Selective synthesis of alkynylated isoquinolines and biisoquinolines via RhIII catalyzed C-H activation/1,3-diyne strategy

Article abstract of DOI:10.1021/acs.joc.7b01867

Described herein is a convenient and highly selective synthesis of alkynylated isoquinolines and biisoquinolines from various aryl ketone O-pivaloyloxime derivatives and 1,3-diynes via rhodium-catalyzed C-H bond activation. In this transformations, alkynylated isoquinolines, 3,4′- and 3,3′-biisoquinolines could be obtained respectively through changing the reaction conditions. Mechanistic investigation revealed that the C-H activation of aryl ketone O-pivaloyloxime was the key step to this reaction.

Full text of DOI:10.1021/acs.joc.7b01867

Subscriber access provided by AUBURN UNIV AUBURN
Article
Selective Synthesis of Alkynylated Isoquinolines and
Biisoquinolines via RhIII Catalyzed C-H Activation/1,3-Diyne Strategy
Ruokun Feng, Hanqi Ning, Han Su, Yuan Gao, Haotian Yin, Yudan Wang, Zhen Yang, and Chen-Ze Qi
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01867 • Publication Date (Web): 11 Sep 2017
Downloaded from http://pubs.acs.org on September 11, 2017
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 free 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 accessible to all
readers and 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.
The Journal of Organic Chemistry 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 22
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Selective Synthesis of Alkynylated Isoquinolines and
Biisoquinolines via RhIII Catalyzed CꢀH
Activation/1,3ꢀDiyne Strategy
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
Ruokun Feng, Hanqi Ning, Han Su, Yuan Gao, Haotian Yin, Yudan Wang, Zhen Yang, ∗ Chenze
Qi∗
Zhejiang Key Laboratory of Alternative Technologies for Fine Chemicals Process, Department of
Chemistry, Shaoxing University, Shaoxing 312000, China
Fax: +86ꢀ575ꢀ88345681; Tel: +86ꢀ575ꢀ88345681
Eꢀmail: fengshenghm@usx.edu.cn; qichenze@usx.edu.cn
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required
according to the journal that you are submitting your paper to)
Table of Content Graphic:
Abstract: Described herein is a convenient and highly selective synthesis of alkynylated isoquinolines
and biisoquinolines from various aryl ketone Oꢀpivaloyloxime derivatives and 1,3ꢀdiynes via
rhodiumꢀcatalyzed CꢀH bond activation. In this transformations, alkynylated isoquinolines, 3,4'ꢀ and
3,3'ꢀbiisoquinolines could be obtained respectively through changing the reaction conditions.
Mechanistic investigation revealed that the CꢀH activation of aryl ketone Oꢀpivaloyloxime was the key
step to this reaction.
INTRODUCTION
Alkynylated isoquinolines and biisoquinolines have been recognized as an important class of
heterocycles which are widely found in numerous bioactive natural products, ligands, and functional
materials (Scheme 1). 1The synthesis of isoquinoline compounds through C−H activation has also been
well developed in recent decade.2 For example, sequential C−H activation/annulation of aromatic
oximes,3 imines,4 hydrazone,5 azines6 and azides7 with internal alkynes catalyzed by Rh, Ru or Co were
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 22
1
2
3
4
5
6
7
8
9
achieved to access isoquinolines (Scheme 2). However, those substrates are limited to internal alkynes.
Moreover, the achievements on alkynylated isoquinolines and biisoquinolines were still less reported.8
1,3ꢀDiynes have emerged as important raw materials for the synthesis of arenes and heteroarenes,
since the found of Glaser coupling reaction in 1869.9 However, there are only a few examples of
synthesis of heterocycles from 1,3ꢀdiynes via the widely used transitionꢀmetal catalysis strategy, due to
its hardly control of the chemselectivity and regioselectivity. 10 Herein, we report the selective synthesis
of alkynylated isoquinolines and biisoquinolines from 1,3ꢀdiynes via rhodiumꢀcatalyzed CꢀH bond
activation.
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
Scheme 1. The potential application of alkynylated isoquinolines and biisoquinolines.
The potential application of alkynylated isoquinolines
R1
TfO
R2, R3 = Ar
N
N
R3
R2
N
HN
R1
benzo[a]phenanthridine derivatives [5g]
Cytoxicity of Sempervirine Analogue [5j]
The potential application of biisoquinolines
N
N
O
N
R
O
N
R
O
O
metal-based molecular shuttle [8]
Scheme 2. The construction of isoquinolines via tandem C−H activation/annulation
RESULTS AND DISCUSSION
In the preliminary investigation, we explored the formation of alkynylated isoquinolines which are
important starting materials for the preparation of benzophenanthridines that are widely used as
distributed alkaloids, DNAꢀchain intercalating reagents, potent antitumor and antiinfectious drugs.11
Initially, we examined the reaction of 1ꢀphenylethanꢀ1ꢀone Oꢀpivaloyl oxime (1a) and
1,4ꢀdiphenylbutaꢀ1,3ꢀdiyne (2a) in the presence of [Cp*RhCl2]2 (5 mol%), AgSbF6 (20 mol%), NaOAc
(2.0
equiv.)
in
DCE
at
50
oC
for
12
h.
Gratifyingly,
the
desired
1ꢀmethylꢀ4ꢀphenylꢀ3ꢀ(phenylethynyl)isoquinoline (3aa) was obtained in 53% yield (Table 1, entry 1).
Importantly, the structure of 3aa was confirmed by singleꢀcrystal Xꢀray analysis (see Supporting
Information).12a Other catalysts were investigated. No desired product was achieved when
[RuCl2(pꢀcymene)]2, and Pd(OAc)2 were used as catalysts (Table 1, entries 2 and 3). In the accordance
with previous experience from our own study, the additives always significantly influence the rhodium
ACS Paragon Plus Environment

Page 3 of 22
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
catalyzed CꢀH activation.13 The absence of AgSbF6 resulted in only 31% yield of 3aa (Table 1, entry 4).
Additives such as AgOAc, AgBF4 and KPF6 were found to be inferior for this transformation,
providing 3aa in 35%, 42%, and 33% yields, respectively (Table1, entries 5ꢀ7). No reaction was
observed in the absence of a base (Table 1, entry 8). It was found that the introduction of Li2CO3 under
otherwise identical conditions improved the yield to 86% (Table1, entry 12). Other bases such as
KOAc, K2CO3, Na2CO3, K3PO4 were failed to give a yield better than Li2CO3 (Table 1, entries 9ꢀ13). It
was observed that DCE was superior to CHCl3, CH2Cl2, MeOH, tꢀAmylOH and DMF used as solvent
(Table 1, entries 14ꢀ18). Lower and higher temperatures were both inferior for this reaction (Table 1,
entries 19ꢀ21). Finally, the optimal reaction conditions were obtained: [Cp*RhCl2]2 (5 mol%), AgSbF6
(20 mol%), Li2CO3 (2.0 equiv.) in DCE (2.0 mL) at 50 oC for 12 h.
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
Table 1 Optimization of the reaction conditionsa
entry
1
catalyst
additive
AgSbF6
AgSbF6
AgSbF6
—
base
solvent
DCE
yield (%)
53
[Cp*RhCl2]2
[RuCl2(pꢀcymene)]2
Pd(OAc)2
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
—
2
DCE
N.R.
N.R.
31
3
DCE
4
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
DCE
5
AgOAc
AgBF4
KPF6
DCE
35
6
DCE
42
7
DCE
33
8
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
DCE
N.R.
48
9
KOAc
K2CO3
Na2CO3
Li2CO3
K3PO4
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
DCE
10
11
12
13
14
15
16
17
18
19
20
21
DCE
43
DCE
45
DCE
DCE
86
38
CHCl3
CH2Cl2
MeOH
tꢀAmylOH
DMF
DCE
54
67
28
N.R.
N.R.
traceb
83c
DCE
DCE
traced
aReaction conditions: 1a (22 mg, 0.1 mmol), 2a (30 mg, 0.15 mmol), catalyst (5 mol%), additive (20
o
b
mol%), base (0.2 mmol), solvent (2 mL), 50 C under air for 12 h. temperature is room temperature.
ctemperature is 60 oC. dtemperature is 100 oC.
With the optimized conditions established, we began to use them for the preparation of
alkynylated isoquinolines with diverse functional groups. Firstly, the reaction of
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 22
1
2
3
4
5
6
7
8
9
1,4ꢀdiphenylbutaꢀ1,3ꢀdiyne 2a with various aryl ketone/aldehyde Oꢀpivaloyloxime derivatives 1 were
examined. Benzaldehyde Oꢀpivaloyl oxime 1b failed to afford the products under the reaction
conditions (Table 2, entry 2). 1ꢀPhenylbutanꢀ1ꢀone Oꢀpivaloyl oxime 1c gave the corresponding
products in lower yields compared with 1ꢀphenylethanꢀ1ꢀone Oꢀpivaloyl oxime 1a (Table 2, entry 3).
Aryl ketone Oꢀpivaloyloxime derivatives bearing electronꢀdonating substituents showed higher
reactivity than those with electronꢀwithdrawing groups (Table 2, entries 4ꢀ9). The steric hindrance
played a key role in the reaction. Orthoꢀsubstituted aryl ketone Oꢀpivaloyloxime derivatives generated
the corresponding products in lower yields compared with paraꢀ and metaꢀ substituted compounds
(Table 2, entries 4ꢀ8). It was worth noting that the compatibility of chloride (Table 2, entries 6 and 8),
bromide (Table 2, entry 9) functional groups offered a great opportunity for further functionalization.
The scope of the reaction with regard to a range of the 1,3ꢀdiynes was evaluated, nextly. We were
pleased to observe that both electronꢀrich and electronꢀdeficient diaryl diyne gave moderate to
excellent reaction yields (Table 2, entries 10ꢀ15). Remarkably, not only diaryl diynes, but also dialkyl
diyne 2h and 2i showed good reactivity and selectivity under the identical conditions (Table 2, entry 16
and 17).
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
Table 2 Synthesis of alkynylated isoquinolinesa
entry substrate 1
substrate 2
product
yield
(%)
1
86
2a
1a
1b
3aa
3ba
2
3
0
2a
2a
59
1c
3ca
ACS Paragon Plus Environment

Page 5 of 22
The Journal of Organic Chemistry
1
2
3
4
5
Me
Me
N
6
7
8
9
4
5
6
7
8
9
82
58
53
89
75
79
2a
Ph
Ph
1d
1e
1f
3da
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
2a
2a
2a
2a
2a
3ea
3fa
3ga
3ha
3ia
1g
1h
1i
R3 = pꢀMePh
10
78
1a
2b
3ab
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 22
1
2
3
4
5
6
7
8
R3 = mꢀMePh
11
82
1a
2c
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
3ac
3ad
3ae
3af
Me
N
R3 = pꢀEtPh
12
91
1a
2d
Et
Et
R3 = pꢀnꢀBuPh
13
14
15
85
68
58
1a
1a
1a
2e
R3 = pꢀMeOPh
2f
R3 = pꢀFPh
2g
3ag
ACS Paragon Plus Environment

Page 7 of 22
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
R3 = nꢀamyl
16
90
1a
2h
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
3ah
R3 = C4H6Cl
17
82
1a
2i
3ai
aReaction conditions 1: 1 (0.1 mmol), 2 (0.15 mmol), [Cp*RhCl2]2 (5 mol%), AgSbF6 (20 mol%), Li2CO3
(0.2 mmol), DCE (2 mL), 50 oC under air for 12 h.
Following these results, we then investigated the preparation of biisoquinolines which were used
as a building block to prepare nonꢀsterically hindering chelates, including amacrocyclic system that
was
widely
used
in
metalꢀbased
molecular
shuttle.14
Firstly,
the
1ꢀmethylꢀ4ꢀphenylꢀ3ꢀ(phenylethynyl)isoquinoline 3aa was reacted with 1ꢀphenylethanꢀ1ꢀone
Oꢀpivaloyl oxime 1a under the optimized conditions. Fortunately, biisoquinoline product 4aa was
achieved in 68% yield. However, two different core structures in 4aa were detected from the analysis
of NMR spectrum which was different from the structure reported by Glorius and coꢀworkers.4 Then,
we tried a oneꢀpot synthesis of biisoquinolines 4. Unforturally, the yield was almost low in the
presence of Li2CO3 or PivONa, although the ration of 1a and 2a was 3:1. To our delight, we achieved
the synthesis of selective biisoquinolines 4 in one pot by using conditions 2 in which trimethylacetic
acid was used instead of base. Various highly selective biisoquinolines 4 were synthesized under this
reaction conditions (Table 3). Xꢀray crystallography of 4ae further confirmed that the structure of the
product was 3,4'ꢀbiisoquinoline,12b which were difficult to preparation from traditional methods (see
Supporting Informantion). Unfortunately, the desired product 4ah was obtained in low yield when
dialkyl diyne 2h was used.
Table 3 Synthesis of 3,4'ꢀbiisoquinolinesa
R2
N
Me
Me
[Cp*RhCl2]2
AgSbF6
R2
Me
N
OPiv
+
N
R1
R2
PivOH, DCE
R1
R2
R1
2
1
4
entry
substrate 1
sbustrate 2
product
yield
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 22
1
2
3
4
5
6
7
8
(%)
78
1
2a
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
1a
4aa
2
71
2a
1d
4da
N
Me
Me
N
3
73
2a
Me
1g
Me
4ga
4
65
2a
1h
4ha
5
62
2a
1i
4ia
ACS Paragon Plus Environment

Page 9 of 22
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
6
7
8
63
65
56
1a
1a
1a
2d
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
4ad
4ae
4af
2e
2f
aReaction conditions 2: 1 (0.2 mmol), 2 (0.1 mmol), [Cp*RhCl2]2 (5 mol%), AgSbF6 (20 mol%), PivOH (0.2
mmol), DCE (2 mL), 50 oC under air for 12 h.
Considering the 3,4'ꢀbiisoquinoline 4ah achieved in low yield under the reaction conditions
developed above, we designed two steps to investigate the selectivity of dialkyl diyne due to its lower
steric
hindrance
than
diaryl
diyne.
In
the
first
place,
the
3ꢀ(heptꢀ1ꢀynꢀ1ꢀyl)ꢀ1ꢀmethylꢀ4ꢀpentylisoquinoline 3ah was prepared under the conditions 1. Then, 3ah
was reacted with 1a in the prescience of [Cp*RhCl2]2 (5 mol%), AgSbF6 (20 mol%), Li2CO3 (0.2
mmol). Remarkably, the biisoquinoline 5ah which has two symmetrical core structures was obtained.
The exact structure was confirmed through NMR and HRMS. By using the stepwise approach, we
developed various nonsymmetrical 3,3'ꢀbiisoquinolines in moderate yields with high chemoꢀ and
regioselectivity under the same conditions as shown in Table 4.
Table 4 Synthesis of 3,3'ꢀbiisoquinolinesa
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 22
1
2
3
R1
4
5
6
7
Me
Me
[Cp*RhCl2]2
AgSbF6
8
9
N
Me
N
OPiv
N
Me
N
+
R1
Li2CO3, DCE
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
3ah
5
1
entry
substrate 1
product
yield (%)
1
53
1a
5ah
2
55
1d
5dh
3
58
1g
5gh
ACS Paragon Plus Environment

Page 11 of 22
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
4
5
6
49
42
51
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
1i
5ih
1j
5jh
1k
5kh
aReaction conditions: 1 (0.1 mmol), 3ah (0.1 mmol), [Cp*RhCl2]2 (5 mol%), AgSbF6 (20 mol%),
Li2CO3 (0.2 mmol), DCE (2 mL), 50 oC under air for 12 h.
To probe the preliminary mechanism of the reaction, the kinetic isotope effect of
1ꢀphenylethanꢀ1ꢀone Oꢀpivaloyl oxime 1a and its pentadeuterate analogue dꢀ1a were studied. A kinetic
isotope effect (KIE) of 2.0 (kH/kD) was observed, demonstrated that the CꢀH cleavage might be
involved in this transformation as rateꢀlimiting step (Scheme 3, eq. 1). Asymmetrical alkyne, such as,
butꢀ1ꢀynꢀ1ꢀylbenzene, was examined under the standard reaction conditions, and the desired
isoquinoline was achieved in 86% yield (Scheme 3, eq. 2). According to the literatures reported by
Fagnou15b and others, 3 the experimental evidence indicated that the reaction might go through a CꢀN
bond formation/NꢀO bond cleavage process. The 3aa and 3ai prepared through the standard condition
could be easily reacted with li, giving the corresponding nonsymmetrical biisoquinolines 4ai and 5ii in
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 22
1
2
3
4
5
6
7
8
9
moderate yields (Scheme 3, eq. 3 and eq. 4). The fact demonstrated that the formation of
biisoquinolines might process to steps.
Scheme 3. The study of mechanism.
H/D Me
D
Me
Me
[Cp*RhCl2]2
AgSbF6
D/H
D/H
D
D
OPiv
OPiv
N
N
(1)
N
or
2a
Li2CO3,
D
DCE, 50 oC, 2h
H/D Ph
3aa or d-3aa
Me
Ph
D
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
KIE = 2.0
1a
1a
1a
d- , 96% D
Me
[Cp*RhCl2]2
AgSbF6
Et
N
OPiv
OPiv
N
(2)
+
Ph
Et
Li2CO3,DCE
50 oC, 12h
2j
Me
3aj 86% yield
,
Me
Me
N
Ph
[Cp*RhCl2]2
AgSbF6
N
N
N
+
(3)
Li2CO3,DCE
50 oC, 12h
Ph
Br
Br
Me
Cl
Ph
3aa
Ph
1i
4ai, 53% yield
Me
Me
Me
[Cp*RhCl2]2
AgSbF6
N
OPiv
N
N
+
Br
(4)
Li2CO3,DCE
50 oC, 12h
Br
N
Me
Cl
Cl
Cl
1i
3ai
5ii, 45% yield
On the basis of these results and literature precedents, 2ꢀ7, 15, 16 a plausible reaction mechanism was
proposed as shown in Scheme 4. First, anion exchange of [Cp*RhCl2]2 with AgSbF6 afforded the
reactive Rh(III) species A, which selectively activates the CꢀH of 1ꢀphenylethanꢀ1ꢀone Oꢀpivaloyl
oxime 1a to form the intermediate B. Subsequent insertion of B to diynes affords the sevenꢀmembered
intermediate C. The firstꢀstep product 3 was gave by CꢀN bond formation and NꢀO bond cleavage of
intermediate C via a redox neutral manner. And the active Rh(III) species was regenerated for the next
catalytic cycle. The intermediate B might be reacted with product 3 to form biisoquinoline 4 in the
presence of trimethylacetic acid. The formation of compound 4 may demonstrate that the order of
migratory insertion is alkynyl, phenyl, isoquinolinyl, alkyl group.
Scheme 4. The proposed mechanism.
ACS Paragon Plus Environment

Page 13 of 22
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
CONCLUSION
In summary, we have developed a novel method to the synthesis of alkynylated isoquinolines,
3,4'ꢀ and 3,3'ꢀbiisoquinolines with high selectivity via rhodiumꢀcatalyzed CꢀH activation/1,3ꢀdiyne
strategy. Various symmetrical and asymmetrical biisoquinolines were obtained in high regioselectivity.
Further studies on the application of CꢀH activation/1,3ꢀdiyne strategy to synthesize useful
bisheterocycles were ongoing in our laboratory.
EXPERIMENTAL SECTION
General The reagents and solvents were purchased from common commercial sources and used
without additional purification, if there is no special version. The starting materials of aryl ketone
Oꢀpivaloyloxime derivatives were prepared according to the known methods.17 NMR spectra were
1
recorded for H NMR at 400 MHz, and 13C NMR at 100 MHz using TMS as internal standard. The
following abbreviations were used to describe peak patterns where appropriate: singlet (s), doublet (d),
triplet (t), quintuplet (q), multiplet (m), doublet of doublet (dd), broad resonances (br). Mass
spectroscopy data of the products were collected on an HRMSꢀEIꢀTOF instrument. UV/vis spectra
were measured on SHIMADZU UVꢀ2550.
General Procedure for Preparation of products 3
A 25 mL sealed tube with a magnetic stir bar was charged with [Cp*RhCl2]2 (5 mol%), AgSbF6
(20 mol%), Li2CO3 (2.0 equiv.), 1 (0.1 mmol), diyne (0.15 mmol), DCE (2.0 mL). Then the sealed tube
o
was sealed and heated to 50 C with stirring for 12 h. After cooling down, the mixture was filtered
through a plug of Celite, and then the residue was concentrated and purified by flash column
chromatography with ethyl acetate (EA) and petroleum ether (Pet) (PE/EA = 50:1) as eluent to afford
the corresponding products.
General Procedure for Preparation of products 4
A 25 mL sealed tube with a magnetic stir bar was charged with [Cp*RhCl2]2 (5 mol%), AgSbF6
(20 mol%), PivOH (2.0 equiv.), 1 (0.2 mmol), diyne (0.1 mmol), DCE (2.0 mL). Then the sealed tube
o
was sealed and heated to 50 C with stirring for 12 h. After cooling down, the mixture was filtered
through a plug of Celite, and then the residue was concentrated and purified by flash column
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 22
1
2
3
4
5
6
chromatography with ethyl acetate (EA) and petroleum ether (Pet) (PE/EA = 30:1) as eluent to afford
the corresponding products.
General Procedure for Preparation of products 5
A 25 mL sealed tube with a magnetic stir bar was charged with [Cp*RhCl2]2 (5 mol%), AgSbF6 (20
mol%), Li2CO3 (2.0 equiv.), 3ah, 3ai or 3aa (0.1 mmol), 1 (0.1 mmol), DCE (2.0 mL). Then the sealed
tube was sealed and heated to 50 oC with stirring for 12 h. After cooling down, the mixture was filtered
through a plug of Celite, and then the residue was concentrated and purified by flash column
chromatography with ethyl acetate (EA) and petroleum ether (Pet) (PE/EA = 30:1) as eluent to afford
the corresponding products.
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
Isotopically labeled experiment
A 25 mL sealed tube with a magnetic stir bar was charged with [Cp*RhCl2]2 (5 mol%), AgSbF6
(20 mol%), Li2CO3 (2.0 equiv.), 1a (0.05 mmol), dꢀ1a (0.05 mmol), diyne (0.15 mmol), DCE (2.0 mL).
o
Then the sealed tube was sealed and heated to 50 C with stirring for 2 h. After cooling down, the
mixture was filtered through a plug of Celite, and then the residue was concentrated and purified by
flash column chromatography with ethyl acetate (EA) and petroleum ether (Pet) as eluent to afford the
corresponding products.
Characterization data of the products
1ꢀmethylꢀ4ꢀphenylꢀ3ꢀ(phenylethynyl)isoquinoline (3aa) white solid (27 mg, 86%); mp (oC): 205–206;
1H NMR (400 Hz, CDCl3, TMS) δ 3.06 (s, 3H), 7.25–7.27 (m, 5H), 7.51–7.56 (m, 5H), 7.61–7.66 (m,
3H), 8.18–8.20 (m, 1H); 13C NMR (100 Hz, CDCl3, TMS) δ 22.7, 89.6, 92.2, 122.9, 125.8, 126.1,
126.6, 127.4, 127.9, 128.1, 128.2, 128.4, 130.4, 130.9, 131.8, 134.1, 135.1, 135.4, 136.8, 158.5. IR ν
2926, 1610, 1556, 1505, 1447, 1397, 1262, 764 cmꢀ1; HRMS (EI) Calcd for C24H17N (M+) 319.1361,
Found 319.1363.
4ꢀphenylꢀ3ꢀ(phenylethynyl)ꢀ1ꢀpropylisoquinoline (3ca) white solid (20 mg, 59%); mp (oC) 121–122;
1H NMR (400 Hz, CDCl3, TMS) δ 1.15 (t, 3H, J = 7.2 Hz), 1.97 (q, 2H, J = 8.0 Hz), 3.35ꢀ3.39 (m, 2H),
7.23–7.27 (m, 5H), 7.51–7.62 (m, 7H), 7.65ꢀ7.68 (m, 1H), 8.21ꢀ8.24 (m, 1H); 13C NMR (100 Hz,
CDCl3, TMS) δ 14.5, 23.7, 37.9, 89.8, 92.2, 122.9, 125.6, 125.9, 126.3, 127.3, 127.9, 128.1, 128.2,
128.3, 130.2, 130.9, 131.8, 134.3, 135.3, 135.4, 136.9, 162.3. IR ν 2923, 2839, 1632, 1536, 1457, 1252,
746 cmꢀ1; HRMS (EI) Calcd for C26H21N (M+) 347.1674, Found 347.1671.
1,7ꢀdimethylꢀ4ꢀphenylꢀ3ꢀ(phenylethynyl)isoquinoline (3da) white solid (27 mg, 82%); mp (oC):
1
138–139; H NMR (400 Hz, CDCl3, TMS) δ 2.58 (s, 3H), 3.03 (s, 3H), 7.25–7.27 (m, 5H), 7.45–7.47
(m, 1H), 7.52–7.58 (m, 6H), 7.95 (s, 1H); 13C NMR (100 Hz, CDCl3, TMS) δ 22.0, 22.7, 89.7, 91.8,
123.0, 124.9, 126.0, 126.7, 127.8, 128.1(2C), 128.2, 130.9, 131.7, 132.5, 133.2, 133.3, 135.3, 136.9,
137.5, 157.8. IR ν 2924, 2846, 1660, 1638, 1569, 1548, 1488, 1459, 865, 818, 775 cmꢀ1; HRMS (EI)
Calcd for C25H19N (M+) 333.1517, Found 333.1519.
1,8ꢀdimethylꢀ4ꢀphenylꢀ3ꢀ(phenylethynyl)isoquinoline (3ea) white solid (19 mg, 58%); mp (oC) 113–
1
114; H NMR (400 Hz, CDCl3, TMS) δ 3.00 (s, 3H), 3.25 (s, 3H), 7.22–7.27 (m, 5H), 7.42–7.55 (m,
8H); 13C NMR (100 Hz, CDCl3, TMS) δ 26.0, 29.6, 89.0, 92.7, 122.8, 125.1, 127.5, 127.8, 128.1, 128.2,
128.4, 129.9, 130.8, 131.2, 131.8, 133.2, 135.9, 136.5, 137.2, 137.4, 158.7. IR ν 2846, 1611, 1521,
1457, 1290, 815, 732 cmꢀ1; HRMS (EI) Calcd for C25H19N (M+) 333.1517, Found 333.1520.
8ꢀchloroꢀ1ꢀmethylꢀ4ꢀphenylꢀ3ꢀ(phenylethynyl)isoquinoline (3fa) white solid (19 mg, 53%); mp (oC):
ACS Paragon Plus Environment

Page 15 of 22
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
136–137; 1H NMR (400 Hz, CDCl3, TMS) δ 3.39 (s, 3H), 7.21–7.28 (m, 5H), 7.44–7.47 (m, 3H), 7.52–
7.57 (m, 4H), 7.67 (d, 1H, J = 7.2 Hz); 13C NMR (100 Hz, CDCl3, TMS) δ 29.8, 88.7, 93.3, 122.6,
124.9, 125.8, 128.1 (2C), 128.4, 128.6, 129.9, 130.5, 130.7, 131.8, 132.7, 134.4, 135.3, 136.8, 138.3,
158.3. IR ν 2941, 1600, 1540, 1446, 1391, 1357, 818, 758, 703 cmꢀ1; HRMS (EI) Calcd for C24H16ClN
(M+) 353.0971, Found 353.0973.
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
1,6ꢀdimethylꢀ4ꢀphenylꢀ3ꢀ(phenylethynyl)isoquinoline (3ga) white solid (29 mg, 89%); mp (oC):119–
1
120; H NMR (400 Hz, CDCl3, TMS) δ 2.45 (s, 3H), 3.03 (s, 3H), 7.24–7.27 (m, 5H), 7.41 (s, 1H),
7.44–7.46 (m, 1H), 7.50–7.57 (m, 5H), 8.08 (d, 1H, J = 8.4 Hz); 13C NMR (100 Hz, CDCl3, TMS) δ
22.1, 22.6, 89.7, 92.2, 123.0, 124.9, 125.0, 125.7, 127.8, 128.1, 128.2, 128.3, 129.5, 130.9, 131.7, 134.2,
135.0, 135.3, 137.0, 140.9, 158.2. IR ν 2924, 1622, 1571, 1550, 1491, 1443, 1390, 1262, 733, 698 cmꢀ1;
HRMS (EI) Calcd for C25H19N (M+) 333.1517, Found 333.1520.
6ꢀchloroꢀ1ꢀmethylꢀ4ꢀphenylꢀ3ꢀ(phenylethynyl)isoquinoline (3ha) white solid (26 mg, 75%); mp (oC):
187–188; 1H NMR (400 Hz, CDCl3, TMS) δ 3.05 (s, 3H), 7.24–7.27 (m, 5H), 7.48–7.63 (m, 7H), 8.12
(d, 1H, J = 8.8 Hz); 13C NMR (100 Hz, CDCl3, TMS) δ 22.5, 88.9, 93.3, 122.6, 124.7, 125.0, 127.6,
128.2, 128.3 (2C), 128.4, 128.6, 130.7, 131.8, 134.5, 135.1, 136.0, 136.2, 137.1, 158.4. IR ν 2921, 2818,
1628, 1544, 1346, 748 cmꢀ1; HRMS (EI) Calcd for C24H16ClN (M+) 353.0971, Found 353.0968.
6ꢀbromoꢀ1ꢀmethylꢀ4ꢀphenylꢀ3ꢀ(phenylethynyl)isoquinoline (3ia) white solid (31 mg, 79%); mp (oC):
182–183; 1H NMR (400 Hz, CDCl3, TMS) δ 3.04 (s, 3H), 7.23–7.27 (m, 5H), 7.48–7.51 (m, 2H), 7.54–
7.60 (m, 3H), 7.69–7.71 (m, 1H), 7.80 (m, 1H), 8.05 (d, 1H, J = 8.8 Hz); 13C NMR (100 Hz, CDCl3,
TMS) δ 22.6, 89.2, 93.0, 122.6, 124.9, 125.6, 127.5, 128.2 (2C), 128.3, 128.4, 128.6, 130.8 (2C), 131.8,
134.3, 135.3, 136.1, 136.4, 158.6. IR ν 2955, 2849, 1601, 1564, 1488, 1388, 742 cmꢀ1; HRMS (EI)
Calcd for C24H16BrN (M+) 397.0466, Found 397.0466.
1ꢀmethylꢀ4ꢀ(pꢀtolyl)ꢀ3ꢀ(pꢀtolylethynyl)isoquinoline (3ab) white solid (27 mg, 78%); mp (oC) 103–
1
104; H NMR (400 Hz, CDCl3, TMS) δ 2.33 (s, 3H), 2.50 (s, 3H), 3.10 (s, 3H), 7.06–7.08 (m, 2H),
7.18–7.21 (m, 2H), 7.35ꢀ7.37 (m, 2H), 7.40ꢀ7.42 (m, 2H), 7.62ꢀ7.65 (m, 2H), 7.70ꢀ7.72 (m, 1H),
8.18ꢀ8.20 (m, 1H); 13C NMR (100 Hz, CDCl3, TMS) δ 21.4, 21.6, 22.6, 89.2, 92.3, 120.0, 125.8, 126.2,
126.5, 127.2, 128.8, 128.9, 130.3, 130.8, 131.7, 133.7, 134.3, 135.1, 135.2, 137.5, 138.5, 158.3. IR ν
2928, 2856, 1663, 1630, 1553, 1515, 1475, 818, 767 cmꢀ1; HRMS (EI) Calcd for C26H21N (M+)
347.1674, Found 347.1676.
1ꢀmethylꢀ4ꢀ(mꢀtolyl)ꢀ3ꢀ(mꢀtolylethynyl)isoquinoline (3ac) light brown solid (28 mg, 82%); mp (oC):
105–106; 1H NMR (400 Hz, CDCl3, TMS) δ 2.29 (s, 3H), 2.47 (s, 3H), 3.05 (s, 3H), 7.07–7.09 (m, 3H),
7.13–7.16 (m, 1H), 7.30ꢀ7.34 (m, 3H), 7.43ꢀ7.46 (m, 1H), 7.59ꢀ7.61 (m, 2H), 7.68ꢀ7.70 (m, 1H),
8.15ꢀ8.17 (m, 1H); 13C NMR (100 Hz, CDCl3, TMS) δ 21.2, 21.6, 22.6, 89.4, 92.5, 122.8, 125.8, 126.2,
126.5, 127.3, 128.0 (2C), 128.1, 128.6, 128.7, 129.3, 130.3, 131.5, 132.4, 134.1, 135.1, 135.4, 136.7,
137.7 (2C), 158.4. IR ν 2919, 2855, 1603, 1569, 1544, 1488, 1442, 1390, 788, 760, 738, 689 cmꢀ1;
HRMS (EI) Calcd for C26H21N (M+) 347.1674, Found 347.1673.
4ꢀ(4ꢀethylphenyl)ꢀ3ꢀ((4ꢀethylphenyl)ethynyl)ꢀ1ꢀmethylisoquinoline (3ad) white solid (34 mg, 91%);
1
mp (oC): 75–76; H NMR (400 Hz, CDCl3, TMS) δ 1.21 (t, 3H, J = 8.0 Hz), 1.38 (t, 3H, J = 7.6 Hz),
2.62 (q, 2H, J = 7.6 Hz), 2.81 (q, 2H, J = 7.6 Hz), 3.06 (s, 3H), 7.07–7.09 (m, 2H), 7.15–7.17 (m, 2H),
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 22
1
2
3
4
5
6
7
8
7.38ꢀ7.44 (m, 4H), 7.60ꢀ7.63 (m, 2H), 7.70ꢀ7.72 (m, 1H), 8.16ꢀ8.19 (m, 1H); 13C NMR (100 Hz, CDCl3,
TMS) δ 15.3, 15.9, 22.6, 28.9, 29.7, 89.1, 92.7, 120.1, 125.8, 126.2, 126.5, 127.2, 127.7, 130.3, 130.9,
131.8, 134.0, 134.3, 135.2, 135.3, 143.9, 144.8, 158.2. IR ν 2908, 2823, 1636, 1545 1483, 1290, 810,
736 cmꢀ1; HRMS (EI) Calcd for C28H25N (M+) 375.1987, Found 375.1989.
4ꢀ(4ꢀbutylphenyl)ꢀ3ꢀ((4ꢀbutylphenyl)ethynyl)ꢀ1ꢀmethylisoquinoline (3ae) white solid (37 mg, 85%);
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
1
mp (oC): 67–68; H NMR (400 Hz, CDCl3, TMS) δ 0.91 (t, 3H, J = 7.6 Hz), 1.01 (t, 3H, J = 7.6 Hz),
1.30–1.37 (m, 2H), 1.43–1.49 (m, 2H), 1.52–1.60 (m, 2H), 1.70–1.77 (m, 2H), 2.57 (t, 2H, J = 7.6 Hz),
2.76 (t, 2H, J = 7.6 Hz), 3.04 (s, 3H), 7.04–7.06 (m, 2H), 7.14–7.16 (m, 2H), 7.35ꢀ7.37 (m, 2H),
7.40ꢀ7.42 (m, 2H), 7.58–7.61 (m, 2H), 7.68–7.70 (m, 1H), 8.15–8.17 (m, 1H); 13C NMR (100 Hz,
CDCl3, TMS) δ 13.9, 14.1, 22.3, 22.4, 22.6, 33.4, 33.9, 35.6 (2C), 89.3, 92.5, 120.1, 125.7, 126.2,
126.5, 127.2, 128.2, 130.2, 130.8, 131.7, 134.0, 134.4, 135.2, 135.3, 142.5, 143.5, 158.2. IR ν 2950,
2928, 2856, 1660, 1587, 1548, 1510, 1433, 1266, 737 cmꢀ1; HRMS (EI) Calcd for C32H33N (M+)
431.2613, Found 431.2615.
4ꢀ(4ꢀmethoxyphenyl)ꢀ3ꢀ((4ꢀmethoxyphenyl)ethynyl)ꢀ1ꢀmethylisoquinoline (3af) light yellow solid
(26 mg, 68%); mp (oC): 116–117; 1H NMR (400 Hz, CDCl3, TMS) δ 3.03 (s, 3H), 3.79 (s, 3H), 3.92 (s,
3H), 6.78–6.80 (m, 2H), 7.07–7.09 (m, 2H), 7.23ꢀ7.25 (m, 2H), 7.44ꢀ7.46 (m, 2H), 7.57ꢀ7.62 (m, 2H),
7.68ꢀ7.70 (m, 1H), 8.14ꢀ8.16 (m, 1H); 13C NMR (100 Hz, CDCl3, TMS) δ 22.7, 55.3, 55.4, 88.7, 92.2,
113.6, 113.8, 115.1, 125.8, 126.1, 126.5, 127.1, 129.0, 130.2, 132.1, 133.3, 134.4, 134.6, 135.4, 158.2,
159.3, 159.7. IR ν 2920, 1605, 1548, 1512, 1460, 1436, 1388, 1247, 1171, 1034, 829 cmꢀ1; HRMS (EI)
Calcd for C26H21NO2 (M+) 379.1572, Found 379.1574.
4ꢀ(4ꢀfluorophenyl)ꢀ3ꢀ((4ꢀfluorophenyl)ethynyl)ꢀ1ꢀmethylisoquinoline (3ag) white solid (21 mg,
58%); mp (oC) 124–125; 1H NMR (400 Hz, CDCl3, TMS) δ 3.06 (s, 3H), 7.00–7.01 (m, 2H), 7.24–7.30
(m, 4H), 7.48–7.51 (m, 2H), 7.64–7.65 (m, 3H), 8.19–8.21 (m, 1H); 13C NMR (100 Hz, CDCl3, TMS)
δ 22.7, 89.0, 91.3, 115.1, 115.4, 115.5, 115.7, 118.8, 125.8, 125.9, 126.6, 127.5, 130.6, 132.5, 132.6,
133.6, 133.7, 134.1, 134.2, 135.1, 158.9, 161.4, 163.8, 163.9. IR ν 2936, 2817, 1658, 1536, 1487, 1268,
758 cmꢀ1; HRMS (EI) Calcd for C24H15F2N (M+) 355.1173, Found 355.1175.
3ꢀ(heptꢀ1ꢀynꢀ1ꢀyl)ꢀ1ꢀmethylꢀ4ꢀpentylisoquinoline (3ah) white solid (28 mg, 90%); mp (oC): 60–61;
1H NMR (400 Hz, CDCl3, TMS) δ 0.91–0.96 (m, 6H), 1.34–1.52 (m, 8H), 1.66–1.71 (m, 4H), 2.54 (t,
2H, J = 7.2), 2.94 (s, 3H), 3.18–3.22 (m, 2H),7.57 (t, 1H, J = 7.2 Hz), 7.71 (t, 1H, J = 7.2 Hz), 7.99 (d,
1H, J = 8.4 Hz), 8.11 (d, 1H, J = 8.8 Hz); 13C NMR (100 Hz, CDCl3, TMS) δ 14.0, 14.1, 19.8, 22.3,
22.4, 22.6, 28.4, 29.4, 30.1, 31.3, 32.2, 80.0, 93.6, 123.9, 126.3, 126.6 (2C), 130.0, 133.1, 134.7 (2C),
156.7. IR ν 2958, 2928, 2856, 1604, 1565, 1548, 1467, 1391, 766, 741 cmꢀ1; HRMS (EI) Calcd for
C22H29N (M+) 307.2300, Found 307.2300.
4ꢀ(4ꢀchlorobutyl)ꢀ3ꢀ(6ꢀchlorohexꢀ1ꢀynꢀ1ꢀyl)ꢀ1ꢀmethylisoquinoline (3ai) light yellow oil (28 mg,
1
82%); H NMR (400 Hz, CDCl3, TMS) δ 1.81–1.89 (m, 4H), 1.94–2.06 (m, 4H), 2.61–2.63 (m, 2H),
2.93 (s, 3H), 3.25 (t, 2H, J = 7.6 Hz), 3.60–3.65 (m, 4H), 7.57–7.61 (m, 1H), 7.70–7.74 (m, 1H), 7.98
(d, 1H, J = 8.4 Hz), 8.12 (d, 1H, J = 7.6 Hz); 13C NMR (100 Hz, CDCl3, TMS) δ 19.1, 22.5, 25.9, 27.4,
28.5, 31.8, 32.5, 44.6, 44.8, 80.6, 92.5, 123.7, 126.4, 126.7, 126.9, 130.3, 132.1, 134.5, 134.7, 157.2. IR
ACS Paragon Plus Environment

Page 17 of 22
The Journal of Organic Chemistry
1
2
3
4
5
ν 2926, 1738, 1456, 1238, 1045 cmꢀ1; HRMS (EI) Calcd for C20H23Cl2N (M+) 347.1208, Found
347.1210.
1,1'ꢀdimethylꢀ3',4ꢀdiphenylꢀ3,4'ꢀbiisoquinoline (4aa) white solid (34 mg, 78%); mp (oC): 187–188;
1H NMR (400 Hz, CDCl3, TMS) δ 2.98 (s, 3H), 3.18 (s, 3H), 6.06–6.08 (m, 1H), 6.56–6.58 (m, 1H),
6.83–6.87 (m, 1H), 7.00–7.04 (m, 1H) 7.06–7.14 (m, 6H) 7.42–7.44 (m, 1H) 7.52–7.67 (m, 5H) 8.14–
8.16 (m, 1H) 8.28–8.30 (m, 1H); 13C NMR (100 Hz, CDCl3, TMS) δ 22.5, 22.7, 125.7, 126.1 (2C),
126.4 (2C), 126.5, 126.9, 127.0, 127.1, 127.3 (2C), 127.5, 129.0, 130.0, 130.2, 130.3, 130.7, 132.1,
135.7, 136.0, 137.1, 140.5, 147.0, 149.3, 157.6, 158.2. IR ν 2923, 2851, 1694, 1612, 1485, 1442, 1386,
1271, 1147, 737 cmꢀ1; HRMS (EI) Calcd for C32H24N2 (M+) 436.1939, Found 436.1935.
1,1',7,7'ꢀtetramethylꢀ3',4ꢀdiphenylꢀ3,4'ꢀbiisoquinoline (4da) white solid (33 mg, 71%); mp (oC):
234–235; 1H NMR (400 Hz, CDCl3, TMS) δ 2.57 (s, 3H), 2.60 (s, 3H), 2.93 (s, 3H), 3.14 (s, 3H), 6.04–
6.06 (m, 1H), 6.55–6.56 (m, 1H), 6.83–6.86 (m, 1H), 6.98–7.01 (m, 1H), 7.05–7.11 (m, 6H) 7.32–7.34
(m, 1H), 7.36–7.38 (m, 1H), 7.43 (m, 2H), 7.89 (m, 1H),8.04 (m, 1H); 13C NMR (100 Hz, CDCl3, TMS)
δ 21.9, 22.0, 22.7 (2C), 124.6 (2C), 126.0, 126.3, 126.6, 126.7, 126.8, 127.2, 127.3, 127.4, 129.0, 130.3,
130.7, 131.8, 132.0, 132.1, 134.2, 135.3, 136.0, 136.1, 136.8, 141.0, 146.5, 148.7, 156.8, 157.3. IR ν
2924, 2855, 1629, 1569, 1553, 1445, 1401, 1276, 829, 762, 741, 701 cmꢀ1; HRMS (EI) Calcd for
C34H28N2 (M+) 464.2252, Found 464.2252.
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
1,1',6,6'ꢀtetramethylꢀ3',4ꢀdiphenylꢀ3,4'ꢀbiisoquinoline (4ga) white solid (34 mg, 73%); mp (oC):
202–203; 1H NMR (400 Hz, CDCl3, TMS) δ 2.39 (s, 3H), 2.44 (s, 3H), 2.93 (s, 3H), 3.15 (s, 3H), 6.06–
6.08 (m, 1H), 6.56–6.58 (m, 1H), 6.84–6.87 (m, 1H), 7.00–7.12 (m, 7H) 7.20 (m, 1H), 7.27 (m, 1H),
7.38–7.40 (m, 1H) 7.46–7.49 (m, 1H), 8.02 (d, 1H, J = 8.4 Hz), 8.20 (d, 1H, J = 8.4 Hz); 13C NMR
(100 Hz, CDCl3, TMS) δ 22.0, 22.2, 22.6, 22.7, 124.5, 124.8, 125.0, 125.3, 125.5, 125.6, 126.8, 126.9,
127.2 (2C), 127.4, 127.6, 128.6, 129.0, 130.3, 130.8, 131.5, 136.0, 136.3, 137.3, 140.2, 140.3, 141.0,
147.5, 149.5, 157.2, 157.7. IR ν 2919, 2864, 1621, 1565, 1496, 1445, 1390, 1262, 732, 702 cmꢀ1;
HRMS (EI) Calcd for C34H28N2 (M+) 464.2252, Found 464.2252.
6,6'ꢀdichloroꢀ1,1'ꢀdimethylꢀ3',4ꢀdiphenylꢀ3,4'ꢀbiisoquinoline (4ha) yellow solid (33 mg, 65%); mp
(oC): 221–222; 1H NMR (400 Hz, CDCl3, TMS) δ 2.94 (s, 3H), 3.17 (s, 3H), 6.02–6.04 (m, 1H), 6.55–
6.57 (m, 1H), 6.88–6.92 (m, 1H), 7.03–7.15 (m, 7H), 7.40 (m, 1H), 7.49–7.53 (m, 2H), 7.59–7.61 (m,
1H), 8.08–8.10 (m, 1H) 8.23–8.25 (m, 1H); 13C NMR (100 Hz, CDCl3, TMS) δ 22.7, 22.8, 124.3, 124.8,
125.0 (2C), 126.9, 127.3, 127.4, 127.5 (2C), 127.6 (2C), 127.7, 128.1, 129.0, 130.2, 130.5, 131.7, 134.9,
136.6, 136.7, 137.1, 140.3, 147.7, 150.6, 157.9, 158.3. IR ν 2916, 2849, 1610, 1564, 1483, 1387, 1090,
759 cmꢀ1; HRMS (EI) Calcd for C32H22Cl2N2 (M+) 504.1160, Found 504.1161.
6,6'ꢀdibromoꢀ1,1'ꢀdimethylꢀ3',4ꢀdiphenylꢀ3,4'ꢀbiisoquinoline (4ia) yellow solid (37 mg, 62%); mp
(oC): 191–192; 1H NMR (400 Hz, CDCl3, TMS) δ 2.96 (s, 3H), 3.16 (s, 3H), 6.04–6.06 (m, 1H), 6.56–
6.58 (m, 1H), 6.89–6.93 (m, 1H), 7.05–7.15 (m, 7H) 7.58–7.59 (m, 1H), 7.66–7.68 (m, 2H), 7.73–7.76
(m, 1H), 8.01–8.03 (m, 1H) 8.15–8.17 (m, 1H); 13C NMR (100 Hz, CDCl3, TMS) δ 22.5, 22.7, 124.5,
125.0, 125.4, 125.5, 126.9, 127.4, 127.5 (2C), 127.6 (2C), 127.7, 128.3, 129.0, 130.2, 130.3, 130.5,
130.8, 131.6, 134.8, 137.3, 138.2, 147.5, 150.5, 158.0, 158.4. IR ν 2926, 2844, 1618, 1532, 1497, 1461,
1266, 1230, 1166, 732, 696 cmꢀ1; HRMS (EI) Calcd for C32H22Br2N2 (M+) 592.0150, Found 592.0152.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 22
1
2
3
4
5
6
7
8
9
3',4ꢀbis(4ꢀethylphenyl)ꢀ1,1'ꢀdimethylꢀ3,4'ꢀbiisoquinoline (4ad) white solid (31 mg, 63%); mp (oC):
246–247; 1H NMR (400 Hz, CDCl3, TMS) δ 1.12–1.18 (m, 6H), 2.51–2.54 (m, 4H), 2.96 (s, 3H), 3.16
(s, 3H), 6.01–6.03 (m, 1H), 6.45–6.47 (m, 1H), 6.65–6.67 (m, 1H), 6.82–6.84 (m, 1H), 6.89–6.91 (m,
2H) 7.01–7.03 (m, 2H), 7.46–7.65 (m, 6H), 8.12–8.14 (m, 1H), 8.26–8.28 (m, 1H); 13C NMR (100 Hz,
CDCl3, TMS) δ 15.4, 15.8, 22.7 (2C), 28.5, 28.6, 125.6 (2C), 126.2, 126.4 (2C), 126.7, 126.8 (2C),
126.9, 127.8, 128.8, 129.8, 129.9, 130.2, 130.6, 132.1, 132.9, 136.3, 137.1, 138.3, 142.6, 143.1, 147.3,
149.6, 157.3, 157.9. IR ν 2924, 1608, 1512, 1436, 1130, 752, 676 cmꢀ1; HRMS (EI) Calcd for C36H32N2
(M+) 492.2565, Found 492.2568.
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
3',4ꢀbis(4ꢀethylphenyl)ꢀ1,1'ꢀdimethylꢀ3,4'ꢀbiisoquinoline (4ae) white solid (36 mg, 65%); mp (oC):
222–223; 1H NMR (400 Hz, CDCl3, TMS) δ 0.87–0.95 (m, 6H), 1.26–1.33 (m, 4H), 1.45–1.55 (m, 4H),
2.47–2.53 (m, 4H), 2.98 (s, 3H), 3.18 (s, 3H), 6.01–6.02 (m, 1H), 6.45–6.46 (m, 1H), 6.64–6.66 (m,
1H), 6.81–6.83 (m, 1H), 6.89–6.91 (m, 2H) 7.03–7.04 (m, 2H), 7.50–7.65 (m, 6H), 8.13–8.15 (m, 1H),
8.28–8.30 (m, 1H); 13C NMR (100 Hz, CDCl3, TMS) δ 13.9, 14.0, 22.2, 22.6, 22.7, 26.9, 33.4, 33.6,
35.2, 35.3, 125.6 (2C), 126.0, 126.1, 126.3, 126.4 (2C), 126.8, 127.3, 127.4 (2C), 127.8, 128.8, 129.8,
129.9, 130.1, 130.6, 132.1, 132.9, 136.2, 137.1, 141.3, 141.6, 147.4, 157.2, 157.9. IR ν 2865, 1645,
1536, 1423, 873, 733 cmꢀ1; HRMS (EI) Calcd for C40H40N2 (M+) 548.3191, Found 548.3189.
3',4ꢀbis(4ꢀmethoxyphenyl)ꢀ1,1'ꢀdimethylꢀ3,4'ꢀbiisoquinoline (4af) light yellow solid (28 mg, 56%);
1
mp (oC): 212–213; H NMR (400 Hz, CDCl3, TMS) δ 2.96 (s, 3H), 3.16 (s, 3H), 3.71 (d, 6H, J = 7.2
Hz), 6.07–6.10 (m, 1H), 6.37–6.40 (m, 1H), 6.45–6.48 (m, 1H), 6.56–6.59 (m, 1H), 6.61–6.64 (m, 2H),
7.08–7.10 (m, 2H), 7.45–7.65 (m, 6H), 8.11–8.13 (m, 1H), 8.26–8.28 (m, 1H); 13C NMR (100 Hz,
CDCl3, TMS) δ 22.7, 55.1, 55.2, 112.6, 112.8, 113.0, 125.7, 125.9, 126.2, 126.4, 126.8, 127.5, 128.1,
129.9, 130.0 (2C), 130.1, 131.5, 131.7, 131.8, 133.6, 136.4, 137.1, 140.0, 157.4, 157.9, 158.4, 158.8.
IR ν 2934, 1663, 1584, 1529, 1496, 784, 723 cmꢀ1; HRMS (EI) Calcd for C34H28N2O2 (M+) 496.2151,
Found 496.2148.
6'ꢀbromoꢀ1,1'ꢀdimethylꢀ3',4ꢀdiphenylꢀ3,4'ꢀbiisoquinoline (4ai) light yellow solid (27 mg, 53%); mp
(oC): 151–152; 1H NMR (400 Hz, CDCl3, TMS) δ 2.95 (s, 3H), 3.20 (s, 3H), 6.07–6.09 (m, 1H), 6.59–
6.61 (m, 1H), 6.89–6.93 (m, 1H), 7.01–7.05 (m, 1H), 7.09–7.15 (m, 6H), 7.44–7.46 (m, 1H), 7.55–7.59
(m, 1H),7.65–7.68 (m, 2H), 7.71 (m, 1H), 8.01 (d, 1H, J = 9.2 Hz), 8.32 (d, 1H, J = 7.6 Hz); 13C NMR
(100 Hz, CDCl3, TMS) δ 22.7, 22.8, 124.5, 125.2, 125.8, 126.2, 126.6, 127.0, 127.1, 127.2, 127.3,
127.4, 127.6, 128.5, 129.1, 129.9, 130.1, 130.3, 130.6, 132.3, 135.6, 136.0, 138.4, 140.5, 146.3, 150.7,
158.0, 158.2. IR ν 2921, 1600, 1566, 1484, 1390, 762 cmꢀ1; HRMS (EI) Calcd for C32H23BrN2 (M+)
514.1045, Found 514.1050.
1
1,1'ꢀdimethylꢀ4,4'ꢀdipentylꢀ3,3'ꢀbiisoquinoline (5ah) white solid (22 mg, 53%); mp (oC): 85–86; H
NMR (400 Hz, CDCl3, TMS) δ 0.76 (t, 6H, J = 7.2 Hz), 1.16–1.19 (m, 8H), 1.66 (m, 4H), 2.76 (m, 4H),
2.99 (s, 6H), 7.63 (t, 2H, J = 7.6 Hz), 7.76 (t, 1H, J = 7.6 Hz), 8.09 (d, 1H, J = 8.4 Hz), 8.21 (d, 1H, J =
8.0 Hz); 13C NMR (100 Hz, CDCl3, TMS) δ 13.9, 22.2, 22.3, 28.8, 30.1, 32.3, 124.2, 126.3, 127.1,
128.6, 129.7, 135.7, 150.0, 155.8. IR ν 2955, 2923, 2860, 1613, 1558, 1502, 1462, 1387, 752 cmꢀ1;
HRMS (EI) Calcd for C30H36N2 (M+) 424.2878, Found 424.2880.
ACS Paragon Plus Environment

Page 19 of 22
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1,1',7ꢀtrimethylꢀ4,4'ꢀdipentylꢀ3,3'ꢀbiisoquinoline (5dh) white solid (24 mg, 55%); mp (oC) 91–92; 1H
NMR (400 Hz, CDCl3, TMS) δ 0.75–0.78 (m, 6H), 1.17–1.20 (m, 8H), 1.65–1.81 (m, 5H), 2.62 (s, 3H),
2.78 (m, 3H), 2.97 (d, 6H, J = 11.2 Hz), 7.58–7.65 (m, 2H), 7.33–7.77 (m, 1H), 7.97–8.01 (m, 2H),
8.09 (d, 1H, J = 8.4 Hz), 8.21 (d, 1H, J = 8.4 Hz); 13C NMR (100 Hz, CDCl3, TMS) δ 13.9, 21.9, 22.3
(2C), 28.8, 29.7, 30.1 (2C), 32.3 (2C), 124.1, 124.2, 125.3, 126.1, 126.2, 127.0, 127.3, 128.3, 128.5,
129.6, 131.8, 133.8, 135.7, 135.9, 149.4, 150.3, 155.1, 155.8. IR ν 2962, 2924, 2864, 1621, 1566, 1506,
1463, 1391, 1266, 737 cmꢀ1; HRMS (EI) Calcd for C31H38N2 (M+) 438.3035, Found 438.3038.
1,1',6ꢀtrimethylꢀ4,4'ꢀdipentylꢀ3,3'ꢀbiisoquinoline (5gh) white solid (25 mg, 58%); mp (oC): 95–96;
1H NMR (400 Hz, CDCl3, TMS) δ 0.75–0.78 (m, 6H), 1.18–1.19 (m, 8H), 1.65 (m, 4H), 2.62–2.82 (s,
7H), 2.97 (d, 6H, J = 13.2 Hz), 7.44–7.46 (m, 1H), 7.60–7.64 (m, 1H), 7.73–7.77 (m, 1H), 7.83 (m,
1H), 8.07–8.11 (m, 2H), 8.19–8.22 (m, 1H); 13C NMR (100 Hz, CDCl3, TMS) δ 13.9, 22.3 (2C), 22.4
(2C), 28.7, 28.8, 30.0, 30.1, 32.2, 32.3, 123.2, 124.2, 125.4, 126.2 (2C), 127.0, 127.9, 128.4 (2C), 129.6,
135.7, 135.9, 139.7, 150.2, 150.3, 155.5, 155.8. IR ν 2932, 2835, 1601, 1536, 1488, 1298, 743 cmꢀ1;
HRMS (EI) Calcd for C31H38N2 (M+) 438.3035, Found 438.3036.
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
6ꢀbromoꢀ1,1'ꢀdimethylꢀ4,4'ꢀdipentylꢀ3,3'ꢀbiisoquinoline (5ih) yellow solid (25 mg, 49%); mp (oC):
121–122; 1H NMR (400 Hz, CDCl3, TMS) δ 0.74–0.78 (m, 6H), 1.16–1.20 (m, 8H), 1.65 (m, 4H), 2.74
(m, 4H), 2.97 (d, 6H, J = 9.6 Hz), 7.61–7.65 (m, 1H), 7.69–7.71 (m, 1H), 7.74–7.77 (m, 1H), 8.05–8.09
(m, 2H), 8.20–8.22 (m, 2H); 13C NMR (100 Hz, CDCl3, TMS) δ 13.9 (2C), 22.2, 22.3 (2C), 22.4, 28.7
(2C), 30.0, 30.1, 32.1, 32.2, 124.2, 124.8, 125.5, 126.3, 126.4, 126.7, 127.1, 127.8, 128.0, 128.5, 129.7,
135.6, 137.1, 149.7, 151.4, 156.0 (2C). IR ν 2953, 2928, 1601, 1584, 1478, 1288, 721 cmꢀ1; HRMS (EI)
Calcd for C30H35BrN2 (M+) 502.1984, Found 502.1984.
1,1'ꢀdimethylꢀ6ꢀnitroꢀ4,4'ꢀdipentylꢀ3,3'ꢀbiisoquinoline (5jh) white solid (20 mg, 42%); mp (oC) 133–
134; 1H NMR (400 Hz, CDCl3, TMS) δ 0.74–0.78 (m, 6H), 1.16–1.26 (m, 8H), 1.68 (m, 4H), 2.82 (m,
3H), 2.99 (s, 3H), 3.04 (s, 3H), 7.64–7.68 (m, 1H), 7.76–7.80 (m, 1H), 8.10 (d, 1H, J = 8.4 Hz), 8.22 (d,
1H, J = 8.4 Hz), 8.37 (m, 2H), 9.02 (s, 1H); 13C NMR (100 Hz, CDCl3, TMS) δ 13.8, 13.9, 22.2, 22.3,
22.4, 22.6, 28.8, 30.1, 30.5, 32.1, 32.2, 119.7, 120.8, 124.2, 126.3, 126.6, 127.2, 128.4, 128.6, 128.8,
129.9, 130.4, 135.4, 135.5, 148.0, 149.1, 152.5, 156.2, 156.3. IR ν 2926, 2849, 1632, 1559, 1532, 1348,
742 cmꢀ1; HRMS (EI) Calcd for C30H35N3O2 (M+) 469.2729, Found 469.2730.
1ꢀethylꢀ1'ꢀmethylꢀ4,4'ꢀdipentylꢀ3,3'ꢀbiisoquinoline (5kh) light yellow solid (22 mg, 51%); mp (oC):
118–119; 1H NMR (400 Hz, CDCl3, TMS) δ 0.75–0.78 (m, 6H), 1.20 (m, 8H), 1.42–1.45 (m, 3H), 1.68
(m, 4H), 2.68–2.99 (m, 7H), 3.35–3.37 (m, 2H), 7.62–7.65 (m, 2H), 7.72–7.77 (m, 2H), 8.09 (d, 2H, J
= 8.4 Hz), 8.20–8.26 (m, 2H); 13C NMR (100 Hz, CDCl3, TMS) δ 13.9, 14.5, 22.4, 28.9, 30.1, 30.2,
32.3, 124.2, 124.4, 126.0, 126.2, 126.3, 127.1, 128.4, 128.5, 129.5, 129.6, 135.7, 136.1, 150.4, 155.8,
160.7. IR ν 2958, 2924, 2856, 1617, 1553, 1463, 1386, 758 cmꢀ1; HRMS (EI) Calcd for C31H38N2 (M+)
438.3035, Found 438.3035.
6ꢀbromoꢀ4,4'ꢀbis(4ꢀchlorobutyl)ꢀ1,1'ꢀdimethylꢀ3,3'ꢀbiisoquinoline (5ii) light yellow solid (24 mg,
45%); mp (oC): 145–146; 1H NMR (400 Hz, CDCl3, TMS) δ 1.66–1.73 (m, 6H), 1.84 (m, 3H), 2.80 (s,
3H), 2.99 (d, 6H, J = 9.6), 3.39 (t, 4H, J = 6.8 Hz), 7.65–7.69 (m, 1H), 7.72–7.75 (m, 1H), 7.77–7.81
(m, 1H), 8.09 (d, 2H, J = 8.8 Hz), 8.22–8.24 (m, 2H); 13C NMR (100 Hz, CDCl3, TMS) δ 22.4 (2C),
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 22
1
2
3
4
5
6
7
8
9
27.4, 27.5, 27.8, 27.9,32.5, 32.6, 44.5, 44.6, 124.0, 125.1, 125.5, 126.4, 126.5, 126.6, 126.9, 127.1,
127.6, 128.1, 130.0, 130.1, 135.4, 136.9, 149.7, 151.4, 156.5 (2C). IR ν 2923, 1602, 1564, 1462, 1391,
812, 759 cmꢀ1; HRMS (EI) Calcd for C28H29BrCl2N2 (M+) 542.0891, Found 542.0897.
4ꢀethylꢀ1ꢀmethylꢀ3ꢀphenylisoquinoline (3aj) 15d, 18 light yellow solid (21 mg, 86%); mp (oC): 112–113;
1H NMR (400 Hz, CDCl3, TMS) δ 1.36–1.31 (m, 3H), 3.00–3.05 (m, 5H), 7.42–7.55 (m, 5H), 7.63–
7.65 (m, 1H), 7.66–7.67 (m, 1H), 8.11 (d, 1H, J = 8.4 Hz), 8.20 (d, 1H, J = 8.4 Hz); 13C NMR (100 Hz,
CDCl3, TMS) δ 15.7, 21.7, 22.5, 124.2, 126.2, 126.3, 126.7, 127.4, 128.2, 128.6, 129.2, 129.8, 135.2,
141.9, 150.7, 155.9.
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
Supporting Information
Xꢀray crystallography of 3aa and 4ae, UVꢀVis absorption spectra, and 1H NMR, 13C NMR spectra.
This material is available free of charge via the Internet at http://pubs.acs.org.
ACKNOWLEDGMENTS
Funding from Science Technology Department of Zhejiang Province (No. LQ15B020002, Feng, R. K.
and LQ13B020002, Yang, Z.) and NSFC (No. 21172149, Qi, C. Z. and 21302129, Yang, Z.) is highly
acknowledged.
REFERENCES
(1) (a) Phillipson, J. D.; Roberts, M. F.; Zenk, M. H. (Eds.), The Chemistry and Biology of Isoquinoline
Alkaloids, Springer Verlag, Berlin, 1985; (b) Lehn, J.ꢀM.; Pietraszkiewicz, M.; Karpiuk, J. Helv. Chim.
Acta, 1990, 73, 106; (c) Bentley, K. W. The Isoquinoline Alkaloids, Hardwood Academic, Amsterdam,
The Netherlands, 1998, vol. 1; (d) Bhadra, K.; Kumar, G. S. Med. Res. Rev. 2011, 31, 821; (e) Bentley,
K. W. Nat. Prod. Rep. 2006, 23, 444; (f) Kartsev, V. G. Med. Chem. Res. 2004, 13, 325; (g) Kashiwada,
Y.; Aoshima, A.; Ikeshiro, Y.; Chen, Y. P.; Furukawa, H.; Itoigawa, M.; Fujioka, T.; Mihashi, K.;
Cosentino, L. M.; MorrisꢀNatschke, S. L.; Lee, K. H. Bioorg. Med. Chem. 2005, 13, 443; (h) Sweetman,
B. A.; MullerꢀBunz, H.; Guiry, P. J. Tetrahedron Lett. 2005, 46, 4643. (i) Liu, Q.; Zhao, S.; Shi, M.;
Wang, C.; Yu, M.; Li, L.; Li, F.; Yi, T.; Huang, C. Inorg. Chem. 2006, 45, 6152.
(2) For reviews see: (a) Zhang, M.; Zhang, Y.; Jie, X.; Zhao, H.; Li, G.; Su, W. Org. Chem. Front. 2014,
1, 843; (b) R. He, Z.ꢀT. Huang, Q.ꢀY. Zheng and C. Wang, Tetrahedron Lett. 2014, 55, 5705; (c) Huang,
H.; Ji, X.; Wu, W.; Jiang, H. Chem. Soc. Rev. 2015, 44, 1155; (d) Chen, Z.; Wang, B.; Zhang, J.; Yu, W.;
Liu, Z.; Zhang, Y. Org. Chem. Front. 2015, 2, 1107; (e) Moselage, M.; Li, J.; Ackermann, L. ACS Catal.
2016, 6, 498; (f) Wei, D.; Zhu, X.; Niu, J.ꢀL.; Song, M.ꢀP. ChemCatChem 2016, 8, 1242.
(3) (a) Chinnagolla, R. K.; Pimparkar, S.; and Jeganmohan, M. Org. Lett. 2012, 14, 3032; (b)
Muralirajan, K.; Kuppusamy, R.; Prakash, S.; Cheng, C.ꢀH. Adv. Synth. Catal. 2016, 358, 774 and
references cited therein.
(4) (a) Lim, S.ꢀG.; Lee, J. H.; Moon, C. W.; Hong, J.ꢀB. Jun, C.ꢀH. Org. Lett. 2003, 5, 2759; (b) Colby,
D. A.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2008, 130, 3645; (c) Guimond, N.; Fagnou, K.
ACS Paragon Plus Environment

Page 21 of 22
The Journal of Organic Chemistry
1
2
3
4
5
6
J. Am. Chem. Soc. 2009, 131, 12050; (d) Fukutani, T.; Umeda, N.; Hirano, K.; Satoh, T.; Miura, M.
Chem. Commun. 2009, 5141.
(5) (a) Chuang, S.ꢀC.; Gandeepan, P.; and Cheng, C.ꢀH. Org. Lett. 2013, 15, 5750; (b) Huang, X.ꢀC.;
Yang, X.ꢀH.; Song, R.ꢀJ.; and Li, J.ꢀH.; J. Org. Chem. 2014, 79, 1025.
7
8
(6) Han, W.; Zhang, G.; Li, G.; Huang, H. Org. Lett. 2014, 16, 3532.
9
(7) (a) Wang, Y.ꢀF.; Toh, K. K.; Lee, J.ꢀY.; Chiba, S. Angew. Chem. Int. Ed. 2011, 50, 5927; (b) Gupta,
S.; Han, J.; Kim, Y.; Lee, S. W.; Rhee, Y. H.; Park, J. J. Org. Chem. 2014, 79, 9094; (c) Qiu, L.; Huang,
D.; Xu, G.; Dai Z.; Sun, J. Org. Lett. 2015, 17, 1810.
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
(8) Okamoto, S. Heterocycles 2012, 85, 1579.
(9) (a) Glaser, C. Ber. Dtsch. Chem. Ges. 1869, 2, 422; (b) Hay, A. S. J. Org. Chem. 1960, 25, 1275; (c)
Hay, A. S. J. Org. Chem. 1962, 27, 3320; (d) Yuan, C.; Chang, C.ꢀT.; Axelrod, A.; Siegel, D. J. Am.
Chem. Soc. 2010, 132, 5924; (e) Jiang, H.; Zeng, W.; Li, Y.; Wu, W.; Huang, L.; Fu, W. J. Org. Chem.
2012, 77, 5179; (f) Shi, W.; Lei, A. Tetrahedron Lett. 2014, 55, 2763; (g) Mo, J.; Eom, D.; Lee, E.; Lee,
P. H. Org. Lett. 2012, 14, 3684; (h) Mo.J.; Choi, W.; Min, J.; Kim, C.ꢀE.; Eom, D.; Kim, S. H.; Lee, P.
H. J. Org. Chem. 2013, 78, 11382; (i) Itoh, M.; Shimizu, M.; Hirano, K.; Satoh, T.; Miura, M. J. Org.
Chem. 2013, 78, 11427.
(10) (a) Doherty, S.; Knight, J. G.; Smyth, C. H.; Harrington, R. W.; Clegg, W. Org. Lett. 2007, 9, 4925;
(b) Nishida, G.; Ogaki, S.; Yusa, Y.; Yokozawa, T.; Noguchi, K.; Tanaka, K. Org. Lett. 2008, 10, 2849;
(c) Yu, D.ꢀG.; de Azambuja, F.; Gensch, T.; Daniliuc, C. G.; Glorius, F. Angew. Chem. Int. Ed. 2014, 53,
9650; (d) Li, D. Y.; Chen, H. J.; Liu, P. N. Org. Lett. 2014, 16, 6176; (e) Mayakrishnan, S.; Arun, Y.;
Balachandran, C.; Emi, N.; Muralidharan, D.; Perumal, P. T. Org. Biomol. Chem. 2016, 14, 1958.
(11) (a) Shiraiwa, M.; Sakamoto, T.; Yamanaka, H. Chem. Pharm. Bull. 1983, 31, 2275; (b) Mandadapu,
A. K.; Dathi, M. D.; Arigela, R. K.; Kundu, B. Tetrahedron 2012, 68, 8207 and references cited therein;
(c) Pan, X.; Yang, C.; Cleveland, J. L.; Bannister, T. D. J. Org. Chem. 2016, 81, 2194.
(12) (a) CCDCꢀ1519039 contains the supplementary crystallographic data for 3aa; (b) CCDCꢀ1519235
contains the supplementary crystallographic data for 4ae. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
(13) Feng, R.; Yu, W.; Wang, K.; Liu, Z.; Zhang, Y. Adv. Synth. Catal. 2014, 356, 1501.
(14) (a) Durola, F.; Lux, J.; Sauvage, J.ꢀP. Chem. Eur. J. 2009, 15, 4124; (b) Durola, F.; Sauvage, J.ꢀP.;
Wenger, O. S. Helv. Chim. Acta 2007, 90, 1439; (c) Collin, J.ꢀP.; Durola, F.; Lux, J.; Sauvage, J.ꢀP.
Angew. Chem. Int. Ed. 2009, 48, 8532; (d) Collin, J.ꢀP.; Durola, F.; Lux, J.; Sauvage, J.ꢀP. New J. Chem.
2010, 34, 34; (e) Durola, F.; Sauvage, J.ꢀP.; Wenger, O. S. Chem. Comun. 2006, 171. (f) Prikhoďko, A.
I.; Sauvage, J.ꢀP. J. Am. Chem. Soc. 2009, 131, 6794.
(15) (a) Zhang, X.; Chen, D.; Zhao, M.; Zhao, J.; Jia, A.; Li, X. Adv. Synth. Catal. 2011, 353, 719; (b)
Guimond, N.; Gorelsky, S. I.; Fagnou, K. J. Am. Chem. Soc. 2011, 133, 6449; (c) Liu, B.; Hu, F.; Shi,
B.ꢀF. Adv. Synth. Catal. 2014, 356, 2688; (d) Muralirajan, K.; Kuppusamy, R.; Prakash, S.; Cheng,
C.ꢀH. Adv. Synth. Catal. 2016, 358, 774.
(16) (a) Gong, T.ꢀJ.; Xiao, B.; Liu, Z.ꢀJ.; Wan, J.; Xu, J.; Luo, D.ꢀF.; Fu, Y.; Liu, L. Org. Lett. 2011, 13,
3235; (b) Gong, T.ꢀJ.; Su, W.; Liu, Z.ꢀJ.; Cheng, W.ꢀM.; Xiao, B.; Fu, Y. Org. Lett. 2014, 16, 330.
(17) (a) Zhang, Z.ꢀW.; Lin, A.; Yang, J. J. Org. Chem. 2014, 79, 7041ꢀ7050; (b) Zhao, D.; Lied, F.;
Glorius, F. Chem. Sci. 2014, 5, 2869ꢀ2873; (c) Hay, A. S. J. Org. Chem. 1960, 25, 1275. (d) Hay, A. S.
J. Org. Chem. 1962, 27, 3320; (e) Fairlamb, I. J. S.; Bäuerlein, P. S.; Marrison, L. R.; Dickinson, J. M.
Chem. Commun. 2003, 632.
(18) (a) Parthasarathy, K.; Cheng, C.ꢀH. J. Org. Chem. 2009, 74, 9359; (b) Kornhaaβ, C.; Li, J.;
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 22
1
2
3
4
5
Ackermann, L. J. Org. Chem. 2012, 77, 9190; (c) Sen, M.; Kalsi, D.; Sundararaju, B. Chem. Eur. J.
2015, 21, 15529.
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
ACS Paragon Plus Environment