0 Hz, 1H), 7.18 (d, J = 8.2 Hz, 1H), 7.25 (s, 1H), 10.75 (s, 1H); 13C-NMR (125 MHz,
DMSO-d6) δ 171.5 (CO), 134.2 (C, Ar), 130.5 (C, Ar), 127.1 (C, Ar), 124.1 (C, Ar), 122.0 (CH, Ar), 117.6
(CH, Ar), 114.8 (C, Ar), 110.8 (CH, Ar), 59.2 (C), 33.3 (CH2), 33.2 (CH2), 30.2 (CH2), 25.0 (CH3), 22.8
(CH2), 21.3 (CH3); ESI-LRMS m/z: 255 [M + H]+; ESI-HRMS m/z calcd for M + H+ 255.1492, found:
255.1489. The characterization data is in accordance with that reported in [43].
3.3. General Procedure for the Preparation of Compounds SF1c, SF2–SF4, SF5d, SF5e and SF6–SF46
A suspension of alkynoic acids
1 (0.6 mmol), amine nucleophiles 2 or 3 (0.5 mmol), and
AuPPh3Cl/AgSbF6 (with the amount indicated) in H2O (4.0 mL) was stirred at the temperature
indicated for 20 h. Then the reaction mixture was cooled to room temperature, and CF3COOH
(0.5 mmol) was added, and the resulting mixture was stirred for another 4 h at the temperature
indicated. At ambient temperature, saturated Na2CO3 solution (25.0 mL) was added to the reaction
mixture. The resulting mixture was then extracted with ethyl acetate (3
×
15 mL). The combined
organic layers were washed with brine, and dried over Na2SO4. After filtration and removal of the
solvents in vacuo, the crude product was purified by flash chromatography on silica gel to yield the
desired product.
12b-Methyl-1,2,3,6,7,12b-hexahydroindolo[2,3-a]quinolizin-4(12H)-one (SF2a): white solid (82.6 mg, yield
65%), mp 255–256 ◦C. 1H-NMR (500 MHz, DMSO-d6)
δ 1.60 (s, 3H), 1.80–1.68 (m, 2H), 1.97–1.86 (m,
1H), 2.32–2.21 (m, 1H), 2.45–2.32 (m, 2H), 2.61–2.53 (m, 1H), 2.69–2.62 (m, 1H), 2.99–2.87 (m, 1H),
4.90–4.81 (m, 1H), 7.00–6.93 (m, 1H), 7.10–7.02 (m, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.39 (d, J = 7.8 Hz,
1H), 10.92 (s, 1H); 13C-NMR (125 MHz, DMSO-d6)
δ 167.9 (CO), 139.7 (C, Ar), 136.0 (C, Ar), 126.2 (C,

Molecules 2019, 24, 988
14 of 30
Ar), 120.9 (CH, Ar), 118.5 (CH, Ar), 117.9 (CH, Ar), 111.1 (CH, Ar), 105.8 (C, Ar), 56.4 (C), 35.6 (CH2),
34.8 (CH2), 31.8 (CH2), 25.3 (CH3), 21.0 (CH2), 16.3 (CH2); ESI-LRMS m/z: 255 [M + H]+; ESI-HRMS
m/z calcd for M + H+ 255.1492, found: 255.1488. The characterization data is in accordance with that
reported in [43].
9-Methoxy-12b-methyl-1,2,3,6,7,12b-hexahydroindolo[2,3-a]quinolizin-4(12H)-one (SF2b): pale yellow solid
(95.4 mg, yield 67%), mp 190–191 ◦C. 1H-NMR (400 MHz, DMSO-d6)
δ 1.59 (s, 3H), 1.79–1.66 (m, 2H),
1.97–1.84 (m, 1H), 2.42–2.21 (m, 3H), 2.66–2.51 (m, 2H), 2.99–2.86 (m, 1H), 3.74 (s, 3H), 4.90–4.79 (m, 1H),
6.70 (dd, J = 8.7, 2.4 Hz, 1H), 6.89 (d, J = 2.4 Hz, 1H), 7.20 (d, J = 8.7 Hz, 1H), 10.73 (s, 1H); 13C-NMR
(125 MHz, DMSO-d6) δ 167.9 (CO), 153.2 (C, Ar), 140.4 (C, Ar), 131.0 (C, Ar), 126.5 (C, Ar), 111.7 (CH,
Ar), 110.7 (CH, Ar), 105.7 (C, Ar), 100.1 (CH, Ar), 56.4 (C), 55.4 (OCH3), 35.6 (CH2), 34.8 (CH2), 31.8
(CH2), 25.4 (CH3), 21.1 (CH2), 16.3 (CH2); ESI-LRMS m/z: 285 [M + H]+; ESI-HRMS m/z calcd for
M + H+ 285.1598, found: 285.1593. The characterization data is in accordance with that reported in [43].
13b-Methyl-7,8,13,13b-tetrahydro-5H-benzo[1,2]indolizino[8,7-b]indol-5-one (SF3a): white solid (119.4 mg,
yield 83%), mp 283–284 ◦C. 1H-NMR (400 MHz, DMSO-d6)
δ 1.86 (s, 3H), 2.75–2.63 (m, 1H), 2.85–2.75
(m, 1H), 3.47–3.36 (m, 1H), 4.59–4.47 (m, 1H), 7.03–6.93 (m, 1H), 7.15–7.05 (m, 1H), 7.44–7.34 (m,
2H), 7.58–7.49 (m, 1H), 7.79–7.68 (m, 2H), 8.32 (d, J = 7.9 Hz, 1H), 11.35 (s, 1H); 13C-NMR (100 MHz,
DMSO-d6) δ 167.2 (CO), 149.3 (C, Ar), 136.2 (C, Ar), 135.2 (C, Ar), 132.2 (CH, Ar), 130.3 (C, Ar), 128.6
(CH, Ar), 126.0 (C, Ar), 123.2 (CH, Ar), 122.8 (CH, Ar), 121.6 (CH, Ar), 118.9 (CH, Ar), 118.3 (CH, Ar),
111.2 (CH, Ar), 106.3 (C, Ar), 62.0 (C), 35.4 (CH2), 25.9 (CH3), 21.4 (CH2); ESI-LRMS m/z: 289 [M + H]+;
ESI-HRMS m/z calcd for M + H+ 289.1335, found: 289.1330. The characterization data is in accordance
with that reported in [43].
10-Methoxy-13b-methyl-7,8,13,13b-tetrahydro-5H-benzo[1,2]indolizino[8,7-b]indol-5-one (SF3b): white solid
◦
(146.9 mg, yield 92%), mp 164–165 C. 1H-NMR (400 MHz, DMSO-d6)
δ 1.84 (s, 3H), 2.72–2.60 (m, 1H),
2.81–2.73 (m, 1H), 3.45–3.35 (m, 1H), 3.73 (s, 3H), 4.57–4.45 (m, 1H), 6.73 (dd, J = 8.7, 2.1 Hz, 1H), 6.89
(d, J = 2.1 Hz, 1H), 7.26 (d, J = 8.7 Hz, 1H), 7.58–7.47 (m, 1H), 7.77–7.67 (m, 2H), 8.29 (d, J = 7.9 Hz, 1H),
11.18 (s, 1H); 13C-NMR (125 MHz, DMSO-d6)
δ 167.2 (CO), 153.3 (C, Ar), 149.4 (C, Ar), 135.8 (C, Ar),
132.2 (CH, Ar), 131.2 (C, Ar), 130.2 (C, Ar), 128.6 (CH, Ar), 126.3 (C, Ar), 123.2 (CH, Ar), 122.8 (CH, Ar),
111.9 (CH, Ar), 111.5 (CH, Ar), 106.2 (C, Ar), 100.3 (CH, Ar), 62.0 (C), 55.4 (OCH3), 35.5 (CH2), 26.0
(CH3), 21.5 (CH2); ESI-LRMS m/z: 319 [M + H]+; ESI-HRMS m/z calcd for M + H+ 319.1441, found:
319.1435. The characterization data is in accordance with that reported in [43].
14b-Methyl-8,9,14,14b-tetrahydroindolo[20◦,30:3,4]pyrido[2,1-a]isoquinolin-6(5H)-one (SF4a): pale yellow
solid (120.7 mg, yield 80%), mp 137–138 C. 1H-NMR (400 MHz, DMSO-d6)
δ 1.84 (s, 3H), 2.50–2.41 (m,
1H), 2.86–2.75 (m, 1H), 2.96–2.86 (m, 1H), 3.63 (d, J = 19.4 Hz, 1H), 4.08 (d, J = 19.2 Hz, 1H), 4.96–4.85
(m, 1H), 7.08–6.98 (m, 1H), 7.18–7.12 (m, 1H), 7.24–7.18 (m, 1H), 7.31–7.24 (m, 2H), 7.52–7.43 (m, 3H),
11.56 (s, 1H); 13C-NMR (100 MHz, DMSO-d6)
δ169.0 (CO), 139.9 (C, Ar), 136.1 (C, Ar), 135.1 (C, Ar),
132.3 (C, Ar), 127.8 (CH, Ar), 127.5 (CH, Ar), 126.4 (CH, Ar), 126.0 (C, Ar), 124.1 (CH, Ar), 121.4 (CH,
Ar), 118.8 (CH, Ar), 118.2 (CH, Ar), 111.3 (CH, Ar), 109.2 (C, Ar), 60.9 (C), 38.0 (CH2), 37.9 (CH2), 26.2
(CH3), 21.0 (CH2); ESI-LRMS m/z: 303 [M + H]+; ESI-HRMS m/z calcd for M + H+ 303.1492, found:
303.1487. The characterization data is in accordance with that reported in [43].
10-Fluoro-11c-methyl-5,6,7,11c-tetrahydro-1H-indolizino[7,8-b]indol-3(2H)-one (SF5d): pale yellow solid
(95.1 mg, yield 74%), mp 104–105 ◦C. 1H-NMR (400 MHz, DMSO-d6)
δ
1.52 (s, 3H), 1.99–1.87 (m, 1H),
2.28–2.16 (m, 1H), 2.64–2.51 (m, 2H), 2.83–2.67 (m, 2H), 3.16–3.01 (m, 1H), 4.28–4.15 (m, 1H), 6.93–6.82
(m, 1H), 7.34–7.21 (m, 2H), 11.00 (s, 1H); 13C-NMR (100 MHz, DMSO-d6)
171.5 (CO), 156.7 (d, JC–F
δ
=
231.1 Hz, CF, Ar), 132.9 (C, Ar), 132.5 (C, Ar), 124.0 (d, JC–F = 10.1 Hz, C, Ar), 115.7 (d, JC–F = 4.5 Hz,
C, Ar), 111.9 (d, JC–F = 9.9 Hz, CH, Ar), 108.3 (d, JC–F = 25.8 Hz, CH, Ar), 102.9 (d, JC–F = 23.4 Hz, CH,
Ar), 59.0 (C), 33.1 (CH2), 32.9 (CH2), 30.1 (CH2), 24.8 (CH3), 22.9 (CH2); ESI-LRMS m/z: 259 [M + H]+;
ESI-HRMS m/z calcd for M + H+ 259.1241, found: 259.1238. The characterization data is in accordance
with that reported in [43].

Molecules 2019, 24, 988
15 of 30
11c-Benzyl-5,6,7,11c-tetrahydro-1H-indolizino[7,8-b]indol-3(2H)-one (SF5e): pale yellow oil (69.4 mg, yield
1
44%). H-NMR (500 MHz, CDCl3)
δ 1.78–1.65 (m, 1H), 2.22–2.09 (m, 2H), 2.72–2.60 (m, 2H), 2.97–2.85
(m, 1H), 3.08–2.98 (m, 1H), 3.21 (d, J = 13.9 Hz, 1H), 3.30 (d, J = 13.9 Hz, 1H), 4.50 (dd, J = 12.9, 6.4 Hz,
1H), 7.12–7.06 (m, 2H), 7.22–7.13 (m, 2H), 7.26–7.23 (m, 3H), 7.35 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 7.6 Hz,
1H), 8.33 (s, 1H); 13C-NMR (125 MHz, CDCl3)
130.2 (2 CH, Ar), 128.5 (2
118.5 (CH, Ar), 115.9 (C, Ar), 111.3 (CH, Ar), 63.8 (C), 44.6 (CH2), 34.3 (CH2), 31.6 (CH2), 31.0 (CH2),
23.1 (CH2); ESI-LRMS m/z: 317 [M + H]+; ESI-HRMS m/z calcd for M + H+ 317.1648, found: 317.1651.
The characterization data is in accordance with that reported in [43].
δ
174.3 (CO), 136.7 (C, Ar), 136.2 (C, Ar), 130.6 (C, Ar),
×
×
CH, Ar), 127.0 (CH, Ar), 124.4 (C, Ar), 121.8 (CH, Ar), 119.9 (CH, Ar),
12c-Methyl-1,2,3,6,7,12c-hexahydroindolo[3,2-a]quinolizin-4(8H)-one (SF6a): white solid (86.8 mg, yield
68%), mp 132–133 ◦C. 1H-NMR (400 MHz, DMSO-d6)
δ 1.63 (s, 3H), 1.77–1.65 (m, 2H), 2.01–1.85 (m,
1H), 2.32–2.19 (m, 1H), 2.43–2.32 (m, 1H), 2.78–2.60 (m, 3H), 3.01–2.89 (m, 1H), 4.92–4.80 (m, 1H),
6.99–6.90 (m, 1H), 7.07–6.99 (m, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 7.8 Hz, 1H), 10.91 (s, 1H);
13C-NMR (125 MHz, DMSO-d6)
δ 168.1 (CO), 136.1 (C, Ar), 131.9 (C, Ar), 124.0 (C, Ar), 120.3 (CH, Ar),
118.6 (CH, Ar), 118.5 (CH, Ar), 115.7 (C, Ar), 111.1 (CH, Ar), 57.0 (C), 35.6 (CH2), 34.7 (CH2), 31.9 (CH2),
25.1 (CH3), 23.3 (CH2), 16.5 (CH2); ESI-LRMS m/z: 255 [M + H]+; ESI-HRMS m/z calcd for M + H+
255.1492, found: 255.1488. The characterization data is in accordance with that reported in [43].
12c-Benzyl-1,2,3,6,7,12c-hexahydroindolo[3,2-a]quinolizin-4(8H)-one (SF6b): pale yellow oil (57.9 mg, yield
35%). 1H-NMR (400 MHz, DMSO-d6)
δ 1.52–1.41 (m, 1H), 1.68–1.54 (m, 1H), 1.90–1.78 (m, 1H),
2.24–2.05 (m, 2H), 2.61–2.53 (m, 1H), 2.81–2.64 (m, 3H), 3.24 (d, J = 13.6 Hz, 1H), 3.41 (d, J = 13.5 Hz,
1H), 4.85–4.74 (m, 1H), 6.94–6.86 (m, 1H), 7.06–6.96 (m, 3H), 7.23–7.14 (m, 3H), 7.29 (d, J = 8.0 Hz,
1H), 7.33 (d, J = 7.9 Hz, 1H), 10.95 (s, 1H); 13C-NMR (150 MHz, DMSO-d6)
δ
169.2 (CO), 137.8 (C, Ar),
136.0 (C, Ar), 133.0 (C, Ar), 130.4 (2
×
CH, Ar), 127.9 (2
×
CH, Ar), 126.4 (CH, Ar), 124.3 (C, Ar), 120.2
(CH, Ar), 119.0 (CH, Ar), 118.5 (CH, Ar), 114.2 (C, Ar), 111.1 (CH, Ar), 60.9 (C), 44.3 (CH2), 35.0 (CH2),
33.9 (CH2), 31.7 (CH2), 23.0 (CH2), 16.3 (CH2); ESI-LRMS m/z: 331 [M + H]+; ESI-HRMS m/z calcd
for M + H+ 331.1805, found: 331.1812. The characterization data is in accordance with that reported
in [43].
13b-Methyl-6,7-dihydro-5H-benzo[1,2]indolizino[7,8-b]indol-9(13bH)-one (SF7a): pale yellow solid (116.4
◦
1
mg, yield 81%), mp 235–236 C. H-NMR (500 MHz, DMSO-d6)
δ 1.90 (s, 3H), 2.80–2.70 (m, 1H),
2.91–2.80 (m, 1H), 3.45–3.37 (m, 1H), 4.56–4.46 (m, 1H), 7.12–7.03 (m, 2H), 7.34–7.26 (m, 1H), 7.52–7.44
(m, 1H), 7.69–7.64 (m, 1H), 7.71 (d, J = 7.5 Hz, 1H), 8.12–8.03 (m, 1H), 8.27 (d, J = 7.8 Hz, 1H), 11.10
(s, 1H); 13C-NMR (125 MHz, DMSO-d6)
δ 167.3 (CO), 151.4 (C, Ar), 135.9 (C, Ar), 132.3 (C, Ar), 132.0
(CH, Ar), 130.2 (C, Ar), 128.1 (CH, Ar), 124.3 (C, Ar), 123.2 (CH, Ar), 123.1 (CH, Ar), 120.7 (CH, Ar),
119.0 (CH, Ar), 119.0 (CH, Ar), 111.6 (C, Ar), 111.3 (CH, Ar), 63.6 (C), 34.6 (CH2), 25.7 (CH3), 23.4
(CH2); ESI-LRMS m/z: 289 [M + H]+; ESI-HRMS m/z calcd for M + H+ 289.1335, found: 289.1330.
The characterization data is in accordance with that reported in [43].
13b-Benzyl-6,7-dihydro-5H-benzo[1,2]indolizino[7,8-b]indol-9(13bH)-one (SF7b): white solid (121.1 mg,
yield 66%), mp 281–282 ◦C. 1H-NMR (500 MHz, DMSO-d6)
δ 2.91–2.72 (m, 2H), 3.49–3.38 (m, 1H),
3.57 (d, J = 13.8 Hz, 1H), 3.85 (d, J = 13.9 Hz, 1H), 4.53 (dd, J = 13.0, 5.6 Hz, 1H), 6.95–6.87 (m, 2H),
7.08–6.98 (m, 3H), 7.20–7.08 (m, 2H), 7.39–7.30 (m, 2H), 7.46 (d, J = 7.4 Hz, 1H), 7.66–7.58 (m, 1H), 8.32
(d, J = 7.8 Hz, 1H), 8.43 (d, J = 7.8 Hz, 1H), 11.14 (s, 1H); 13C-NMR (125 MHz, DMSO-d6)
δ
167.7 (CO),
148.8 (C, Ar), 135.9 (C, Ar), 135.7 (C, Ar), 132.8 (C, Ar), 131.4 (CH, Ar), 131.0 (C, Ar), 130.0 (2 CH,
Ar), 127.8 (CH, Ar), 127.3 (2 CH, Ar), 126.2 (CH, Ar), 124.4 (C, Ar), 123.9 (CH, Ar), 122.6 (CH, Ar),
×
×
120.7 (CH, Ar), 119.4 (CH, Ar), 119.1 (CH, Ar), 111.3 (CH, Ar), 111.1 (C, Ar), 67.1 (C), 42.7 (CH2), 34.8
(CH2), 23.4 (CH2); ESI-LRMS m/z: 365 [M + H]+; ESI-HRMS m/z calcd for M + H+ 365.1648, found:
365.1649. The characterization data is in accordance with that reported in [43].
13b-Pentyl-6,7-dihydro-5H-benzo[1,2]indolizino[7,8-b]indol-9(13bH)-one (SF7c): pale yellow oil (68.7 mg,
1
yield 40%). H-NMR (400 MHz, CDCl3)
δ 0.77 (t, J = 6.7 Hz, 3H), 0.89–0.83 (m, 1H), 1.20–1.02 (m, 5H),

Molecules 2019, 24, 988
16 of 30
2.24–2.10 (m, 1H), 2.76–2.58 (m, 2H), 3.13–2.98 (m, 1H), 3.38–3.24 (m, 1H), 4.77 (dd, J = 13.1, 6.1 Hz,
1H), 7.23–7.12 (m, 2H), 7.31 (d, J = 7.8 Hz, 1H), 7.45–7.38 (m, 1H), 7.62–7.54 (m, 1H), 7.85 (d, J = 7.5 Hz
1H), 7.99 (d, J = 7.7 Hz, 1H), 8.06 (d, J = 7.7 Hz, 1H), 8.23 (s, 1H); 13C-NMR (150 MHz, CDCl3)
169.4
,
δ
(CO), 149.6 (C, Ar), 136.1 (C, Ar), 132.0 (CH, Ar), 131.9 (C, Ar), 131.8 (C, Ar), 128.1 (CH, Ar), 124.9
(C, Ar), 123.9 (CH, Ar), 122.9 (CH, Ar), 121.7 (CH, Ar), 120.0 (CH, Ar), 119.4 (CH, Ar), 113.5 (C, Ar),
111.4 (CH, Ar), 67.4 (C), 38.2 (CH2), 35.3 (CH2), 31.8 (CH2), 24.1 (CH2), 23.1 (CH2), 22.5 (CH2), 14.1
(CH3); ESI-LRMS m/z: 345 [M + H]+; ESI-HRMS m/z calcd for M + H+ 345.1961, found: 345.1966.
The characterization data is in accordance with that reported in [43].
14c-Methyl-8,9,10,14c-tetrahydroindol◦o[30,2’:3,4]pyrido[2,1-a]isoquinolin-6(5H)-one (SF8a): yellow solid
(129.8 mg, yield 86%), mp 250–251 C. 1H-NMR (400 MHz, DMSO-d6)
δ 1.89 (s, 3H), 2.72–2.60 (m,
1H), 2.84–2.73 (m, 1H), 3.02–2.89 (m, 1H), 3.62 (d, J = 19.4 Hz, 1H), 4.10 (d, J = 19.2 Hz, 1H), 4.95–4.86
(m, 1H), 7.15–7.04 (m, 3H), 7.30–7.19 (m, 2H), 7.44–7.38 (m, 2H), 7.59 (d, J = 7.6 Hz, 1H), 11.26 (s, 1H);
13C-NMR (100 MHz, DMSO-d6)
δ 169.3 (CO), 141.4 (C, Ar), 136.0 (C, Ar), 134.5 (C, Ar), 132.4 (C, Ar),
127.7 (CH, Ar), 127.1 (CH, Ar), 126.2 (C, Ar), 126.1 (CH, Ar), 124.7 (CH, Ar), 120.5 (CH, Ar), 120.2
(CH, Ar), 119.2 (CH, Ar), 111.5 (CH, Ar), 111.2 (C, Ar), 61.5 (C), 38.2 (CH2), 36.9 (CH2), 25.7 (CH3),
23.3 (CH2); ESI-LRMS m/z: 303 [M + H]+; ESI-HRMS m/z calcd for M + H+ 303.1492, found: 303.1486.
The characterization data is in accordance with that reported in [43].
14c-Benzyl-8,9,10,14c-tetrahydroindolo[3’,2’:3,4]pyrido[2,1-a]isoquinolin-6(5H)-one (SF8b): pale yellow oil
1
(66.5 mg, yield 35%). H-NMR (500 MHz, CDCl3)
δ 1.84–1.73 (m, 1H), 2.48–2.38 (m, 1H), 2.67–2.56
(m, 1H), 3.40 (d, J = 13.8 Hz, 1H), 3.96–3.76 (m, 3H), 4.79 (dd, J = 12.7, 4.3 Hz, 1H), 6.80–6.71 (m, 2H),
7.08–7.00 (m, 2H), 7.16–7.08 (m, 2H), 7.28–7.20 (m, 2H), 7.33–7.28 (m, 2H), 7.50–7.42 (m, 1H), 7.66 (d,
J = 7.9 Hz, 1H), 7.96–7.88 (m, 1H), 8.36 (s, 1H); 13C-NMR (125 MHz, CDCl3)
δ
170.6 (CO), 141.0 (C,
Ar), 136.4 (C, Ar), 136.1 (C, Ar), 135.7 (C, Ar), 132.3 (C, Ar), 130.4 (2
×
CH, Ar), 128.2 (2 CH, Ar),
×
128.0 (CH, Ar), 127.7 (CH, Ar), 127.3 (C, Ar), 126.9 (CH, Ar), 126.8 (CH, Ar), 126.0 (CH, Ar), 121.6 (CH,
Ar), 121.4 (CH, Ar), 120.5 (CH, Ar), 111.7 (CH, Ar), 109.9 (C, Ar), 66.5 (C), 45.0 (CH2), 39.1 (CH2), 38.7
(CH2), 23.3 (CH2); ESI-LRMS m/z: 379 [M + H]+; ESI-HRMS m/z calcd for M + H+ 379.1805, found:
379.1815. The characterization data is in accordance with that reported in [43].
12b-Methyl-1,5,6,12b-tetrahydropyrrolo[2’,1’:3,4]pyrazino[1,2-a]indol-3(2H)-one (SF9a): white solid (107.8
◦
1
mg, yield 90%), mp 121–122 C. H-NMR (400 MHz, DMSO-d6)
δ 1.59 (s, 3H), 2.33–2.17 (m, 2H),
2.47–2.36 (m, 1H), 2.65–2.53 (m, 1H), 3.49–3.38 (m, 1H), 3.81–3.68 (m, 1H), 4.34–4.22 (m, 2H), 6.34 (s,
1H), 7.08–7.01 (m, 1H), 7.15–7.09 (m, 1H), 7.38 (d, J = 8.1 Hz, 1H), 7.51 (d, J = 7.7 Hz, 1H); 13C-NMR
(125 MHz, DMSO-d6)
δ 172.1 (CO), 142.1 (C, Ar), 135.2 (C, Ar), 127.6 (C, Ar), 120.7 (CH, Ar), 119.9 (CH,
Ar), 119.8 (CH, Ar), 109.6 (CH, Ar), 95.5 (CH, Ar), 58.6 (C), 40.9 (CH2), 34.3 (CH2), 33.6 (CH2), 29.7
(CH2), 27.2 (CH3); ESI-LRMS m/z: 241 [M + H]+; ESI-HRMS m/z calcd for M + H+ 241.1335, found:
241.1330. The characterization data is in accordance with that reported in [43].
11,12b-Dimethyl-1,5,6,12b-tetrahydropyrrolo[2’,1’:3,4]pyrazino[1,2-a]indol-3(2H)-one (SF9b): pale yellow
1
oil (111.3 mg, yield 88%). H-NMR (300 MHz, CDCl3)
δ 1.65 (s, 3H), 2.49–2.37 (m, 3H), 2.54 (s, 3H),
2.73–2.57 (m, 1H), 3.47–3.32 (m, 1H), 3.96–3.81 (m, 1H), 4.20 (dd, J = 11.7, 4.7 Hz, 1H), 4.52 (dd, J = 13.6
,
5.1 Hz, 1H), 6.30 (s, 1H), 6.98–6.89 (m, 1H), 7.15–7.09 (m, 2H); 13C-NMR (100 MHz, CDCl3)
δ
173.2 (CO),
141.1 (C, Ar), 135.4 (C, Ar), 130.0 (C, Ar), 127.9 (C, Ar), 121.8 (CH, Ar), 120.7 (CH, Ar), 106.8 (CH, Ar),
94.8 (CH, Ar), 59.5 (C), 41.3 (CH2), 35.0 (CH2), 34.3 (CH2), 30.4 (CH2), 27.8 (CH3), 18.8 (CH3); ESI-LRMS
m/z: 255 [M + H]+; ESI-HRMS m/z calcd for M + H+ 255.1492, found: 255.1488. The characterization
data is in accordance with that reported in [45].
12b-Methyl-3-oxo-1,2,3,5,6,12b-hexahydropyrrolo[2’,1’:3,4]pyrazino[1,2-a]indole-11-carbonitrile
(SF9c):
1
yellow oil (104.3 mg, yield 79%). H-NMR (300 MHz, CDCl3)
δ
1.66 (s, 3H), 2.54–2.32 (m, 3H), 2.73–2.59
(m, 1H), 3.49–3.33 (m, 1H), 4.02–3.88 (m, 1H), 4.26 (dd, J = 11.7, 4.8 Hz, 1H), 4.56 (dd, J = 13.7, 5.2 Hz,
1H), 6.52 (s, 1H), 7.26–7.19 (m, 1H), 7.52–7.44 (m, 2H); 13C-NMR (125 MHz, CDCl3)
173.1 (CO), 144.6
(C, Ar), 135.4 (C, Ar), 129.7 (C, Ar), 125.7 (CH, Ar), 121.2 (CH, Ar), 118.7 (CN), 113.9 (CH, Ar), 102.8 (C,
δ

Molecules 2019, 24, 988
17 of 30
Ar), 95.6 (CH, Ar), 59.3 (C), 41.5 (CH2), 34.8 (CH2), 33.9 (CH2), 30.2 (CH2), 27.6 (CH3); ESI-LRMS m/z:
266 [M + H]+; ESI-HRMS m/z calcd for M + H+ 266.1288, found: 266.1282. The characterization data is
in accordance with that reported in [45].
9-Fluoro-12b-methyl-1,5,6,12b-tetrahydropyrr◦olo[2’,1’:3,4]pyrazino[1,2-a]indol-3(2H)-one (SF9d): pale
yellow solid (43.6 mg, yield 68%), mp 71–72 C. 1H-NMR (500 MHz, DMSO-d6)
δ 1.58 (s, 3H), 2.30–2.18
(m, 2H), 2.44–2.36 (m, 1H), 2.63–2.52 (m, 1H), 3.49–3.38 (m, 1H), 3.77–3.67 (m, 1H), 4.32–4.22 (m, 2H),
6.36 (s, 1H), 6.94–6.86 (m, 1H), 7.26 (dd, J = 10.2, 2.2 Hz, 1H), 7.50 (dd, J = 8.6, 5.4 Hz, 1H); 13C-NMR
(125 MHz, DMSO-d6)
δ 172.1 (CO), 158.5 (d, JC–F = 234.3 Hz, CF, Ar), 142.9 (d, JC–F = 3.7 Hz, C, Ar),
135.2 (d, JC–F = 12.5 Hz, C, Ar), 124.2 (C, Ar), 120.9 (d, JC–F = 10.0 Hz, CH, Ar), 108.1 (d, JC–F = 24.3 Hz,
CH, Ar), 96.3 (d, JC–F = 26.3 Hz, CH, Ar), 95.6 (CH, Ar), 58.6 (C), 41.1 (CH2), 34.3 (CH2), 33.5 (CH2), 29.6
(CH2), 27.3 (CH3); ESI-LRMS m/z: 259 [M + H]+; ESI-HRMS m/z calcd for M + H+ 259.1241, found:
259.1238.
10-Chloro-12b-methyl-1,5,6,12b-tetrahydropyrrolo[2’,1’:3,4]pyrazino[1,2-a]indol-3(2H)-one (SF9e): pale
1
yellow oil (87.5 mg, yield 64%). H-NMR (300 MHz, CDCl3)
δ 1.63 (s, 3H), 2.52–2.32 (m, 3H), 2.71–2.56
(m, 1H), 3.45–3.32 (m, 1H), 3.94–3.81 (m, 1H), 4.17 (dd, J = 11.6, 4.6 Hz, 1H), 4.52 (dd, J = 13.7, 5.0 Hz,
1H), 6.23 (s, 1H), 7.20–7.11 (m, 2H), 7.52 (s, 1H); 13C-NMR (100 MHz, CDCl3)
173.1 (CO), 143.0 (C,
δ
Ar), 134.1 (C, Ar), 129.1 (C, Ar), 126.1 (C, Ar), 121.8 (CH, Ar), 119.9 (CH, Ar), 110.1 (CH, Ar), 96.0
(CH, Ar), 59.4 (C), 41.3 (CH2), 34.8 (CH2), 34.0 (CH2), 30.2 (CH2), 27.7 (CH3); ESI-LRMS m/z: 277
([M + H]+, Cl37), 275 ([M + H]+, Cl35); ESI-HRMS m/z calcd for M + H+ 275.0946, found: 275.0943.
The characterization data is in accordance with that reported in [45].
13b-Methyl-2,3,6,7-tetrahydro-1H-pyrido[2’,1’:3,4]pyrazino[1,2-a]indol-4(13bH)-one (SF10a): white solid
(73.5 mg, yield 58%), mp 113–114 ◦C. 1H-NMR (500 MHz, DMSO-d6)
δ 1.67 (s, 3H), 1.78–1.69 (m, 1H),
1.98–1.88 (m, 1H), 2.07–1.99 (m, 1H), 2.42–2.26 (m, 3H), 3.40–3.25 (m, 1H), 3.81–3.70 (m, 1H), 4.33–4.24
(m, 1H), 4.95–4.85 (m, 1H), 6.34 (s, 1H), 7.06–7.01 (m, 1H), 7.14–7.07 (m, 1H), 7.37 (d, J = 8.1 Hz, 1H),
7.50 (d, J = 7.8 Hz, 1H); 13C-NMR (125 MHz, DMSO-d6)
δ 168.1 (CO), 142.4 (C, Ar), 135.1 (C, Ar),
127.7 (C, Ar), 120.6 (CH, Ar), 119.8 (CH, Ar), 119.7 (CH, Ar), 109.4 (CH, Ar), 95.2 (CH, Ar), 56.7 (C),
41.2 (CH2), 36.6 (CH2), 34.5 (CH2), 31.7 (CH2), 28.2 (CH3), 16.9 (CH2); ESI-LRMS m/z: 255 [M + H]+;
ESI-HRMS m/z calcd for M + H+ 255.1492, found: 255.1488. The characterization data is in accordance
with that reported in [43].
12,13b-Dimethyl-2,3,6,7-tetrahydro-1H-pyrido[2’,1’:3,4]pyrazino[1,2-a]indol-4(13bH)-one (SF10b): colorless
1
oil (95.4 mg, yield 71%). H-NMR (300 MHz, CDCl3)
δ 1.73 (s, 3H), 2.06–1.86 (m, 2H), 2.26–2.11 (m,
1H), 2.50–2.32 (m, 2H), 2.65–2.51 (m, 4H), 3.39–3.23 (m, 1H), 4.01–3.87 (m, 1H), 4.22–4.10 (m, 1H), 5.16
(dd, J = 13.7, 4.5 Hz, 1H), 6.26 (s, 1H), 6.99–6.88 (m, 1H), 7.18–7.07 (m, 2H); 13C-NMR (100 MHz, CDCl3)
δ
169.5 (CO), 141.4 (C, Ar), 135.2 (C, Ar), 129.9 (C, Ar), 127.9 (C, Ar), 121.6 (CH, Ar), 120.5 (CH, Ar),
106.6 (CH, Ar), 94.3 (CH, Ar), 57.4 (C), 41.7 (CH2), 37.5 (CH2), 35.3 (CH2), 32.2 (CH2), 28.9 (CH3), 18.8
(CH3), 17.4 (CH2); ESI-LRMS m/z: 269 [M + H]+; ESI-HRMS m/z calcd for M + H+ 269.1648, found:
269.1645. The characterization data is in accordance with that reported in [45].
11-Chloro-13b-methyl-2,3,6,7-tetrahydro-1H-pyrido[2’,1’:3,4]pyrazino[1,2-a]indol-4(13bH)-one (SF10c): pale
1
yellow oil (75.5 mg, yield 52%). H-NMR (300 MHz, CDCl3)
δ 1.70 (s, 3H), 2.20–1.83 (m, 3H), 2.63–2.27
(m, 3H), 3.37–3.22 (m, 1H), 3.98–3.86 (m, 1H), 4.14 (dd, J = 11.6, 4.2 Hz, 1H), 5.16 (dd, J = 13.8, 4.2 Hz,
1H), 6.18 (s, 1H), 7.22–7.09 (m, 2H), 7.55–7.48 (m, 1H); 13C-NMR (100 MHz, CDCl3)
169.4 (CO), 143.4
δ
(C, Ar), 134.0 (C, Ar), 129.1 (C, Ar), 126.0 (C, Ar), 121.6 (CH, Ar), 119.8 (CH, Ar), 110.0 (CH, Ar), 95.5
(CH, Ar), 57.3 (C), 41.7 (CH2), 37.4 (CH2), 35.1 (CH2), 32.1 (CH2), 28.7 (CH3), 17.3 (CH2); ESI-LRMS
m/z: 291 ([M + H]+, Cl37), 289 ([M + H]+, Cl35); ESI-HRMS m/z calcd for M + H+ 289.1102, found:
289.1099. The characterization data is in accordance with that reported in [45].
13b-Methyl-6,7-dihydroisoindolo[1’,2’:3,4]pyrazino[1,2-a]indol-9(13bH)-one (SF11a): pale yellow solid (95.6
◦
1
mg, yield 66%), mp 149–150 C. H-NMR (400 MHz, DMSO-d6)
δ 1.91 (s, 3H), 3.90–3.75 (m, 2H),
4.45–4.31 (m, 1H), 4.68–4.57 (m, 1H), 6.84 (s, 1H), 7.08–7.00 (m, 1H), 7.17–7.09 (m, 1H), 7.38 (d, J = 8.1 Hz
,

Molecules 2019, 24, 988
18 of 30
1H), 7.59–7.48 (m, 2H), 7.80–7.69 (m, 2H), 8.24 (d, J = 7.6 Hz, 1H); 13C-NMR (100 MHz, DMSO-d6)
166.6 (CO), 150.3 (C, Ar), 137.8 (C, Ar), 135.2 (C, Ar), 132.8 (CH, Ar), 129.9 (C, Ar), 128.7 (CH, Ar), 127.3
δ
(C, Ar), 123.1 (2
×
CH, Ar), 121.2 (CH, Ar), 120.0 (2
×
CH, Ar), 109.9 (CH, Ar), 97.8 (CH, Ar), 61.4 (C),
41.1 (CH2), 34.2 (CH2), 28.2 (CH3); ESI-LRMS m/z: 289 [M + H]+; ESI-HRMS m/z calcd for M + H+
289.1335, found: 289.1332. The characterization data is in accordance with that reported in [43].
15b-Methyl-8,9-dihydro-5H-indolo[2’,1’:3,4]pyrazino[2,1-a]isoquinolin-6(15bH)-one (SF12a): yellow solid
(77.6 mg, yield 51%), mp 235–236 ◦C. 1H-NMR (400 MHz, DMSO-d6)
δ 1.89 (s, 3H), 3.20–3.08 (m, 1H),
3.68 (d, J = 19.5 Hz, 1H), 3.81–3.72 (m, 1H), 4.10 (d, J = 19.4 Hz, 1H), 4.40–4.31 (m, 1H), 4.99–4.90 (m,
1H), 6.83 (s, 1H), 7.15–7.08 (m, 1H), 7.23–7.15 (m, 2H), 7.33–7.25 (m, 2H), 7.44–7.38 (m, 2H), 7.67 (d,
J = 7.7 Hz, 1H); 13C-NMR (125 MHz, DMSO-d6)
δ 168.3 (CO), 138.6 (C, Ar), 136.9 (C, Ar), 136.5 (C, Ar),
132.1 (C, Ar), 128.0 (CH, Ar), 127.6 (CH, Ar), 127.2 (C, Ar), 126.5 (CH, Ar), 124.2 (CH, Ar), 121.4 (CH,
Ar), 120.3 (CH, Ar), 119.9 (CH, Ar), 109.7 (CH, Ar), 101.4 (CH, Ar), 61.8 (C), 42.8 (CH2), 37.7 (CH2), 37.4
(CH2), 28.6 (CH3); ESI-LRMS m/z: 303 [M + H]+; ESI-HRMS m/z calcd for M + H+ 303.1492, found:
303.1487. The characterization data is in accordance with that reported in [43].
13b-Methyl-5,6,7,13b-tetrahydro-1H-pyrrolo[2’,1’:3,4][1,4]diazepino[1,2-a]indol-3(2H)-one (SF13a): colorless
1
oil (91.6 mg, yield 72%). H-NMR (400 MHz, CDCl3)
δ 1.72 (s, 3H), 2.14–1.88 (m, 3H), 2.53–2.42 (m,
2H), 2.80–2.70 (m, 1H), 3.17–3.04 (m, 1H), 4.20 (ddd, J = 14.8, 9.1, 2.5 Hz, 1H), 4.56–4.33 (m, 2H), 6.45 (s,
1H), 7.13–7.06 (m, 1H), 7.24–7.19 (m, 1H), 7.30 (d, J = 8.3 Hz, 1H), 7.57 (d, J = 7.8 Hz, 1H); 13C-NMR
(100 MHz, CDCl3) δ 174.2 (CO), 142.5 (C, Ar), 137.7 (C, Ar), 126.9 (C, Ar), 122.0 (CH, Ar), 120.7 (CH,
Ar), 119.9 (CH, Ar), 109.0 (CH, Ar), 99.6 (CH, Ar), 62.4 (C), 43.4 (CH2), 38.5 (CH2), 35.0 (CH2), 30.5
(CH2), 28.0 (CH2), 26.4 (CH3); ESI-LRMS m/z: 255 [M + H]+; ESI-HRMS m/z calcd for M + H+ 255.1492,
found: 255.1489. The characterization data is in accordance with that reported in [45].
11-Bromo-13b-methyl-5,6,7,13b-tetrahydro-1H-pyrrolo[2’,1’:3,4][1,4]diazepino[1,2-a]indol-3(2H)-one (SF13b):
1
pale yellow oil (89.3 mg, yield 54%). H-NMR (300 MHz, CDCl3)
δ 1.71 (s, 3H), 2.15–1.91 (m, 3H),
2.51–2.40 (m, 2H), 2.77–2.66 (m, 1H), 3.16–3.03 (m, 1H), 4.18 (ddd, J = 14.8, 8.8, 2.7 Hz, 1H), 4.46–4.32
(m, 2H), 6.37 (s, 1H), 7.14 (d, J = 8.8 Hz, 1H), 7.30–7.26 (m, 1H), 7.66 (d, J = 1.9 Hz, 1H); 13C-NMR
(100 MHz, CDCl3) δ 174.1 (CO), 143.7 (C, Ar), 136.4 (C, Ar), 128.5 (C, Ar), 124.8 (CH, Ar), 123.1 (CH,
Ar), 112.9 (C, Ar), 110.6 (CH, Ar), 99.1 (CH, Ar), 62.3 (C), 43.7 (CH2), 38.5 (CH2), 34.9 (CH2), 30.4 (CH2),
27.9 (CH2), 26.3 (CH3); ESI-LRMS m/z: 335 ([M + H]+, Br81), 333 ([M + H]+, Br79); ESI-HRMS m/z calcd
for M + H+ 333.0597, found: 333.0595. The characterization data is in accordance with that reported
in [45].
12,13b-Dimethyl-5,6,7,13b-tetrahydro-1H-pyrrolo[2’,1’:3,4][1,4]diazepino[1,2-a]indol-3(2H)-one
colorless oil (107.1 mg, yield 80%). 1H-NMR (300 MHz, CDCl3)
1.73 (s, 3H), 2.03–1.82 (m, 2H),
2.17–2.07 (m, 1H), 2.54–2.44 (m, 2H), 2.55 (s, 3H), 2.85–2.70 (m, 1H), 3.17–3.04 (m, 1H), 4.25–4.13 (m,
1H), 4.52–4.33 (m, 2H), 6.46 (s, 1H), 6.95–6.88 (m, 1H), 7.18–7.12 (m, 2H); 13C-NMR (100 MHz, CDCl3)
(SF13c):
δ
δ
174.0 (CO), 141.8 (C, Ar), 137.3 (C, Ar), 130.1 (C, Ar), 126.5 (C, Ar), 122.1 (CH, Ar), 120.0 (CH, Ar), 106.6
(CH, Ar), 97.9 (CH, Ar), 62.3 (C), 43.5 (CH2), 38.4 (CH2), 34.8 (CH2), 30.4 (CH2), 28.0 (CH2), 26.3 (CH3),
18.6 (CH3); ESI-LRMS m/z: 269 [M + H]+; ESI-HRMS m/z calcd for M + H+ 269.1648, found: 269.1644.
The characterization data is in accordance with that reported in [45].
14b-Methyl-1,14b-dihydroindolo[◦1,2-a]pyrrolo[2,1-c]quinoxalin-3(2H)-one (SF14a): pale yellow solid (123.5
1
mg, yield 86%), mp 179–180 C. H-NMR (400 MHz, DMSO-d6)
δ
1.39 (s, 3H), 2.69–2.45 (m, 3H),
2.95–2.81 (m, 1H), 6.64 (s, 1H), 7.25–7.17 (m, 1H), 7.35–7.26 (m, 2H), 7.46–7.39 (m, 1H), 7.67 (d, J = 7.7 Hz
,
1H), 8.13–8.04 (m, 2H), 8.16 (d, J = 8.1 Hz, 1H); 13C-NMR (100 MHz, DMSO-d6)
δ
172.2 (CO), 142.7 (C,
Ar), 133.1 (C, Ar), 129.3 (C, Ar), 128.8 (C, Ar), 125.8 (CH, Ar), 125.7 (C, Ar), 124.1 (CH, Ar), 123.0 (CH,
Ar), 122.7 (CH, Ar), 121.4 (CH, Ar), 121.2 (CH, Ar), 117.2 (CH, Ar), 111.8 (CH, Ar), 97.6 (CH, Ar), 59.4
(C), 31.2 (CH2), 30.0 (CH2), 25.9 (CH3); ESI-LRMS m/z: 289 [M + H]+; ESI-HRMS m/z calcd for M + H+
289.1335, found: 289.1331. The characterization data is in accordance with that reported in [43].

Molecules 2019, 24, 988
19 of 30
2-Hexyl-14b-methyl-1,14b-dihydroindolo[1,2-a]pyrrolo[2,1-c]quinoxalin-3(2H)-one (SF14b): pale yellow oil
(159.8 mg, yield 86% (dr = 1.5:1)), and the two diastereomers were inseparable by chromatography.
1H-NMR (600 MHz, CDCl3)
δ 1.00–0.80 (m, 3.02H), 1.53–1.22 (m, 11.93H), 2.09–1.96 (m, 1.03H),
2.14–2.08 (m, 0.34H), 2.35–2.27 (m, 0.53H), 2.62–2.52 (m, 0.31H), 2.81–2.73 (m, 0.53H), 2.91–2.82 (m,
0.53H), 3.03–2.94 (m, 0.32H), 6.44 (s, 0.51H), 6.47 (s, 0.34H), 7.25–7.15 (m, 1.61H), 7.36–7.27 (m, 1.91H),
7.43–7.37 (m, 0.41H), 7.68–7.61 (m, 0.92H), 7.86 (dd, J = 7.9, 1.3 Hz, 0.34H), 8.06–7.95 (m, 1.91H), 8.28
(dd, J = 8.1, 1.4 Hz, 0.53H); 13C-NMR (150 MHz, CDCl3)
δ
175.3 (CO), 174.1 (CO), 143.4 (C, Ar), 141.9
(C, Ar), 134.4 (C, Ar), 133.6 (C, Ar), 130.6 (C, Ar), 129.8 (C, Ar), 129.5 (C, Ar), 129.4 (C, Ar), 126.4 (CH,
Ar), 126.2 (C, Ar), 125.6 (CH, Ar), 125.4 (CH, Ar), 124.3 (2 CH, Ar), 123.1 (2 CH, Ar), 122.8 (CH,
Ar), 121.6 (CH, Ar), 121.3 (2 CH, Ar), 117.2 (CH, Ar), 117.1 (CH, Ar), 111.9 (CH, Ar), 111.7 (CH, Ar),
×
×
×
97.4 (CH, Ar), 97.1 (CH, Ar), 58.3 (C), 41.9 (CH), 41.5 (CH), 39.5 (CH2), 37.7 (CH2), 32.1 (CH2), 31.9
(CH2), 31.8 (CH2), 30.9 (CH2), 29.3 (CH2), 29.3 (CH2), 28.9 (CH3), 27.6 (CH2), 27.2 (CH2), 26.2 (CH3),
22.8 (CH2), 22.7 (CH2), 14.2 (2
373.2274, found: 373.2273.
×
CH3); ESI-LRMS m/z: 373 [M + H]+; ESI-HRMS m/z calcd for M + H+
15b-Methyl-2,3-dihydro-1H-indolo[1,2-a]pyrido[2,1-c]quinoxalin-4(15bH)-one (SF15): pale yellow oil (89.4
1
mg, yield 59%). H-NMR (400 MHz, DMSO-d6)
δ 1.29 (s, 3H), 1.97–1.75 (m, 2H), 2.42–2.28 (m, 2H),
2.71–2.56 (m, 2H), 6.60 (s, 1H), 7.23–7.17 (m, 1H), 7.33–7.24 (m, 2H), 7.47–7.40 (m, 1H), 7.71–7.64 (m,
2H), 8.08–8.01 (m, 2H); 13C-NMR (100 MHz, DMSO-d6)
168.2 (CO), 142.5 (C, Ar), 133.2 (C, Ar), 130.5
(C, Ar), 129.1 (C, Ar), 128.4 (CH, Ar), 127.8 (C, Ar), 126.6 (CH, Ar), 123.4 (CH, Ar), 122.8 (CH, Ar), 121.2
δ
(2
×
CH, Ar), 116.9 (CH, Ar), 111.5 (CH, Ar), 96.8 (CH, Ar), 57.3 (C), 33.3 (CH2), 32.9 (CH2), 27.7 (CH3),
17.1 (CH2); ESI-LRMS m/z: 303 [M + H]+; ESI-HRMS m/z calcd for M + H+ 303.1492, found: 303.1486.
The characterization data is in accordance with that reported in [43].
15b-Mmethylindolo[1,2-a]isoindolo[1,2-c]quinoxalin-11(15bH)-one (SF16): white solid (100.5 mg, yield
60%), mp 149–150 ◦C. 1H-NMR (400 MHz, DMSO-d6)
δ 1.65 (s, 3H), 6.77 (s, 1H), 7.24–7.18 (m, 1H),
7.35–7.29 (m, 1H), 7.47–7.40 (m, 1H), 7.57–7.51 (m, 1H), 7.65 (d, J = 7.5 Hz, 1H), 7.76–7.68 (m, 1H),
7.96–7.87 (m, 2H), 8.04 (dd, J = 7.9, 1.5 Hz, 1H), 8.15 (d, J = 8.4 Hz, 1H), 8.31–8.26 (m, 1H), 8.35 (d,
J = 7.6 Hz, 1H); 13C-NMR (100 MHz, DMSO-d6)
δ 164.1 (CO), 146.4 (C, Ar), 137.1 (C, Ar), 133.9 (C,
Ar), 133.5 (CH, Ar), 129.7 (C, Ar), 129.5 (CH, Ar), 129.3 (C, Ar), 128.9 (C, Ar), 126.5 (CH, Ar), 124.6
(C, Ar), 124.4 (CH, Ar), 124.0 (CH, Ar), 123.9 (CH, Ar), 123.7 (CH, Ar), 123.5 (CH, Ar), 121.6 (CH, Ar),
121.3 (CH, Ar), 117.5 (CH, Ar), 111.9 (CH, Ar), 99.3 (CH, Ar), 61.2 (C), 26.3 (CH3); ESI-LRMS m/z: 337
[M + H]+; ESI-HRMS m/z calcd for M + H+ 337.1335, found: 337.1329. The characterization data is in
accordance with that reported in [43].
11b-Methyl-4,5-dihydro-3H-pyrrolo[3’,2’:3,4]pyrido[2,1-a]isoindol-7(11bH)-one (SF17): pale yellow solid
(77.1 mg, yield 65%), mp 237–238 ◦C. 1H-NMR (500 MHz, DMSO-d6)
δ
1.66 (s, 3H), 2.66–2.54 (m, 2H),
3.41–3.27 (m, 1H), 4.48–4.37 (m, 1H), 6.31–6.26 (m, 1H), 6.62–6.55 (m, 1H), 7.49–7.42 (m, 1H), 7.68–7.60
(m, 2H), 7.97 (d, J = 7.6 Hz, 1H), 10.56 (s, 1H); 13C-NMR (100 MHz, DMSO-d6)
166.8 (CO), 152.2 (C,
δ
Ar), 131.9 (CH, Ar), 130.0 (C, Ar), 127.8 (CH, Ar), 122.7 (CH, Ar), 122.7 (C, Ar), 122.3 (CH, Ar), 119.9 (C,
Ar), 116.8 (CH, Ar), 104.0 (CH, Ar), 62.3 (C), 34.5 (CH2), 27.7 (CH3), 22.6 (CH2); ESI-LRMS m/z: 239
[M + H]+; ESI-HRMS m/z calcd for M + H+ 239.1179, found: 239.1175. The characterization data is in
accordance with that reported in [43].
12b-Methyl-5,6-dihydropyrrolo[2’,1’:3,4]pyrazino[2,1-a]isoindol-8(12bH)-one (SF18): pale yellow solid (110.9
◦
1
mg, yield 93%), mp 156–157 C. H-NMR (500 MHz, DMSO-d6)
δ 1.76 (s, 3H), 3.69–3.60 (m, 1H),
3.78–3.70 (m, 1H), 4.08 (dd, J = 12.0, 3.6 Hz, 1H), 4.45 (dd, J = 13.3, 4.2 Hz, 1H), 6.06–5.98 (m, 1H),
6.39–6.31 (m, 1H), 6.67–6.60 (m, 1H), 7.55–7.47 (m, 1H), 7.75–7.65 (m, 2H), 8.06 (d, J = 7.9 Hz, 1H);
13C-NMR (100 MHz, DMSO-d6)
δ 166.8 (CO), 151.1 (C, Ar), 132.6 (CH, Ar), 130.0 (C, Ar), 129.6 (C, Ar),
128.4 (CH, Ar), 122.9 (CH, Ar), 122.8 (CH, Ar), 119.4 (CH, Ar), 107.8 (CH, Ar), 104.2 (CH, Ar), 61.3 (C),
43.8 (CH2), 34.9 (CH2), 28.5 (CH3); ESI-LRMS m/z: 239 [M + H]+; ESI-HRMS m/z calcd for M + H+
239.1179, found: 239.1175. The characterization data is in accordance with that reported in [43].

Molecules 2019, 24, 988
20 of 30
9a-Methyl-4,5,9,9a-tetrahydrothieno[2,3-g]indolizin-7(8H)-one (SF19): pale yellow solid (65.1 mg, yield
63%), mp 128–129 ◦C. 1H-NMR (400 MHz, DMSO-d6)
1.42 (s, 3H), 1.90–1.79 (m, 1H), 2.31–2.15 (m,
2H), 2.61–2.52 (m, 1H), 2.74–2.62 (m, 1H), 2.85–2.76 (m, 1H), 3.09–2.98 (m, 1H), 4.15 (dd, J = 13.2, 5.6 Hz,
1H), 6.99 (d, J = 5.2 Hz, 1H), 7.37 (d, J = 5.1 Hz, 1H); 13C-NMR (100 MHz, DMSO-d6)
171.6 (CO), 141.8
δ
δ
(C, Ar), 131.3 (C, Ar), 124.2 (CH, Ar), 124.1 (CH, Ar), 60.4 (C), 33.7 (CH2), 33.4 (CH2), 30.1 (CH2), 25.8
(CH3), 24.3 (CH2); ESI-LRMS m/z: 208 [M + H]+; ESI-HRMS m/z calcd for M + H+ 208.0791, found:
208.0788. The characterization data is in accordance with that reported in [43].
11b-Methyl-4,5-dihydrothieno[3’,2’:3,4]pyrido[2,1-a]isoindol-7(11bH)-one (SF20): yellow solid (105.6 mg,
yield 83%), mp 199–200 ◦C. 1H-NMR (400 MHz, DMSO-d6)
δ
1.75 (s, 3H), 2.82–2.71 (m, 1H), 2.93–2.84
(m, 1H), 3.46–3.38 (m, 1H), 4.47 (dd, J = 13.4, 5.7 Hz, 1H), 7.39 (d, J = 5.3 Hz, 1H), 7.56–7.48 (m, 2H),
7.74–7.63 (m, 2H), 8.16 (d, J = 7.6 Hz, 1H); 13C-NMR (100 MHz, DMSO-d6)
166.8 (CO), 150.2 (C, Ar),
137.8 (C, Ar), 132.8 (C, Ar), 132.3 (CH, Ar), 130.1 (C, Ar), 128.4 (CH, Ar), 125.3 (CH, Ar), 124.0 (CH,
δ
Ar), 123.0 (2
×
CH, Ar), 63.4 (C), 34.7 (CH2), 27.0 (CH3), 24.8 (CH2); ESI-LRMS m/z: 256 [M + H]+;
ESI-HRMS m/z calcd for M + H+ 256.0791, found: 256.0785. The characterization data is in accordance
with that reported in [43].
9a-Methyl-4,5,9,9a-tetrahydrothieno[3,2-g]indolizin-7(8H)-one (SF21): colorless oil (93.3 mg, yield 90%).
1H-NMR (500 MHz, DMSO-d6)
δ
1.50 (s, 3H), 2.03–1.92 (m, 1H), 2.32–2.19 (m, 2H), 2.61–2.51 (m, 2H),
2.72–2.63 (m, 1H), 3.07–2.96 (m, 1H), 4.11 (dd, J = 13.3, 6.2 Hz, 1H), 6.80 (d, J = 5.1 Hz, 1H), 7.40 (d,
J = 5.0 Hz, 1H); 13C-NMR (100 MHz, DMSO-d6)
171.7 (CO), 141.8 (C, Ar), 132.3 (C, Ar), 127.1 (CH,
δ
Ar), 123.5 (CH, Ar), 60.4 (C), 35.1 (CH2), 33.6 (CH2), 30.2 (CH2), 27.9 (CH3), 25.1 (CH2); ESI-LRMS m/z:
208 [M + H]+; ESI-HRMS m/z calcd for M + H+ 208.0791, found: 208.0788. The characterization data is
in accordance with that reported in [43].
11b-Methyl-4,5-dihydrothieno[2’,3’:3,4]pyrido[2,1-a]isoindol-7(11bH)-one (SF22): pale yellow solid (108.6
mg, yield 85%), mp 137–138 ◦C. 1H-NMR (500 MHz, DMSO-d6)
δ 1.82 (s, 3H), 2.62 (ddd, J = 16.2, 11.7,
6.5 Hz, 1H), 2.76 (dd, J = 16.2, 4.5 Hz, 1H), 3.40 (ddd, J = 13.4, 12.0, 4.7 Hz, 1H), 4.43 (dd, J = 13.5, 6.2 Hz,
1H), 6.82 (d, J = 5.1 Hz, 1H), 7.45 (d, J = 5.1 Hz, 1H), 7.57–7.49 (m, 1H), 7.76–7.67 (m, 2H), 7.97–7.90 (m,
1H); 13C-NMR (100 MHz, DMSO-d6)
δ 166.5 (CO), 150.2 (C, Ar), 138.0 (C, Ar), 133.4 (C, Ar), 132.5 (CH,
Ar), 130.0 (C, Ar), 128.7 (CH, Ar), 127.1 (CH, Ar), 124.4 (CH, Ar), 123.1 (CH, Ar), 122.4 (CH, Ar), 63.1
(C), 34.3 (CH2), 28.8 (CH3), 25.6 (CH2); ESI-LRMS m/z: 256 [M + H]+; ESI-HRMS m/z calcd for M + H+
256.0791, found: 256.0789. The characterization data is in accordance with that reported in [43].
12b-Methyl-8,12b-dihydro-4H-thieno[2’,3’:3,4]pyrido[2,1-a]isoquinolin-7(5H)-one (SF23): pale yellow solid
(63.4 mg, yield 47%), mp 155–156 ◦C. 1H-NMR (500 MHz, DMSO-d6)
δ 1.87 (s, 3H), 2.50–2.44 (m, 1H),
2.76–2.68 (m, 1H), 3.10–2.99 (m, 1H), 3.64 (d, J = 20.3 Hz, 1H), 3.97 (d, J = 20.2 Hz, 1H), 4.90–4.79 (m,
1H), 6.91 (d, J = 5.1 Hz, 1H), 7.32–7.22 (m, 3H), 7.55 (d, J = 5.1 Hz, 1H), 7.77–7.71 (m, 1H); 13C-NMR
(100 MHz, DMSO-d6) δ 167.9 (CO), 139.0 (C, Ar), 138.8 (C, Ar), 136.4 (C, Ar), 131.3 (C, Ar), 128.0 (CH,
Ar), 127.6 (CH, Ar), 127.4 (CH, Ar), 126.5 (CH, Ar), 124.8 (CH, Ar), 124.5 (CH, Ar), 62.6 (C), 37.0 (CH2),
36.7 (CH2), 31.7 (CH3), 25.2 (CH2); ESI-LRMS m/z: 270 [M + H]+; ESI-HRMS m/z calcd for M + H+
270.0947, found: 270.0942. The characterization data is in accordance with that reported in [43].
8,9-Dimethoxy-10b-methyl-1,5,6,10b-tetrahydropyrrolo[2,1-a]isoquinolin-3(2H)-one (SF24a): white solid
(114.5 mg, yield 88%), mp 53–54 ◦C. 1H-NMR (500 MHz, DMSO-d6)
δ
1.45 (s, 3H), 1.93–1.82 (m, 1H),
2.25–2.15 (m, 1H), 2.45–2.37 (m, 1H), 2.59–2.47 (m, 1H), 2.70–2.62 (m, 2H), 3.05–2.96 (m, 1H), 3.71 (s,
3H), 3.75 (s, 3H), 4.08–4.00 (m, 1H), 6.66 (s, 1H), 6.78 (s, 1H); 13C-NMR (100 MHz, DMSO-d6)
171.3
δ
(CO), 147.7 (C, Ar), 147.4 (C, Ar), 134.9 (C, Ar), 124.1 (C, Ar), 111.9 (CH, Ar), 108.7 (CH, Ar), 60.3 (C),
55.8 (OCH3), 55.5 (OCH3), 34.3 (CH2), 33.4 (CH2), 30.2 (CH2), 27.7 (CH2), 26.8 (CH3); ESI-LRMS m/z:
262 [M + H]+; ESI-HRMS m/z calcd for M + H+ 262.1438, found: 262.1434. The characterization data is
in accordance with that reported in [43].
2-Hexyl-8,9-dimethoxy-10b-methyl-1,5,6,10b-tetrahydropyrrolo[2,1-a]isoquinolin-3(2H)-one (SF24b): white
solid (81.2 mg, yield 47% (dr = 4:1)), mp 65–67 ◦C, and the two diastereomers were inseparable by

Molecules 2019, 24, 988
21 of 30
1
chromatography. H-NMR (400 MHz, DMSO-d6)
δ
0.85–0.72 (m, 3H), 1.37–0.99 (m, 10H), 1.47–1.35
(m, 3H), 1.73–1.57 (m, 1H), 2.43–2.35 (m, 1H), 2.52–2.44 (m, 1H), 2.70–2.52 (m, 2H), 3.12–2.88 (m, 1H),
3.65–3.59 (m, 3H), 3.68 (s, 3H), 4.00–3.89 (m, 1H), 6.61–6.51 (m, 1H), 6.77–6.69 (m, 1H); 13C-NMR
(100 MHz, DMSO-d6) δ 174.9 (CO), 147.5 (C, Ar), 147.4 (C, Ar), 134.7 (C, Ar), 124.4 (C, Ar), 112.0 (CH,
Ar), 108.8 (CH, Ar), 59.5 (C, Ar), 55.7 (OCH3), 55.4 (OCH3), 41.2 (CH), 39.5 (CH2), 34.2 (CH2), 31.8
(CH2), 31.2 (CH2), 30.8 (CH3), 28.6 (CH2), 27.0 (CH2), 26.9 (CH2), 22.0 (CH2), 14.0 (CH3); ESI-LRMS
m/z: 346 [M + H]+; ESI-HRMS m/z calcd for M + H+ 346.2377, found: 346.2375.
9,10-Dimethoxy-11b-methyl-2,3,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-4(11bH)-one (SF25): white solid
(84.4 mg, yield 61%), mp 75–76 ◦C. 1H-NMR (400 MHz, DMSO-d6)
δ 1.55 (s, 3H), 1.64–1.57 (m, 1H),
1.75–1.64 (m, 1H), 1.96–1.81 (m, 1H), 2.37–2.16 (m, 2H), 2.49–2.41 (m, 1H), 2.68–2.53 (m, 2H), 2.87–2.75
(m, 1H), 3.71 (s, 3H), 3.74 (s, 3H), 4.75–4.63 (m, 1H), 6.65 (s, 1H), 6.84 (s, 1H); 13C-NMR (100 MHz,
DMSO-d6) δ 167.7 (CO), 147.4 (C, Ar), 147.2 (C, Ar), 135.2 (C, Ar), 125.5 (C, Ar), 111.7 (CH, Ar), 109.3
(CH, Ar), 58.2 (C), 55.8 (OCH3), 55.4 (OCH3), 36.7 (CH2), 34.8 (CH2), 31.5 (CH2), 28.5 (CH2), 27.3 (CH3),
16.6 (CH2); ESI-LRMS m/z: 276 [M + H]+; ESI-HRMS m/z calcd for M + H+ 276.1594, found: 276.1589.
The characterization data is in accordance with that reported in [43].
2,3-Dimethoxy-12b-methyl-5,6-dihydroisoindolo[1,2-a]isoquinolin-8(12bH)-one (SF26): white solid (118.8
◦
1
mg, yield 77%), mp 187–188 C. H-NMR (500 MHz, DMSO-d6)
3.42–3.34 (m, 1H), 3.69 (s, 3H), 3.83 (s, 3H), 4.39–4.31 (m, 1H), 6.69 (s, 1H), 7.39 (s, 1H), 7.53–7.47 (m,
1H), 7.72–7.65 (m, 2H), 8.30 (d, J = 7.7 Hz, 1H); 13C-NMR (125 MHz, DMSO-d6)
166.5 (CO), 151.1 (C,
δ 1.82 (s, 3H), 2.83–2.67 (m, 2H),
δ
Ar), 147.8 (C, Ar), 147.5 (C, Ar), 132.2 (CH, Ar), 130.8 (C, Ar), 130.3 (C, Ar), 128.3 (CH, Ar), 125.3 (C,
Ar), 123.4 (CH, Ar), 122.8 (CH, Ar), 112.2 (CH, Ar), 110.2 (CH, Ar), 63.4 (C), 56.1 (OCH3), 55.5 (OCH3),
34.6 (CH2), 28.7 (CH2), 28.2 (CH3); ESI-LRMS m/z: 310 [M + H]+; ESI-HRMS m/z calcd for M + H+
310.1438, found: 310.1432. The characterization data is in accordance with that reported in [43].
3a-Methyl-2,3,3a,4-tetrahydropyrrolo[1,2-a]quinazoline-1,5-dione (SF27a): white solid (91.2 mg, yield 84%),
mp 177–178 ◦C. 1H-NMR (500 MHz, DMSO-d6)
δ
1.42 (s, 3H), 2.30–2.19 (m, 2H), 2.56–2.49 (m, 1H),
2.78–2.68 (m, 1H), 7.32–7.25 (m, 1H), 7.65–7.57 (m, 1H), 7.91 (dd, J = 7.7, 1.4 Hz, 1H), 8.07 (d, J = 8.0 Hz
1H), 8.94 (s, 1H); 13C-NMR (100 MHz, DMSO-d6)
171.9 (CO), 161.2 (CO), 135.7 (C, Ar), 133.2 (CH,
,
δ
Ar), 127.7 (CH, Ar), 124.5 (CH, Ar), 119.9 (CH, Ar), 119.8 (C, Ar), 74.0 (C), 32.4 (CH2), 29.6 (CH2), 26.4
(CH3); ESI-LRMS m/z: 217 [M + H]+; ESI-HRMS m/z calcd for M + H+ 217.0972, found: 217.0969.
The characterization data is in accordance with that reported in [43].
3a,4-Dimethyl-2,3,3a,4-tetrahydropyrrolo[1,2-a]quinazoline-1,5-dione (SF27b): white solid (97.5 mg, yield
85%), mp 105–107 ◦C. 1H-NMR (600 MHz, CDCl3)
δ
1.46 (s, 3H), 2.30 (ddd, J = 12.0, 6.1, 4.0 Hz, 1H),
2.48–2.39 (m, 1H), 2.70–2.63 (m, 2H), 3.07 (s, 3H), 7.27–7.24 (m, 1H), 7.56–7.51 (m, 1H), 8.08 (dd, J = 7.8
1.6 Hz, 1H), 8.26 (dd, J = 8.2, 0.8 Hz, 1H); 13C-NMR (150 MHz, CDCl3)
171.3 (CO), 162.1 (CO), 135.2
,
δ
(C, Ar), 133.4 (CH, Ar), 128.6 (CH, Ar), 125.0 (CH, Ar), 119.7 (CH, Ar), 119.4 (C, Ar), 78.5 (C), 32.4 (CH2),
30.3 (CH2), 27.8 (CH3), 21.8 (CH3); ESI-LRMS m/z: 231 [M + H]+; ESI-HRMS m/z calcd for M + H+
231.1128, found: 231.1127. The characterization data is in accordance with that reported in [43].
4a-Methyl-3,4,4a,5-tetrahydro-1H-pyrido[1,2-a]quinazoline-1,6(2H)-dione (SF28a): white solid (70.7 mg,
yield 61%), mp 198–199 ◦C. 1H-NMR (500 MHz, DMSO-d6)
δ
1.35 (s, 3H), 1.90–1.74 (m, 2H), 2.09–2.02
(m, 1H), 2.17–2.09 (m, 1H), 2.48–2.39 (m, 1H), 2.62–2.54 (m, 1H), 7.36–7.28 (m, 1H), 7.60–7.52 (m, 1H),
7.66 (d, J = 8.0 Hz, 1H), 7.86 (dd, J = 7.7, 1.4 Hz, 1H), 8.85 (s, 1H); 13C-NMR (100 MHz, DMSO-d6)
δ
168.8 (CO), 162.3 (CO), 138.1 (C, Ar), 131.8 (CH, Ar), 126.5 (CH, Ar), 126.2 (CH, Ar), 125.2 (CH, Ar),
123.7 (C, Ar), 71.1 (C), 34.7 (CH2), 33.1 (CH2), 28.3 (CH3), 16.6 (CH2); ESI-LRMS m/z: 231 [M + H]+;
ESI-HRMS m/z calcd for M + H+ 231.1128, found: 231.1126. The characterization data is in accordance
with that reported in [43].
4a,5-Dimethyl-3,4,4a,5-tetrahydro-1H-pyrido[1,2-a]quinazoline-1,6(2H)-dione (SF28b): white solid (78.3 mg,
◦
yield 64%), mp 138–139 C. 1H-NMR (600 MHz, CDCl3)
δ
1.39 (s, 3H), 1.98–1.86 (m, 2H), 2.17–2.10 (m,
1H), 2.44–2.36 (m, 1H), 2.63–2.55 (m, 1H), 2.74–2.65 (m, 1H), 3.12 (s, 3H), 7.32–7.28 (m, 1H), 7.54–7.49

Molecules 2019, 24, 988
22 of 30
(m, 1H), 7.62 (dd, J = 8.1, 0.9 Hz, 1H), 8.02 (dd, J = 7.8, 1.6 Hz, 1H); 13C-NMR (150 MHz, CDCl3)
δ 169.3
(CO), 163.6 (CO), 137.4 (C, Ar), 132.0 (CH, Ar), 127.8 (CH, Ar), 126.2 (CH, Ar), 126.0 (CH, Ar), 123.9 (C,
Ar), 75.5 (C), 34.4 (CH2), 33.7 (CH2), 27.5 (CH3), 24.6 (CH3), 16.9 (CH2); ESI-LRMS m/z: 245 [M + H]+;
ESI-HRMS m/z calcd for M + H+ 245.1285, found: 245.1284. The characterization data is in accordance
with that reported in [43].
6a-Methyl-6,6a-dihydroisoindolo[2,1-a]quinazoline-5,11-dione (SF29a): white solid (99.3 mg, yield 75%),
mp 219–220 ◦C. 1H-NMR (400 MHz, DMSO-d6)
δ
1.72 (s, 3H), 7.42–7.36 (m, 1H), 7.70–7.64 (m, 1H),
7.77–7.71 (m, 1H), 7.85–7.78 (m, 1H), 7.89 (d, J = 7.5 Hz, 1H), 7.95 (d, J = 7.6 Hz, 1H), 8.04–7.98 (m,
2H), 9.48 (s, 1H); 13C-NMR (100 MHz, DMSO-d6)
164.4 (CO), 162.5 (CO), 146.0 (C, Ar), 135.2 (C, Ar),
δ
133.7 (CH, Ar), 133.6 (CH, Ar), 130.1 (CH, Ar), 129.4 (C, Ar), 128.0 (CH, Ar), 125.1 (CH, Ar), 124.0 (CH,
Ar), 122.9 (CH, Ar), 121.2 (CH, Ar), 119.8 (C, Ar), 74.2 (C), 27.3 (CH3); ESI-LRMS m/z: 265 [M + H]+;
ESI-HRMS m/z calcd for M + H+ 265.0972, found: 265.0966. The characterization data is in accordance
with that reported in [43].
6,6a-Dimethyl-6,6a-dihydroisoindolo[2,1-a]quinazoline-5,11-dione (SF29b): white solid (97.1 mg, yield 70%),
◦
mp 182–184 C. 1H-NMR (600 MHz, CDCl3)
δ
1.72 (s, 3H), 3.25 (s, 3H), 7.37–7.32 (m, 1H), 7.67–7.63 (m,
2H), 7.76–7.70 (m, 2H), 8.05–7.99 (m, 2H), 8.15 (dd, J = 8.1, 1.0 Hz, 1H); 13C-NMR (150 MHz, CDCl3)
165.0 (CO), 163.0 (CO), 143.3 (C, Ar), 134.8 (C, Ar), 133.5 (CH, Ar), 132.8 (CH, Ar), 131.4 (C, Ar),
δ
130.5 (CH, Ar), 128.9 (CH, Ar), 125.5 (CH, Ar), 125.2 (CH, Ar), 124.6 (CH, Ar), 121.8 (CH, Ar), 120.6 (C,
Ar), 78.1 (C), 29.6 (CH3), 23.3 (CH3); ESI-LRMS m/z: 279 [M + H]+; ESI-HRMS m/z calcd for M + H+
279.1128, found: 279.1127. The characterization data is in accordance with that reported in [43].
4b-Methyl-4bH-isoquinolino[2,1-a]quinazoline-6,12(5H,13H)-dione (SF30a): yellow solid (91.5 mg, yield
◦
66%), mp 225–226 C. 1H-NMR (400 MHz, DMSO-d6)
δ
1.71 (s, 3H), 3.84 (d, J = 21.2 Hz, 1H), 4.16
(d, J = 21.1 Hz, 1H), 7.30–7.23 (m, 1H), 7.45–7.36 (m, 3H), 7.68–7.61 (m, 1H), 7.79–7.71 (m, 1H), 7.82
(d, J = 7.8 Hz, 1H), 7.93 (dd, J = 7.7, 1.5 Hz, 1H), 8.89 (s, 1H); 13C-NMR (100 MHz, DMSO-d6)
165.5
δ
(CO), 161.9 (CO), 137.6 (C, Ar), 133.1 (C, Ar), 132.1 (CH, Ar), 128.8 (CH, Ar), 128.6 (C, Ar), 127.5 (CH,
Ar), 127.2 (CH, Ar), 126.6 (CH, Ar), 126.2 (CH, Ar), 126.1 (CH, Ar), 125.7 (CH, Ar), 123.3 (C, Ar), 73.9
(C), 35.2 (CH2), 30.5 (CH3); ESI-LRMS m/z: 279 [M + H]+; ESI-HRMS m/z calcd for M + H+ 279.1128,
found: 279.1122. The characterization data is in accordance with that reported in [43].
4b,5-Dimethyl-4bH-isoquinolino[2,1-a]quinazoline-6,12(5H,13H)-dione (SF30b): yellow oil (29.1 mg, yield
1
20%). H-NMR (600 MHz, CDCl3)
δ 1.86 (s, 3H), 2.77 (s, 3H), 3.91 (s, 2H), 7.28 (d, J = 7.5 Hz, 1H),
7.45–7.39 (m, 2H), 7.49–7.45 (m, 1H), 7.61–7.55 (m, 2H), 7.63 (d, J = 8.0 Hz, 1H), 8.08 (dd, J = 7.9, 1.3 Hz,
1H); 13C-NMR (150 MHz, DMSO-d6)
δ
169.2 (CO), 162.1 (CO), 138.6 (C, Ar), 131.9 (CH, Ar), 131.8 (C,
Ar), 130.6 (C, Ar), 129.9 (CH, Ar), 128.9 (CH, Ar), 128.0 (CH, Ar), 127.7 (CH, Ar), 127.0 (CH, Ar), 126.9
(CH, Ar), 126.7 (CH, Ar), 125.2 (C, Ar), 76.7 (C), 36.2 (CH2), 29.9 (CH3), 25.7 (CH3); ESI-LRMS m/z: 293
[M + H]+; ESI-HRMS m/z calcd for M + H+ 293.1285, found: 293.1284.
3a-Methyl-2,3,3a,4-tetrahydropyrrolo[2,1-b]quinazolin-1(9H)-one (SF31): white solid (69.4 mg, yield 69%),
◦
1
mp 141–143 C. H-NMR (600 MHz, CDCl3)
2.60–2.52 (m, 1H), 4.17 (d, J = 16.7 Hz, 1H), 5.02 (d, J = 16.8 Hz, 1H), 6.58 (dd, J = 8.0, 0.8 Hz, 1H),
6.81–6.76 (m, 1H), 7.07–6.99 (m, 2H); 13C-NMR (150 MHz, CDCl3)
174.3 (CO), 141.9 (C, Ar), 127.6
δ 1.54 (s, 3H), 2.15–2.05 (m, 2H), 2.52–2.45 (m, 1H),
δ
(CH, Ar), 127.0 (CH, Ar), 119.3 (CH, Ar), 117.4 (C, Ar), 116.5 (CH, Ar), 71.9 (C), 38.6 (CH2), 33.0 (CH2),
29.6 (CH2), 25.6 (CH3); ESI-LRMS m/z: 203 [M + H]+; ESI-HRMS m/z calcd for M+H+ 203.1179, found:
203.1178. The characterization data is in accordance with that reported in [43].
4b-Methyl-4b,5-dihydroisoindolo[1,2-b]quinazolin-12(10H)-one (SF32): pale yellow solid (41.1 mg, yield
33%), mp 222–223 ◦C. 1H-NMR (600 MHz, CDCl3)
δ 1.71 (s, 3H), 4.24 (s, 1H), 4.45 (d, J = 16.9 Hz, 1H),
5.32 (d, J = 17.0 Hz, 1H), 6.69 (d, J = 8.3 Hz, 1H), 6.90–6.85 (m, 1H), 7.12–7.08 (m, 1H), 7.14 (d, J = 7.5 Hz,
1H), 7.56–7.52 (m, 1H), 7.63 (d, J = 3.9 Hz, 2H), 7.88 (d, J = 7.6 Hz, 1H); 13C-NMR (150 MHz, CDCl3)
δ
165.8 (CO), 147.8 (C, Ar), 140.2 (C, Ar), 132.3 (CH, Ar), 131.5 (C, Ar), 129.6 (CH, Ar), 127.9 (CH,
Ar), 127.2 (CH, Ar), 124.4 (CH, Ar), 120.7 (CH, Ar), 120.5 (CH, Ar), 118.7 (C, Ar), 118.1 (CH, Ar), 71.5

Molecules 2019, 24, 988
23 of 30
(C), 38.0 (CH2), 23.9 (CH3); ESI-LRMS m/z: 251 [M + H]+; ESI-HRMS m/z calcd for M + H+ 251.1179,
found: 251.1178. The characterization data is in accordance with that reported in [43].
3a-Methyl-2,3,3a,4-tetrahydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-1-one (SF33): colorless oil (45.1 mg, yield
1
48%). H-NMR (600 MHz, CDCl3)
δ 1.51 (s, 3H), 2.44–2.33 (m, 2H), 2.54 (ddd, J = 16.8, 8.5, 1.6 Hz,
1H), 2.78 (ddd, J = 16.8, 11.7, 8.5 Hz, 1H), 6.68 (dd, J = 7.7, 0.7 Hz, 1H), 6.84–6.79 (m, 1H), 6.98–6.93 (m,
1H), 7.43 (dd, J = 7.6, 1.1 Hz, 1H); 13C-NMR (150 MHz, CDCl3)
δ
173.9 (CO), 142.8 (C, Ar), 128.7 (C,
Ar), 125.4 (CH, Ar), 120.3 (CH, Ar), 115.5 (CH, Ar), 110.7 (CH, Ar), 85.7 (C), 37.8 (CH2), 33.7 (CH2),
26.3 (CH3); ESI-LRMS m/z: 189 [M + H]+; ESI-HRMS m/z calcd for M + H+ 189.1022, found: 189.1023.
The characterization data is in accordance with that reported in [34].
12a-Methyl-12,12a-dihydrobenzo[4,5]imidazo[2,1-a]isoquinolin-6(5H)-one (SF34): colorless oil (26.1 mg,
1
yield 21%). H-NMR (600 MHz, CDCl3)
δ 1.69 (s, 3H), 3.71 (d, J = 19.0 Hz, 1H), 3.88 (d, J = 19.0 Hz,
1H), 4.48 (s, 1H), 6.85 (dd, J = 7.6, 0.5 Hz, 1H), 6.93–6.89 (m, 1H), 7.02–6.97 (m, 1H), 7.24 (d, J = 7.5 Hz,
1H), 7.33–7.30 (m, 1H), 7.37–7.33 (m, 1H), 7.41 (dd, J = 7.6, 0.9 Hz, 1H), 8.02–7.98 (m, 1H);13C-NMR
(150 MHz, CDCl3)
δ 165.5 (CO), 139.3 (C, Ar), 139.1 (C, Ar), 131.3 (C, Ar), 129.8 (C, Ar), 128.4 (CH,
Ar), 128.0 (CH, Ar), 127.6 (CH, Ar), 125.0 (CH, Ar), 123.2 (CH, Ar), 121.6 (CH, Ar), 116.6 (CH, Ar),
112.0 (CH, Ar), 82.3 (C), 38.7 (CH2), 29.5 (CH3); ESI-LRMS m/z: 251 [M + H]+; ESI-HRMS m/z calcd
for M + H+ 251.1179, found: 251.1178. The characterization data is in accordance with that reported
in [43].
3a-Methyl-3,3a-dihydro-1H-benzo[d]pyrrolo[2,1-b][1,3]oxazine-1,5(2H)-dione (SF35a): white solid (98.9 mg,
yield 91%), mp 114–115 ◦C. 1H-NMR (400 MHz, DMSO-d6)
δ
1.63 (s, 3H), 2.48–2.41 (m, 2H), 2.68–2.59
(m, 1H), 2.82–2.71 (m, 1H), 7.44–7.36 (m, 1H), 7.83–7.76 (m, 1H), 8.08–7.92 (m, 2H); 13C-NMR (125 MHz,
DMSO-d6)
δ 171.7 (CO), 161.1 (CO), 136.1 (C, Ar), 135.7 (CH, Ar), 129.9 (CH, Ar), 125.5 (CH, Ar), 120.5
(CH, Ar), 115.7 (C, Ar), 95.4 (C), 31.7 (CH2), 29.1 (CH2), 24.0 (CH3); ESI-LRMS m/z: 218 [M + H]+;
ESI-HRMS m/z calcd for M + H+ 218.0812, found: 218.0809. The characterization data is in accordance
with that reported in [43].
2-Hexyl-3a-methyl-3,3a-dihydro-1H-benzo[d]pyrrolo[2,1-b][1,3]oxazine-1,5(2H)-dione (SF35b): colorless oil
(75.4 mg, yield 50% (dr = 5.5:1)), and the two diastereomers were inseparable by chromatography.
1H-NMR (600 MHz, DMSO-d6) for the major isomer:
δ 0.91–0.84 (m, 3H), 1.42–1.21 (m, 9H), 1.65–1.61
(m, 3H), 1.85–1.78 (m, 1H), 2.13–2.07 (m, 1H), 2.71–2.62 (m, 1H), 2.91–2.83 (m, 1H), 7.41–7.37 (m, 1H),
7.81–7.78 (m, 1H), 8.00 (dd, J = 7.8, 1.5 Hz, 1H), 8.10–8.07 (m, 1H); 13C-NMR (150 MHz, DMSO-d6) for
major isomer:
δ 173.0 (CO), 161.0 (CO), 136.0 (CH, Ar), 135.8 (CH, Ar), 129.9 (CH, Ar), 125.3 (CH, Ar),
119.8 (CH, Ar), 115.1 (C, Ar), 93.5 (C, Ar), 39.8 (CH), 38.5 (CH2), 31.2 (CH2), 29.6 (CH2), 28.6 (CH2),
26.3 (CH2), 23.5 (CH3), 22.1 (CH2), 14.0 (CH3); ESI-LRMS m/z: 302 [M + H]+; ESI-HRMS m/z calcd for
M + H+ 302.1751, found: 302.1750.
4a-Methyl-2,3,4,4a-tetrahydrobenzo[d]pyrido[2,1-b][1,3]oxazine-1,6-dione (SF36): colorless oil (88.5 mg,
1
yield 77%). H-NMR (500 MHz, DMSO-d6)
δ
1.55 (s, 3H), 1.86–1.77 (m, 1H), 1.95–1.86 (m, 1H), 2.31–2.21
(m, 2H), 2.55–2.48 (m, 1H), 2.68–2.58 (m, 1H), 7.46–7.39 (m, 1H), 7.77–7.70 (m, 2H), 7.98–7.93 (m, 1H);
13C-NMR (125 MHz, DMSO-d6)
169.0 (CO), 161.8 (CO), 138.6 (C, Ar), 134.1 (CH, Ar), 128.7 (CH, Ar),
126.1 (2 CH, Ar), 119.9 (C, Ar), 92.7 (C), 34.9 (CH2), 32.9 (CH2), 25.9 (CH3), 16.1 (CH2); ESI-LRMS
δ
×
m/z: 232 [M + H]+; ESI-HRMS m/z calcd for M + H+ 232.0968, found: 232.0965. The characterization
data is in accordance with that reported in ref.43. The characterization data is in accordance with that
reported in [43].
6a-Methyl-5H-benzo[4,5][1,3]oxazino[2,3-a]isoindole-5,11(6aH)-dione (SF37): pale yellow solid (83.6 mg,
yield 63%), mp 138–139 ◦C. 1H-NMR (400 MHz, DMSO-d6)
δ
1.94 (s, 3H), 7.51–7.45 (m, 1H), 7.79–7.73
(m, 1H), 7.93–7.85 (m, 2H), 7.95 (d, J = 7.5 Hz, 1H), 8.06–8.00 (m, 2H), 8.08 (dd, J = 7.8, 1.2 Hz, 1H);
13C-NMR (125 MHz, DMSO-d6)
164.1 (CO), 161.3 (CO), 143.8 (C, Ar), 136.0 (CH, Ar), 135.7 (C, Ar),
δ
134.4 (CH, Ar), 131.3 (CH, Ar), 130.2 (CH, Ar), 129.4 (C, Ar), 125.7 (CH, Ar), 124.2 (CH, Ar), 123.2
(CH, Ar), 121.2 (CH, Ar), 115.3 (C, Ar), 92.5 (C), 23.4 (CH3); ESI-LRMS m/z: 266 [M + H]+; ESI-HRMS

Molecules 2019, 24, 988
24 of 30
m/z calcd for M + H+ 266.0812, found: 266.0807. The characterization data is in accordance with that
reported in [43].
3a-Methyl-3,3a-dihydro-1H-naphtho[2,3-d]pyrrolo[2,1-b][1,3]oxazine-1,5(2H)-dione (SF38): yellow solid
(128.1 mg, yield 96%), mp 228–230 ◦C. 1H-NMR (600 MHz, CDCl3)
δ
1.72 (s, 3H), 2.50–2.42 (m, 1H),
2.68–2.61 (m, 1H), 2.76–2.68 (m, 1H), 2.84–2.77 (m, 1H), 7.56–7.51 (m, 1H), 7.67–7.62 (m, 1H), 7.91 (d,
J = 8.3 Hz, 1H), 7.95 (d, J = 8.2 Hz, 1H), 8.44 (s, 1H), 8.72 (s, 1H); 13C-NMR (150 MHz, CDCl3)
171.7
δ
(CO), 162.3 (CO), 136.7 (C, Ar), 133.2 (CH, Ar), 131.1 (C, Ar), 130.5 (C, Ar), 129.9 (CH, Ar), 129.7 (CH,
Ar), 128.0 (CH, Ar), 126.9 (CH, Ar), 119.4 (CH, Ar), 115.7 (C, Ar), 95.7 (C), 32.3 (CH2), 29.6 (CH2), 25.7
(CH3); ESI-LRMS m/z: 268 [M + H]+; ESI-HRMS m/z calcd for M + H+ 268.0968, found: 268.0962.
The characterization data is in accordance with that reported in [35].
4a-Methyl-2,3,4,4a-tetrahydronaphtho[2,3-d]pyrido[2,1-b][1,3]oxazine-1,6-dione (SF39): pale yellow oil
1
(103.7 mg, yield 74%). H-NMR (600 MHz, CDCl3)
δ 1.64 (s, 3H), 1.94–1.87 (m, 1H), 2.22–2.12 (m, 2H),
2.52–2.46 (m, 1H), 2.74–2.61 (m, 2H), 7.57–7.53 (m, 1H), 7.66–7.61 (m, 1H), 7.90 (d, J = 8.3 Hz, 1H), 7.96
(d, J = 8.2 Hz, 1H), 8.22 (s, 1H), 8.67 (s, 1H); 13C-NMR (150 MHz, CDCl3)
δ
169.3 (CO), 163.3 (CO),
135.9 (C, Ar), 133.0 (C, Ar), 131.8 (CH, Ar), 130.8 (C, Ar), 129.6 (CH, Ar), 129.5 (CH, Ar), 128.2 (CH,
Ar), 127.1 (CH, Ar), 124.9 (CH, Ar), 119.2 (C, Ar), 92.5 (C), 36.3 (CH2), 33.7 (CH2), 27.7 (CH3), 16.7
(CH2); ESI-LRMS m/z: 282 [M + H]+; ESI-HRMS m/z calcd for M + H+ 282.1125, found: 282.1117.
The characterization data is in accordance with that reported in [43].
4b-Methyl-4bH-naphtho[2’,3’:4,5][1,3]oxazino[2,3-a]isoindole-6,14-dione (SF40): white solid (113.2 mg,
yield 72%), mp 210–212 ◦C. 1H-NMR (600 MHz, CDCl3)
δ
1.98 (s, 3H), 7.58–7.54 (m, 1H), 7.69–7.64
(m, 2H), 7.78–7.74 (m, 1H), 7.81–7.79 (m, 1H), 8.02–7.95 (m, 3H), 8.49 (s, 1H), 8.79 (s, 1H); 13C-NMR
(150 MHz, CDCl3) 164.7 (CO), 162.4 (CO), 144.0 (C, Ar), 136.9 (C, Ar), 133.9 (CH, Ar), 133.5 (CH,
δ
Ar), 131.1 (CH, Ar), 130.9 (C, Ar), 130.4 (C, Ar), 130.3 (C, Ar), 130.0 (CH, Ar), 129.9 (CH, Ar), 128.0
(CH, Ar), 126.8 (CH, Ar), 124.8 (CH, Ar), 122.6 (CH, Ar), 119.4 (CH, Ar), 115.0 (C, Ar), 92.7 (C), 25.0
(CH3); ESI-LRMS m/z: 316 [M + H]+; ESI-HRMS m/z calcd for M + H+ 316.0968, found: 316.0959.
The characterization data is in accordance with that reported in [43].
6a-Methyl-7,8-dihydro-5H-pyrido[2,3-d]pyrrolo[2,1-b][1,3]oxazine-5,9(6aH)-dione (SF41): colorless oil (65.1
mg, yield 60%). 1H-NMR (600 MHz, CDCl3)
δ
1.72 (s, 3H), 2.52–2.41 (m, 1H), 2.68–2.60 (m, 1H),
2.86–2.69 (m, 2H), 7.36 (dd, J = 7.7, 4.9 Hz, 1H), 8.42 (dd, J = 7.7, 1.9 Hz, 1H), 8.81 (dd, J = 4.9, 1.9 Hz,
1H); 13C-NMR (150 MHz, CDCl3)
171.6 (CO), 161.3 (CO), 155.1 (CH, Ar), 149.1 (C, Ar), 139.4 (CH,
δ
Ar), 122.0 (CH, Ar), 113.0 (C, Ar), 96.1 (C), 32.3 (CH2), 29.8 (CH2), 25.4 (CH3); ESI-LRMS m/z: 219
[M + H]+; ESI-HRMS m/z calcd for M + H+ 219.0764, found: 219.0763. The characterization data is in
accordance with that reported in [35].
3a-Methyl-2,3,3a,5-tetrahydro-1H-benzo[d]pyrrolo[2,1-b][1,3]oxazin-1-one (SF42): pale yellow oil (33.8 mg,
1
yield 33%). H-NMR (500 MHz, DMSO-d6)
δ 1.45 (s, 3H), 2.07–1.97 (m, 1H), 2.29–2.19 (m, 1H), 2.43
(ddd, J = 17.1, 10.0, 2.1 Hz, 1H), 2.76–2.65 (m, 1H), 4.88 (d, J = 16.0 Hz, 1H), 4.99 (d, J = 16.0 Hz, 1H),
7.16–7.10 (m, 1H), 7.21–7.16 (m, 1H), 7.32–7.25 (m, 1H), 8.20 (d, J = 8.1 Hz, 1H); 13C-NMR (125 MHz,
DMSO-d6)
δ 170.9 (CO), 132.6 (C, Ar), 127.1 (CH, Ar), 124.7 (CH, Ar), 123.7 (CH, Ar), 123.2 (C, Ar),
119.2 (CH, Ar), 89.6 (C), 62.0 (CH2), 32.5 (CH2), 29.7 (CH2), 20.7 (CH3); ESI-LRMS m/z: 204 [M + H]+;
ESI-HRMS m/z calcd for M + H+ 204.1019, found: 204.1017. The characterization data is in accordance
with that reported in [43].
6a-Methyl-5H-benzo[4,5][1,3]oxazino[2,3-a]isoindol-11(6aH)-one (SF43): colorless oil (22.4 mg, yield 18%).
1H-NMR (600 MHz, CDCl3)
δ
1.74 (s, 3H), 4.98 (d, J = 15.3 Hz, 1H), 5.20 (d, J = 15.3 Hz, 1H), 7.14–7.10
(m, 1H), 7.19–7.15 (m, 1H), 7.40–7.35 (m, 1H), 7.59–7.54 (m, 1H), 7.68–7.60 (m, 2H), 7.91 (d, J = 7.5 Hz,
1H), 8.25 (d, J = 8.2 Hz, 1H); 13C-NMR (150 MHz, CDCl3)
165.2 (CO), 146.1 (C, Ar), 133.1 (CH, Ar),
132.6 (C, Ar), 131.2 (C, Ar), 130.2 (CH, Ar), 127.9 (CH, Ar), 124.3 (2 CH, Ar), 124.2 (CH, Ar), 123.0
(C, Ar), 121.8 (CH, Ar), 121.5 (CH, Ar), 88.1 (C), 63.3 (CH2), 20.8 (CH3); ESI-LRMS m/z: 252 [M + H]+;
δ
×

Molecules 2019, 24, 988
25 of 30
ESI-HRMS m/z calcd for M + H+ 252.1019, found: 252.1018. The characterization data is in accordance
with that reported in [43].
3.4. General Procedure of the Reductive Preparation of Compounds SF47–SF55
To a solution of substrates (0.3 mmol) in dry THF was added AlCl3 (0.6 mmol), then LiAlH4
(0.6 mmol) was added portionwise at 0 ◦C. After that, the mixture was heated to reflux for 4 h. After
the reaction was cooled, the rea◦ction mixture was diluted with dichloromethane (120.0 mL), and then
water was added dropwise at 0 C to quench the reaction under vigorous stirring conditions. The solid
which precipitated out was removed by filtration, and the organic layer obtained was dried over
Na2SO4. After the removal of the solvents in vacuo, the residue was purified to give SF47–SF55.
11b-Methyl-2,3,5,6,11,11b-hexahydro-1H-indolizino[8,7-b]indole (SF47): pale yellow oil (40.5 mg, yield
1
60%). H-NMR (400 MHz, DMSO-d6)
δ 1.67–1.54 (m, 1H), 1.80 (s, 3H), 2.04–1.93 (m, 1H), 2.20–2.08
(m, 1H), 2.94–2.85 (m, 1H), 3.07–2.96 (m, 1H), 3.30–3.22 (m, 2H), 3.56–3.47 (m, 3H), 7.05–6.99 (m, 1H),
7.15–7.09 (m, 1H), 7.35 (d, J = 8.1 Hz, 1H), 7.47 (d, J = 7.8 Hz, 1H), 11.28 (s, 1H); 13C-NMR (125 MHz,
DMSO-d6)
δ 136.3 (C, Ar), 125.7 (C, Ar), 121.8 (CH, Ar), 119.0 (CH, Ar), 118.3 (CH, Ar), 111.3 (CH, Ar),
104.5 (C, Ar), 48.9 (CH2), 42.5 (CH2), 36.4 (CH2), 24.1 (CH3), 21.0 (CH2), 15.3 (CH2); ESI-LRMS m/z:
227 [M + H]+; ESI-HRMS m/z calcd for M + H+ 227.1543, found: 227.1540.
13b-Methyl-7,8,13,13b-tetrahydro-5H-benzo[1,2]indolizino[8,7-b]indole (SF48a): pale yellow solid (52.3 mg,
yield 64%), mp 204–206 ◦C. 1H-NMR (400 MHz, CDCl3)
δ
1.95 (s, 3H), 2.62–2.53 (m, 1H), 3.28–3.13
(m, 1H), 3.54–3.38 (m, 2H), 4.27–4.18 (m, 2H), 7.13–7.03 (m, 2H), 7.21–7.13 (m, 2H), 7.31–7.22 (m, 2H),
7.85–7.74 (m, 2H), 7.93 (s, 1H); 13C-NMR (125 MHz, DMSO-d6)
135.5 (C, Ar), 131.8 (C, Ar), 126.5 (CH,
δ
Ar), 126.4 (CH, Ar), 124.9 (C, Ar), 122.8 (CH, Ar), 122.4 (CH, Ar), 120.2 (CH, Ar), 119.0 (CH, Ar), 118.3
(CH, Ar), 110.8 (CH, Ar), 52.7 (CH2), 41.0 (CH2), 26.2 (CH3), 17.1 (CH2); ESI-LRMS m/z: 275 [M + H]+;
ESI-HRMS m/z calcd for M + H+ 275.1543, found: 275.1541. The characterization data is in accordance
with that reported in [43].
10-Methoxy-13b-methyl-7,8,13,13b-tetrahydro-5H-benzo[1,2]indolizino[8,7-b]indole (SF48b): pale yellow oil
1
(59.2 mg, yield 65%). H-NMR (400 MHz, CDCl3)
δ
1.86 (s, 3H), 2.60 (ddd, J = 15.8, 4.3, 1.4 Hz, 1H),
3.13 (ddd, J = 16.2, 11.1, 6.4 Hz, 1H), 3.54–3.43 (m, 2H), 3.84 (s, 3H), 4.26–4.15 (m, 2H), 6.78 (dd, J = 8.7,
2.5 Hz, 1H), 6.93 (d, J = 2.4 Hz, 1H), 7.15 (d, J = 8.7 Hz, 1H), 7.25–7.18 (m, 2H), 7.33–7.27 (m, 1H), 7.45
(d, J = 7.4 Hz, 1H), 7.60 (s, 1H); 13C-NMR (100 MHz, CDCl3)
δ 154.2 (C, Ar), 144.9 (C, Ar), 139.0 (C, Ar),
137.8 (C, Ar), 131.3 (C, Ar), 127.7 (CH, Ar), 127.7 (C, Ar), 127.4 (CH, Ar), 123.4 (CH, Ar), 121.1 (CH,
Ar), 111.7 (CH, Ar), 111.7 (CH, Ar), 106.9 (C, Ar), 100.9 (CH, Ar), 65.0 (C), 56.1 (OCH3), 53.2 (CH2),
41.7 (CH2), 26.0 (CH3), 16.4 (CH2); ESI-LRMS m/z: 305 [M + H]+; ESI-HRMS m/z calcd for M + H+
305.1648, found: 305.1645. The characterization data is in accordance with that reported in [43].
14b-Methyl-5,6,8,9,14,14b-hexahydroindolo[2’,3’:3,4]pyrido[2,1-a]isoquinoline (SF49): pale yellow oil (60.2
mg, yield 70%). 1H-NMR (400 MHz, CDCl3)
δ 1.95 (s, 3H), 2.85–2.66 (m, 2H), 3.07–2.91 (m, 2H),
3.14–3.07 (m, 1H), 3.19–3.15 (m, 1H), 3.26 (ddd, J = 13.8, 6.1, 2.6 Hz, 1H), 3.76 (ddd, J = 13.9, 10.0, 5.8 Hz,
1H), 7.19–7.05 (m, 3H), 7.25–7.20 (m, 1H), 7.31–7.27 (m, 1H), 7.37–7.31 (m, 1H), 7.49 (d, J = 7.6 Hz, 1H),
7.65 (d, J = 7.8 Hz, 1H), 7.87 (s, 1H); 13C-NMR (100 MHz, CDCl3)
δ140.0 (C, Ar), 137.5 (C, Ar), 135.8 (C,
Ar), 134.5 (C, Ar), 130.1 (CH, Ar), 127.7 (C, Ar), 126.8 (CH, Ar), 126.6 (CH, Ar), 126.0 (CH, Ar), 121.8
(CH, Ar), 119.6 (CH, Ar), 118.5 (CH, Ar), 111.0 (CH, Ar), 105.9 (C, Ar), 58.3 (C), 46.8 (CH2), 45.5 (CH2),
30.4 (CH3), 28.8 (CH2), 17.9 (CH2); ESI-LRMS m/z: 289 [M + H]+; ESI-HRMS m/z calcd for M + H+
289.1699, found: 289.1695. The characterization data is in accordance with that reported in [43].
11c-Methyl-2,3,5,6,7,11c-hexahydro-1H-indolizino[7,8-b]indole (SF50): pale yellow solid (62.2 mg, yield
92%), mp 249–250 ◦C. 1H-NMR (400 MHz, DMSO-d6)
δ 1.66–1.51 (m, 1H), 1.82 (s, 3H), 2.04–1.92 (m,
1H), 2.27–2.15 (m, 1H), 2.61–2.52 (m, 1H), 3.02–2.87 (m, 1H), 3.24–3.13 (m, 1H), 3.31–3.25 (m, 1H),
3.60–3.44 (m, 3H), 7.04–6.97 (m, 1H), 7.13–7.07 (m, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 7.9 Hz, 1H),
11.24 (s, 1H); 13C-NMR (125 MHz, DMSO-d6)
δ 136.2 (C, Ar), 129.5 (C, Ar), 123.3 (C, Ar), 121.3 (CH,

Molecules 2019, 24, 988
26 of 30
Ar), 119.0 (CH, Ar), 118.0 (CH, Ar), 111.4 (CH, Ar), 48.7 (CH2), 41.8 (CH2), 36.1 (CH2), 24.3 (CH3), 21.2
(CH2), 16.8 (CH2); ESI-LRMS m/z: 227 [M + H]+; ESI-HRMS m/z calcd for M + H+ 227.1543, found:
227.1541.
14c-Methyl-5,6,8,9,10,14c-hexahydroindolo[3’,2’:3,4]pyrido[2,1-a]isoquinoline (SF51): pale yellow oil (63.5
1
mg, yield 73%). H-NMR (600 MHz, CDCl3)
δ 2.21 (s, 3H), 2.82–2.75 (m, 1H), 2.97 (dd, J = 17.9, 6.5 Hz,
1H), 3.23–3.17 (m, 1H), 3.32–3.27 (m, 2H), 3.42–3.38 (m, 1H), 3.50–3.43 (m, 1H), 4.15–4.07 (m, 1H),
7.10–7.05 (m, 2H), 7.14–7.10 (m, 2H), 7.20–7.16 (m, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.65 (d, J = 7.9 Hz,
1H), 7.79 (d, J = 7.9 Hz, 1H), 9.64 (s, 1H); 13C-NMR (150 MHz, CDCl3)
δ
142.9 (C, Ar), 136.6 (C, Ar),
132.7 (C, Ar), 131.2 (C, Ar), 129.2 (CH, Ar), 128.1 (CH, Ar), 127.3 (C, Ar), 126.3 (2 CH, Ar), 120.8
×
(CH, Ar), 120.7 (CH, Ar), 119.5 (CH, Ar), 115.3 (C, Ar), 111.2 (CH, Ar), 59.8 (C), 45.8 (CH2), 45.3 (CH2),
29.9 (CH3), 23.6 (CH2), 23.1 (CH2); ESI-LRMS m/z: 289 [M + H]+; ESI-HRMS m/z calcd for M + H+
289.1699, found: 289.1698.
15b-Methyl-6,8,9,15b-tetrahydro-5H-indolo[2’,1’:3,4]pyrazino[2,1-a]isoquinoline (SF52): pale yellow oil (34.3
mg, yield 40%). 1H-NMR (600 MHz, CDCl3)
δ 1.94 (s, 3H), 2.92–2.83 (m, 1H), 3.07–2.99 (m, 1H),
3.17–3.09 (m, 1H), 3.40–3.32 (m, 1H), 3.55–3.47 (m, 1H), 3.63–3.56 (m, 1H), 4.08–4.01 (m, 1H), 4.15–4.10
(m, 1H), 6.55 (s, 1H), 7.15–7.10 (m, 2H), 7.20–7.15 (m, 3H), 7.27 (d, J = 8.0 Hz, 1H), 7.63–7.57 (m, 2H);
13C-NMR (150 MHz, CDCl3)
δ 140.9 (C, Ar), 139.8 (C, Ar), 136.7 (C, Ar), 132.8 (C, Ar), 129.5 (CH, Ar),
128.0 (C, Ar), 127.8 (CH, Ar), 126.6 (CH, Ar), 126.1 (CH, Ar), 121.2 (CH, Ar), 120.3 (CH, Ar), 120.1 (CH,
Ar), 109.1 (CH, Ar), 100.6 (CH, Ar), 59.2 (C), 45.7 (CH2), 45.6 (CH2), 40.4 (CH2), 31.5 (CH3), 25.3 (CH2);
ESI-LRMS m/z: 289 [M + H]+; ESI-HRMS m/z calcd for M + H+ 289.1699, found: 289.1696.
11b-Methyl-4,5,7,11b-tetrahydro-3H-pyrrolo[3’,2’:3,4]pyrido[2,1-a]isoindole (SF53): pale yellow oil (57.2 mg,
1
yield 85%). H-NMR (600 MHz, CDCl3)
δ
1.78 (s, 3H), 3.07–2.97 (m, 1H), 3.49–3.36 (m, 2H), 3.72–3.65
(m, 1H), 4.18–4.11 (m, 1H), 4.28–4.20 (m, 1H), 6.08–6.04 (m, 1H), 6.62–6.58 (m, 1H), 7.19–7.14 (m, 2H),
7.29–7.23 (m, 1H), 7.45–7.40 (m, 1H), 7.83 (s, 1H); 13C-NMR (150 MHz, CDCl3)
148.1 (C, Ar), 137.8 (C,
δ
Ar), 127.2 (CH, Ar), 126.8 (CH, Ar), 122.9 (C, Ar), 122.7 (CH, Ar), 121.9 (1CH + 1C, Ar), 116.6 (CH, Ar),
105.2 (CH, Ar), 65.8 (C), 53.5 (CH2), 42.1 (CH2), 28.2 (CH3), 17.2 (CH2); ESI-LRMS m/z: 225 [M + H]+;
ESI-HRMS m/z calcd for M + H+ 225.1386, found: 225.1385.
11b-Methyl-4,5,7,11b-t◦etrahydrothieno[3’,2’:3,4]pyrido[2,1-a]isoindole (SF54): pale yellow solid (57.9 mg,
δ 1.76 (s, 3H), 2.60 (ddd, J = 16.5, 4.4, 1.5 Hz, 1H),
yield 80%), mp 73–74 C. 1H-NMR (600 MHz, CDCl3)
3.22–3.13 (m, 1H), 3.49–3.38 (m, 2H), 4.20–4.12 (m, 2H), 6.94 (d, J = 5.2 Hz, 1H), 7.00 (dd, J = 5.3, 0.7 Hz,
1H), 7.21–7.17 (m, 2H), 7.28–7.25 (m, 1H), 7.45 (d, J = 7.6 Hz, 1H); 13C-NMR (150 MHz, CDCl3)
146.7
(C, Ar), 139.5 (C, Ar), 138.6 (C, Ar), 132.4 (C, Ar), 127.1 (2 CH, Ar), 125.6 (CH, Ar), 122.8 (CH, Ar),
δ
×
122.3 (CH, Ar), 122.1 (CH, Ar), 67.0 (C, Ar), 53.6 (CH2), 42.1 (CH2), 27.9 (CH3), 19.2 (CH2); ESI-LRMS
m/z: 242 [M + H]+; ESI-HRMS m/z calcd for M + H+ 242.0998, found: 242.0997.
11b-Methyl-4,5,7,11b-tetrahydrothieno[2’,3’:3,4]pyrido[2,1-a]isoindole (SF55): yellow oil (68.6 mg, yield
1
95%). H-NMR (600 MHz, CDCl3)
δ 1.85 (s, 3H), 2.47 (ddd, J = 16.4, 4.5, 1.4 Hz, 1H), 3.07–2.97 (m, 1H),
3.45–3.30 (m, 2H), 4.22–4.12 (m, 2H), 6.69 (d, J = 5.1 Hz, 1H), 7.11 (d, J = 5.0 Hz, 1H), 7.18–7.16 (m, 1H),
7.21–7.18 (m, 1H), 7.30–7.26 (m, 1H), 7.46 (d, J = 7.6 Hz, 1H); 13C-NMR (150 MHz, CDCl3)
147.2 (C,
Ar), 142.4 (C, Ar), 138.4 (C, Ar), 132.5 (C, Ar), 127.3 (2 CH, Ar), 126.9 (CH, Ar), 123.1 (CH, Ar), 122.8
δ
×
(CH, Ar), 122.1 (CH, Ar), 67.0 (C), 53.7 (CH2), 41.8 (CH2), 29.8 (CH3), 20.2 (CH2); ESI-LRMS m/z: 242
[M + H]+; ESI-HRMS m/z calcd for M + H+ 242.0998, found: 242.0997.
4. Conclusions
In conclusion, a green and general tandem reaction between alkynoic acids and amine
nucleophiles through gold catalysis in water has been developed. This process proceeds with high
efficiency leading to the formation of two rings and three new bonds in a single operation. This
approach features low catalyst loading, good to excellent yields, high efficiency in bond formation,
high step economy, excellent selectivity, great functional group tolerance, and extraordinarily

Molecules 2019, 24, 988
27 of 30
broad substrate scope, and has been successfully employed to construct a high-quality library of
indole/thiophene/pyrrole/pyridine/naphthalene/benzene-fused N-heterocycles. In addition, five
antimicrobial compounds were discovered from the library, suggesting the value of our strategy to
identify APIs. This is the first example of the generation of pDOS compound library encompassing
skeletal diversity, molecular complexity, and drug-like properties from readily available materials
through gold catalysis in water. We anticipate that these valuable N-heterocycles will find more
pharmaceutical applications after our further investigations.
Supplementary Materials: The following are available online. Table S1: Survey of the solvents on the yield
of product SF1a, Figures S1–S12: NMR (1H-NMR, 13C-NMR, HSQC, HMBC, and 1H-1H COSY) and ESI(+)MS
spectrum of SF5a
,
[D]n-SF5a
,
SF5b
,
[D]n-SF5b
, SF1a, and [D]n-SF1a. Figure S13: preliminary screening of
antibacterial activities of compounds at 100
µ
g/mL. Figures S14–S19: time-kill results of SF9d
,
SF29b
,
SF33
,
SF36
,
and SF41 against S. aureus strain. Figures S20–S24: CFU results of compounds SF9d
,
SF29b
,
SF33 SF36 and SF41
,
;
copies of 1H and 13C-NMR spectra of new compounds.
Author Contributions: Conceptualization, H.L. and F.Z.; Methodology, X.J. and X.L.; Formal Analysis, J.Y., J.L.,
and F.Z.; Investigation, X.J., P.L., and J.L.; Resources, Y.C. and X.L.; Writing—Original Draft Preparation, J.L. and
F.Z.; Writing—Review and Editing, F.Z., J.W., and H.L.; Visualization, F.Z.; Supervision, H.L. and F.Z.; Project
Administration, F.Z.; Funding Acquisition, J.L., H.L., and F.Z.
Funding: This research was funded by the National Natural Science Foundation of China (grants 21602022,
81620108027, and 21632008), the Major Project of Chinese National Programs for Fundamental Research
and Development (grant 2015CB910304), Sichuan Science and Technology Program (grants 2018JY0345
and 2018HH007), and Chengdu Municipal Government Program of Science and Technology (grant
2016-XT00-00023-GX). The APC was funded by Chengdu University New Faculty Start-up Funding (grant
2081915037).
Acknowledgments: F.Z. gratefully acknowledges the support from the 1000 Talents Program of Sichuan Province
and Chengdu Talents Program.
Conflicts of Interest: The authors declare no conflict of interest.
References
1.
2.
3.
Yarmush, M.L.; Jayaraman, A. Advances in proteomic technologies. Annu. Rev. Biomed. Eng. 2002, 4, 349–373.
[CrossRef] [PubMed]
Aebersold, R.; Cravatt, B.F. Proteomics–advances, applications and the challenges that remain. Trends
Biotechnol. 2002, 20, S1–S2. [CrossRef]
Yee, A.; Pardee, K.; Christendat, D.; Savchenko, A.; Edwards, A.M.; Arrowsmith, C.H. Structural proteomics:
Toward high-throughput structural biology as a tool in functional genomics. Acc. Chem. Res. 2003, 36,
183–189. [CrossRef] [PubMed]
4.
5.
6.
7.
8.
9.
Cottingham, K. Government & society: New cancer center will focus on proteomics and genomics. J. Proteome
Res. 2007, 6, 3369.
Yates, J.R.; Osterman, A.L. Introduction: Advances in genomics and proteomics. Chem. Rev. 2007, 107,
3363–3366.
Bleicher, K.H.; Böhm, H.J.; Müller, K.; Alanine, A.I. A guide to drug discovery: Hit and lead generation:
Beyond high-throughput screening. Nat. Rev. Drug Discov. 2003, 2, 369–378. [CrossRef] [PubMed]
Drewry, D.H.; Macarron, R. Enhancements of screening collections to address areas of unmet medical need:
An industry perspective. Curr. Opin. Chem. Biol. 2010, 14, 289–298. [CrossRef] [PubMed]
Dandapani, S.; Marcaurelle, L.A. Grand challenge commentary: Accessing new chemical space for
‘undruggable’ targets. Nat. Chem. Biol. 2010, 6, 861–863. [CrossRef] [PubMed]
Sauer, W.H.B.; Schwarz, M.K. Molecular shape diversity of combinatorial libraries: A prerequisite for broad
bioactivity. J. Chem. Inf. Comput. Sci. 2003, 43, 987–1003. [CrossRef] [PubMed]
10. Haggarty, S.J. The principle of complementarity: Chemical versus biological space. Curr. Opin. Chem. Biol.
2005, 9, 296–303. [CrossRef] [PubMed]
11. Quinn, R.J.; Carroll, A.R.; Pham, N.B.; Baron, P.; Palframan, M.E.; Suraweera, L.; Pierens, G.K.; Muresan, S.
Developing a drug-like natural product library. J. Nat. Prod. 2008, 71, 464–468. [CrossRef] [PubMed]
12. Camp, D.; Davis, R.A.; Campitelli, M.; Ebdon, J.; Quinn, R.J. Drug-like properties: Guiding principles for the
design of natural product libraries. J. Nat. Prod. 2012, 75, 72–81. [CrossRef] [PubMed]

Molecules 2019, 24, 988
28 of 30
13. Dandapani, S.; Rosse, G.; Southall, N.; Salvino, J.M.; Thomas, C.J. Selecting, acquiring, and using small
molecule libraries for high-throughput screening. Curr. Protoc. Chem. Biol. 2012, 4, 177–191. [PubMed]
14. Rzuczek, S.G.; Southern, M.R.; Disney, M.D. Studying a drug-like, RNA-focused small molecule library
identifies compounds that inhibit RNA toxicity in myotonic dystrophy. ACS Chem. Biol. 2015, 10, 2706–2715.
[CrossRef] [PubMed]
15. Evans, B.E.; Rittle, K.E.; Bock, M.G.; DiPardo, R.M.; Freidinger, R.M.; Whitter, W.L.; Lundell, G.F.; Veber, D.F.;
Anderson, P.S.; Chang, R.S.L.; et al. Methods for drug discovery: Development of potent, selective, orally
effective cholecystokinin antagonists. J. Med. Chem. 1988, 31, 2235–2246. [CrossRef] [PubMed]
16. Horton, D.A.; Bourne, G.T.; Smythe, M.L. The combinatorial synthesis of bicyclic privileged structures or
privileged substructures. Chem. Rev. 2003, 103, 893–930. [CrossRef] [PubMed]
17. DeSimone, R.W.; Currie, K.S.; Mitchell, S.A.; Darrow, J.W.; Pippin, D.A. Privileged structures: Applications
in drug discovery. Comb. Chem. High Throughput Screen. 2004, 7, 473–494. [CrossRef] [PubMed]
18. Welsch, M.E.; Snyder, S.A.; Stockwell, B.R. Privileged scaffolds for library design and drug discovery.
Curr. Opin. Chem. Biol. 2010, 14, 347–361. [CrossRef] [PubMed]
19. González, J.F.; Ortín, I.; de la Cuesta, E.; Menéndez, J.C. Privileged scaffolds in synthesis:
2,5-piperazinediones as templates for the preparation of structurally diverse heterocycles. Chem. Soc.
Rev. 2012, 41, 6902–6915. [CrossRef] [PubMed]
20. Schreiber, S.L. Target-oriented and diversity-oriented organic synthesis in drug discovery. Science 2000, 287,
1964–1969. [CrossRef] [PubMed]
21. Reayi, A.; Arya, P. Natural product-like chemical space: Search for chemical dissectors of macromolecular
interactions. Curr. Opin. Chem. Biol. 2005, 9, 240–247. [CrossRef] [PubMed]
22. Spandl, R.J.; Bender, A.; Spring, D.R. Diversity-oriented synthesis; a spectrum of approaches and results.
Org. Biomol. Chem. 2008, 6, 1149–1158. [CrossRef] [PubMed]
23. Oh, S.; Park, S.B. A design strategy for drug-like polyheterocycles with privileged substructures for discovery
of specific small-molecule modulators. Chem. Commun. 2011, 47, 12754–12761. [CrossRef] [PubMed]
24. Liu, H. Construction of biologically potential library by diversity-oriented synthesis. Org. Chem. Curr. Res.
2013, 2, 1000e123. [CrossRef]
25. Kim, H.; Tung, T.T.; Park, S.B. Privileged substructure-based diversity-oriented synthesis pathway for diverse
pyrimidine-embedded polyheterocycles. Org. Lett. 2013, 15, 5814–5817. [CrossRef] [PubMed]
26. Kim, J.; Jung, J.; Koo, J.; Cho, W.; Lee, W.S.; Kim, C.; Park, W.; Park, S.B. Diversity-oriented synthetic strategy
for developing a chemical modulator of protein–protein interaction. Nat. Commun. 2016, 7, 13196. [CrossRef]
[PubMed]
27. Zhang, X.; Ye, D.; Sun, H.; Guo, D.; Wang, J.; Huang, H.; Zhang, X.; Jiang, H.; Liu, H. Microwave-assisted
synthesis of quinazolinone derivatives by efficient and rapid iron-catalyzed cyclization in water. Green Chem.
2009, 11, 1881–1888. [CrossRef]
28. Ye, D.; Wang, J.; Zhang, X.; Zhou, Y.; Ding, X.; Feng, E.; Sun, H.; Liu, G.; Jiang, H.; Liu, H. Gold-catalyzed
intramolecular hydroamination of terminal alkynes in aqueous media: Efficient and regioselective synthesis
of indole-1-carboxamides. Green Chem. 2009, 11, 1201–1208. [CrossRef]
29. Zhou, Y.; Zhai, Y.; Li, J.; Ye, D.; Jiang, H.; Liu, H. Metal-free tandem reaction in water: An efficient and
regioselective synthesis of 3-hydroxyisoindolin-1-ones. Green Chem. 2010, 12, 1397–1404. [CrossRef]
30. Zhang, X.; Zhou, Y.; Wang, H.; Guo, D.; Ye, D.; Xu, Y.; Jiang, H.; Liu, H. Silver-catalyzed intramolecular
hydroamination of alkynes in aqueous media: Efficient and regioselective synthesis for fused benzimidazoles.
Green Chem. 2011, 13, 397–405. [CrossRef]
31. Xu, S.; Zhou, Y.; Xu, J.; Jiang, H.; Liu, H. Gold-catalyzed Michael addition/intramolecular annulation cascade:
An effective pathway for the chemoselective- and regioselective synthesis of tetracyclic indole derivatives in
water. Green Chem. 2013, 15, 718–726. [CrossRef]
32. Yang, T.; Campbell, L.; Dixon, D.J. A Au(I)-catalyzed N-acyl iminium ion cyclization cascade. J. Am.
Chem. Soc. 2007, 129, 12070–12071. [CrossRef] [PubMed]
33. Muratore, M.E.; Holloway, C.A.; Pilling, A.W.; Storer, R.I.; Trevitt, G.; Dixon, D.J. Enantioselective Brønsted
acid-catalyzed N-acyliminium cyclization cascades. J. Am. Chem. Soc. 2009, 131, 10796–10797. [CrossRef]
[PubMed]

Molecules 2019, 24, 988
29 of 30
34. Patil, N.T.; Mutyala, A.K.; Lakshmi, P.G.V.V.; Gajula, B.; Sridhar, B.; Pottireddygari, G.R.; Rao, T.P.
Au(I)-catalyzed cascade reaction involving formal double hydroamination of alkynes bearing tethered
carboxylic groups: An easy access to fused dihydrobenzimidazoles and tetrahydroquinazolines. J. Org.
Chem. 2010, 75, 5963–5975. [CrossRef] [PubMed]
35. Feng, E.; Zhou, Y.; Zhang, D.; Zhang, L.; Sun, H.; Jiang, H.; Liu, H. Gold(I)-catalyzed tandem
transformation: A simple approach for the synthesis of pyrrolo/pyrido[2,1-a][1,3]benzoxazinones and
pyrrolo/pyrido[2,1-a]quinazolinones. J. Org. Chem. 2010, 75, 3274–3282. [CrossRef] [PubMed]
36. Zhou, Y.; Zhai, Y.; Ji, X.; Liu, G.; Feng, E.; Ye, D.; Zhao, L.; Jiang, H.; Liu, H. Gold(I)-catalyzed one-pot tandem
coupling/cyclization: An efficient synthesis of pyrrolo-/pyrido[2,1-b]benzo[d][1,3]oxazin-1-ones. Adv. Synth.
Catal. 2010, 352, 373–378. [CrossRef]
37. Zhou, Y.; Li, J.; Ji, X.; Zhou, W.; Zhang, X.; Qian, W.; Jiang, H.; Liu, H. Silver- and gold-mediated domino
transformation: A strategy for synthesizing benzo[e]indolo[1,2-a]pyrrolo/pyrido[2,1-c][1,4]diazepine-3,9-
diones. J. Org. Chem. 2011, 76, 1239–1249. [CrossRef] [PubMed]
38. Patil, N.T.; Lakshmi, P.G.V.V.; Sridhar, B.; Patra, S.; Bhadra, M.P.; Patra, C.R. New linearly and angularly
fused quinazolinones: Synthesis through gold(I)-catalyzed cascade reactions and anticancer activities. Eur. J.
Org. Chem. 2012, 1790–1799. [CrossRef]
39. Li, Z.; Li, J.; Yang, N.; Chen, Y.; Zhou, Y.; Ji, X.; Zhang, L.; Wang, J.; Xie, X.; Liu, H. Gold(I)-catalyzed cascade
approach for the synthesis of tryptamine-based polycyclic privileged scaffolds as α1-adrenergic receptor
antagonists. J. Org. Chem. 2013, 78, 10802–10811. [CrossRef] [PubMed]
40. Ji, X.; Zhou, Y.; Wang, J.; Zhao, L.; Jiang, H.; Liu, H. Au(I)/Ag(I)-catalyzed cascade approach for the synthesis
of benzo[4,5]imidazo[1,2-c]pyrrolo[1,2-a]quinazolinones. J. Org. Chem. 2013, 78, 4312–4318. [CrossRef]
[PubMed]
41. Patil, N.T.; Shinde, V.S.; Sridhar, B. Relay catalytic branching cascade: A technique to access diverse molecular
scaffolds. Angew. Chem. Int. Ed. 2013, 52, 2251–2255. [CrossRef] [PubMed]
42. Naidu, S.; Reddy, S.R. Copper-catalyzed tandem reaction in ionic liquid: An efficient reusable catalyst and
solvent media for the synthesis of fused poly hetero cyclic compounds. RSC Adv. 2016, 6, 62742–62746.
[CrossRef]
43. Qiao, J.; Jia, X.; Li, P.; Liu, X.; Zhao, J.; Zhou, Y.; Wang, J.; Liu, H.; Zhao, F. Gold-catalyzed rapid construction
of nitrogen-containing heterocyclic compound library with scaffold diversity and molecular complexity.
Adv. Synth. Catal. 2019, 361. [CrossRef]
44. Zhou, Y.; Ji, X.; Liu, G.; Zhang, D.; Zhao, L.; Jiang, H.; Liu, H. Gold(I)-catalyzed cascade for synthesis of
pyrrolo[1,2-a:20,10-c]-/Pyrido[2,1-c]pyrrolo[1,2-a]quinoxalinones. Adv. Synth. Catal. 2010, 352, 1711–1717.
[CrossRef]
45. Feng, E.; Zhou, Y.; Zhao, F.; Chen, X.; Zhang, L.; Jiang, H.; Liu, H. Gold-catalyzed tandem reaction in
water: An efficient and convenient synthesis of fused polycyclic indoles. Green Chem. 2012, 14, 1888–1895.
[CrossRef]
46. Aplander, K.; Hidestal, O.; Katebzadeh, K.; Lindstrom, U.M. A green and facile route to
γ- and δ-lactones
via efficient Pinner-cyclization of hydroxynitriles in water. Green Chem. 2006, 8, 22–24. [CrossRef]
47. Li, C.J.; Chen, L. Organic chemistry in water. Chem. Soc. Rev. 2006, 35, 68–82. [CrossRef] [PubMed]
48. Chanda, A.; Fokin, V.V. Organic synthesis “on water”. Chem. Rev. 2009, 109, 725–748. [CrossRef] [PubMed]
49. Kumaravel, K.; Vasuki, G. Multi-component reactions in water. Curr. Org. Chem. 2009, 13, 1820–1841.
[CrossRef]
50. Gupta, M.; Paul, S.; Gupta, R. General aspects of 12 basic principles of green chemistry with applications.
Curr. Sci. 2010, 99, 1341–1360.
51. Butler, R.N.; Coyne, A.G. Water: Nature’s reaction enforcer—Comparative effects for organic synthesis
“in-water” and “on-water”. Chem. Rev. 2010, 110, 6302–6337. [CrossRef] [PubMed]
52. Hashmi, A.S.K. Gold-catalyzed organic reactions. Chem. Rev. 2007, 107, 3180–3211. [CrossRef] [PubMed]
53. Corma, A.; Leyva-Pérez, A.; Sabater, M.J. Gold-catalyzed carbon
Chem. Rev. 2011, 111, 1657–1712. [CrossRef] [PubMed]
−
heteroatom bond-forming reactions.
54. Huang, H.; Zhou, Y.; Liu, H. Recent advances in the gold-catalyzed additions to C–C multiple bonds.
Beilstein J. Org. Chem. 2011, 7, 897–936. [CrossRef] [PubMed]
55. Krause, N.; Winter, C. Gold-catalyzed nucleophilic cyclization of functionalized allenes: A powerful access
to carbo- and heterocycles. Chem. Rev. 2011, 111, 1994–2009. [CrossRef] [PubMed]

Molecules 2019, 24, 988
30 of 30
56. Dorel, R.; Echavarren, A.M. Gold(I)-catalyzed activation of alkynes for the construction of molecular
complexity. Chem. Rev. 2015, 115, 9028–9072. [CrossRef] [PubMed]
57. Gao, F.; Zhou, Y.; Liu, H. Recent advances in the synthesis of heterocycles via gold-catalyzed cascade
reactions: A review. Curr. Org. Chem. 2017, 21, 1530–1566. [CrossRef]
58. Dalpozzo, R. Strategies for the asymmetric functionalization of indoles: An update. Chem. Soc. Rev. 2015, 44,
742–778. [CrossRef] [PubMed]
59. Lindner, A.; Claassen, V.; Hendriksen, T.W.J.; Kralt, T. Reserpine analogs; phenethylamine derivatives1.
J. Med. Chem. 1963, 6, 97–101. [CrossRef] [PubMed]
60. Daugan, A.; Grondin, P.; Ruault, C.; de Gouville, A.C.L.M.; Coste, H.; Kirilovsky, J.; Hyafil, F.;
Labaudinière, R. The discovery of Tadalafil: A novel and highly selective PDE5 inhibitor. 1:
0
0
5,6,11,11a-tetrahydro-1H-imidazo[1 ,5 :1,6]pyrido[3,4-b]indole-1,3(2H)-dione analogues. J. Med. Chem. 2003
,
46, 4525–4532. [CrossRef] [PubMed]
61. Daugan, A.; Grondin, P.; Ruault, C.; de Gouville, A.C.L.M.; Coste, H.; Linget, J.M.; Kirilovsky, J.;
Hyafil, F.; Labaudinière, R. The discovery of Tadalafil: A novel and highly selective PDE5 inhibitor. 2:
0
0
2,3,6,7,12,12a-hexahydropyrazino[1 ,2 :1,6]pyrido[3,4-b]indole-1,4-dione analogues. J. Med. Chem. 2003, 46,
4533–4542. [CrossRef] [PubMed]
62. Kochanowska-Karamyan, A.J.; Hamann, M.T. Marine indole alkaloids: Potential new drug leads for the
control of depression and anxiety. Chem. Rev. 2010, 110, 4489–4497. [CrossRef] [PubMed]
63. Silvestri, R. New prospects for vinblastine analogues as anticancer agents. J. Med. Chem. 2013, 56, 625–627.
[CrossRef] [PubMed]
64. Sun, H.; Zhu, L.; Yang, H.; Qian, W.; Guo, L.; Zhou, S.; Gao, B.; Li, Z.; Zhou, Y.; Jiang, H.; et al. Asymmetric
total synthesis and identification of tetrahydroprotoberberine derivatives as new antipsychotic agents
possessing a dopamine D1, D2 and serotonin 5-HT1A multi-action profile. Bioorg. Med. Chem. 2013, 21,
856–868. [CrossRef] [PubMed]
65. Guo, D.; Li, J.; Lin, H.; Zhou, Y.; Chen, Y.; Zhao, F.; Sun, H.; Zhang, D.; Li, H.; Shoichet, B.K.; et al. Design,
synthesis, and biological evaluation of novel tetrahydroprotoberberine derivatives (THPBs) as selective
α1A-adrenoceptor antagonists. J. Med. Chem. 2016, 59, 9489–9502. [CrossRef] [PubMed]
66. Stempel, E.; Gaich, T. Cyclohepta[b]indoles: A privileged structure motif in natural products and drug
design. Acc. Chem. Res. 2016, 49, 2390–2402. [CrossRef] [PubMed]
67. Homer, J.A.; Sperry, J. Mushroom-derived indole alkaloids. J. Nat. Prod. 2017, 80, 2178–2187. [CrossRef]
[PubMed]
68. Klas, K.R.; Kato, H.; Frisvad, J.C.; Yu, F.; Newmister, S.A.; Fraley, A.E.; Sherman, D.H.; Tsukamoto, S.;
Williams, R.M. Structural and stereochemical diversity in prenylated indole alkaloids containing the
bicyclo[2.2.2]diazaoctane ring system from marine and terrestrial fungi. Nat. Prod. Rep. 2018, 35, 532–558.
[CrossRef] [PubMed]
69. Sun, H.; Huang, H.; Zhang, D.; Feng, E.; Qian, W.; Zhang, L.; Chen, K.; Liu, H. Synthesis of
4-aryl-2(5H)-furanones by gold(I)-catalyzed intramolecular annulation. Adv. Synth. Catal. 2011, 353,
1413–1419. [CrossRef]
Sample Availability: Samples of the compounds SF1–SF43, SF47–SF55 are available from the authors.
©
2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).