N-heterocyclic carbene catalyzed enantioselective [3 + 2] dearomatizing annulation of saturated carboxylic esters with n-iminoisoquinolinium ylides

Article abstract of DOI:10.1021/acs.joc.8b00227

The dearomatizing annulation reaction is a significant challenge in organic chemistry. The direct activation of α-carbons of simple saturated esters, as nucleophiles, is an important synthesis strategy. In the present study, we disclose [3 + 2] dearomatizing annulation reactions with direct activating α-carbons of saturated carboxylic esters and N-iminoisoquinolinium ylides, which possess highly enantioselective characteristics, catalyzed by N-heterocyclic carbenes (NHCs). The protocol achieves isoquinoline dearomatization and the construction of tricyclic chiral products under mild conditions with good yield, substrate tolerance, and diastereoselectivity as well as excellent enantioselectivity.

Full text of DOI:10.1021/acs.joc.8b00227

Subscriber access provided by - Access paid by the | UCSB Libraries
N-Heterocyclic Carbene Catalyzed Enantioselective [3+2] Dearomatizing
Annulation of Saturated Carboxylic Esters with N-Imimoisoquinolinium Ylides
Pengfei Zhang, Yu Zhou, Xu Han, Jinyi Xu, and Hong Liu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00227 • Publication Date (Web): 16 Mar 2018
Downloaded from http://pubs.acs.org on March 16, 2018
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 24
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
N-Heterocyclic Carbene Catalyzed Enantioselective [3+2] Dearomatizing
Annulation of Saturated Carboxylic Esters with N-Imimoisoquinolinium Ylides
Pengfei Zhang, †,‡,§ Yu Zhou, ‡,#,¶,§ Xu Han, ‡,#,¶ Jinyi Xu, *,† and Hong Liu*,‡,#,¶
†State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical
University, 24 Tong Jia Xiang, Nanjing, Jiangsu 210009, China.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
‡State key Laboratory of Drug Research and #Key Laboratory of Receptor Research, Shanghai Institute of Materia
Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China.
¶University of Chinese Academy of Sciences, No.19AYuquan Road, Beijing 100049, China.
Email: jinyixu@china.com (for Jinyi Xu), hliu@simm.ac.cn (for Hong Liu)
Abstract
The dearomatizing annulation reaction is a significant challenge in organic chemistry. The
direct activation of αꢀcarbons of simple saturated esters, as nucleophiles, is an important synthesis
strategy. In the present study, we disclose [3+2] dearomatizing annulation reactions with direct
activating αꢀcarbons of saturated carboxylic esters and Nꢀiminoisoquinolinium ylides, which
possess highly enantioselective characteristics, catalyzed by Nꢀheterocyclic carbenes (NHCs). The
protocol achieves isoquinoline dearomatization and the construction of tricyclic chiral products
under mild conditions with good yield, substrate tolerance, diastereoselectivity, and excellent
enantioselectivity.
Introduction
Enantioselective dearomatization of πꢀconjugated heterocyclic molecules has practical
significance, because most natural compounds are nonaromatic or less aromatic, and their specific
configuration is required to maintain their bioactivity (Figure 1a). However, it is a significant
challenge to identify suitable and mild reaction conditions to break the stabilization of large
aromatic conjugated structure. Recently, transition metals, such as Pd, Ir, Fe, Rh, Ag, and Cu1,
have been frequently employed to achieve the dearomatization transformation to build intriguing
nonaromatic structures, which has enlarged the scope of available substrates and obtainable
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 24
1
2
3
4
5
6
7
8
9
dearomatized products. Further specific bioactive chiral compounds are desired; however,
traditional synthetic methods can barely realize highly enantioselective and efficient synthesis
under green and mild reaction conditions. Therefore, research into enantioselective
dearomatization is currently in the preliminary stage and requires further effort.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
As stable and isolable cabenes, which were first reported by Arduengo et al.2, Nꢀheterocyclic
carbenes (NHCs, Figure 1b) have exhibited an enormous capacity for CꢀH activation3 and
enantioselective CꢀC bond formation4 to efficiently generate various chiral compounds for a wide
range of application in organic chemistry5. Although NHCs have undergone rapid development in
asymmetric organocatalysis, dearomatization reaction with NHC catalysts6 is rare because of the
difficulty of discovering suitable substrates7. Futher research on NHCꢀcatalyzed dearomatization
is required considering the distinctive umpolung nature and high enantioselective characteristics
of NHC catalysis, which represent an excellent and convenient strategy to build diversified chiral
naturalꢀlike heterocyclic compounds8. Recently, Glorius and coꢀworkers6b reported a series of
tricyclic dihydroisoquinolines with a 1,4ꢀdiamine unit, generated by isoquinoline through an
NHCꢀdearomatization method, could be easily synthesized to indolizidine alkaloids, a class of
unique scaffolds9 that are widely present in naturally occurring molecules and have extensive
biological and medicinal applications10.
Meanwhile, varied carbonyl compounds11 and other substrates, like alkenyl12 have been
employed to react with NHCs. Chi and coꢀworkers13 reported that direct activation of βꢀcarbons of
simple saturated esters, as nucleophiles, is a good strategy to synthesize cyclopentenes, offering
new ideas for NHCs chemistry14. By contrast, activating the αꢀcarbons of saturated esters is rarely
reported15, despite being easily accomplished in aldehyde compounds16. Thus, it seems that there
are generally applicable barriers of common saturated carbonyl compounds with direct activating
αꢀcarbons, as nucleophiles, to participate in various NHCsꢀcatalyzed reactions. In line with our
efforts in the field of NHCsꢀdearomaticity crossing8,17, we herein report novel and mild
NHCꢀcatalyzed dearomatizing [3+2] annulation reactions to synthesize highly enantioselective
tricyclic dihydroisoquinolines with direct activating αꢀcarbons of saturated carboxylic esters and
Nꢀimimoisoquinolinium ylides.
ACS Paragon Plus Environment

Page 3 of 24
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 1. a) Examples of naturally occurring and biologically active indolizidine alkaloids. b) NHC precatalysts
used in this work. c) Our current work to generate chiral indolizidine alkaloid.
Results and Discussion
Experimentally, we set out to achieve dearomatizing annulation to prepare the target tricyclic
dihydroisoquinolines using saturated carboxylic ester 1a and Nꢀimimoisoquinolinium ylide 2a as
model substrates. The key experimental results of conditions screening and optimization are
summarized in Table 1. With imidazolium A as the NHC precatalyst, K2CO3 as the base and
tetrahydrofuran (THF) as the solvent, we observed the desired dearomatizing annulation product
3a in a suitable yield of 80% and with a moderate enantioselectivity of 75% e.e. (Table 1, entry 1).
Meanwhile, other NHC precatalysts were also tested for this transformation, but no improvements
in yield and enantioselectivity were obtained (Table 1, entries 2ꢀ5). It seems that catalyst A is the
best choice for this reaction. In addition, we further explored the influences of different solvents,
and the results showed that toluene, dichloromethane and ethyl acetate gave better yields (more
than 80%) and increased the enantioselectivity to 87ꢀ95% e.e. (Table 1, entries 6ꢀ9). However,
when using N,Nꢀdimethylformamide as the reaction solvent, the target product 3a could barely be
detected (Table 1, entry 10). Subsequently, screening of different bases revealed that the inorganic
bases Cs2CO3 gave the best result (Table 1, entries 11ꢀ16). In brief, the optimum result could be
obtained when ester 1a (0.1 mmol, 1.0 equiv.) and ylide 2a (0.1 mmol, 1.0 equiv.) were treated
with Cs2CO3 (0.2 mmol, 2.0 equiv.) under 10 mol% NHC catalyst A at room temperature to
produce 3a.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 24
1
2
3
4
5
Table 1. Optimization of reaction conditionsa
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
entry
1
catalystb
base
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
EtONa
tꢀBuOK
TEA
solvent
THF
yield(%)c
80
d.r.d
8:1
4:1
4:1
2:1
ꢀf
e.e.(%)e
75
56
40
6
A
B
C
D
E
A
A
A
A
A
A
A
A
A
A
A
2
THF
75
3
THF
70
4
THF
50
5
THF
0
ꢀf
6
toluene
CH2Cl2
EtOAc
dioxane
DMF
80
8:1
ꢀ f
92
87
95
76
ꢀf
7
80
8
82
10:1
ꢀ f
9
75
10
11
12
13
14
15
16
2
ꢀf
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
15
8:1
10:1
ꢀf
93
95
90
91
91
99
70
50
DIPEA
DBU
50
6:1
5:1
10:1
60
Cs2CO3
80
aUnless other specified, all the reactions were carried out using ester 1a (0.1 mmol, 1.0 equiv.) and ylide 2a (0.1
mmol, 1.0 equiv.), base (0.2 mmol, 2.0 equiv.) with 10 mol% NHC precatalyst at room temperature (r.t.) under Ar
protection for 3ꢀ6 hours. bAll NHC precatalysts in this work are showed in Figure 1b. Isolated yields after
c
d
1
e
chromatography. Determined by crude H NMR spectroscopy. Enantiomeric excess of 3a determined via chiral
HPLC analysis. fNot determined.
With the optimized catalysis condition identified, the applicability of the dearomatizing strategy
was further demonstrated using a variety of esters as substrate 1. The results are summarized in
Table 2. Initially, we investigated the tolerances for different substituents on the phenyl ring of 1a.
The results showed that some electron donating (Table 2, entries 2ꢀ4) and halogens (Table 2,
entries 5ꢀ9) groups on the phenyl ring could generate the desired dearomatizing annulation
products 3a-3i with excellent yield, diastereoselectivities and enantioselectivities (e.e. > 95%). In
addition, the involvement of heterocyclic substituent R1 (such as a 2ꢀfuryl group) produced 3j with
excellent yield of 80% and enantioselectivity of 97% e.e. (Table 2, entry 10). Alkly groups were
also introduced into the R1 group to explore the substrate tolerances (Table 2, entries 11ꢀ13).
Although the introduction of alkyl groups led to a decrease in yields, excellent enantioselectivities
ACS Paragon Plus Environment

Page 5 of 24
The Journal of Organic Chemistry
1
2
3
4
5
were still obtained (e.e. = 95ꢀ97%).
Table 2. Studies on the variation of substrate 1a
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
entry
1
R1
Ph
product
3a
yield (%) of 3b
d.r.c
10:1
8:1
e.e.d
99
98
98
96
97
95
96
96
96
97
95
98
97
80
80
75
80
80
65
80
78
75
80
75
75
70
2
4ꢀMeC6H4
4ꢀOMeC6H4
3ꢀOMeC6H4
4ꢀFC6H4
4ꢀClC6H4
4ꢀBrC6H4
3ꢀBrC6H4
2ꢀBrC6H4
2ꢀFuryl
Me
3b
3c
3
14:1
14:1
19:1
17:1
20:1
8:1
4
3d
3e
5
6
3f
7
3g
8
3h
3i
9
20:1
6:1
10
11
12
13
3j
3k
3l
20:1
7:1
nꢀPr
Cy
3m
15:1
aUnless other specified, all the reactions were carried out using ester 1 (0.1 mmol, 1.0 equiv.) and ylide 2a (0.1
mmol, 1.0 equiv.), Cs2CO3 (0.2 mmol, 2.0 equiv.) in EA with 10 mol% NHC precatalyst A at room temperature
(r.t.) under Ar protection for 3ꢀ6 hours. Isolated yields after chromatography. Determined by crude 1H NMR
spectroscopy. dEnantiomeric excess of 3 determined via chiral HPLC analysis.
b
c
The generality of this strategy with different Nꢀiminoisoquinolinium ylides 2b-j was then
investigated, as outlined in Table 3. Introducing an electronꢀdonating group (6ꢀMe) into the
isoquinoline ring of ylide 2a was feasible to generate 8ꢀMe substituted product 4d with 72% yield
and 92% e.e. (Table 3, entry 3). However, when we tested 5ꢀ, 6ꢀ, or 7ꢀmethoxy substituted ylides,
the dearomatizing annulation product could not be detected. We speculated that it might be caused
by the weak reactive properties of methoxyꢀsubstituted ylides (not shown in Table 3). By contrast,
the introduction of halogens, such as Fꢀ, Clꢀ and Brꢀ substitutes, into the R2 group (Table 3, entries
1, 2, entries 4ꢀ9) was favorable to produce the target products (4b, 4c, 4e-4j), which indicated
good tolerance for halogen groups. We further found that 6ꢀbromine substituted ylide 2g generated
the best yield (75%) and enantioselectivity (98% e.e.) to form the dearomatizing tricyclic
compound 4g (Table 3, entry 6), and four bromine substituted products (4c, 4g, 4i, 4j) with good
enantioselectivities (96ꢀ98%), diastereoselectivities (11:1ꢀ20:1) and moderate yield (60ꢀ75%)
(Table 3, entries 2, 6, 8, 9) demonstrated that bromine was a stable and useful group for the
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 24
1
2
3
4
5
dearomatizing strategy.
Table 3. Studies on the variation of substrate 2a
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
entry
R2
product
4b
4c
yield (%) of 4b
d.r.c
20:1
20:1
8:1
e.e.d
98
97
92
97
95
98
97
98
96
1
2
3
4
5
6
7
8
9
7ꢀCl
7ꢀBr
8ꢀMe
8ꢀF
60
65
72
70
71
75
65
75
60
4d
4e
16:1
20:1
20:1
20:1
20:1
11:1
8ꢀCl
8ꢀBr
9ꢀCl
9ꢀBr
10ꢀBr
4f
4g
4h
4i
4j
aUnless other specified, all the reactions were carried out using ester 1a (0.1 mmol, 1.0 equiv.) and ylide 2 (0.1
mmol, 1.0 equiv.), Cs2CO3 (0.2 mmol, 2.0 equiv.) in EA with 10 mol% NHC precatalyst A at room temperature
(r.t.) under Ar protection for 3ꢀ6 hours. Isolated yields after chromatography. Determined by crude 1H NMR
spectroscopy. dEnantiomeric excess of 4 determined via chiral HPLC analysis.
b
c
Indolizidine alkaloids are important structural motifs18 (Figure 1a). In our studies, we found that
some Nꢀsubstituent tricyclic indolizidine scaffold derivatives could be easily synthesized from 3a
by a simple reduction step. As shown in Figure 2, product 3a of the dearomatizing annulation
reaction could be further transformed into Nꢀsubstituent indolizidine derivative 5a with treatment
of NaBH3CN in 60% total yield and 95% e.e. (Figure 2). Brꢀsubstituent product 3g also could be
transformed into indolizidine derivative 5g at the same reaction condition in 62% total yield and
97% e.e., better than the performance of 3a (Figure 2).
Figure 2. Derivatization of products 3 to give indolizidine derivatives 5 by one step.
A plausible mechanism is proposed in Figure 3. The addition of NHC catalyst to ester substrate
1a gives an NHCꢀbound ester intermediate I, which bears acidic αꢀCHs and can undergo
deprotonation to form an enolate intermediate II. Deprotonation of the αꢀCH of enolate II
ACS Paragon Plus Environment

Page 7 of 24
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
produces the acylazolium intermediate III, containing the αꢀcarbon as a nucleophilic center.
Intermediate III then reacts with Nꢀiminoisoquinolinium ylide 2a to generate intermediate IV,
which undergoes an intramolecular acylation in proper conformation (intermediate V) to give the
final annulation product 3a and regenerate the NHC catalyst.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 3. Postulated catalytic cycle for the NHCꢀcatalyzed dearomatizing annulation reaction.
In summary, we developed a novel NHCꢀcatalyzed dearomatizing [3+2] annulation reaction
with direct activating αꢀcarbons of saturated esters and Nꢀiminoisoquinolinium ylides to generate
chiral tricyclic products with good yield, moderate diastereoselectivity and high enantioselectivity
in mild conditions. The reaction works well for different kinds of esters and has good tolerance for
a diverse array of ylides. The resulting tricyclic product can be easily transformed to useful
derivatives, such as indolizidine alkaloids, making this strategy potentially practical for the
synthesis of bioactive molecules.
EXPERIMENTAL SECTION
General information: The reagents (chemicals) and solvents were purchased from commercial
sources and used without further purification. All reactions were carried out under an atmosphere
of argon in preꢀdried glassware. Analytical thin layer chromatography (TLC) was HSGF 254
1
(0.15ꢀ0.2 mm thickness), visualized by irradiation with UV light (254 nm). H and 13CꢀNMR
spectra were recorded in deuterochloroform (CDCl3) on 400, 500 and 600 MHz instruments.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 24
1
2
3
4
5
6
7
8
9
Chemical shifts (δ) are given in parts per million (ppm) relative to tetramethylsilane (TMS).
Proton coupling patterns are described as singlet (s), doublet (d), triplet (t), quartet (q), multiplet
(m), and broad (br). ESI mass spectra were recorded on Agilen G6520 QꢀTOF LC/MS. And EI
mass spectra were recorded on ThermoꢀDFS high performance double focusing magnetic sector
GC/MS. Optical rotations were measured on an Auto pol V PLVS matic polarimeter at 20oC using
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
a quartz glass cell (1 dm path length) and are reported as follows: [α]20 (c, in solvent). The
D
enantiomeric ratio (e.e.) was determined by HPLC analysis using chiral column OD.
General procedure for the preparation of saturated carboxylic esters15c: To a solution of
propionic acid (6.0 mmol, 1.0 equiv) in ethyl acetate (20 mL) was added pꢀnitrophenol (6.6 mmol,
1.1 equiv), then dicyclohexylcarbodiimide (12.0 mmol, 2.0 equiv) was added slowly to the
solution. The reaction mixture was stirred overnight at room temperature. Upon filtering off the
solid, ethyl acetate was removed under reduced pressure. The residue was purified by column
chromatography on silica gel (Hexanes : Ethyl acetate = 20:1) to afford substrate 1.
General procedure for the preparation of N-iminoisoquinolinium ylides6b: To a solution of
isoquinoline (6.0 mmol, 1.0 equiv) in acetonitrile (25 mL) was added Oꢀ(2,4ꢀdinitrophenyl)hyꢀ
droxylamine (6.6 mmol, 1.1 equiv). The reaction flask was sealed and the reaction mixture was
stirred for 24 h at room temperature. Upon filtering off the solvent, the orange precipitate was
dissolved in THF/H2O (30 mL, 1:1). The reaction mixture was added K2CO3 (21.0 mml, 3.5equiv)
at room temperature, and 4ꢀtoluenesulfonyl chloride (12.0 mmol, 2.0 equiv) was slowly added.
After 12 h, the reaction was diluted with 20 mL of H2O and extracted three times with
dichloromethane. The combined organic phases were dried over anhydrous Na2SO4, concentrated
under reduced pressure and purified by column chromatography on silica gel (Ethyl acetate) to
afford substrate 2.
General procedure for enantioselective synthesis of 3 or 4 by formal [3+2] cycloaddition of
saturated carboxylic esters with N-iminoisoquinolinium ylides: A dried and argonꢀfilled
Schlenk flask was charged with Nꢀiminoisoquinolinium ylide 2 (0.1 mmol, 1.0 equiv) and Cs2CO3
(0.2 mmol, 2.0 equiv). Then, saturated carboxylic ester 1 (0.1 mmol, 1.0 equiv) was added quickly
to the mixture. Subsequently, triazolium salt A (0.01 mmol, 10 mol%) in 2.5 mL EA was added to
the mixture. The mixture was stirred at r.t. for 3ꢀ6 h. After purification by column chromatography
on silica gel (Hexanes : Ethyl acetate = 20:1), the desired product 3 or 4 was obtained.
ACS Paragon Plus Environment

Page 9 of 24
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Synthetic Transformation of product 3 to produce 5: To a solution of 3 (0.2 mmol, 1.0 equiv)
in dichloromethane (3 mL) was added acetic acid (3 mL) at room temperature. NaBH3CN (0.3
mmol, 3.0 equiv) was added and reaction mixture was stirring until the disappearance of the
starting material. The mixture was quenched with aq. NaHCO3 solution and extracted with
dichloromethane three times. The combined organic layers were dried over anhydrous Na2SO4 and
concentrated. Purification of the residue by column chromatography on silica gel (Hexanes : Ethyl
acetate = 20:1) gave the corresponding product 5.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4ꢀnitrophenyl 3ꢀphenylpropanoate (1a): White solid (1.6g, 97% yield): mp 98ꢀ99 oC. 1H NMR
(400 MHz, CDCl3) δ 8.18 (d, J = 2.2 Hz, 1H), 8.16 (d, J = 2.2 Hz, 1H), 7.29ꢀ7.26 (m, 1H), 7.25 (s,
1H), 7.21ꢀ7.17 (m, 3H), 7.12 (d, J = 2.2 Hz, 1H), 7.10 (d, J = 2.2 Hz, 1H), 3.01 (t, J = 7.5 Hz, 2H),
2.89ꢀ2.83 (m, 2H). 13C NMR (126 MHz, CDCl3) δ 170.4, 155.4, 145.4, 139.6, 128.7, 128.7, 128.4,
128.4, 126.7, 125.2, 125.2, 122.4, 122.4, 35.9, 30.8. HRMS (EIꢀDF) m/z [M]+ calcd for
C15H13NO4 271.0845, found 271.0844.
4ꢀnitrophenyl 3ꢀ(pꢀtolyl)propanoate (1b): White solid (1.6g, 96% yield): mp 105ꢀ106 oC. 1H NMR
(400 MHz, CDCl3) δ 8.25 (d, J = 9.2 Hz, 2H), 7.19 (d, J = 9.2 Hz, 2H), 7.15 (s, 4H), 3.04 (t, J =
7.6 Hz, 2H), 2.96ꢀ2.85 (m, 2H), 2.34 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 170.5, 155.4, 145.3,
136.6, 136.2, 129.4, 129.4, 128.2, 128.2, 125.2, 125.2, 122.4, 122.4, 36.1, 30.4, 21.0. HRMS
(EIꢀDF) m/z [M]+ calcd for C16H15NO4 285.1001, found 285.0993.
4ꢀnitrophenyl 3ꢀ(4ꢀmethoxyphenyl)propanoate (1c): White solid (1.7g, 95% yield): mp 117ꢀ119 oC.
1H NMR (400 MHz, CDCl3) δ 8.34ꢀ8.14 (m, 2H), 7.22ꢀ7.14 (m, 4H), 6.90ꢀ6.83 (m, 2H), 3.80 (s,
3H), 3.03 (t, J = 7.4 Hz, 2H), 2.94ꢀ2.85 (m, 2H). 13C NMR (126 MHz, CDCl3) δ 170.5, 158.4,
155.4, 145.3, 131.7, 129.4, 129.4, 125.2, 125.2, 122.4, 122.4, 114.1, 114.1, 55.3, 36.2, 30.0.
HRMS (EIꢀDF) m/z [M]+ calcd for C16H15NO5 301.0950, found 301.0949.
4ꢀnitrophenyl 3ꢀ(3ꢀmethoxyphenyl)propanoate (1d): White solid (1.7g, 95% yield): mp 122ꢀ123
oC. 1H NMR (400 MHz, CDCl3) δ 8.33ꢀ8.17 (m, 2H), 7.25 (ddd, J = 7.6, 6.2, 2.0 Hz, 1H),
7.22ꢀ7.18 (m, 2H), 6.85 (d, J = 7.8 Hz, 1H), 6.80 (dd, J = 7.7, 1.8 Hz, 2H), 3.81 (s, 3H), 3.06 (t, J
= 7.5 Hz, 2H), 2.98ꢀ2.88 (m, 2H). 13C NMR (126 MHz, CDCl3) δ 170.4, 159.9, 155.4, 145.4,
141.2, 129.7, 125.2, 125.2, 122.4, 122.4, 120.7, 114.3, 111.8, 55.2, 35.8, 30.8. HRMS (EIꢀDF) m/z
[M]+ calcd for C16H15NO5 301.0950, found 301.0959.
4ꢀnitrophenyl 3ꢀ(4ꢀfluorophenyl)propanoate (1e): White solid (1.6g, 93% yield): mp 135ꢀ137 oC.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 24
1
2
3
4
5
6
7
8
9
1H NMR (400 MHz, CDCl3) δ 8.29ꢀ8.20 (m, 2H), 7.25ꢀ7.16 (m, 4H), 7.06ꢀ6.96 (m, 2H), 3.06 (t, J
= 7.5 Hz, 2H), 2.96ꢀ2.88 (m, 2H). 13C NMR (126 MHz, CDCl3) δ 170.3, 162.7, 155.3, 145.4,
135.3, 129.9, 129.8, 125.2, 125.2, 122.4, 122.4, 115.6, 115.4, 36.0, 29.9. HRMS (EIꢀDF) m/z [M]+
calcd for C15H12FNO4 289.0750, found 289.0742.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4ꢀnitrophenyl 3ꢀ(4ꢀchlorophenyl)propanoate (1f): White solid (1.7g, 92% yield): mp 129ꢀ131 oC.
1H NMR (400 MHz, CDCl3) δ 8.30ꢀ8.18 (m, 2H), 7.32ꢀ7.27 (m, 2H), 7.21 (t, J = 2.0 Hz, 2H),
7.20ꢀ7.16 (m, 2H), 3.05 (t, J = 7.4 Hz, 2H), 2.95ꢀ2.88 (m, 2H). 13C NMR (126 MHz, CDCl3) δ
170.2, 155.2, 145.4, 138.1, 132.5, 129.8, 129.8, 128.8, 128.8, 125.2, 125.2, 122.4, 122.4, 35.7,
30.1. HRMS (EIꢀDF) m/z [M]+ calcd for C15H12ClNO4 305.0455, found 305.0452.
4ꢀnitrophenyl 3ꢀ(4ꢀbromophenyl)propanoate (1g): White solid (2.0g, 95% yield): mp 141ꢀ142 oC.
1H NMR (400 MHz, CDCl3) δ 8.30ꢀ8.19 (m, 2H), 7.45 (d, J = 8.3 Hz, 2H), 7.22ꢀ7.16 (m, 2H),
7.14 (d, J = 8.3 Hz, 2H), 3.04 (t, J = 7.4 Hz, 2H), 2.91 (dd, J = 11.4, 4.1 Hz, 2H). 13C NMR (126
MHz, CDCl3) δ 170.1, 155.2, 145.4, 138.6, 131.8, 131.8, 130.1, 130.1, 125.2, 125.2, 122.4, 122.4,
120.5, 35.6, 30.1. HRMS (EIꢀDF) m/z [M + H]+ calcd for C15H13BrNO4 350.0028, found
349.9994.
4ꢀnitrophenyl 3ꢀ(3ꢀbromophenyl)propanoate (1h): White solid (1.9g, 94% yield): mp 140ꢀ141 oC.
1H NMR (400 MHz, CDCl3) δ 8.29ꢀ8.22 (m, 2H), 7.44ꢀ7.35 (m, 2H), 7.24ꢀ7.16 (m, 4H), 3.05 (t, J
= 7.3 Hz, 2H), 2.96ꢀ2.89 (m, 2H). 13C NMR (126 MHz, CDCl3) δ 170.1, 155.2, 145.4, 142.0,
131.5, 130.3, 129.8, 127.1, 125.2, 125.2, 122.7, 122.4, 122.4, 35.6, 30.3. HRMS (EIꢀDF) m/z [M +
H]+ calcd for C15H13BrNO4 350.0028, found 349.9999.
4ꢀnitrophenyl 3ꢀ(2ꢀbromophenyl)propanoate (1i): White solid (1.9g, 93% yield): mp 133ꢀ135 oC.
1H NMR (400 MHz, CDCl3) δ 8.30ꢀ8.21 (m, 2H), 7.58 (dd, J = 8.0, 1.1 Hz, 1H), 7.30 (ddd, J =
8.4, 7.4, 1.5 Hz, 2H), 7.27ꢀ7.20 (m, 2H), 7.17ꢀ7.08 (m, 1H), 3.20 (t, J = 7.6 Hz, 2H), 2.97 (t, J =
7.6 Hz, 2H). 13C NMR (126 MHz, CDCl3) δ 170.2, 155.3, 145.4, 138.9, 133.1, 130.6, 128.5, 127.7,
125.2, 125.2, 124.4, 122.4, 122.4, 34.2, 31.3. HRMS (EIꢀDF) m/z [M + H]+ calcd for
C15H13BrNO4 350.0028, found 349.9996.
4ꢀnitrophenyl 3ꢀ(furanꢀ2ꢀyl)propanoate (1j): White solid (1.4g, 92% yield): mp 95ꢀ97 oC. 1H
NMR (400 MHz, CDCl3) δ 8.33ꢀ8.18 (m, 2H), 7.35 (dd, J = 1.7, 0.6 Hz, 1H), 7.27ꢀ7.26 (m, 1H),
7.25ꢀ7.22 (m, 1H), 6.32 (dd, J = 3.1, 1.9 Hz, 1H), 6.11 (dd, J = 3.2, 0.8 Hz, 1H), 3.11 (t, J = 7.3
Hz, 2H), 2.95 (dd, J = 11.2, 4.0 Hz, 2H). 13C NMR (126 MHz, CDCl3) δ 170.1, 155.4, 153.2,
ACS Paragon Plus Environment

Page 11 of 24
The Journal of Organic Chemistry
1
2
3
4
5
145.4, 141.6, 125.2, 125.2, 122.4, 122.4, 110.4, 105.9, 33.0, 23.4. HRMS (EIꢀDF) m/z [M]+ calcd
for C13H11NO5 261.0637, found 261.0642.
6
7
8
9
4ꢀnitrophenyl butyrate (1k): Yellow oil (1.1g, 90% yield). 1H NMR (400 MHz, CDCl3) δ
8.40ꢀ8.08 (m, 2H), 7.43ꢀ7.06 (m, 2H), 2.59 (t, J = 7.4 Hz, 2H), 1.80 (dd, J = 14.8, 7.4 Hz, 2H),
1.06 (t, J = 7.4 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 171.1, 155.5, 145.3, 125.2, 125.2, 122.4,
125.4, 36.1, 18.3, 13.6. HRMS (EIꢀDF) m/z [M]+ calcd for C10H11NO4 209.0688, found 209.0688.
4ꢀnitrophenyl hexanoate (1l): Yellow oil (1.3g, 91% yield). 1H NMR (400 MHz, CDCl3) δ
8.37ꢀ8.13 (m, 2H), 7.37ꢀ7.17 (m, 2H), 2.60 (t, J = 7.5 Hz, 2H), 1.85ꢀ1.62 (m, 2H), 1.47ꢀ1.26 (m,
4H), 1.03ꢀ0.79 (m, 3H). 13C NMR (126 MHz, CDCl3) δ 171.3, 155.6, 145.3, 125.2, 125.2, 122.4,
122.4, 34.3, 31.2, 24.4, 22.3, 13.9. HRMS (EIꢀDF) m/z [M]+ calcd for C12H15NO4 237.1001, found
237.0998.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4ꢀnitrophenyl 3ꢀcyclohexylpropanoate (1m): White solid (1.5g, 90% yield): mp 91ꢀ93 oC. 1H
NMR (400 MHz, CDCl3) δ 8.38ꢀ8.10 (m, 2H), 7.38ꢀ7.08 (m, 2H), 2.72ꢀ2.45 (m, 2H), 1.80ꢀ1.68
(m, 5H), 1.66 (dd, J = 9.7, 5.8 Hz, 2H), 1.36ꢀ1.25 (m, 2H), 1.25ꢀ1.15 (m, 2H), 0.97 (td, J = 11.6,
2.4 Hz, 2H). 13C NMR (126 MHz, CDCl3) δ 171.6, 155.6, 145.3, 125.2, 125.2, 122.4, 122.4, 37.2,
33.0, 33.0, 32.1, 32.0, 26.5, 26.2, 26.2. HRMS (EIꢀDF) m/z [M]+ calcd for C15H19NO4 277.1314,
found 277.1309.
isoquinolinꢀ2ꢀiumꢀ2ꢀyl(tosyl)amide (2a): White solid (1.0g, 60% yield): mp 223ꢀ224 oC. 1H NMR
(400 MHz, CDCl3) δ 9.22 (s, 1H), 8.10ꢀ7.96 (m, 2H), 7.94ꢀ7.83 (m, 2H), 7.82ꢀ7.71 (m, 2H), 7.58
(d, J = 8.2 Hz, 2H), 7.09 (d, J = 8.0 Hz, 2H), 2.28 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 147.0,
141.6, 139.0, 137.8, 134.6, 134.3, 130.5, 129.3, 129.3, 128.7, 128.1, 127.2, 127.2, 126.9, 124.6,
21.4. HRMS (ESIꢀTOF) m/z [M + H]+ calcd for C16H15N2O2S 299.0854, found 299.0856.
(5ꢀchloroisoquinolinꢀ2ꢀiumꢀ2ꢀyl)(tosyl)amide (2b): Yellow solid (0.7g, 30% yield): mp 259ꢀ260
oC. 1H NMR (400 MHz, CDCl3) δ 9.32 (s, 1H), 8.17ꢀ8.09 (m, 2H), 7.97ꢀ7.86 (m, 2H), 7.72ꢀ7.64
(m, 1H), 7.63ꢀ7.56 (m, 2H), 7.10 (d, J = 7.9 Hz, 2H), 2.29 (s, 3H). 13C NMR (126 MHz, CDCl3) δ
145.8, 141.8, 138.9, 138.3, 133.7, 132.0, 131.8, 130.8, 129.4, 129.4, 129.3, 127.4, 127.2, 127.2,
121.7, 21.4. HRMS (ESIꢀTOF) m/z [M + H]+ calcd for C16H14ClN2O2S 333.0465, found 333.0459.
(5ꢀbromoisoquinolinꢀ2ꢀiumꢀ2ꢀyl)(tosyl)amide (2c): Brown solid (0.9g, 40% yield): mp 271ꢀ273 oC.
1H NMR (400 MHz, CDCl3) δ 9.32 (s, 1H), 8.13 (d, J = 1.3 Hz, 2H), 8.09 (dd, J = 7.6, 0.9 Hz,
1H), 7.99 (d, J = 8.3 Hz, 1H), 7.60 (dt, J = 7.6, 3.8 Hz, 3H), 7.10 (d, J = 8.0 Hz, 2H), 2.29 (s, 3H).
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 24
1
2
3
4
5
6
7
13C NMR (126 MHz, CDCl3) δ 145.9, 141.8, 138.8, 138.4, 137.4, 133.4, 131.0, 129.4, 128.4,
129.3, 128.3, 127.2, 127.2, 124.2, 121.8, 21.4. HRMS (ESIꢀTOF) m/z [M + H]+ calcd for
C16H14BrN2O2S 376.9956, found 376.9956.
8
9
(6ꢀmethylisoquinolinꢀ2ꢀiumꢀ2ꢀyl)(tosyl)amide (2d): Yellow solid (0.7g, 40% yield): mp 167ꢀ168
oC. 1H NMR (400 MHz, CDCl3) δ 9.11 (s, 1H), 7.97 (dd, J = 7.0, 1.5 Hz, 1H), 7.88 (d, J = 8.5 Hz,
1H), 7.67 (d, J = 6.9 Hz, 2H), 7.62ꢀ7.48 (m, 3H), 7.07 (d, J = 7.9 Hz, 2H), 2.56 (s, 3H), 2.28 (s,
3H). 13C NMR (126 MHz, CDCl3) δ 147.0, 146.2, 141.4, 139.2, 138.0, 135.0, 132.8, 129.2, 129.2,
128.5, 127.2, 127.2, 126.3, 125.9, 123.8, 22.5, 21.4. HRMS (ESIꢀTOF) m/z [M + H]+ calcd for
C17H17N2O2S 313.1011, found 313.1002.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(6ꢀfluoroisoquinolinꢀ2ꢀiumꢀ2ꢀyl)(tosyl)amide (2e): Yellow solid (0.7g, 35% yield): mp 266ꢀ268
oC. 1H NMR (400 MHz, CDCl3) δ 9.27 (s, 1H), 8.08 (ddd, J = 14.0, 8.0, 3.2 Hz, 2H), 7.75 (d, J =
7.1 Hz, 1H), 7.62ꢀ7.46 (m, 4H), 7.10 (d, J = 7.9 Hz, 2H), 2.29 (s, 3H). 13C NMR (126 MHz,
CDCl3) δ 166.6, 164.5, 147.0, 141.8, 138.6, 136.6, 132.2, 129.4, 129.4, 127.3, 127.3, 125.2, 123.9,
121.5, 111.2, 21.4. HRMS (ESIꢀTOF) m/z [M + H]+ calcd for C16H14FN2O2S 317.0760, found
317.0756.
(6ꢀchloroisoquinolinꢀ2ꢀiumꢀ2ꢀyl)(tosyl)amide (2f): Yellow solid (0.5g, 26% yield): mp 252ꢀ253
oC. 1H NMR (400 MHz, CDCl3) δ 9.33 (s, 1H), 8.14 (dd, J = 7.0, 1.5 Hz, 1H), 8.05 (d, J = 8.9 Hz,
1H), 7.95 (d, J = 1.6 Hz, 1H), 7.82–7.71 (m, 2H), 7.64 (d, J = 8.2 Hz, 2H), 7.16 (d, J = 7.9 Hz,
2H), 2.35 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 146.5, 141.8, 141.2, 138.8, 138.7, 135.0, 131.8,
130.1, 129.4, 129.4, 127.2, 127.2, 126.4, 125.9, 123.6, 21.4. HRMS (ESIꢀTOF) m/z [M + H]+
calcd for C16H14ClN2O2S 333.0465, found 333.0467.
(6ꢀbromoisoquinolinꢀ2ꢀiumꢀ2ꢀyl)(tosyl)amide (2g): Brown solid (1.0g, 45% yield): mp 282ꢀ283
oC. 1H NMR (400 MHz, CDCl3) δ 9.31 (s, 1H), 8.14 (s, 2H), 7.93 (dd, J = 21.4, 8.7 Hz, 2H), 7.77
(d, J = 6.9 Hz, 1H), 7.64 (d, J = 7.9 Hz, 2H), 7.16 (d, J = 7.8 Hz, 2H), 2.35 (s, 3H). 13C NMR (126
MHz, CDCl3) δ 146.6, 141.8, 138.8, 138.7, 135.1, 134.3, 129.9, 129.8, 129.4, 129.4, 129.2, 127.2,
127.2, 126.6, 123.5, 21.4. HRMS (ESIꢀTOF) m/z [M + H]+ calcd for C16H14BrN2O2S 376.9956,
found 376.9961.
(7ꢀchloroisoquinolinꢀ2ꢀiumꢀ2ꢀyl)(tosyl)amide (2h): Yellow solid (0.4g, 20% yield): mp 245ꢀ247
oC. 1H NMR (400 MHz, CDCl3) δ 9.24 (s, 1H), 8.19 (d, J = 6.6 Hz, 1H), 8.03 (s, 1H), 7.97ꢀ7.75
(m, 3H), 7.66 (d, J = 7.6 Hz, 2H), 7.17 (d, J = 7.5 Hz, 2H), 2.36 (s, 3H). 13C NMR (126 MHz,
ACS Paragon Plus Environment

Page 13 of 24
The Journal of Organic Chemistry
1
2
3
4
5
6
CDCl3) δ 144.9, 141.9, 138.7, 137.9, 136.9, 135.0, 132.5, 129.4, 129.4, 128.9, 128.4, 127.2, 127.2,
126.9, 124.6, 21.4. HRMS (ESIꢀTOF) m/z [M + H]+ calcd for C16H14ClN2O2S 333.0465, found
333.0465.
7
8
9
(7ꢀbromoisoquinolinꢀ2ꢀiumꢀ2ꢀyl)(tosyl)amide (2i): Brown solid (0.8g, 36% yield): mp 277ꢀ278 oC.
1H NMR (400 MHz, CDCl3) δ 9.15 (s, 1H), 8.20–8.08 (m, 2H), 7.90 (dd, J = 8.7, 1.9 Hz, 1H),
7.77 (dd, J = 7.9, 3.2 Hz, 2H), 7.66ꢀ7.56 (m, 2H), 7.11 (d, J = 7.9 Hz, 2H), 2.29 (s, 3H). 13C NMR
(126 MHz, CDCl3) δ 144.7, 141.9, 138.7, 138.0, 137.5, 132.6, 130.2, 129.4, 129.4, 129.2, 128.3,
127.2, 127.2, 125.0, 124.6, 21.4. HRMS (ESIꢀTOF) m/z [M + H]+ calcd for C16H14BrN2O2S
376.9956, found 376.9960.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(8ꢀbromoisoquinolinꢀ2ꢀiumꢀ2ꢀyl)(tosyl)amide (2j): Brown solid (0.7g, 31% yield): mp 269ꢀ270 oC.
1H NMR (400 MHz, CDCl3) δ 9.38 (d, J = 0.7 Hz, 1H), 8.21 (dd, J = 7.0, 1.5 Hz, 1H), 7.94 (dd, J
= 7.6, 0.8 Hz, 1H), 7.83 (dd, J = 11.8, 7.6 Hz, 2H), 7.65 (dd, J = 12.1, 5.1 Hz, 3H), 7.12 (d, J = 7.9
Hz, 2H), 2.29 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 145.0, 142.0, 138.4, 138.2, 135.5, 134.4,
134.1, 129.4, 129.4, 127.6, 127.5, 127.5, 126.5, 125.0, 122.6, 21.4. HRMS (ESIꢀTOF) m/z [M +
H]+ calcd for C16H14BrN2O2S 376.9956, found 376.9947.
(1S,10bS)ꢀ1ꢀbenzylꢀ3ꢀtosylꢀ1,10bꢀdihydropyrazolo[5,1ꢀa]isoquinolinꢀ2(3H)ꢀone (3a): White
viscous oil (34.4 mg, 80% yield). 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 8.3 Hz, 2H), 7.26 (s,
1H), 7.23 (s, 1H), 7.22ꢀ7.12 (m, 4H), 7.03 (ddd, J = 8.5, 6.5, 1.3 Hz, 3H), 6.97 (d, J = 7.5 Hz, 1H),
6.75 (d, J = 7.5 Hz, 1H), 6.27 (d, J = 7.9 Hz, 1H), 5.66 (d, J = 7.9 Hz, 1H), 3.95 (d, J = 12.4 Hz,
1H), 3.72 (ddd, J = 12.4, 6.5, 3.9 Hz, 1H), 2.93 (dd, J = 14.9, 3.9 Hz, 1H), 2.69 (dd, J = 15.0, 6.5
Hz, 1H), 2.45 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 173.2, 145.4, 137.9, 136.6, 134.6, 129.9,
129.9, 129.7, 129.7, 129.2, 129.0, 128.4, 128.4, 128.3, 128.1, 128.1, 126.9, 126.7, 126.6, 125.5,
107.6, 64.2, 46.9, 30.4, 21.8. HRMS (ESIꢀTOF) m/z [M + H]+ calcd for C25H23N2O3S 431.1429,
found 431.1422. [α]20D = +60 (c = 0.18, CHCl3). The product was analyzed by HPLC to determine
the enantiomeric excess: 99% e.e. (ODꢀH, hexane/iꢀPrOH = 70/30, detector: 254 nm, flow rate: 1
mL/min), t1 (major) = 14.5 min, t2 (minor) = 20.4 min.
The absolute configuration of product 3a is deemed on three reasons. Firstly, the 1H NMR and 13
C
NMR spectra of product 3a is highly consistent with the compound 4a of Glorius’s work6b, which
are the same structure theoretically. Secondly, the optical rotation of product 3a ([α]20 = +60) is
D
close to the value of compound 4a ([α]26D= +41) of Glorius’s work. Thirdly, retention time of
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 24
1
2
3
4
5
6
7
8
9
product 3a on HPLC test is t1 (major) = 14.5 min and t2 (minor) = 20.4 min (ODꢀH,
hexane/iꢀPrOH = 70/30, detector: 254 nm, flow rate: 1 mL/min), and compound 4a of Glorius’s
work is t1(major) = 13.8 min and t2(minor) = 20.5 min (ASꢀH, hexane/iꢀPrOH = 70/30, detector:
230 nm, flow rate: 1mL/min). Based on comprehensive results, we deem the absolute
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
conformation
of
product
3a
is
(1S,10bS)ꢀ1ꢀbenzylꢀ3ꢀtosylꢀ1,10bꢀdihydropyrazolo[5,1ꢀa]isoquinolineꢀ2(3H)ꢀone.
(1S,10bS)ꢀ1ꢀ(4ꢀmethylbenzyl)ꢀ3ꢀtosylꢀ1,10bꢀdihydropyrazolo[5,1ꢀa]isoquinolinꢀ2(3H)ꢀone (3b):
Yellow viscous oil (35.5 mg, 80% yield). 1H NMR (500 MHz, CDCl3) δ 7.81 (d, J = 8.3 Hz, 2H),
7.29 (s, 1H), 7.25 (dd, J = 12.5, 4.6 Hz, 2H), 7.21 (dd, J = 7.5, 1.1 Hz, 1H), 7.05 (td, J = 7.5, 1.0
Hz, 1H), 6.98 (dd, J = 16.8, 8.1 Hz, 4H), 6.79 (d, J = 7.5 Hz, 1H), 6.30 (d, J = 7.9 Hz, 1H), 5.68 (d,
J = 7.9 Hz, 1H), 3.96 (d, J = 12.4 Hz, 1H), 3.71 (ddd, J = 12.4, 6.5, 3.7 Hz, 1H), 2.96 (dd, J = 15.0,
3.6 Hz, 1H), 2.65 (dd, J = 14.9, 6.5 Hz, 1H), 2.48 (s, 3H), 2.34 (s, 3H). 13C NMR (126 MHz,
CDCl3) δ 173.2, 145.4, 137.9, 136.1, 134.7, 133.4, 129.8, 129.8, 129.6, 129.6, 129.1, 129.1, 129.1,
129.0, 128.4, 128.1, 128.1, 126.9, 126.7, 125.5, 107.6, 63.9, 47.0, 29.8, 21.8, 21.0. HRMS
(ESIꢀTOF) m/z [M ꢀ H]ꢀ calcd for C26H23N2O3S 443.1429, found 443.1436. [α]20D = +20 (c = 0.10,
CHCl3). The product was analyzed by HPLC to determine the enantiomeric excess: 98% e.e.
(ODꢀH, hexane/iꢀPrOH = 70/30, detector: 254 nm, flow rate: 1 mL/min), t1 (major) = 11.4 min, t2
(minor) = 17.6 min.
(1S,10bS)ꢀ1ꢀ(4ꢀmethoxybenzyl)ꢀ3ꢀtosylꢀ1,10bꢀdihydropyrazolo[5,1ꢀa]isoquinolinꢀ2(3H)ꢀone (3c):
Yellow viscous oil (34.5 mg, 75% yield). 1H NMR (500 MHz, CDCl3) δ 7.91 (d, J = 8.3 Hz, 2H),
7.41ꢀ7.31 (m, 3H), 7.19 (td, J = 7.5, 1.0 Hz, 1H), 7.14 (t, J = 8.0 Hz, 3H), 6.95 (d, J = 7.5 Hz, 1H),
6.88ꢀ6.81 (m, 2H), 6.43 (d, J = 7.9 Hz, 1H), 5.81 (d, J = 7.9 Hz, 1H), 4.10 (d, J = 12.4 Hz, 1H),
3.95 (s, 3H), 3.82 (ddd, J = 12.4, 6.2, 3.8 Hz, 1H), 3.08 (dd, J = 15.0, 3.7 Hz, 1H), 2.76 (dd, J =
15.0, 6.2 Hz, 1H), 2.60 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 173.2, 158.3, 145.4, 137.4, 134.7,
130.9, 130.9, 129.8, 129.8, 129.2, 129.0, 128.5, 128.3, 128.1, 128.1, 126.8, 126.7, 125.5, 113.7,
113.7, 107.6, 63.7, 55.2, 47.2, 29.4, 21.8. HRMS (ESIꢀTOF) m/z [M ꢀ H]ꢀ calcd for C26H23N2O4S
459.1379, found 459.1389. [α]20D = +51 (c = 0.16, CHCl3). The product was analyzed by HPLC to
determine the enantiomeric excess: 98% e.e. (ODꢀH, hexane/iꢀPrOH = 70/30, detector: 254 nm,
flow rate: 1 mL/min), t1 (major) = 15.3 min, t2 (minor) = 23.1 min.
ACS Paragon Plus Environment

Page 15 of 24
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
(1S,10bS)ꢀ1ꢀ(3ꢀmethoxybenzyl)ꢀ3ꢀtosylꢀ1,10bꢀdihydropyrazolo[5,1ꢀa]isoquinolinꢀ2(3H)ꢀone (3d):
Yellow viscous oil (36.8 mg, 80% yield). 1H NMR (500 MHz, CDCl3) δ 7.79 (d, J = 8.3 Hz, 2H),
7.25 (s, 1H), 7.24 (s, 1H), 7.19 (td, J = 7.5, 1.1 Hz, 1H), 7.07 (t, J = 7.9 Hz, 1H), 7.02 (td, J = 7.5,
1.2 Hz, 1H), 6.97 (d, J = 7.5 Hz, 1H), 6.79 (d, J = 7.3 Hz, 1H), 6.72 (dd, J = 8.2, 2.1 Hz, 1H),
6.67ꢀ6.65 (m, 1H), 6.62 (d, J = 7.6 Hz, 1H), 6.26 (d, J = 7.9 Hz, 1H), 5.66 (d, J = 7.9 Hz, 1H),
3.93 (d, J = 12.4 Hz, 1H), 3.76 (s, 3H), 3.71 (ddd, J = 12.3, 6.3, 4.0 Hz, 1H), 2.88 (dd, J = 14.9,
4.0 Hz, 1H), 2.69 (dd, J = 14.9, 6.4 Hz, 1H), 2.44 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 173.2,
159.6, 145.4 , 138.2, 137.8, 134.6, 129.9, 129.9, 129.3, 129.2, 129.0, 128.3, 128.1, 128.1, 126.9,
126.7, 125.5, 121.9, 115.4, 112.2, 107.7, 64.4, 55.2, 46.9, 29.7, 21.8. HRMS (ESIꢀTOF) m/z [M ꢀ
H]ꢀ calcd for C26H23N2O4S 459.1379, found 459.1391. [α]20D = +60 (c = 0.12, CHCl3). The
product was analyzed by HPLC to determine the enantiomeric excess: 96% e.e. (ODꢀH,
hexane/iꢀPrOH = 70/30, detector: 254 nm, flow rate: 1 mL/min), t1 (major) = 16.4 min, t2 (minor)
= 23.6 min.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(1S,10bS)ꢀ1ꢀ(4ꢀfluorobenzyl)ꢀ3ꢀtosylꢀ1,10bꢀdihydropyrazolo[5,1ꢀa]isoquinolinꢀ2(3H)ꢀone (3e):
Yellow viscous oil (35.9 mg, 80% yield). 1H NMR (500 MHz, CDCl3) δ 7.79 (d, J = 8.3 Hz, 2H),
7.25 (s, 2H), 7.21 (td, J = 7.5, 1.1 Hz, 1H), 7.07ꢀ7.01 (m, 3H), 6.99 (d, J = 7.5 Hz, 1H), 6.84 (t, J =
8.7 Hz, 2H), 6.77 (d, J = 7.4 Hz, 1H), 6.28 (d, J = 7.9 Hz, 1H), 5.67 (d, J = 7.9 Hz, 1H), 3.94 (d, J
= 12.4 Hz, 1H), 3.69 (ddd, J = 12.4, 6.3, 4.0 Hz, 1H), 2.90 (dd, J = 15.0, 3.8 Hz, 1H), 2.65 (dd, J =
15.0, 6.3 Hz, 1H), 2.46 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 173.0, 162.6, 160.7, 145.6, 137.9,
134.7, 132.1, 131.4, 131.3, 129.9, 129.9, 129.3, 129.0, 128.2, 128.0, 128.0, 126.7, 125.6, 115.2,
115.0, 107.6, 64.0, 47.0, 29.5, 21.7. HRMS (ESIꢀTOF) m/z [M + H]+ calcd for C25H22FN2O3S
449.1335, found 449.1343. [α]20D = +12 (c = 0.06, CHCl3). The product was analyzed by HPLC to
determine the enantiomeric excess: 96% e.e. (ODꢀH, hexane/iꢀPrOH = 70/30, detector: 254 nm,
flow rate: 1 mL/min), t1 (major) = 13.8 min, t2 (minor) = 20.4 min.
(1S,10bS)ꢀ1ꢀ(4ꢀchlorobenzyl)ꢀ3ꢀtosylꢀ1,10bꢀdihydropyrazolo[5,1ꢀa]isoquinolinꢀ2(3H)ꢀone (3f):
Yellow viscous oil (30.2 mg, 65% yield). 1H NMR (500 MHz, CDCl3) δ 7.80 (d, J = 8.3 Hz, 2H),
7.29 (s, 1H), 7.28 (s, 1H), 7.24 (td, J = 7.5, 1.1 Hz, 1H), 7.17ꢀ7.12 (m, 2H), 7.07 (td, J = 7.5, 1.1
Hz, 1H), 7.02 (t, J = 8.1 Hz, 3H), 6.79 (d, J = 7.5 Hz, 1H), 6.30 (d, J = 7.9 Hz, 1H), 5.70 (d, J =
7.9 Hz, 1H), 3.92 (d, J = 12.4 Hz, 1H), 3.72 (ddd, J = 12.5, 6.3, 3.9 Hz, 1H), 2.95 (dd, J = 15.0,
3.8 Hz, 1H), 2.65 (dd, J = 15.0, 6.2 Hz, 1H), 2.49 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 172.9,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 24
1
2
3
4
5
6
7
8
9
145.7, 137.9, 134.9, 134.6, 132.6, 131.3, 131.3, 129.9, 129.9, 129.3, 129.0, 128.4, 128.4, 128.2,
128.0, 128.0, 126.8, 126.7, 125.6, 107.7, 63.8, 47.0, 29.6, 21.7. HRMS (ESIꢀTOF) m/z [M ꢀ H]ꢀ
calcd for C25H20ClN2O3S 463.0883, found 463.0888. [α]20D = +18 (c = 0.08, CHCl3). The product
was analyzed by HPLC to determine the enantiomeric excess: 95% e.e. (ODꢀH, hexane/iꢀPrOH =
70/30, detector: 254 nm, flow rate: 1 mL/min), t1 (major) = 13.8 min, t2 (minor) = 20.4 min.
(1S,10bS)ꢀ1ꢀ(4ꢀbromobenzyl)ꢀ3ꢀtosylꢀ1,10bꢀdihydropyrazolo[5,1ꢀa]isoquinolinꢀ2(3H)ꢀone (3g):
Yellow viscous oil (40.7 mg, 80% yield). 1H NMR (500 MHz, CDCl3) δ 7.80 (d, J = 8.3 Hz, 2H),
7.32ꢀ7.29 (m, 3H), 7.28ꢀ7.27 (m, 1H), 7.24 (t, J = 7.5 Hz, 1H), 7.07 (t, J = 7.5 Hz, 1H), 7.01 (d, J
= 7.5 Hz, 1H), 6.97 (d, J = 8.3 Hz, 2H), 6.79 (d, J = 7.5 Hz, 1H), 6.30 (d, J = 7.9 Hz, 1H), 5.70 (d,
J = 7.9 Hz, 1H), 3.91 (d, J = 12.4 Hz, 1H), 3.72 (ddd, J = 12.4, 6.2, 3.9 Hz, 1H), 2.94 (dd, J = 15.0,
3.9 Hz, 1H), 2.63 (dd, J = 14.9, 6.2 Hz, 1H), 2.50 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 172.9,
145.7, 137.9, 135.4, 134.6, 131.6, 131.6, 131.4, 131.4, 129.9, 129.9, 129.3, 129.0, 128.2, 128.0,
128.0, 126.8, 126.7, 125.6, 120.7, 107.7, 63.8, 46.9, 29.7, 21.8. HRMS (ESIꢀTOF) m/z [M ꢀ H]ꢀ
calcd for C25H20BrN2O3S 507.0378, found 507.0390. [α]20D = +22 (c = 0.10, CHCl3). The product
was analyzed by HPLC to determine the enantiomeric excess: 96% e.e. (ODꢀH, hexane/iꢀPrOH =
70/30, detector: 254 nm, flow rate: 1 mL/min), t1 (major) = 14.9 min, t2 (minor) = 22.1 min.
(1S,10bS)ꢀ1ꢀ(3ꢀbromobenzyl)ꢀ3ꢀtosylꢀ1,10bꢀdihydropyrazolo[5,1ꢀa]isoquinolinꢀ2(3H)ꢀone (3h):
Yellow viscous oil (39.7 mg, 78% yield). 1H NMR (500 MHz, CDCl3) δ 7.83 (d, J = 8.3 Hz, 2H),
7.35ꢀ7.32 (m, 1H), 7.31 (s, 1H), 7.30 (d, J = 1.6 Hz, 1H), 7.28 (d, J = 1.5 Hz, 1H), 7.26 (d, J = 6.9
Hz, 1H), 7.23 (dd, J = 7.6, 1.1 Hz, 1H), 7.07 (dd, J = 10.1, 4.9 Hz, 2H), 7.01 (d, J = 7.5 Hz, 1H),
6.77 (d, J = 7.5 Hz, 1H), 6.31 (d, J = 7.9 Hz, 1H), 5.70 (d, J = 7.9 Hz, 1H), 3.92 (d, J = 12.4 Hz,
1H), 3.73 (ddd, J = 12.3, 6.5, 4.2 Hz, 1H), 2.84 (dd, J = 14.9, 4.2 Hz, 1H), 2.70 (dd, J = 14.9, 6.6
Hz, 1H), 2.48 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 172.9, 145.6, 139.0, 137.7, 134.5, 132.7,
130.0, 130.0, 129.9, 129.8, 129.4, 129.0, 128.4, 128.1, 128.1, 128.0, 126.8, 126.8, 125.6, 122.4,
107.8, 64.6, 46.7, 29.7, 21.8. HRMS (ESIꢀTOF) m/z [M + H]+ calcd for C25H22BrN2O3S 509.0535,
found 509.0521. [α]20D = +18 (c = 0.14, CHCl3). The product was analyzed by HPLC to determine
the enantiomeric excess: 96% e.e. (ODꢀH, hexane/iꢀPrOH = 70/30, detector: 254 nm, flow rate: 1
mL/min), t1 (major) = 16.3 min, t2 (minor) = 24.4 min.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(1S,10bS)ꢀ1ꢀ(2ꢀbromobenzyl)ꢀ3ꢀtosylꢀ1,10bꢀdihydropyrazolo[5,1ꢀa]isoquinolinꢀ2(3H)ꢀone (3i):
Yellow viscous oil (38.2 mg, 75% yield). 1H NMR (600 MHz, CDCl3) δ 7.98 (d, J = 8.3 Hz, 2H),
ACS Paragon Plus Environment

Page 17 of 24
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
7.42 ꢀ 7.38 (m, 3H), 7.30 (dd, J = 7.7, 1.4 Hz, 1H), 7.18 (td, J = 7.5, 1.0 Hz, 1H), 7.11 (td, J = 7.6,
1.1 Hz, 1H), 6.99 (ddd, J = 11.9, 9.3, 4.6 Hz, 3H), 6.73 (d, J = 7.4 Hz, 1H), 6.26 (d, J = 7.9 Hz,
1H), 5.69 (d, J = 7.9 Hz, 1H), 3.94 (d, J = 12.4 Hz, 1H), 3.85 (ddd, J = 12.5, 6.9, 5.9 Hz, 1H), 2.74
(d, J = 6.3 Hz, 2H), 2.50 (s, 3H). 13C NMR (151 MHz, CDCl3) δ 173.9, 145.8, 137.5, 136.6, 134.7,
132.7, 131.7, 130.1, 130.1, 129.3, 129.0, 128.3 , 128.3, 128.3, 127.8, 127.2, 127.2, 126.8, 125.3,
124.3, 108.0, 66.6, 44.7, 31.5, 21.9. HRMS (ESIꢀTOF) m/z [M + H]+ calcd for C25H22BrN2O3S
509.0535, found 509.0531. [α]20D = +16 (c = 0.04, CHCl3). The product was analyzed by HPLC to
determine the enantiomeric excess: 96% e.e. (ODꢀH, hexane/iꢀPrOH = 70/30, detector: 254 nm,
flow rate: 1 mL/min), t1 (major) = 13.7 min, t2 (minor) = 18.3 min.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(1S,10bS)ꢀ1ꢀ(furanꢀ2ꢀylmethyl)ꢀ3ꢀtosylꢀ1,10bꢀdihydropyrazolo[5,1ꢀa]isoquinolinꢀ2(3H)ꢀone (3j):
Yellow viscous oil (33.6 mg, 80% yield). 1H NMR (600 MHz, CDCl3) δ 7.76 (d, J = 8.3 Hz, 2H),
7.24 (d, J = 8.1 Hz, 2H), 7.20 (td, J = 7.4, 1.4 Hz, 1H), 7.11 (d, J = 1.1 Hz, 1H), 7.07 (ddd, J =
20.9, 10.5, 3.9 Hz, 2H), 6.97 (d, J = 7.5 Hz, 1H), 6.28 (d, J = 7.9 Hz, 1H), 6.19 (dd, J = 3.0, 1.9
Hz, 1H), 6.01 (d, J = 3.0 Hz, 1H), 5.64 (d, J = 7.9 Hz, 1H), 3.95 (d, J = 12.5 Hz, 1H), 3.61 (ddd, J
= 12.5, 5.1, 3.6 Hz, 1H), 3.07 (dd, J = 15.8, 3.5 Hz, 1H), 2.66 (dd, J = 15.8, 5.2 Hz, 1H), 2.44 (s,
3H). 13C NMR (151 MHz, CDCl3) δ 172.1, 150.5, 145.3, 141.4, 137.7, 134.6, 129.9, 129.9, 129.1,
128.8, 128.4, 128.1, 128.1, 127.0, 127.0, 125.4, 110.5, 109.0, 107.4, 63.4, 46.0, 22.7, 21.8. HRMS
(ESIꢀTOF) m/z [M + H]+ calcd for C23H21N2O4S 421.1222, found 421.1222. [α]20D = +40 (c = 0.16,
CHCl3). The product was analyzed by HPLC to determine the enantiomeric excess: 97% e.e.
(ODꢀH, hexane/iꢀPrOH = 70/30, detector: 254 nm, flow rate: 1 mL/min), t1 (major) = 13.2 min, t2
(minor) = 22.6 min.
(1S,10bS)ꢀ1ꢀethylꢀ3ꢀtosylꢀ1,10bꢀdihydropyrazolo[5,1ꢀa]isoquinolinꢀ2(3H)ꢀone
(3k):
Yellow
viscous oil (27.6 mg, 75% yield). 1H NMR (500 MHz, CDCl3) δ 7.93 (d, J = 7.8 Hz, 2H), 7.35 (d,
J = 7.7 Hz, 2H), 7.19 (t, J = 7.3 Hz, 1H), 7.10ꢀ6.86 (m, 2H), 6.69 (d, J = 7.2 Hz, 1H), 6.27 (d, J =
7.7 Hz, 1H), 5.63 (d, J = 7.7 Hz, 1H), 3.94 (d, J = 12.5 Hz, 1H), 3.38ꢀ3.21 (m, 1H), 2.47 (s, 3H),
1.54 (d, J = 3.7 Hz, 1H), 1.45ꢀ1.30 (m, 1H), 1.26 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 174.0,
145.7, 137.9, 135.0, 129.9, 129.9, 129.2, 129.0, 128.6, 128.2, 128.2, 126.7, 126.5, 125.4, 107.2,
64.3, 46.3, 21.8, 17.5, 9.6. HRMS (ESIꢀTOF) m/z [M + H]+ calcd for C20H21N2O3S 369.1273,
found 369.1275. [α]20 = +130 (c = 0.20, CHCl3). The product was analyzed by HPLC to
D
determine the enantiomeric excess: 95% e.e. (ODꢀH, hexane/iꢀPrOH = 70/30, detector: 254 nm,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 24
1
2
3
4
flow rate: 1 mL/min), t1 (major) = 9.7 min, t2 (minor) = 12.8 min.
5
6
7
8
(1S,10bS)ꢀ1ꢀbutylꢀ3ꢀtosylꢀ1,10bꢀdihydropyrazolo[5,1ꢀa]isoquinolinꢀ2(3H)ꢀone (3l): Yellow
viscous oil (29.7 mg, 75% yield). 1H NMR (500 MHz, CDCl3) δ 7.94 (d, J = 8.3 Hz, 2H), 7.36 (d,
J = 8.0 Hz, 2H), 7.23ꢀ7.16 (m, 1H), 7.05 (td, J = 7.5, 1.1 Hz, 1H), 6.97 (d, J = 7.2 Hz, 1H), 6.70 (d,
J = 7.5 Hz, 1H), 6.27 (d, J = 7.9 Hz, 1H), 5.63 (d, J = 7.9 Hz, 1H), 3.94 (d, J = 12.5 Hz, 1H), 3.31
(ddd, J = 12.5, 6.5, 3.9 Hz, 1H), 2.47 (s, 3H), 1.44 ꢀ 1.35 (m, 2H), 1.24ꢀ1.14 (m, 2H), 0.96ꢀ0.86 (m,
2H), 0.81 (t, J = 7.2 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 174.2, 145.7, 137.9, 135.0, 129.9,
129.9, 129.2, 129.0, 128.6, 128.2, 128.2, 126.7, 126.5, 125.4, 107.1, 64.9, 45.5, 27.5, 24.4, 22.8,
21.8, 13.8. HRMS (ESIꢀTOF) m/z [M ꢀ H]ꢀ calcd for C22H23N2O3S 395.1429, found 395.1431.
[α]20D = +142 (c = 0.16, CHCl3). The product was analyzed by HPLC to determine the
enantiomeric excess: 98% e.e. (ODꢀH, hexane/iꢀPrOH = 70/30, detector: 254 nm, flow rate: 1
mL/min), t1 (major) = 7.9 min, t2 (minor) = 10.2 min.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(1S,10bS)ꢀ1ꢀ(cyclohexylmethyl)ꢀ3ꢀtosylꢀ1,10bꢀdihydropyrazolo[5,1ꢀa]isoquinolinꢀ2(3H)ꢀone
(3m): Yellow viscous oil (30.5 mg, 70% yield). 1H NMR (500 MHz, CDCl3) δ 7.96 (d, J = 8.3 Hz,
2H), 7.38 (d, J = 8.0 Hz, 2H), 7.23 (td, J = 7.5, 1.1 Hz, 1H), 7.06 (td, J = 7.5, 1.1 Hz, 1H), 7.00 (d,
J = 7.2 Hz, 1H), 6.77 (d, J = 7.5 Hz, 1H), 6.31 (d, J = 7.9 Hz, 1H), 5.67 (d, J = 7.9 Hz, 1H), 3.85
(d, J = 12.4 Hz, 1H), 3.41 (ddd, J = 12.1, 7.8, 4.1 Hz, 1H), 2.49 (s, 3H), 1.67ꢀ1.49 (m, 5H),
1.47ꢀ1.32 (m, 4H), 1.13ꢀ1.01 (m, 4H). 13C NMR (126 MHz, CDCl3) δ 174.4, 145.6, 137.9, 134.8,
130.0, 130.0, 129.2, 129.0, 128.4, 128.2, 128.2, 126.8, 126.6, 125.4, 107.4, 66.7, 42.7, 34.4, 33.7,
33.0, 32.5, 26.3, 26.0, 25.9, 21.8. HRMS (ESIꢀTOF) m/z [M + H]+ calcd for C25H29N2O3S
437.1899, found 437.1905. [α]20D = +180 (c = 0.14, CHCl3). The product was analyzed by HPLC
to determine the enantiomeric excess: 97% e.e. (ODꢀH, hexane/iꢀPrOH = 70/30, detector: 254 nm,
flow rate: 1 mL/min), t1 (major) = 7.5 min, t2 (minor) = 9.3 min.
(1S,10bS)ꢀ1ꢀbenzylꢀ7ꢀchloroꢀ3ꢀtosylꢀ1,10bꢀdihydropyrazolo[5,1ꢀa]isoquinolinꢀ2(3H)ꢀone (4b):
Yellow viscous oil (27.9 mg, 60% yield). 1H NMR (600 MHz, CDCl3) δ 7.80 (d, J = 8.2 Hz, 1H),
7.27 (s, 1H), 7.26 (s, 1H), 7.22 (d, J = 8.1 Hz, 1H), 7.16 (dt, J = 5.4, 4.1 Hz, 3H), 7.05ꢀ7.00 (m,
2H), 6.92 (t, J = 7.8 Hz, 1H), 6.61 (d, J = 7.5 Hz, 1H), 6.36 (d, J = 8.1 Hz, 1H), 6.05 (d, J = 8.1 Hz,
1H), 3.95 (d, J = 12.4 Hz, 1H), 3.74 (ddd, J = 12.3, 6.4, 4.1 Hz, 1H), 2.92 (dd, J = 15.0, 4.0 Hz,
1H), 2.70 (dd, J = 15.1, 6.4 Hz, 1H), 2.45 (s, 3H). 13C NMR (151 MHz, CDCl3) δ 172.7, 145.6,
139.3, 136.3, 134.5, 130.6, 130.0, 130.0, 130.0, 129.9, 129.5, 129.5, 128.4, 128.4, 128.1, 128.1,
ACS Paragon Plus Environment

Page 19 of 24
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
127.3, 127.0, 126.7, 125.4, 103.6, 64.2, 46.6, 30.4, 21.8. HRMS (ESIꢀTOF) m/z [M + H]+ calcd
for C25H22ClN2O3S 465.1040, found 465.1043. [α]20D = +8.0 (c = 0.06, CHCl3). The product was
analyzed by HPLC to determine the enantiomeric excess: 98% e.e. (ODꢀH, hexane/iꢀPrOH =
70/30, detector: 254 nm, flow rate: 1 mL/min), t1 (major) = 23.7 min, t2 (minor) = 31.0 min.
(1S,10bS)ꢀ1ꢀbenzylꢀ7ꢀbromoꢀ3ꢀtosylꢀ1,10bꢀdihydropyrazolo[5,1ꢀa]isoquinolinꢀ2(3H)ꢀone (4c):
Yellow viscous oil (33.1 mg, 65% yield). 1H NMR (600 MHz, CDCl3) δ 7.82 (d, J = 8.3 Hz, 2H),
7.42 (d, J = 7.5 Hz, 1H), 7.29 (s, 1H), 7.28ꢀ7.26 (m, 1H), 7.18 (d, J = 6.8 Hz, 3H), 7.10ꢀ6.99 (m,
2H), 6.86 (t, J = 7.8 Hz, 1H), 6.66 (d, J = 7.5 Hz, 1H), 6.36 (d, J = 8.1 Hz, 1H), 6.04 (d, J = 8.1 Hz,
1H), 3.94 (d, J = 12.4 Hz, 1H), 3.77 (ddd, J = 12.3, 6.4, 4.1 Hz, 1H), 2.94 (dd, J = 15.1, 4.0 Hz,
1H), 2.71 (dd, J = 15.1, 6.5 Hz, 1H), 2.47 (s, 3H). 13C NMR (151 MHz, CDCl3) δ 172.3, 145.2,
139.2, 135.9, 134.0, 132.9, 129.6, 129.5, 129.5, 129.1, 129.1, 128.2, 128.0, 128.0, 127.7, 127.7,
127.1, 126.3, 125.7, 120.6, 105.7 , 63.8, 46.1, 30.0, 21.4. HRMS (ESIꢀTOF) m/z [M ꢀ H]ꢀ calcd for
C25H20BrN2O3S 507.0378, found 507.0383. [α]20D = +10 (c = 0.08, CHCl3). The product was
analyzed by HPLC to determine the enantiomeric excess: 97% e.e. (ODꢀH, hexane/iꢀPrOH =
70/30, detector: 254 nm, flow rate: 1 mL/min), t1 (major) = 19.5 min, t2 (minor) = 25.8 min.
(1S,10bS)ꢀ1ꢀbenzylꢀ8ꢀmethylꢀ3ꢀtosylꢀ1,10bꢀdihydropyrazolo[5,1ꢀa]isoquinolinꢀ2(3H)ꢀone (4d):
Yellow viscous oil (32.0 mg, 72% yield). 1H NMR (500 MHz, CDCl3) δ 7.81 (d, J = 8.3 Hz, 2H),
7.26 (d, J = 8.1 Hz, 2H), 7.19 (dd, J = 5.0, 2.1 Hz, 3H), 7.08 (dd, J = 7.2, 2.1 Hz, 2H), 6.90ꢀ6.79
(m, 2H), 6.69 (d, J = 7.6 Hz, 1H), 6.29 (d, J = 7.9 Hz, 1H), 5.65 (d, J = 7.9 Hz, 1H), 3.94 (d, J =
12.4 Hz, 1H), 3.69 (ddd, J = 12.3, 6.6, 3.7 Hz, 1H), 2.96 (dd, J = 14.9, 3.7 Hz, 1H), 2.68 (dd, J =
14.9, 6.6 Hz, 1H), 2.47 (s, 3H), 2.30 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 173.4, 145.4, 139.0,
137.8, 136.7, 134.6, 129.9, 129.9, 129.7, 129.7, 128.8, 128.4, 128.4, 128.1, 128.1, 127.2, 126.8,
126.6, 126.3, 125.4, 107.7, 64.0, 47.0, 30.3, 21.8, 21.1. HRMS (ESIꢀTOF) m/z [M + H]+ calcd for
C26H25N2O3S 445.1586, found 445.1584. [α]20D = +30 (c = 0.16, CHCl3). The product was
analyzed by HPLC to determine the enantiomeric excess: 92% e.e. (ODꢀH, hexane/iꢀPrOH =
70/30, detector: 254 nm, flow rate: 1 mL/min), t1 (major) = 14.9 min, t2 (minor) = 18.2 min
(1S,10bS)ꢀ1ꢀbenzylꢀ8ꢀfluoroꢀ3ꢀtosylꢀ1,10bꢀdihydropyrazolo[5,1ꢀa]isoquinolinꢀ2(3H)ꢀone (4e):
Yellow viscous oil (31.4 mg, 70% yield). 1H NMR (500 MHz, CDCl3) δ 7.84 (d, J = 8.3 Hz, 2H),
7.30 (s, 2H), 7.19 (t, J = 5.7 Hz, 3H), 7.04 (dd, J = 7.4, 1.8 Hz, 2H), 6.74ꢀ6.65 (m, 3H), 6.36 (d, J
= 7.9 Hz, 1H), 5.64 (d, J = 7.9 Hz, 1H), 3.97 (d, J = 12.3 Hz, 1H), 3.72 (ddd, J = 12.3, 6.4, 4.2 Hz,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 24
1
2
3
4
5
6
7
8
9
1H), 2.92 (dd, J = 15.0, 4.2 Hz, 1H), 2.74 (dd, J = 15.0, 6.4 Hz, 1H), 2.48 (s, 3H). 13C NMR (126
MHz, CDCl3) δ 173.0, 145.6, 139.0, 136.4, 134.6, 131.3, 131.2, 130.0, 130.0, 129.5, 129.5, 128.5,
128.5, 128.4, 128.1, 128.1, 126.7, 123.8, 112.9, 112.5, 106.8, 64.0, 46.8, 30.5, 21.8. HRMS
(ESIꢀTOF) m/z [M + H]+ calcd for C25H22FN2O3S 449.1335, found 449.1319. [α]20D = +10 (c =
0.04, CHCl3). The product was analyzed by HPLC to determine the enantiomeric excess: 97% e.e.
(ODꢀH, hexane/iꢀPrOH = 70/30, detector: 254 nm, flow rate: 1 mL/min), t1 (major) = 21.5 min, t2
(minor) = 25.6 min.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(1S,10bS)ꢀ1ꢀbenzylꢀ8ꢀchloroꢀ3ꢀtosylꢀ1,10bꢀdihydropyrazolo[5,1ꢀa]isoquinolinꢀ2(3H)ꢀone (4f):
Yellow viscous oil (33.0 mg, 71% yield). 1H NMR (500 MHz, CDCl3) δ 7.82 (d, J = 8.2 Hz, 2H),
7.29 (s, 1H), 7.28 (s, 1H), 7.19 (q, J = 5.9 Hz, 3H), 7.04 (d, J = 6.2 Hz, 2H), 7.01 ꢀ 6.95 (m, 2H),
6.66 (d, J = 8.7 Hz, 1H), 6.34 (d, J = 7.9 Hz, 1H), 5.62 (d, J = 7.9 Hz, 1H), 3.96 (d, J = 12.4 Hz,
1H), 3.72 (ddd, J = 12.3, 6.4, 4.1 Hz, 1H), 2.93 (dd, J = 15.0, 4.0 Hz, 1H), 2.71 (dd, J = 15.0, 6.4
Hz, 1H), 2.48 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 172.3, 145.1, 138.6, 135.8, 134.5, 134.0,
130.3, 129.5, 129.5, 129.0, 129.0, 128.0, 128.0, 127.6, 127.6, 127.6, 126.2, 126.0, 125.9, 124.8,
106.0, 63.3, 46.3, 29.9, 21.3. HRMS (ESIꢀTOF) m/z [M + H]+ calcd for C25H22ClN2O3S 465.1040,
found 465.1039. [α]20D = +14 (c = 0.12, CHCl3). The product was analyzed by HPLC to determine
the enantiomeric excess: 95% e.e. (ODꢀH, hexane/iꢀPrOH = 70/30, detector: 254 nm, flow rate: 1
mL/min), t1 (major) = 21.5 min, t2 (minor) = 25.6 min.
(1S,10bS)ꢀ1ꢀbenzylꢀ8ꢀbromoꢀ3ꢀtosylꢀ1,10bꢀdihydropyrazolo[5,1ꢀa]isoquinolinꢀ2(3H)ꢀone (4g):
Yellow viscous oil (38.2 mg, 75% yield). 1H NMR (600 MHz, CDCl3) δ 7.81 (d, J = 8.2 Hz, 2H),
7.28 (s, 1H), 7.27ꢀ7.26 (m, 1H), 7.22ꢀ7.15 (m, 3H), 7.15ꢀ7.10 (m, 2H), 7.03 (d, J = 6.7 Hz, 2H),
6.59 (d, J = 8.6 Hz, 1H), 6.33 (d, J = 7.9 Hz, 1H), 5.60 (d, J = 7.9 Hz, 1H), 3.94 (d, J = 12.4 Hz,
1H), 3.72 (ddd, J = 12.3, 6.4, 4.1 Hz, 1H), 2.93 (dd, J = 15.0, 3.9 Hz, 1H), 2.70 (dd, J = 15.0, 6.4
Hz, 1H), 2.47 (s, 3H). 13C NMR (151 MHz, CDCl3) δ 172.3, 145.2, 138.7, 135.8, 134.1, 130.6,
129.5, 129.5, 129.1, 129.1, 128.9, 128.0, 128.0, 127.9, 127.8, 127.7, 127.7, 126.6, 126.3, 122.7,
106.0, 63.4, 46.3, 29.3, 21.4. HRMS (ESIꢀTOF) m/z [M + Na]+ calcd for C25H21BrN2O3SNa
531.0354, found 531.0354. [α]20D = +7.5 (c = 0.04, CHCl3). The product was analyzed by HPLC
to determine the enantiomeric excess: 98% e.e. (ODꢀH, hexane/iꢀPrOH = 70/30, detector: 254 nm,
flow rate: 1 mL/min), t1 (major) = 22.1 min, t2 (minor) = 26.1 min.
ACS Paragon Plus Environment

Page 21 of 24
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
(1S,10bS)ꢀ1ꢀbenzylꢀ9ꢀchloroꢀ3ꢀtosylꢀ1,10bꢀdihydropyrazolo[5,1ꢀa]isoquinolinꢀ2(3H)ꢀone (4h):
Yellow viscous oil (30.2 mg, 65% yield). 1H NMR (500 MHz, CDCl3) δ 7.83 (d, J = 8.3 Hz, 2H),
7.30 (d, J = 8.0 Hz, 2H), 7.19 (dd, J = 5.0, 1.9 Hz, 3H), 7.15 (dd, J = 8.1, 2.1 Hz, 1H), 7.04 (dd, J
= 6.5, 2.9 Hz, 2H), 6.90 (d, J = 8.1 Hz, 1H), 6.67 (d, J = 2.0 Hz, 1H), 6.31 (d, J = 7.9 Hz, 1H),
5.65 (d, J = 7.9 Hz, 1H), 3.91 (d, J = 12.4 Hz, 1H), 3.75 (ddd, J = 12.4, 6.2, 4.5 Hz, 1H), 2.92 (dd,
J = 15.1, 4.5 Hz, 1H), 2.78 (dd, J = 15.1, 6.2 Hz, 1H), 2.49 (s, 3H). 13C NMR (126 MHz, CDCl3) δ
172.8, 145.7, 138.2, 136.2, 134.5, 131.9, 130.0, 130.0, 129.9, 129.4, 129.4, 129.1, 128.5, 128.5,
128.1, 128.1, 127.5, 127.2, 126.8, 126.5, 106.7, 64.1, 46.6, 30.6, 21.8. HRMS (ESIꢀTOF) m/z [M
+ H]+ calcd for C25H22ClN2O3S 465.1040, found 465.1035. [α]20D = +10 (c = 0.12, CHCl3). The
product was analyzed by HPLC to determine the enantiomeric excess: 97% e.e. (ODꢀH,
hexane/iꢀPrOH = 70/30, detector: 254 nm, flow rate: 1 mL/min), t1 (major) = 17.5 min, t2 (minor)
= 28.6 min.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(1S,10bS)ꢀ1ꢀbenzylꢀ9ꢀbromoꢀ3ꢀtosylꢀ1,10bꢀdihydropyrazolo[5,1ꢀa]isoquinolinꢀ2(3H)ꢀone (4i):
Yellow viscous oil (38.2 mg, 75% yield). 1H NMR (600 MHz, CDCl3) δ 7.83 (d, J = 8.2 Hz, 2H),
7.32ꢀ7.28 (m, 3H), 7.19 (dd, J = 5.0, 1.7 Hz, 3H), 7.06ꢀ6.97 (m, 2H), 6.82 (dd, J = 18.3, 4.7 Hz,
2H), 6.32 (d, J = 7.8 Hz, 1H), 5.63 (d, J = 7.9 Hz, 1H), 3.89 (d, J = 12.4 Hz, 1H), 3.82ꢀ3.68 (m,
1H), 2.91 (dd, J = 15.1, 4.4 Hz, 1H), 2.78 (dd, J = 15.1, 6.2 Hz, 1H), 2.49 (s, 3H). 13C NMR (151
MHz, CDCl3) δ 172.3, 145.3, 137.9, 135.7, 134.1, 131.6, 129.7, 129.6, 129.6, 129.5, 129.0, 129.0,
128.1, 128.1, 127.6, 127.6, 127.5, 126.4, 126.3, 119.3, 106.3, 63.5, 46.2, 30.1, 21.4. HRMS
(ESIꢀTOF) m/z [M ꢀ H]ꢀ calcd for C25H20BrN2O3S 507.0378, found 507.0386. [α]20D = +9.5 (c =
0.10, CHCl3). The product was analyzed by HPLC to determine the enantiomeric excess: 98% e.e.
(ODꢀH, hexane/iꢀPrOH = 70/30, detector: 254 nm, flow rate: 1 mL/min), t1 (major) = 14.4 min, t2
(minor) = 22.2 min.
(1S,10bS)ꢀ1ꢀbenzylꢀ10ꢀbromoꢀ3ꢀtosylꢀ1,10bꢀdihydropyrazolo[5,1ꢀa]isoquinolinꢀ2(3H)ꢀone (4j):
Yellow viscous oil (30.5 mg, 60% yield). 1H NMR (500 MHz, CDCl3) δ 7.94 (d, J = 8.3 Hz, 2H),
7.36 (d, J = 8.1 Hz, 2H), 7.09 (dd, J = 7.7, 2.3 Hz, 3H), 7.04 (dd, J = 8.0, 1.1 Hz, 1H), 6.99 (t, J =
7.7 Hz, 1H), 6.91ꢀ6.83 (m, 3H), 6.57 (d, J = 7.8 Hz, 1H), 5.49 (d, J = 7.9 Hz, 1H), 4.66 (d, J = 6.2
Hz, 1H), 3.17 (dd, J = 13.8, 7.8 Hz, 1H), 3.03 (dd, J = 13.8, 7.3 Hz, 1H), 2.94 (dd, J = 13.9, 7.1
Hz, 1H), 2.46 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 173.9, 146.1, 139.4, 136.9, 134.4, 133.5,
130.8, 130.3, 130.1, 130.1, 128.6, 128.6, 128.3, 128.3, 128.2, 128.2, 126.4, 126.3, 124.2, 122.8,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 24
1
2
3
4
5
6
7
8
9
105.0, 63.2, 49.4, 33.2, 21.8. HRMS (ESIꢀTOF) m/z [M ꢀ H]ꢀ calcd for C25H20BrN2O3S 507.0378,
found 507.0373. [α]20D = +8.5 (c = 0.06, CHCl3). The product was analyzed by HPLC to
determine the enantiomeric excess: 96% e.e. (ODꢀH, hexane/iꢀPrOH = 70/30, detector: 254 nm,
flow rate: 1 mL/min), t1 (major) = 13.8 min, t2 (minor) = 35.2 min.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(1S,10bS)ꢀ1ꢀbenzylꢀ3ꢀtosylꢀ1,5,6,10bꢀtetrahydropyrazolo[5,1ꢀa]isoquinolinꢀ2(3H)ꢀone
(5a):
1
White viscous oil (51.9 mg, 60% yield). H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 8.3 Hz, 2H),
7.23 (s, 1H), 7.19 (dd, J = 7.1, 4.0 Hz, 4H), 7.17ꢀ7.12 (m, 2H), 7.10 (dd, J = 9.9, 4.5 Hz, 3H), 4.05
(d, J = 12.3 Hz, 1H), 3.74ꢀ3.59 (m, 1H), 3.37ꢀ3.11 (m, 4H), 3.00ꢀ2.80 (m, 2H), 2.42 (s, 3H). 13C
NMR (101 MHz, CDCl3) δ 174.0, 144.9, 136.4, 135.1, 133.5, 133.3, 129.9, 129.9, 129.7, 129.7,
129.0, 128.4, 128.4, 128.0, 128.0, 127.5, 126.8, 126.6, 126.2, 61.2, 51.1, 48.1, 31.7, 29.1, 21.7.
HRMS (ESIꢀTOF) m/z [M + H]+ calcd for C25H25N2O3S 433.1586, found 433.1579. The product
was analyzed by HPLC to determine the enantiomeric excess: 95% e.e. (ODꢀH, hexane/iꢀPrOH =
70/30, detector: 254 nm, flow rate: 1 mL/min), t1 (major) = 12.5 min, t2 (minor) = 16.9 min.
(1S,10bS)ꢀ1ꢀ(4ꢀbromobenzyl)ꢀ3ꢀtosylꢀ1,5,6,10bꢀtetrahydropyrazolo[5,1ꢀa]isoquinolinꢀ2(3H)ꢀone
(5g): White viscous oil (63.4 mg, 62% yield). 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 8.3 Hz,
2H), 7.26 (s, 1H), 7.25 (s, 1H), 7.19 (dd, J = 11.4, 4.5 Hz, 5H), 7.10 (d, J = 7.6 Hz, 1H), 6.99 (d, J
= 8.4 Hz, 2H), 3.96 (d, J = 12.4 Hz, 1H), 3.76ꢀ3.58 (m, 1H), 3.23 (dddd, J = 12.5, 10.1, 9.3, 3.4
Hz, 4H), 2.98ꢀ2.78 (m, 2H), 2.46 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 173.7, 145.2, 135.2,
135.0, 133.6, 133.2, 131.9, 131.9, 131.4, 131.4, 129.7, 129.7, 129.2, 129.2, 127.9, 127.7, 126.6,
126.3, 120.8, 60.8, 51.2, 48.0, 31.0, 29.2, 21.8. HRMS (ESIꢀTOF) m/z [M + H]+ calcd for
C25H24BrN2O3S 511.0691, found 511.0693. The product was analyzed by HPLC to determine the
enantiomeric excess: 97% e.e. (ODꢀH, hexane/iꢀPrOH = 70/30, detector: 254 nm, flow rate: 1
mL/min), t1 (major) = 14.8 min, t2 (minor) = 33.8 min.
ASSOCIATED CONTENT
Supporting Information
Information not shown in table 3, 1H NMR and 13C NMR spectra, HPLC spectra of products.
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: jinyixu@china.com.
*Eꢀmail: hliu@simm.ac.cn.
ACS Paragon Plus Environment

Page 23 of 24
The Journal of Organic Chemistry
1
2
3
4
5
Author Contributions
§Pengfei Zhang and Yu Zhou contributed equally to this work.
6
7
Notes:
8
9
The authors declare no competing financial interest.
ACKNOWLEDGMENT
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
We are grateful to the National Natural Science Foundation of China (No. 21672232, 81673306,
81703348) for financial support.
REFERENCES
(1) (a) Xu, T.; Alper, H. Org. Lett. 2015, 17, 1569ꢀ1572. (b) Zuo, Z.; Wang, H.; Fan, L.; Liu, J.; Wang, Y.; Luan, X.
Angew. Chem., Int. Edit. 2017, 56, 2767ꢀ2771. (c) Liu, J.; Xu, X.; Li, J.; Liu, B.; Jiang, H.; Yin, B. Chem. Commun.
2016, 52, 9550ꢀ9553. (d) Zhang, Z.; Tang, X.; Dolbier, W. Org. Lett. 2016, 18, 1048ꢀ1051. (e) Kim, C.; Oguma, T.;
Fujitomo, C.; Uchida, T.; Katsuki, T. Chem. Lett. 2016, 45, 1262ꢀ1264. (f) Seoane, A.; Casanova, N.; Quinones, N.;
Mascarenas, J.; Gulias, M. J. Am. Chem. Soc. 2014, 136, 7607ꢀ7610. (g) James, M.; Cuthbertson, J.; O'Brien, P.;
Taylor, R.; Unsworth, W. Angew. Chem., Int. Edit. 2015, 54, 7640ꢀ7643.
(2) (a) Arduengo, A.; Harlow, R.; Kline, M. J. Am. Chem. Soc. 1991, 113, 361ꢀ363. (b) Hopkinson, M.; Richter, C.;
Schedler, M.; Glorius, F. Nature. 2014, 510, 485ꢀ496.
(3) (a) Wang, M.; Huang, Z.; Xu, J.; Chi, Y. J. Am. Chem. Soc. 2014, 136, 1214ꢀ1217. (b) Cheng, J.; Huang, Z.;
Chi, Y. Angew. Chem., Int. Edit. 2013, 52, 8592ꢀ8596. (c) Mo, J.; Shen, L.; Chi, Y. Angew. Chem., Int. Edit. 2013,
52, 8588ꢀ8591.
(4) (a) Enders, D.; Niemeier, O.; Henseler, A. Chem. Rev. 2007, 107, 5606ꢀ5655. (b) Izquierdo, J.; Hutson, G.;
Cohen, D.; Scheidt, K. Angew. Chem., Int. Edit. 2012, 51, 11686ꢀ11698. (c) Vora, H.; Wheeler, P.; Rovis, T. Adv.
Synth. Catal. 2012, 354, 1617ꢀ1639.
(5) (a) Marion, N.; DiezꢀGonzalez, S.; Nolan, S. Angew. Chem., Int. Edit. 2007, 46, 2988ꢀ3000. (b) Cohen, D.;
Scheidt, K. Chem. Sci. 2012, 3, 53ꢀ57. (c) Ryan, S.; Candish, L.; Lupton, D. Chem. Soc. Rev. 2013, 42, 4906ꢀ4917.
(6) (a) JanssenꢀMuller, D.; Fleige, M.; Schluns, D.; Wollenburg, M.; Daniliuc, C.; Neugebauer, J.; Glorius, F. Acs.
Catal. 2016, 6, 5735ꢀ5739. (b) Guo, C.; Fleige, M.; JanssenꢀMuller, D.; Daniliuc, C.; Glorius, F. Nat. Chem. 2015,
7, 842ꢀ847. (c) Xu, J.; Zheng, S.; Zhang, J.; Liu, X.; Tan, B. Angew. Chem., Int. Edit. 2016, 55, 11834ꢀ11839.
(7) (a) Xu, X.; Zavalij, P.; Doyle, M. Angew. Chem., Int. Edit. 2013, 52, 12664ꢀ12668. (b) Zhou, Y.; Li, J.; Ling, L.;
Liao, S.; Sun, X.; Li, Y.; Wang, L.; Tang, Y. Angew. Chem., Int. Edit. 2013, 52, 1452ꢀ1456.
(8) Yao, H.; Zhou, Y.; Chen, X.; Zhang, P.; Xu, J.; Liu, H. J. Org. Chem. 2016, 81, 8888ꢀ8899.
(9) Zhou, Y.; Yang, Q.; Shen, J.; Chen, X.; Peng, Y.; Gong, Y. J. Org. Chem. 2015, 80, 1446ꢀ1456.
(10) Michael, J. Nat. Prod. Rep. 2008, 25, 139ꢀ165.
(11) (a) Sohn, S.; Rosen, E.; Bode, J. J .Am. Chem. Soc. 2004, 126, 14370ꢀ14371. (b) Ryan, S.; Candish, L.;
Lupton, D. J. Am. Chem. Soc. 2009, 131, 14176ꢀ14177. (c) Ni, Q.; Zhang, H.; Grossmann, A.; Loh, C.; Merkens,
C.; Enders, D. Angew. Chem., Int. Edit. 2013, 52, 13562ꢀ13566. (d) Nair, V.; Vellalath, S.; Poonoth, M.; Suresh, E.
J. Am. Chem. Soc. 2006, 128, 8736ꢀ8737. (e) Gao, Z.; Chen, X.; Cheng, J.; Liao, W.; Ye, S. Chem. Commun. 2015,
51, 9328ꢀ9331.
(12) Nakano, Y.; Lupton, D. Angew. Chem., Int. Edit. 2016, 55, 3135ꢀ3139.
(13) Fu, Z.; Xu, J.; Zhu, T.; Leong, W.; Chi, Y. Nat. Chem. 2013, 5, 835ꢀ839.
(14) (a) Fu, Z.; Jiang, K.; Zhu, T.; Torres, J.; Chi, Y. Angew. Chem., Int. Edit. 2014, 53, 6506ꢀ6510. (b) Jin, Z.;
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 24
1
2
3
4
5
6
7
8
Chen, S.; Wang, Y.; Zheng, P.; Yang, S.; Chi, Y. Angew. Chem., Int. Edit. 2014, 53, 13506ꢀ13509.
(15) (a) Hao, L.; Du, Y.; Lv, H.; Chen, X.; Jiang, H.; Shao, Y.; Chi, Y. Org. Lett. 2012, 14, 2154ꢀ2157. (b) Chen, S.;
Hao, L.; Zhang, Y.; Tiwari, B.; Chi, Y. Org. Lett. 2013, 15, 5822ꢀ5825. (c) Hao, L.; Chen, S.; Xu, J.; Tiwari, B.; Fu,
Z.; Li, T.; Lim, J.; Chi, Y. Org. Lett. 2013, 15, 4956ꢀ4959. (d) Hesping, L.; Biswas, A.; Daniliuc, C.;
MuckꢀLichtenfeld, C.; Studer, A. Chem. Sci. 2015, 6, 1252ꢀ1257.
9
(16) Flanigan, D.; RomanovꢀMichailidis, F.; White, N.; Rovis, T. Chem. Rev. 2015, 115, 9307ꢀ9387.
(17) (a) Xiao, Y.; Wang, J.; Xia, W.; Shu, S.; Jiao, S.; Zhou, Y.; Liu, H. Org. Lett. 2015, 17, 3850ꢀ3853. (b) Xia, W.;
Yao, H.; Liu, D.; Zhao, L.; Zhou, Y.; Liu, H. Adv. Synth. Catal. 2016, 358, 1864ꢀ1869. (c) Rong, X.; Yao, H.; Xia,
W.; Du, Y.; Zhou, Y.; Liu, H. Acs. Comb. Sci. 2016, 18, 220ꢀ224.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(18) (a) Xiang, L.; Xing, D.; Wang, W.; Wang, R.; Ding, Y.; Du, L. Phytochemistry. 2005, 66, 2595ꢀ2601. (b) Daly,
J.; Witkop, B.; Tokuyama, T.; Nishikawa, T.; Karle, I. Helvetica. Chimica. Acta. 1977, 60, 1128ꢀ1140.
ACS Paragon Plus Environment