Merging C-H Vinylation with Switchable 6π-Electrocyclizations for Divergent Heterocycle Synthesis

Article abstract of DOI:10.1021/jacs.0c07680

Pyridinium-containing polyheterocycles exhibit distinctive biological properties and interesting electrochemical and optical properties and thus are widely used as drugs, functional materials, and photocatalysts. Here, we describe a unified two-step strategy by merging Rh-catalyzed C-H vinylation with two switchable electrocyclizations, including aza-6π-electrocyclization and all-carbon-6π-electrocyclization, for rapid and divergent access to dihydropyridoisoquinoliniums and dihydrobenzoquinolines. Through computation, the high selectivity of aza-electrocyclization in the presence of an appropriate "HCl"source under either thermal conditions or photochemical conditions is shown to result from the favorable kinetics and symmetries of frontier orbitals. We further demonstrated the value of this protocol by the synthesis of several complex pyridinium-containing polyheterocycles, including the two alkaloids berberine and chelerythrine.

Full text of DOI:10.1021/jacs.0c07680

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Article
Merging C–H Vinylation with Switchable 6#-
Electrocyclizations for Divergent Heterocycle Synthesis
Xunjin Jiang, Zhixiong Zeng, Yuhui Hua, Beibei Xu, Yang Shen,
Jing Xiong, Huijuan Qiu, Yifan Wu, Tianhui Hu, and Yandong Zhang
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c07680 • Publication Date (Web): 12 Aug 2020
Downloaded from pubs.acs.org on August 13, 2020
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Page 1 of 11
Journal of the American Chemical Society
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Merging C–H Vinylation with Switchable 6π-Electrocyclizations for
Divergent Heterocycle Synthesis
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Xunjin Jiang1,§, Zhixiong Zeng1,§, Yuhui Hua1,§, Beibei Xu2, Yang Shen1, Jing Xiong2, Huijuan Qiu1,
Yifan Wu1, Tianhui Hu2,*, and Yandong Zhang1,*
1Department of Chemistry and Key Laboratory of Chemical Biology of Fujian Province, iChEM, College of Chemistry
and Chemical Engineering, Xiamen University, Xiamen, Fujian 361005, China
2Cancer Research Center, School of Medicine, Xiamen University, Xiamen, 361102, China
ABSTRACT: Pyridinium-containing polyheterocycles exhibit distinctive biological properties, interesting electrochemical
and optical properties, and thus are widely used as drugs, functional materials, and photocatalysts. Here, we describe a
unified two-step strategy by merging Rh-catalyzed C–H vinylation with two switchable electrocyclizations, including aza-
6π- and all-carbon 6π-electrocyclizations, for rapid and divergent access to dihydropyridoisoquinoliniums and
dihydrobenzoquinolines. Through computation, the high selectivity of aza-electrocyclization in the presence of an
appropriate “HCl” source under either thermal conditions or photochemical conditions is shown to result from favorable
kinetics and symmetries of frontier orbitals. We further demonstrated the value of this protocol by the synthesis of
several complex pyridinium-containing polyheterocycles, including two alkaloids berberine and chelerythrine.
concise, modular, diversity-oriented approaches towards
PCPs are still lacking. Herein we report the development
of a divergent strategy for the synthesis of two distinct
■ INTRODUCTION
Pyridinium-containing polyheterocycles (PCPs) are
widely found in the architectures of many natural
products, synthetic dyes, pharmaceuticals, and organic
functional materials.1 Their unique properties are closely
related to the permanent positive charge of pyridinium
nitrogen. Polycyclic alkaloids containing pyridinium
moieties,2 such as berberine and chelerythrine (Figure 1a),
display diverse biological activities. Many of these
biological performances are related to the unique
interactions of the highly polar quaternary pyridinium
moieties with DNA or proteins through π-π stacking,
electrostatic interaction, or covalent bond formation.3
azatricycles,
dihydropyridoisoquinoliniums
and
dihydrobenzoquinolines, featuring two switchable 6π
electrocyclizations14 and aromatic C–H bond activation.15
■ RESULTS AND DISCUSSION
As outlined in Figure 1b, we envisioned that
dihydropyridoisoquinoliniums D and benzoquinolines F
could be derived from a common precursor 2-(2-
vinylphenyl)pyridine (B) either through aza-6π-
electrocyclization16 followed by in situ trapping HCl or
through all-carbon 6π-electrocyclization followed by
dehydrogenation. Further quaternization of either E or F
through classical alkylation methods could afford the
corresponding pyridinium salts, which will not be
discussed in this report. We also anticipated that the
intrinsic pyridinyl group of the precursor B could serve as
a natural directing group17 for the introduction of a vinyl
group to the ortho-position of the phenyl ring via
transition-metal catalysis, thus setting 2-phenylpyridine
(A), a broad category of readily available compounds, as
the starting material. If successful, this approach would
be highly desirable due to the high atom-economy and
flexibility of both C–H vinylation and 6π-
electrocyclizations.
Doping of
a nitrogen-cation (within a pyridinium
framework) in the polycyclic aromatic hydrocarbons can
drastically alter the backbone optoelectronic behaviors.4
Based on this concept, not only many functional materials
with unique electro-optical and photophysical properties5
(such as P1-P5 in Figure 1a) have been developed, but also
many organic photocatalysts6 have been invented (such as
P6 in Figure 1a).
The N-alkylation of pyridines with alkyl halides or
triflates is the most commonly used method to generate
quaternary pyridinium cation either at the early stage5d, 7
or at the late stage8 of the polyheterocycle synthesis.
Several syntheses of PCPs through photochemical
electrocyclization involving C–N bond formation have
been reported by Bradsher,9 Arai,10 Fedorova,11 and
Berdnikova12 et al. In recent years, transition metal-
mediated annulation reactions13 were also employed to
synthesize quaternary pyridinium salts, especially for N-
arylpyridinium salts. Despite these advancements,
We were aware that from an ambident substrate like
B, how to achieve two electrocyclization pathways
orthogonally (either all-carbon [6π] or aza-[6π]) without
interference with each other in a substrate-independent
fashion would be extremely challenging. Fundamentally,
the electrocyclization is energetically driven by the
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a) Selected pyridinium-containing functional molecules
OMe
1
2
3
4
5
6
7
Cl
BF4
N
F
F
OMe
Cl
Me
n-Pr
MeO
N
MeO
F
TfO
F
N
O
O
N
O
O
Berberine
Chelerythrine
P1
P2
8
t-Bu
9
Br
N
Br
Me
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
TfO
N
N
N
Me
N
Me
ClO4
n-Bu
Me
ClO4
P3
P4
P5
P6
t-Bu
b) This work: divergent access to azatricycles
Cl
N
aza-[6π]
N
N
+"HCl"
X
Y
Y
Y
X
X
H
B
C
C–H
vinylation
D
dihydropyridoisoquinolinium (
)
N
σ-Bond
rotation
X
Y
A
[6π]
-"H2"
N
Y
N
N
Y
X
X
X
Y
B
E
F
benzoquinoline ( )
Figure 1. Strategy for the divergent polyheterocycle synthesis through C–H vinylation and 6π-electrocyclizations.
inherent structural properties of the substrate itself,
majorly being governed by the frontier molecular orbitals
and far less depending on external factors.18 To selectively
transformation is still unknown for 2-phenylpyridines.
We began our study by an exploration of a transition-
metal catalyzed ortho-C–H vinylation on the model
substrate 2-phenylpyridine (1a). A thorough survey of
transitional metal catalysts, such as Pd(OAc)2, [RuCl2(p-
cymene)]2 and [Cp*RhCl2]2, vinyl source (pinacol
form desired 6π electrocyclization products in
a
substrate-independent fashion remains poorly addressed.
However, the existence of a nitrogen atom could
introduce a tunable site19 to modulate the shape of
HOMO-LUMO. Herein we report the realization of two
switchable 6π-electrocyclizations by tuning additives
under thermal and photochemical conditions. These
reactions represent the first practical synthetic method
for two distinct polyheterocycles through substrate-
independent switchable electrocyclizations.
vinylborate,
potassium
vinyltrifluoroborate,
and
trivinylboroxin), oxidants including Cu(OAc)2, O2,
PhI(OAc)2, and benzoquinone (BQ), solvents (CH2Cl2,
MeCN, and DCE) and the temperature was carried out
(Table S1). We were delighted to find that when 1a was
treated with 5 mol% of [Cp*RhCl2]2, pinacol vinylborate
(1.4 equiv), Cu(OAc)2 (1.0 equiv), and BQ (1.0 equiv) in
CH2Cl2 at 70 °C, the desired vinylated product 1 was
obtained in 76% yield and only a tiny amount of
bisvinylated product was observed (Table S1, entry 7).
Although there is no conclusive explanation for the high
monovinylation selectivity, the combination of Cu(OAc)2
and BQ seems indispensable, and solely using either of
them as oxidant only led to inferior results.
Under the optimized conditions, a wide range of
pyridinylstyrene derivatives could be prepared in
moderate to high yield (32-91%), mostly with a very high
mono/di vinylation ratio (Table 1, entries 2 to 41). The
mild catalytic conditions tolerated various functional
groups, including ethers, halides, ketones, nitrile, esters,
amide, alcohol. It is worth noting that except a tiny
amount of 1 (the direct Suzuki product of 4a) was formed
during the synthesis of 4, other halogen substituents (7,
C–H vinylation: development and scope. Although
several directed ortho-C–H vinylation methodologies
have been reported either using ethylene gas,20 vinyl
acetate,21 vinyl stannane,22 acrylic acid,23 or vinylsilane,24
a
solution with high monovinylation selectivity, broad
substrate scope, and mild reaction conditions remains
elusive. Suzuki-Miyaura coupling25 has been widely used
in organic synthesis and pharmaceutical industry due to
its mild reaction conditions, broad substrate scope, and
thousands of readily available organoboronic acids.
Compared to vinyl sources like pressured and flammable
ethylene gas, toxic vinyl stannanes, or expensive vinyl
silanes, vinyl borates or boronic acids could serve as a
cheaper, safe, environment-benign and easy-to-handle
surrogate to provide a vinyl group in an ortho-C–H
vinylation reaction. To our knowledge, such
a
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Table 1. Substrate scope for the Rh-catalyzed C–H vinylation of 2-aryl pyridinesa
1
2
3
H
N
N
N
5 mol% [Cp*RhCl2]2,
Bpin
4
5
Cu(OAc)2, BQ, CH2Cl2, 70 °C
X
X
X
Y
Y
Y
A
B
G
6
7
8
N
N
N
N
N
X
Y
9
X
X
Me
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
2
3
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
: X = H (76%, 18:1)
: X = Me (91%)
: X = OMe (55%)
[X-ray]
: X = Me (78%, > 20:1)
: X = OMe (58%, > 20:1)
: X = Cl (64%, > 20:1)
: X = Ph (65%)
: X = Me (64%)
25
26
27
28
29
30
31
: Y = Me (79%, > 20:1)
: Y = OMe (82%, > 20:1)
: Y = F (76%,14:1)
: Y = Br (84%, 15:1)
: Y = Ac (74%,14:1)
: Y = CF3 (66%)
22
(57%,10:1)
: X = tBu (70%, > 20:1)
: X = OMe (76%,17:1)
: X = F (52%,7:1)
: X = Cl (73%,16:1)
: X = Br (81%, 8.3:1)
: X = CO2Me (76%,11:1)
: X = CF3 (82%,10:1)
: X = NHTs (32%)
N
4
: X = Cl (70%, 10:1)
: X = CO2Me (78%)
: X = CF3 (88%, > 20:1)
: X = Ac (51%, > 20:1)
: X = CN (68%)
Y
: Y = CH2OH (59%, 16:1)
23
24
: Y = Me (69%,13:1)
: Y = OMe (83%, > 20:1)
N
Y
6
6
N
N
N
N
X
X
Y
Y
MeO
MeO
O
32
33
34
35
36
37
38
: X = OMe, Y = OMe (67%, 10:1)
: X = OMe, Y = F (61%, > 20:1)
: X = OMe, Y = Ac (79%, > 20:1)
: X = OMe, Y = CF3 (60%, > 20:1)
: X = CO2Me, Y = OMe (88%)
: X = CO2Me, Y = F (71%)
2
X
2
O
39
40
41
: X = OMe, Y = Me
(83%, > 20:1)
: X = OMe, Y = CF3
(63%, 16:1)
45
46
47
b
: X = NTs (89%)
: X = O (68%)
: X = S (80%)
42
43
: Y = H (56%)
44
(74%)
: Y = CF3 (60%)
: X = CF3, Y = Me (80%, 11:1)
: X = CO2Me, Y = Ac (77%)
N
N
N
N
N
N
N
N
Boc
c
48
49
50
51
52
(59%,1:10)
(44%)
(40%, 16:1)
(66%, > 20:1)
(67%, 11:1)
aReaction conditions: 2-arylpyridine (0.5 mmol), pinacol vinylborate (1.4 equiv), [Cp*RhCl2]2 (5 mmol%), Cu(OAc)2 (1.0
equiv), and BQ (1.0 equiv), CH2Cl2, 70 °C. Isolated yields. The mono/di vinylation ratios were determined with crude
products by 1H NMR. bThe ratio of C2 and C6 isomers was 4:1. cPinacol vinylborate (2.8 equiv) was used.
16, 17, 18, 27, 28) remained intact in this oxidative C–H
vinylation (i.e., no direct Suzuki product was observed),
thereby keeping the possibility for further derivatization
over the C–X bonds. The electronic effect does not seem
to affect the reactivity dramatically, and the substrates
bearing either electron-donating or electron-withdrawing
group on phenyl ring or pyridinyl ring, or even on both
rings, by and large, gave good yields. Interestingly, the
abnormal regioselectivity of C–H vinylation caused by
methylenedioxy group26 on the phenyl ring (on C2, 42,
and 43) could be reversed by replacement of it by the
dimethoxy group to deliver vinylation product 44 (on C6).
In addition to the phenyl ring, several heterocyclic rings
attached to the pyridinyl ring could also be smoothly
vinylated in moderate to high yield (45-48). Besides the
pyridinyl group, quinolinyl and isoquinolinyl groups
could also assist the ortho-C–H vinylation of the
neighboring phenyl ring (49 and 50). Finally, by adjusting
the amount of pinacol vinylborate (1.4 equiv or 2.8 equiv),
1,4-dipyrdinylbenzene could be converted to either
monovinyl compound 51 or divinyl compound 52.
Switchable 6π electrocyclizations: development
and scope. With the C–H vinylation products prepared,
we turned our attention to the aza-6π- and all-carbon-6π-
electrocyclizations
for
the
generation
of
dihydropyridoisoquinoliniums and benzoquinolines. As
far as we know, there were no precedents for both
transformations on 2-(2-vinylphenyl)pyridine derivatives.
To gain preliminary insight into these two 6π-
electrocyclizations, we first performed computational
studies on the kinetic profile of the two reaction
pathways. Density functional theory (DFT) calculations in
gas phase reveal that the activation energy of the aza-6π-
electrocyclization (28.61 kcal/mol) is much lower than
that of all-carbon-6π-electrocyclization (48.02 kcal/mol),
which indicates the former one is much more kinetically
favorable than the later one under thermal conditions.
These findings agreed with the previous results of Houk
and coworkers on electrocyclization of simple 1-aza-1,3,5-
hexatriene.27 Therefore, we envisioned that in the
presence of a suitable “HCl” source, which is necessary for
this aza-6π-electrocyclization, thermal conditions would
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Table 2. Substrate scope for two switchable 6π-electrocyclizationsa
1
2
3
4
5
6
Cl
NH4Cl (10.0 equiv)
N
N
hν
cyclohexane
H2O, 150 °C
40 h
N
N
Y
Y
X
X
X
Y
Y
X
D
B
B
E
7
8
9
Cl
Cl
N
Cl
N
N
X
N
N
N
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
X
X
60
61
62
63
64
65
: X = OMe (91%)
: X = NHTs (91%)
: X = F (92%)
Me
MeO2C
53
56
57
58
59
: X = H (99%)
(94%, gram scale)
: X = OMe (62%)
: X = Cl (46%)
: X = Ph (35%)
83
84
85
(56%)
(76%)
DDQ
(65%)
: X = Cl (88%)
54
55
b
: X= CO2Me, (92%)
: X = CF3 (89%)
: X = Br (81%)
b
: X = CO2Me (81%)
: X = CF3 (81%)
O
Cl
Cl
N
Cl
N
N
O
MeO
X
Y
N
N
N
MeO
Me
83a
86
87
88
89
90
(80%)
: X = OMe (73%)
: X = CO2Me (69%)
: X = CF3 (63%)
: Y = Me (65%)
: Y = Ac (62%)
66
67
68
(70%)
(68%)
(58%)
Me
Cl
Cl
N
Cl
N
N
X
Y
Y
X
Y
S
N
X
N
N
92
93
69
70
71
72
73
74
77
78
79
91
: X = CF3, Y = Me (60%)
: X = OMe, Y = Me (67%)
94
(66%)
: Y = Me(64%)
: Y = Br (38%)
: Y = Ac (49%)
: Y = CF3 (48%)
: X = OMe, Y = Me
(89%)
: X = OMe, Y = CF3
(30%)
: X = CF3, Y = Me
(89%)
: X = NTs (39%)
: X = O (37%)
: X = S (71%)
(51%)
75
76
: Y = CH2OH (44%)
Boc
Cl
N
Cl
N
Cl
N
N
N
N
N
N
80
81
82
(69%)
(77%)
(46%)
95
96
97
(73%)
(40%)
(40%)
66
[X-ray] of
72
96
[X-ray] of
[X-ray] of
aReaction conditions: (1) Aza-6π-electrocyclization: styrene compound B (0.25 mmol), NH4Cl (2.5 mmol), H2O (2 mL), 155 °C, 40
h. (2) All-carbon-6π-electrocyclization: styrene compound B (0.25 mmol), cyclohexane (180 mL), UV (λ = 254 nm), 23 °C, 48 h.
bThe ester group was hydrolyzed under current reaction conditions and an additional esterification with SOCl2 and MeOH was
performed (see Supporting Information).
be beneficial for a selective aza-6π- electrocyclization; on
the contrary, photochemical conditions in the absence of
an “HCl” source might facilitate a selective all-carbon-6π-
electrocyclization. With this in mind, we evaluated a wide
range of reaction parameters on the model substrate 1,
including the “HCl” source, solvent, reaction temperature,
and light irradiation (Table S2). To our delight, when
amixture of 1 and 10.0 equivalent of NH4Cl in water was
dihydropyridoisoquinolinium compound 53 was obtained
in a quantitative yield. It is worth noting that in this
reaction, there was only a molecule of ammonia being
released as a byproduct. When NH4Cl was replaced with
HCl, the substrate was decomposed upon being heated at
the same temperature. Next, irradiation of
1 in
cyclohexane with λ = 254 nm light smoothly delivered
azatricyclic compound 83 in 76% yield. These results
showed different regioselectivity compared with
heated in
a
sealed tube at 150 °C, the
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a
TS-C2
1
2
3
4
5
6
7
8
TS-C1
58.99
61.70
Aza-[6π]
Electrocyclization
pathway C
Int-C
TS-D2
45.93
TS-D1
45.60
47.28
TS-B1
45.37
43.95
All-Carbon-[6π]
Electrocyclization
pathway B
TS-B2
TS-A1
9
Int-B
28.12
Int-D
28.84
29.20
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
NH4
24.64
Int-A
17.21
N
TS-A2
53
NH3
Aza-[6π]
All-Carbon-[6π]
Electrocyclization
pathway D
–15.36
Electrocyclization
pathway A
Int-E
NH3
NH4
NH3
1.42
–21.70
H
N
–22.22
0.00
N
NH4
98
N
H
N
1
83
H
H
H3N
H
H
N
N
N
N
N
N
TS-A1
TS-A2
TS-B1
TS-B2
TS-C1
TS-C2
H
H
N
N
N
H
N
H
N
N
H
TS-D1
TS-D2
Int-A
Int-B
Int-C
Int-D
H
7
D
7
b
Cl
Cl
N
N
N
ND4Cl (10.0 equiv)
NH4Cl (10.0 equiv)
H2O, 150 °C, 13 h
kH
kD
= 0.94
KIE =
D2O, 150 °C, 13 h
53
1
53-d
e
c
d
H2O, 150 °C, 40 h
N
N
hν
Yes
No
NR
NH4Cl
Yes
1
1
All-C-[6π] + Aza-[6π] Aza-[6π]
Cl
NH4Cl (10.0 equiv)
N
+
EtOH, H2O, hν, 40 h
No
All-C-[6π]
NR
N
53
83
(17% + 3%)
(26%)
Figure 2. Mechanistic investigations. a, Computed free-energy profiles for four 6π-electrocyclization pathways. b-d, Mechanistic
experiments. e, A summary of reaction conditions for the two orthogonal 6π electrocyclizations. TS = transition state, Int =
intermediate.
49
50
51
52
53
54
55
56
57
58
59
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Berdnikova’s examples.12 At this stage, we successfully
realized divergent transformation of the model
substrate to two distinct azatricycles through two
switchable electrocyclizations, and these transformations
have a very high atom economy.
The substrate scope of this divergent protocol was
evaluated under standard conditions (Table 2). In general,
2-(2-vinylphenyl)pyridine derivatives bearing either
electron-donating group or electron-withdrawing group
at the ortho-, meta-, or para- positions (relative to
a
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Page 6 of 11
pyridinyl group) of the phenyl ring could be smoothly
converted to the corresponding
reaction profile of 1 towards 6π-electrocyclizations is
summarized in Figure 2e.
DFT studies also revealed that the protonation of 1
with NH4Cl to generate 98 is kinetically and
thermodynamically viable process; however, both aza-
1
2
3
4
5
6
7
8
dihydropyridoisoquinolinium product (53-67) in good to
high yield. However, we found that the electron density of
the pyridinyl ring significantly affected the reactivity of
the substrates. The 2-(2-vinylphenyl)pyridine derivatives
with an electron-donating group on pyridinyl ring mostly
had higher reactivity, affording desired products in good
to high yield (68, 69, and 74). Nevertheless, the electron-
withdrawing group on the pyridinyl ring decreased the
reactivity towards aza-6π-electrocyclization, and only
moderate yields were obtained (70-72). Besides, two
substrates with sharp contrast in electronic factors, 40
(with MeO on Ph and CF3 on Py) and 41 (with CF3 on Ph
and Me on Py) were examined, and similar trends were
observed (75: 30% yield, 76: 89% yield). Azatricycles
containing two heteroatoms can also be prepared
efficiently (77-80). Finally, tetracyclic core structures of
berberine (81) and its constitutional isomer (82), which
contains a quinoline ring, were successfully constructed
with the current two-step protocol. It is worth
mentioning that, in all the above cases, no all-carbon-6π-
electrocyclization products were observed. Next, under
electrocyclization
(pathway
C)
and
all-carbon-
electrocyclization (pathway D) are kinetically unfavorable
due to the very high energy barriers (61.70 kcal/mol and
45.93 kcal/mol respectively). This is probably the reason
why no electrocyclization products (53 and 83) were
observed except decomposition of the starting material
when 1 was heated with aqueous HCl at 150 °C. Finally,
the mechanism involving a radical anti-Markovnikov
addition of HCl followed by an intramolecular SN2
reaction was also ruled out by a radical quench
experiment (See Supporting Information for details).
Therefore, pathway A is the most favorable under current
thermal conditions in which NH4Cl played a critical role
as a less acidic source of “HCl”.
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Photochemical
aza-6π-electrocyclization:
discovery and frontier molecular orbital (FMO)
studies. Driven by the curiosity for the reactivity of
protonated species 98 towards electrocyclization, we
carried out several experiments that gave rise to some
interesting findings. In the beginning, fortunately, the
single crystal X-ray structure of very hygroscopic salt 98
was obtained (Figure 3). Although the neat sample of 98
remained unchanged under UV irradiation, heating it at
the
standard
conditions
for
all-carbon-6π-
electrocyclization, a variety of azatricyclic compounds
bearing a dihydroquinoline core (83-97) were prepared
efficiently, among which compound 96 bears the central
scaffold of chelerythrine. As an instance for the
dehydrogenation transformation, upon treatment with
DDQ at 155 °C, compound 83 was smoothly converted to
benzoquinoline 83a in 80% yield.
150 °C under argon led to the formation of
pyridoisoindolium salt 99 probably through
a
a
Markovnikov addition, which underwent elimination
upon silica gel chromatography to deliver pyridoisoindole
100 in 76% yield. To our surprise, when a solution of 98 in
methanol was irradiated with UV light (λ = 254 nm),
dihydropyridoisoquinolinium salt 53 was indeed obtained
in 69% yield, and no all-carbon-electrocyclization
product (83) (pathway D, Figure 2) was observed (Figure
3b), which indicated that the aza-electrocyclization
(pathway C, Figure 2) was dominant in this case. At this
point, 53 could be prepared from 1 under both thermal
and photochemical conditions by using different “HCl”
source, NH4Cl and HCl, respectively. The scope of this
photocyclization could be well extended to substrates
bearing either an electron-donating group or an electron-
withdrawing group on the phenyl ring (Figure 3c and 3d).
To gain more insights for aza- and all-carbon-
electrocyclizations of pyridine 1 and get some clue for the
excellent regioselectivity of pyridinium 98 in
photocyclization, we scrutinized the symmetry characters
of their FMOs by DFT calculations. The HOMOs and
LUMOs of the optimized conformers for both aza- and
all-carbon- electrocyclizations were calculated at the
M06-2X/Def2-SVP level (Figure 3e). Not unexpectedly,
the symmetries of HOMOs of the two conformers of 1 and
the two conformers of 98 are all coincidental to the
prediction by the Woodward-Hoffman rules, indicating
that both types of electrocyclization are symmetry-
allowed in the ground-states of 1 and 98. As for the
excited state, the symmetries of LUMOs of the two
conformers of 1 are still allowed for both
Mechanistic study. To better understand the
fundamental reason for the high regioselectivity of the
aza-6π-electrocyclization and the role of NH4Cl, energy
profiles of two possible electrocyclization pathways
(pathways A and B, Figure 2a) were investigated through
DFT calculations. In consideration of the weak acidic
property of NH4Cl in water (pKa = 9.20, 298 K),28 we
cannot exclude that a protonated pyridine species (98)
might be involved in the reaction; thus, two additional
pathways (pathways C and D, Figure 2a) were also
calculated. In pathway A, 1 first undergoes a reversible
aza-electrocyclization through TS-A1 followed by
irreversible protonation through TS-A2; the whole
process is exothermic by 15.36 kcal/mol and requires
activation energy of 29.20 kcal/mol. The rate-determining
step of this pathway is the aza-electrocyclization, which
was further verified by the results of the kinetic isotope
effect experiment (Figure 2b) in conjunction with the
control experiment in the absence of NH4Cl (Figure 2c).
In pathway B, 1 undergoes a reversible all-carbon-
electrocyclization through TS-B1, followed by 1,5-
hydrogen migration through TS-B2. DFT calculation
suggested that pathway A is kinetically more favorable
than pathway B by 16.17 kcal/mol, though the latter one is
thermodynamically more favorable than the former one
by6.86 kcal/mol. However, interestingly, these two
electrocyclizations were competitive in the presence of
NH4Cl under photochemical conditions (Figure 2d). A full
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1
2
3
4
5
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7
8
H
neat
150 °C
H
a
c
Cl
Cl
N
b
Cl
Cl
N
SiO2
76%
hν
N
N
N
MeOH
69%
98
99
100
Cl
98
53
H
Cl
hν
N
N
MeO
MeO
F3C
MeOH
98%
101
60
65
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45
H
Cl
Cl
hν
N
N
d
e
F3C
MeOH
54%
98
[X-ray] of
102
HOMO
Optimized Conformers of Substrates
Aza-electrocyclization of 1
LUMO
disrotatory
conrotatory
All-carbon-electrocyclization of 1
disrotatory
conrotatory
Aza-electrocyclization of salt 98
disrotatory
conrotatory
All-carbon-electrocyclization of salt 98
disrotatory
disrotatory
Figure 3. More mechanistic investigations. a, Thermocyclization of the pyridinium salt 98. b-d, Photocyclization of pyridinium
salts 98, 101, and 102. These salts were in-situ generated by treatment with 1 M HCl solution in methanol. e, Symmetry analysis
of frontier molecular orbitals (isovalue = 0.05).
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electrocyclizations, which agreed with the experimental
phenomena in Figure 2d. By the combination of previous
results of DFT calculated energy profiles (Figure 2a), the
two electrocyclization pathways of 1 were well explained.
As LUMOs of 98 shown, the conrotatory aza-
electrocyclization is symmetry-allowed, but the
conrotatory all-carbon-electrocyclization is symmetry-
forbidden in the excited state (Figure 3b). Furthermore,
the disrotatory ring closure in this system towards the all-
carbon-electrocyclization is also infeasible due to the
geometrical restriction. Therefore, only the aza-
electrocyclization is allowed under the photochemical
conditions, which is in line with the experimental facts.
Synthetic applications and biological assay. The
presented two-step protocol can enable the rapid and
divergent synthesis of two typical azatricycles. We next
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1
2
3
4
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Ph
Ph
N
a
Ph
5 mol% [Cp*RhCl2]2,
*
Cl
6
N
N
N
NH4Cl, H2O
B(OH)2
Cu(OAc)2, BQ, CH2Cl2, 70 °C
50%
150 °C, 40 h
79%
1a
103
104
n-Pr
n-Pr
*
6
Cl
b
N
N
5 mol% RuCl ,
NH4Cl, H2O
n-Pr
3
9
(PhCO2)2, K2CO3
NMP, 150 °C
75%
150 °C, 40 h
61%
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1a
105
106
OMe
c
MeO
MeO
CHO
OMe
AgNO3
Pd(PPh3)2Cl2
CuI, Et3N
MeO
OTBS
OTBS
MeO
CHO
N
Hb
NH4OAc
OTBS
OTBS
+
OTBS
OTBS
THF, reflux
64%
tBuOH
79%
Br
107
108
109
OMe
110
Ha
OMe
Bpin
[Cp*RhCl2]2
Cu(OAc)2, BQ
OMe
MeO
MeO
TBAF;
Cl
N
N
MeO
NH4Cl
H2O, PhMe
CH2Br2, K2CO3
N
THF, 70 °C
DCM, 70 °C
72%
2.3 g scale
111
112
150 °C
37%
57%
OTBS
OTBS
O
O
O
hν, Ph2CO, O2
cyclohexane
43%
Berberine
O
OMe
OMe
Cl
Me
MeO
MeO
N
N
O
O
O
O
Chelerythrine
Norchelerythrine
[X-ray]
Figure 4. Broader scope for C–H vinylation and 6π-electrocyclizations and the utility of this new strategy for polycyclic alkaloid
syntheses.
demonstrated its broader applicability. An internal olefin
could be introduced to 1a either by current Rh-catalyzed
oxidative Suzuki coupling or Ru-catalyzed alkyne
addition,29 delivering β-arylstyrene 103 and β-alkylstyrene
105, which further underwent aza-eletrocyclization to
generate C6-substituted dihydropyridoisoquinolinium
salts 104 and 106 (Figure 4a and 4b). As part of our
continuing interest in developing anti-cancer agents
based on PCPs,30 next, late-stage divergent syntheses of
berberine and norchererythrine were achieved with
OVCR3 and BXPC-3 (Figure S1-S5). To our delight,
compound 82 containing a quinoline moiety exhibited
moderate inhibitory effect against MDA-MB 231 (IC50
82.80 μM), HT-29 (IC50 = 53.78 μM), A549 (IC50 = 43.60
μM) and BXPC-3 (IC50 = 40.62 μM), which were slightly
better than that of berberine (Table S3 and Figure S6).
=
■ CONCLUSIONS
In summary, we have developed a strategy by merging
C–H
electrocyclizations that provides rapid and divergent
access to dihydropyridoisoquinoliniums and
dihydrobenzoquinolines. The pyridine-directed C–H
vinylation with high monovinylation selectivity has been
vinylation
with
two
switchable
6π-
newly-developed
two-step
azatricycle
formation
methodology as the core technology (Figure 4c).
Specifically, Sonogashira coupling of bromide 10731 and
alkyne 108 afforded aldehyde 109, which underwent Ag-
mediated annulation to generate isoquinoline 110.
Through isoquinoline-directed C–H vinylation and
subsequent
electrocyclization, a five-step synthesis of berberine and a
formal synthesis of chelerythrine through
norchelerythrine32 were achieved.
Having harvested many azatricyclic compounds
containing a quaternary pyridinium (Table 2), we next
evaluated their inhibitory activities against five human
cancer cell lines, including MDA-MB 231, HT-29, A549,
achieved through
a Rh-catalyzed oxidative Suzuki
coupling. The regioselectivity of electrocyclizations of the
2-(2-vinylphenyl)pyridine intermediates has been well
controlled: in the presence of NH4Cl, the aza-
electrocyclization is the kinetically most favorable
reaction under thermal conditions, while all-carbon-
electrocyclization is dominant under photochemical
conditions in the absence of an “HCl” source. When HCl
was used, 2-(2-vinylphenyl)pyridine intermediates
aza-electrocyclization
or
all-carbon-
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(1) Śliwa, W. Quaternary Salts of Pyridines and Related
Compounds. Curr. Org. Chem. 2003, 7, 995–1048.
selectively underwent aza-electrocyclization under
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3
4
5
6
7
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photochemical conditions through a pyridinium salt
intermediate (98). DFT calculation studies suggested that
this unusual regioselectivity was due to unfavorable
orbital symmetry character of the all-carbon-
electrocyclization conformer of the pyridinium salt 98 in
the excited state. This is the first successful example of an
additive-controlled regioselectivity switch in electrocyclic
ring-closing reactions. These findings enriched the
applications of Woodward-Hoffman rules. The newly
developed strategy was further successfully applied to the
synthesis of several complex PCPs, including two
alkaloids berberine and chelerythrine. Notably, this
unified strategy provides a facile approach to PCPs, which
are widely found in the architectures of many
pharmaceuticals, and functional materials, and
photocatalysts.
(2) (a) Šimánek, V. Benzophenanthridine Alkaloids. In The
Alkaloids: Chemistry and Pharmacology, Brossi, A., Ed. Academic
Press: 1985; Vol. 26, Chapter 4, pp 185–240. (b) Grycová, L.;
Dostál, J.; Marek, R. Quaternary Protoberberine Alkaloids.
Phytochemistry 2007, 68, 150–175.
(3) Ihmels, H.; Otto, D. Intercalation of Organic Dye
Molecules into Double-Stranded DNA General Principles and
Recent Developments. Top. Curr. Chem. 2005, 258, 161–204.
(4) Fortage, J.; Peltier, C.; Nastasi, F.; Puntoriero, F.; Tuyèras,
F.; Griveau, S.; Bedioui, F.; Adamo, C.; Ciofini, I.; Campagna, S.;
Lainé, P. P. Designing Multifunctional Expanded Pyridiniums:
Properties of Branched and Fused Head-To-Tail Bipyridiniums. J.
Am. Chem. Soc. 2010, 132, 16700–16713.
(5) (a) Wu, D.; Pisula, W.; Enkelmann, V.; Feng, X.; Müllen, K.
Controllable Columnar Organization of Positively Charged
Polycyclic Aromatic Hydrocarbons by Choice of Counterions. J.
Am. Chem. Soc. 2009, 131, 9620–9621. (b) Čížková, M.; Kolivoška,
V.; Císařová, I.; Šaman, D.; Pospíšil, L.; Teplý, F. Nitrogen
Heteroaromatic Cations by [2+2+2] Cycloaddition. Org. Biomol.
Chem. 2011, 9, 450–462. (c) Zhao, E.; Deng, H.; Chen, S.; Hong,
Y.; Leung, C. W. T.; Lam, J. W. Y.; Tang, B. Z. A Dual Functional
AEE Fluorogen as a Mitochondrial-Specific Bioprobe and an
Effective Photosensitizer for Photodynamic Therapy. Chem.
Commun. 2014, 50, 14451–14454. (d) Asanuma, Y.; Eguchi, H.;
Nishiyama, H.; Tomita, I.; Inagi, S. Synthesis of Ring-Fused
Pyridinium Salts by Intramolecular Nucleophilic Aromatic
Substitution Reaction and Their Optoelectronic Properties. Org.
Lett. 2017, 19, 1824–1827. (e) Thevenon, A.; Rosas-Hernández, A.;
Peters, J. C.; Agapie, T. In-Situ Nanostructuring and Stabilization
of Polycrystalline Copper by an Organic Salt Additive Promotes
Electrocatalytic CO2 Reduction to Ethylene. Angew. Chem., Int.
Ed. 2019, 58, 16952–16958.
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ASSOCIATED CONTENT
Supporting Information.
The Supporting Information is available free of charge via the
Internet at http://pubs.acs.org.”
Experimental procedures, characterization data, and NMR
spectra for all products; computed energies and Cartesian
coordinates of all the DFT-optimized structures (PDF)
X-ray crystallographic data for 3 (CCDC 2000756) (CIF)
X-ray crystallographic data for 66 (CCDC 2000754) (CIF)
X-ray crystallographic data for 72 (CCDC 2000757) (CIF)
X-ray crystallographic data for 96 (CCDC 2000758) (CIF)
X-ray crystallographic data for 98 (CCDC 2000755) (CIF)
X-ray crystallographic data for norchelerythrine (CCDC
2000759) (CIF)
(6) Margrey, K. A.; Nicewicz, D. A. A General Approach to
Catalytic Alkene Anti-Markovnikov Hydrofunctionalization
Reactions via Acridinium Photoredox Catalysis. Acc. Chem. Res.
2016, 49, 1997–2006.
(7) (a) Núñez, A.; Cuadro, A. M.; Alvarez-Builla, J.; Vaquero, J.
J. Enyne Ring-Closing Metathesis on Heteroaromatic Cations.
Chem. Commun. 2006, 2690–2692. (b) Toriumi, N.; Asano, N.;
AUTHOR INFORMATION
Corresponding Author
Yandong Zhang − Department of Chemistry, and Key
Laboratory of Chemical Biology of Fujian Province, iChEM,
College of Chemistry and Chemical Engineering, Xiamen
University, Xiamen, Fujian 361005, China; orcid.org/0000-
0002-5558-9436; Phone: +86-592-2181902; Email: ydzhang@
xmu.edu.cn
Miyamoto,
K.;
Muranaka,
A.;
Uchiyama,
M.
N-
Alkynylpyridinium Salts: Highly Electrophilic Alkyne-Pyridine
Conjugates as Precursors of Cationic Nitrogen-Embedded
Polycyclic Aromatic Hydrocarbons. J. Am. Chem. Soc. 2018, 140,
3858–3862.
(8) (a) McIver, A.; Young, D. D.; Deiters, A. A General
Approach to Triphenylenes and Azatriphenylenes: Total
Synthesis of Dehydrotylophorine and Tylophorine. Chem.
Commun. 2008, 4750–4752. (b) Pan, X.; Bannister, T. D.
Sequential Sonagashira and Larock Indole Synthesis Reactions in
a General Strategy to Prepare Biologically Active β-Carboline-
Containing Alkaloids. Org. Lett. 2014, 16, 6124–6127.
(9) Fozard, A.; Bradsher, C. K. A Novel Preparation of
Benzo[c]quinolizinium Compounds. Chem. Commun. 1965, 288–
288.
(10) Arai, S.; Takeuchi, T.; Ishikawa, M.; Takeuchi, T.;
Yamazaki, M.; Hida, M. Syntheses of Condensed Polycyclic
Azonia Aromatic-Compounds by Photocyclization. J. Chem. Soc.,
Perkin Trans. 1 1987, 481–487.
Tianhui Hu − Cancer Research Center, School of Medicine,
Xiamen University, Xiamen 361005, China; Phone: +86-592-
2188223; Email: thu@xmu.edu.cn
Author Contributions
§X.J., Z.Z. and Y.H. contributed equally as first authors.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
Financial support from the National Natural Science
Foundation of China (21772164, 21572187, 31770860, 81572589,
and 81602560) is acknowledged. We thank Professor Mingji
Dai of Purdue University for helpful discussions and
Professor Tingbin Wen and Dr. Zi-Ang Nan of Xiamen
University for solving the X-ray structure.
(11) Fedorova, O. A.; Fedorov, Y. V.; Andryukhina, E. N.;
Gromov, S. P.; Alfimov, M. V.; Lapouyade, R. Photochemical
Electrocyclization of the Indolinylphenylethenes Involving a C–
N Bond Formation. Org. Lett. 2003, 5, 4533–4535.
(12) Gulakova, E. N.; Berdnikova, D. V.; Aliyeu, T. M.; Fedorov,
Y. V.; Godovikov, I. A.; Fedorova, O. A. Regiospecific C–N
REFERENCES
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 10 of 11
Photocyclization of 2-Styrylquinolines. J. Org. Chem. 2014, 79,
5533–5537.
Aromatic C–H Bonds with Alkenyl Acetates. J. Am. Chem. Soc.
2007, 129, 9858–9859. (b) Liu, W.; Li, Y.; Xu, B.; Kuang, C.
Palladium-Catalyzed Olefination and Arylation of 2-Substituted
1,2,3-Triazole N-Oxides. Org. Lett. 2013, 15, 2342–2345. (c)
Ogiwara, Y.; Tamura, M.; Kochi, T.; Matsuura, Y.; Chatani, N.;
Kakiuchi, F. Ruthenium-Catalyzed Ortho-Selective C–H
Alkenylation of Aromatic Compounds with Alkenyl Esters and
Ethers. Organometallics 2014, 33, 402–420. (d) Otley, K. D.;
Ellman, J. A. An Efficient Method for the Preparation of Styrene
Derivatives via Rh(III)-Catalyzed Direct C–H Vinylation. Org.
Lett. 2015, 17, 1332–1335.
1
2
3
4
5
6
7
8
(13) (a) Li, L.; Brennessel, W. W.; Jones, W. D. An Efficient
Low-Temperature Route to Polycyclic Isoquinoline Salt
Synthesis via C–H Activation with [Cp*MCl2]2 (M = Rh, Ir). J.
Am. Chem. Soc. 2008, 130, 12414–12419. (b) Jayakumar, J.;
Parthasarathy, K.; Cheng, C.-H. One-Pot Synthesis of
Isoquinolinium Salts by Rhodium-Catalyzed C–H Bond
Activation: Application to the Total Synthesis of
Oxychelerythrine. Angew. Chem., Int. Ed. 2012, 51, 197–200. (c)
Zhang, G.; Yang, L.; Wang, Y.; Xie, Y.; Huang, H. An Efficient
9
Rh/O2
Catalytic
System
for
Oxidative
C–H
(22) Prakash, S.; Muralirajan, K.; Cheng, C.-H. Rh-Catalyzed
Oxidizing Group-Directed Ortho C–H Vinylation of Arenes by
Vinylstannanes. Chem. Commun. 2015, 51, 13362–13364.
(23) Xu, J.; Chen, C.; Zhao, H.; Xu, C.; Pan, Y.; Xu, X.; Li, H.;
Xu, L.; Fan, B. Rhodium(I)-Catalysed Decarbonylative Direct C–
H Vinylation and Dienylation of Arenes. Org. Chem. Front. 2018,
5, 734–740.
(24) Zhou, J.; Li, X.; Liao, G.; Shi, B.-F. Rhodium(III)-Catalyzed
C–H Vinylation of Arenes: Access to Functionalized Styrenes.
Chin. J. Chem. 2018, 36, 1143–1146.
(25) Kotha, S.; Lahiri, K.; Kashinath, D. Recent Applications of
the Suzuki-Miyaura Cross-Coupling Reaction in Organic
Synthesis. Tetrahedron 2002, 58, 9633–9695.
(26) Orito, K.; Horibata, A.; Nakamura, T.; Ushito, H.;
Nagasaki, H.; Yuguchi, M.; Yamashita, S.; Tokuda, M.
Preparation of Benzolactams by Pd(OAc)2-Catalyzed Direct
Aromatic Carbonylation. J. Am. Chem. Soc. 2004, 126, 14342–
14343.
(27) Walker, M. J.; Hietbrink, B. N.; Thomas, B. E.; Nakamura,
K.; Kallel, E. A.; Houk, K. N. Torquoselectivity Induced by Lone-
Pair Conjugation in the Electrocyclic Reactions of 1-Azapolyenes.
J. Org. Chem. 2001, 66, 6669–6672.
(28) Bordwell, F. G. Equilibrium Acidities in Dimethyl-
Sulfoxide Solution. Acc. Chem. Res. 1988, 21, 456–463.
(29) Cheng, K.; Yao, B.; Zhao, J.; Zhang, Y. RuCl3-Catalyzed
Alkenylation of Aromatic C–H Bonds with Terminal Alkynes.
Org. Lett. 2008, 10, 5309–5312.
(30) Xu, B.; Jiang, X.; Xiong, J.; Lan, J.; Tian, Y.; Zhong, L.;
Wang, X.; Xu, N.; Cao, H.; Zhang, W.; Zhang, H.; Hong, X.; Zhan,
Y.-y.; Zhang, Y.; Hu, T. Structure–Activity Relationship Study
Enables the Discovery of a Novel Berberine Analogue as the
RXRα Activator to Inhibit Colon Cancer. J. Med. Chem. 2020, 63,
5841–5855.
(31) Thomson, P. F.; Parrish, D.; Pradhan, P.; Lakshman, M. K.
Modular, Metal-Catalyzed Cycloisomerization Approach to
Angularly Fused Polycyclic Aromatic Hydrocarbons and Their
Oxidized Derivatives. J. Org. Chem. 2015, 80, 7435-7446.
(32) Ishihara, Y.; Azuma, S.; Choshi, T.; Kohno, K.; Ono, K.;
Tsutsumi, H.; Ishizu, T.; Hibino, S. Total Synthesis of
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
Activation/Annulation: Evidence for Rh(I) to Rh(III) Oxidation
by Molecular Oxygen. J. Am. Chem. Soc. 2013, 135, 8850–8853. (d)
Tang, J.; Li, S.; Liu, Z.; Zhao, Y.; She, Z.; Kadam, V. D.; Gao, G.;
Lan, J.; You, J. Cascade C–H Annulation of Aldoximes with
Alkynes Using O2 as the Sole Oxidant: One-Pot Access to
Multisubstituted Protoberberine Skeletons. Org. Lett. 2017, 19,
604–607.
(14) Trauner, D.; Webster, R., 1,3-Cyclohexadiene Formation
Reactions: 6π and Higher-Order Electrocyclizations. In
Comprehensive Organic Synthesis II (Second Edition), Knochel,
P., Ed. Elsevier: Amsterdam, 2014; pp 783–826.
(15) (a) Colby, D. A.; Bergman, R. G.; Ellman, J. A. Rhodium-
Catalyzed C–C Bond Formation via Heteroatom-Directed C–H
Bond Activation. Chem. Rev. 2010, 110, 624–655. (b) Wencel-
Delord, J.; Dröge, T.; Liu, F.; Glorius, F. Towards Mild Metal-
Catalyzed C–H Bond Activation. Chem. Soc. Rev. 2011, 40, 4740–
4761.
(16) Vargas, D. F.; Larghi, E. L.; Kaufman, T. S. The 6π-
Azaelectrocyclization of Azatrienes. Synthetic Applications in
Natural Products, Bioactive Heterocycles, and Related Fields.
Nat. Prod. Rep. 2019, 36, 354–401.
(17) (a) Zhao, D; Kim, J. H.; Stegemann, L.; Strassert, C. A.;
Glorius, F. Cobalt(III)-Catalyzed Directed C–H Coupling with
Diazo Compounds: Straightforward Access towards Extended π-
Systems. Angew. Chem., Int. Ed. 2015, 54, 4508–4511. (b) Zheng,
G.; Sun, J.; Xu, Y.; Zhai, S.; Li, X. Mn-Catalyzed
Dehydrocyanative Transannulation of Heteroarenes and
Propargyl Carbonates through C–H Activation: Beyond the
Permanent Directing Effects of Pyridines/Pyrimidines. Angew.
Chem., Int. Ed. 2019, 58, 5090–5094. (c) Zhu, C.; Kuniyil, R.;
Ackermann, L. Manganese(I)-Catalyzed C–H Activation/Diels-
Alder/retro-Diels-Alder Domino Alkyne Annulation featuring
Transformable Pyridines. Angew. Chem., Int. Ed. 2019, 58, 5338–
5342.
(18) (a) Desimoni, G.; Faita, G.; Guidetti, S.; Righetti, P. P.
Solvent Effect in Pericyclic Reactions, XI The Electrocyclic
Reactions. Eur. J. Org. Chem. 1999, 1921–1924. (b) Bian, M.; Li, L.;
Ding, H. Recent Advances on the Application of Electrocyclic
Reactions in Complex Natural Product Synthesis. Synthesis 2017,
49, 4383–4413.
Benzo[c]phenanthridine Alkaloids Based on
a Microwave-
Assisted Electrocyclic Reaction of the Aza 6π-Electron System
and Structural Revision of Broussonpapyrine. Tetrahedron 2011,
67, 1320–1333.
(19) (a) Takahashi, A.; Hirose, Y.; Kusama, H.; Iwasawa, N.
Chelation-Assisted Electrocyclic Reactions of 3-Alkenyl-2,2'-
Bipyridines: An Efficient Method for the Synthesis of 5,6-
Dihydro-1,10-phenanthroline
and
1,10-Phenanthroline
Derivatives. Chem. Commun. 2008, 609–611. (b) Shindoh, N.;
Kitaura, K.; Takemoto, Y.; Takasu, K. Catalyst-Controlled
Torquoselectivity Switch in the 4π Ring-Opening Reaction of 2-
Amino-2-azetines
Amidines. J. Am. Chem. Soc. 2011, 133, 8470–8473.
(20) Rakshit, S.; Grohmann, C.; Besset, T.; Glorius, F. Rh(III)-
Catalyzed Directed C–H Olefination Using an Oxidizing
Directing Group: Mild, Efficient, and Versatile. J. Am. Chem. Soc.
2011, 133, 2350–2353.
(21) (a) Matsuura, Y.; Tamura, M.; Kochi, T.; Sato, M.; Chatani,
N.; Kakiuchi, F. The Ru(Cod)(Cot)-Catalyzed Alkenylation of
Giving
β-Substituted
α,β-Unsaturated
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dihydropyridoisoquinolinium
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dihydrobenzoquinoline
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