Sequential C-H and C-C Bond Cleavage: Divergent Constructions of Fused N-Heterocycles via Tunable Cascade

Article abstract of DOI:10.1021/acscatal.9b03091

Streamlining the generation of diverse highly functionalized molecules from abundant feedstocks holds great synthetic promises and challenges in pharmaceutical and material discovery. Herein, we report a tunable selectivity in multiple cascade reactions for the divergent assembly of fused N-heterocycles, comprising sequential activation of C-H and C-C bonds. Isolatable indene-type intermediates might be responsible for the generation of densely substituted fused pyridines, azepines, and azafluorenones products. The tolerance of strongly coordinating N-heterocycles, and those readily applicable for the late-stage modifications of pharmaceuticals and material molecules precursors, further demonstrated the synthetic robustness of this transformation.

Full text of DOI:10.1021/acscatal.9b03091

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Letter
Sequential C#H and C#C Bond Cleavage: Divergent
Constructions of Fused N-Heterocycles via Tunable Cascade
Xianwei Li, Jianhang Rao, Wensen Ouyang, Qian Chen, Ning Cai, Yu-Jing Lu, and Yanping Huo
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b03091 • Publication Date (Web): 22 Aug 2019
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Sequential C‒H and C‒C Bond Cleavage: Divergent Constructions of
Fused N-Heterocycles via Tunable Cascade
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Xianwei Li,* Jianhang Rao, Wensen Ouyang, Qian Chen, Ning Cai, Yu-Jing Lu, Yanping Huo
School of Chemical Engineering and Light Industry, Guangdong University of Technology, Guangzhou, 510006, China.
ABSTRACT: Streamlining generation of diverse highly functionalized molecules from abundant feedstocks, holds great synthetic
promises and challenges in pharmaceutical and material discovery. Herein, we report a tunable selectivity in multiple cascade
reactions for the divergent assembly of fused N-heterocycles, comprising sequential activation of C-H and C-C bonds. Isolatable
indene type intermediates might be responsible for the generation of densely substituted fused pyridines, azepines and
azafluorenones products. The tolerance of strongly coordinating N-heterocycles and readily applicable for the late-stage
modifications of pharmaceuticals and material molecules precursors, further demonstrated the synthetic robustness of this
transformation.
KEYWORDS: multiple oxidative cascade • C-H and C-C cleavage • tunable selectivity • traceless directing group • fused
N-heterocycles.
1) Skeleton recognization via C-C activation strategy:
In pursuing green processes for the rapid construction of
target molecules via economically and environmentally benign
routes, catalytic cascade reaction has emerged as a powerful
strategy.1 Fruitful results in the cascade transformations have
been achieved, however, the exploration of C-H activation
initiated multiple cascade,2 especially for the precise control of
the selectivity in cascade reactions that involved the cleavage
and reconstruction of multiple chemical bonds, is still elusive.
Moreover, sequential activation of inert C-H and C-C bonds
triggered multiple cascade for the divergent constructions of
complex molecules, remained underexplored.
Selective transformations of inert C-C bonds3 have
enriched the synthetic arsenal for the constructions of complex
skeletons, while typical strategies relied on the use of strained
structures or directing groups. In this context, the use of
unstrained substrates and traceless directing moiety to
facilitate C-C activation cascade, enabling the diversity-
oriented synthesis (DOS)4, would be extremely attractive.
Herein, we reported a sequential C-H and C-C cleavage
cascade with switchable selectivity, affording to divergent
delivery of fused N-heterocycles (Scheme 1-2). Significantly,
selective C-H and C-C bond activation of acyclic system in
this transformation could be well tuned, by the choice of
oxidant or solvent.
X
C
Y
C
X
C
Y
C
X
C
Y
C
[M]
C
C
X
Y
or
or
2) Sequential C-H and C-C activation cascade:
R
N
C1-C(O) cleavage
R1
R3
OEt
R
Ha
NH
R1
NH2
N
C-Ha/N-H cleavage
R
O
Rh(III)
O
C1
C2
R3
R1
R1
R2
OH
30 min
R2
R
R2
OH
R3
R3
isolatable intermediates
N
C2-C(R3) and C-C(O) cleavage
R1
O2
O
3) Fused nitrogen heterocycles in bioactive and material molecules:
Cl
Cl
H
N
O
O
Cl
HO
NH2
N
O
N
N
Pd
N
N
O
N
Strongly Phosphorescent
Pd(II) Complex
Buttpark 104\40-64
thrombin inhibitor
O
O
O
R2
O
O
, R1 = R2 = H, R3 = Me
(+)-ribasine
MeO
, R1 = H, R2 = OH, R3 = Me
(+)-ribasidine
O
, R1 = R2 = R3 = H
N
Fused N-heterocycles such as pyridines, azepines and
azafluorenones,5-6 serve as important structural motifs that
occurred widely in natural products, pharmaceuticals and
functional materials (Scheme 1-3).7 Notable strategies toward
their efficient assembly included condensation of carbonyls
with amine precursors and cycloaddition of C-C unsaturated
bonds with nitrogen functionalities. However, certain
limitations such as multiple steps and troublesome selectivity,
were often suffered. Thus, expedient methodologies to
efficiently access to these valuable molecular architectures are
highly desirable.
(+)-norribasine
R1
MeO
N
O
R3
AI-III-52
O
O
O
Me
N
NH
HO
N
R
O
NH
O
Onychine
, R = H
indolobenzazepinone
(antimitotic activity)
Cephalotaxine
Dielsine
, R = OH
Scheme 1. Sequential activation of C-H and C-C bonds
strategy for Fused N-heterocycles Synthesis.
We commenced our study by choosing imidate 1a and
allylic alcohols 2a as the model substrates under metal
catalysis (Table 1).8,9 After extensive screen of catalytic
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parameters, we found that with [Cp*RhCl2]2 and AgNTf2 as
the catalyst, NaOAc as the additive, Cu(OAc)2•H2O and
molecular oxygen as the terminal oxidant, sequential C-H and
C-C bond activation to afford fused pyridine 3a in good
yield.11,12 No desired product 3a was obtained in the absence
of Rh(III) complex, while Pd(II) and Ir(III) complexes showed
no catalytic efficiency, [Ru(p-cymene)Cl2]2 showed relatively
lower efficiency. Cu(OAc)2•H2O played a critical role, since
low conversion of substrate 1a was observed with AgOAc
instead. Moreover, DTBP oxidant totally shut down this
reaction. Inferior results were obtained in the absence of either
Cu(OAc)2•H2O or NaOAc. Additional base or acid exhibited
no significant effect to this oxidative cascade. The use of HFIP
or t-Amyl-OH as the solvent led to moderated yields of the
desired product 3a.
alcohols could also serve as suitable substrates in this cascade
reaction. However, pyridine and thiozole-derived allyl
alcohols delivered moderate yield of the corresponding fused
pyridine products. The structure of the obtained fused pyridine
was unambiguously confirmed by X-ray analysis (3x).
Notably, regioselective C-H functionalization took place at
steric hindered position (3y-3z), probably due to the directing
effect of the fluoro and OMe groups.13 Further investigation
revealed that the use of meta-Cl benzimidate ester under
standard Rh(III) catalysis led to 1:1 regioisomers of fused
pyridines; while the reaction took place at less steric hindered
C-H position with the use of meta-CF3 benzimidate ester. This
sequential C-H and C-C activation cascade could be applied to
imidates with two different allylic alcohols (3zf-3zo), indene
intermediates might be generated with the addition of 1,2-
disubstituted allylic alcohols first, and subsequently added
mono-substituted allylic alcohols to the reaction systems,
various fused pyridines could be obtained.
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Table 1. Variation of standard conditions.a
[Cp*RhCl2]2 (2 mol%)
H
OEt
NH
N
AgNTf2 (4 mol%)
NaOAc (10 mol%)
OH
1) Capture of the released carboxylic byproduct derived from C-C cleavage:
OH
-
HCO2
(30 mol%)
Cu(OAc)2 H2O
O2 (1 atm), DCE, 120 oC, 18 h
Ph
1a
2a
2a
OEt
NH
3a
N
Ph
OH
O
OH
1) 'standard condition'
2) MeI, K2CO3
Me
Ph
O
Ph
Entry
Variation of standard condition
None
Yieldb (%)
1a
2c
2c
isolated
3u
, 75%
1
2
3
4
5
6
7
8
90
n.r.
72
2) Isolation of oxidative Heck products as the intermediates in this multiple cascade:
R2
R2
OEt
PdCl2 or [IrCp*Cl2]2 instead of [RhCp*Cl2]2
NH2
Rh(III) cat.
OH
N
NH
O
H
2
standard condition
(1.25 equiv.)
[Ru(p-cymene)2Cl2]2 instead of [RhCp*Cl2]2
1a
120 oC, 16 h
30 min
Me
Me
OH
Me
AgOAc or tBuOOtBu instead of Cu(OAc)2 H2O
< 10 or n.r.
22
.
A
intermediate , 95%;
2
2a
, R = H;
2
R2 = Me;
2b
,
R1
A'
intermediate , 93%
3zf
A
A'
, R = H, 86% from ; 83% from
;
, R1 = H (1.25 equiv.);
, R1 = Me (1.25 equiv.)
.
2d
2e
Without Cu(OAc)2 H2O
2
3zg
A
A'
, R = Me, 82% from ; 80% from
Without NaOAc
37
Scheme 2. Preliminary mechanism studies.
Addition of Cs2CO3 or PivOH (30 mol%)
HFIP or tAmyl-OH as the solvent
88, 76
81, 77
Regioselective C-H functionalization of multiple substituted
arenes holds significant utility in the late-stage modification of
bioactive molecules and materials. Nevertheless, the search for
proper catalytic system for the effective discrimination of
specific C-H bond in the complex molecules remained
challenging. In this context, Yu, Dai, and Ackermann have
developed efficient C-H transformations that could overcome
the commonly encountered limitations of C-H activation with
strongly coordinating N-heterocycles. 14
We were also intrigued of the directing priority towards
multiple functionalized arenes in this C-H functionalization
initiated multiple cascade reaction. To our delight, imine
functionality outcompete ketone (4a, 4b), carboxlic acid ester
(4c), phenol ester OPiv (4d) and NHPiv (4e), leading to the
a
Standard conditions: 1a (0.20 mmol), 2a (0.50 mmol), [Cp*RhCl2]2 (2 mol%),
AgNTf2 (4 mol%), NaOAc (10 mol%), Cu(OAc)2 .H2O (30 mol%), DCE (1 mL)
under air for 18 h. b Isolated yield.
In order to obtain insight into this multiple cascade, some
control experiments were conducted (Scheme 2), and the
results revealed that: 1) With addition of MeI to this reaction
under standard condition, methyl benzoate product was
obtained, which might derive from C-C bond cleavage of
allylic alcohol moiety; 2) Oxidative Heck product A and A’
were isolated within 30 minutes with 1a and 1,2-disubstituted
olefins 2d, and further addition of 2a into this catalytic system
led to densely substituted fused pyridines in high yields in
one-pot manner. This observation indicated that indene might
serve as the key intermediate in this multiple cascade.
With the optimal condition, we next explored the synthetic
generality of this C-H/C-C activation cascade, broad substrate
scope with great functional group tolerance was observed
(Scheme 3). (Pseudo)halides including F (3b), Cl (3c), Br
(3d), I (3e), CF3 (3g), OTs (3i) and OTf (3k) could be well
tolerated, providing new opportunities for the further
diversification. Readily transformable functionality including
nitro (3h), benzylic chloride (3l), ester (3m), phenolic
hydroxyl (3j), amine (3n) and ethers (3o-3p) were compatible.
Methyl (3q-3t), ethyl (3zc), phenyl (3u-3x) and heterocycles
including furan (3zd) and thiophene (3ze) derived allylic
desired products in
a selective manner. Significantly,
heterocycles that are widely used in materials and
pharmaceuticals included pyridine (4f), pyrimidine (4g) and
pyrazine (4h), could also be compatible in this transformation.
To further exploration of the synthetic utility of this
reaction, we selected fused heterocycles that were frequently
used in materials for the diversification. Naphthalene (5a),
indoles (5b), benzothiophene (5c), tertiary aromatic amine
(5d), fluorenone (5e), dibenzo[b,d]thiophene (5f), carbazole
(5g), thiophene (3zi) derived highly fused heterocycle could
be readily accessed, which might provide inspiration into
organic optoelectronic materials discovery.15,16
This transformation also enabled late-stage modification of
bioactive molecules, including pioglitazone (5h), probenecid
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(5i), ibuprofen (5j) and estrone (5k), demonstrating their
1
synthetic potential in pharmaceutical discovery.
2
3
4
5
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7
R2
[Cp*RhCl2]2 (2 mol%)
OEt
N
R2
R2
OH
R3
R1
AgNTf2 (4 mol%)
NH
R1
NaOAc (10 mol%), Cu(OAc)2 • H2O (30 mol%)
O2 (1 atm), DCE, 120 oC, 18 h
OH
R3
3, 4, 5
2
(1.25 equiv.)
2
(1.25 equiv.)
1
1) functional group tolerance:
N
N
N
N
N
N
N
MeO
F
Cl
Br
I
F3
C
O2N
8
3f
, 91%
3b
3c
3d
3e
3g
3h
, 88%
, 87%
, 89%
, 82%
, 90%
, 81%
9
N
N
N
N
N
N
N
MeO
Br
Cl
10
11
12
13
14
15
16
17
18
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TsO
HO
N
TfO
TsHN
TsO
O
O
3m
3s
, 78%
85%
3o
, 83%
3i
3j
3k
3l
3n, 72%
, 92%
, 59%
, 79%
, 73%
Me
Ph
Me
Me
Me
N
N
N
N
N
MsO
O
F3
C
Br
3q
3p
3r
3t
3u
, 84%
,88%
, 81%
, 87%
H
, 75%
H
Ph
Ph
Ph
N
N
N
N
N
F3
C
TsO
Br
F
MeO
3v
3w
3x,
3x
3y
, 82%
3z, 89%
, 77%
, 72%
73%
X-ray structure of
OEt
Cl
NH
Et
from
N
N
N
N
N
F3
C
O
S
Cl
N
Cl
3za
, 87%
3zc
, 81%
3zb 3zb'
:
= 1:1, 80%
3zd
3ze
, 83%
, 91%
2) Oxidative C-H and C-C actviation cascade of imidates with two different allylic alcohols:
R2
Me
Me
Me
N
N
N
N
N
N
O
O
NiPr2
O
3
S
S
O
R1
O
N
Cl
O
Me
, 73%
Me
Me
Me
Me
O
, R1 = H, R2 = Ph, 81%;
, R1 = H, R2 = 2-thiophene, 72%
, R1 = Cl, R2 = Me, 79%
3zh
3zi
3zl
3zm
3zn
3zo
, 78%
, 67%
, 67%
3zk
, 70%
3zj
3) Directing groups priority:
R
N
N
N
N
N
N
H
H
H
O
H
O
N
N
H
H
O
N
EtO
X
N
N
O
O
4d
4e
, X = O, 59%
O
4a
4b
, R = H, 82%
4c
, 85%
4f
, 63%
4g
4h
, 66%
, 78%
, X = NH, 61%
, R = Ph, 62%
4) Synthetic utility in materials precurors and pharmaceuticals:
N
N
O
N
N
N
N
S
N
N
S
Ts
Ts
5a
5c
5d
5e
5g
, 67%
, 87%
5b
, 52%
, 54%
, 71%
, 65%
OMe
O
N
iBu
Et
O
O
N
H
NiPr2
O
S
N
N
3O
O
N
H
H
O
N
O
O
3 O
N
pioglitazone
5h
analog, , 78%
probenecid
, 5i
analog , 64%
ibuprofen
, 5j
analog , 76%
estrone
5k
analog, , 51%
5f
, 81%
OMe
Scheme 3. Sequential C-H and C-C activation for assembly of fused pyridines: 1) functional group tolerance; 2) imidates with two
different allylic alcohols; 3) directing groups priority; 4) synthetic utility in material and pharmaceuticals.
Intriguingly, oxidative double C-H Heck cascade reaction of
arylimidates with allylic alcohols took place in the absence of
Cu(II) salt under lower temperature. Further optimization
revealed that with isolatable indenes, which were obtained
from imidates with 1,2-disubstituted allylic alcohols under
Rh(III) catalysis in 30 minutes; subsequent addition of another
mono-substituted allylic alcohol, affording to the densely
fused azepines under 70 oC within 3 hours (Scheme 4).
Halogens such as F (6d), Cl (6e), OTs (6h) and alkyl chloride
(6g) could be well compatible, leading to densely substituted
azepines. Moreover, fused azepines (6i, 6j) were also readily
accessible from indole and naphthalene substrates, providing a
valuable platform for the rapid construction of molecular
libraries of azepines. The moderated efficiency that observed
might be contributed to the insufficient directing abilities for
the oxidative Heck reaction and partial decomposition of the
primary amine moieties.
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Me
R
NH2
Me
Me
OH
OEt
NH
N
Rh(III) cat.
[Cp*RhCl2]2 (2 mol%)
AgNTf2 (5 mol%)
OEt
NH
2b
O
N
1
2
3
4
5
6
7
8
standard conditions
R2
OH
R3
R
O
H
R1
30 min
92%
1a
R1
HOAc, O2, 120 oC, 48 h
NaOPiv (30 mol%)
1,4-dioxane/DCE (4:1)
O2 (1 atm), 70 oC, 3 h
O
OH
R2
7a, 81%
intermediate A
Me
OH
R3
Oxidative C-H & C-C activation cascade
1
2
2
6
2d
2b
Rh(III) cat.
N
R
Me
R
Me
Rh(III), [O]
Me
Me
Me
N
N
N
N
N
N
O
O
O
O
HOAc, O2
HOAc, O2
H
H
H
F
Cl
HO
Me
Me
3zg
Me
Me
Me
R = Me,
Me
8
7a', 12%
6a
6b
, R = Me, 68%
, R = Ph, 56%
Me
6d
,
6f
55%
, 54%
6c
,
65%
Me
6e
, R = Ph, 51%
N
N
N
N
N
9
Me
Me
Me
MeO
Cl
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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40
41
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60
N
N
N
N
O
O
I
O
O
O
O
O
O
O
O
O
7e, 81%
7a, 81%
7b, 83%
7c, 85%
7d, 79%
N
H
H
H
H
TsO
Ph
Ts
O
N
Me
, 50%
Me
Me
, 55%
Me
6j
, 61%
N
6g
6h
6i
, 48%
O
O
N
N
S
O
3
N
O
Scheme 4. Fused azepines synthesis via multiple oxidative C-
H Heck reaction using allyl alcohols.
O
Ts
O
N
O
O
O
7f, 83%
7h, 74%
7g, 62%
Notably, with isolatable intermediate A and further addition
of 2b in HOAc under Rh(III) catalysis, azafluorenone products
were obtained (Scheme 5). Readily transformable functional
groups including iodo (7c), ketone (7d), ester (7e), OTs (7f)
and strong coordination nitrogen heterocycles (7g) could be
Scheme 5. Azafluorenones synthesis via multiple oxidative C-
H/C-C activation cascade.
compatible.
Moreover,
late-stage
modification
of
pharmaceuticals such as Probenecid was also operational,
demonstrating the synthetic potential of this transformation.
Control experiments with fused pyridine 3zg under standard
conditions in HOAc solvent revealed that the azafluorenone
product 7a could be isolated, together with detectable amount
of benzylic C-H oxygenated fused pyridine 7a’. We
speculated that a benzylic C-H oxidation followed by
dehydration to give the olefin intermediate 8, and subsequent
oxidative cleavage of C-C double bonds might be involved.17
Considering fused N-heterocycles that are widely existed in
natural products and pharmaceuticals, we further demonstrate
the synthetic application of this transformation for the concise
delivery of onychine using our methodology. As depicted in
Scheme 6, by using benzimidate ester 1a and terminal allylic
alcohol 2c under Rh(III) catalysis for 30 minutes, and
subsequent addition of the second 1,2-disubstituted allylic
alcohol 2d in HOAc under molecular oxygen atmosphere for
48 hours, onychine could be obtained. The observed moderate
efficiency of the overall transformation is probably due to the
steric hinderance of the second added 1,2-disubstituted allylic
alcohol.
Inspired by Chang’s work on catalytic C-H amidation using
NH2
OEt
NH
O
1
2
base
Rh(III)
[O]
indene intermediates
R2
R2
R1
R1
a
O
Rh(III), base
R
O
(III)Rh
NH
N
NH
R1
Rh(III)
HN
R1
NH
R2
O
2
R
Rh(III)
O
O
O
120 o
C
70 o
C
condensation
R2
oxidative Heck
reaction
R1
O
h
R2
R1
R2
R2
R1
d
b
e
c
2
oxidative Heck
reaction
H2O, Cu(II), base
R
re-aromatization induced
C-C(O) cleavage
or retro-Claisen
reaction
HO
R
N
Rh(III)
NH
R
R
N
N
HOAc
R2
O
O
O
HOAc,
2
R2
O
O
R1
H
f
R1
i
R1
fused pyridines 3, 4, 5
7a' isolated
(
,
when R1 = R = Me)
g
-H elimination
MeI
, K2CO3
O
R
C=C oxidative
cleavage
O
Rh(III), HOAc,
O
2
R
condensation &
oxidative
aromatization
N
Me
R2
NH2
Me
R2
O
N
O
O
R2 = Ph
isolated
R1
fused azepines 6
R1
O
7
a
j
azides as the amidation reagents,18 we investigated the
reactivity of TsN3 in this multiple cascade reaction.
Intriguingly, with indene intermediate that could be readily
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accessed from imidate ester 1a with allylic alcohol 2e under
Rh(III) catalysis, further addition of TsN3 under standard
condition revealed that a C-H and C-C bond action for the
amidation reaction took place, and further efforts toward the
optimization and synthetic application of this transformation is
in progress.
1
2
3
4
5
6
7
8
9
O
[Cp*RhCl2]2 (2 mol%)
AgNTf2 (4 mol%)
OEt
NH
Me
Ph
OH
2c
Me
OH
NaOAc (30 mol%)
Cu(OAc)2• H2O (30 mol%)
DCE/HOAc = 1:4
N
1a
2d
9
, onychine, 43%
O2 (1 atm), 120 oC, 48 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
NHTs
[Cp*RhCl2]2 (2 mol%)
AgNTf2 (4 mol%)
NH2
OEt
NH
Me
Me
OH
TsN3
NHTs
NaOAc (30 mol%)
Cu(OAc)2• H2O (30 mol%)
DCE, 60 oC, 12 h
Me
1a
2e
(1.25 equiv.)
(2.5 equiv.)
10
, 51%
Scheme 6. Synthetic applications: 1) concise synthesis of
Onychine; 2) amidation reaction via C-H and C-C activation
cascade.
Scheme 7. Possible mechanism for the sequential C-H and C-C bond activation cascade.
According to precedent literatures and the experimental
observations, a tentative mechanism was proposed (Scheme
7): with the assistance of acetate ion, Rh(III) catalyzed C-H
activation of imines 1 with alkenes 2 took place, which
followed by β-H elimination8,19 and condensation to give key
In summary, we have successfully accomplished an
attractive strategy for the modular delivery of densely
functionalized fused N-heterocycles via sequential C-H and C-
C bond cleavage. Significantly, tunable selectivity for the
diverse products generation was obtained, which might be
contributed to the retro-Claisen type reaction or re-
aromatization as the driving force. This methodology features
broad substrate scope and great functional group tolerance,
and enabled divergent access of building blocks that might be
used in organic optoelectronic materials and bioactive
molecules. This strategy might provide new insight into C-C
bond activation, showcasing the viability of late-stage
modification of complex molecules toward a diversity-oriented
synthesis.
indene intermediates (eg. al.,
A or A’). Subsequent
coordination of Rh(III) or Cu(II) to indene intermediates led to
two pathways, which might be controlled by the temperature,
solvent and Cu(II) salt as a Lewis acid and oxidant20 (See
Supporting Information for details):
1) When the reaction was conducted at 120 oC in the
presence of Cu(OAc)2·H2O, Rh(III) intermediate b might be
generated, which followed by oxidative Heck reaction.
Further condensation and C-C bond cleavage took place to
afford the desired fused pyridines products, together with the
release of carboxylic acid derivatives, which could be captured
by the addition of MeI, to generate PhCO2Me (detected by
GC-MS). We assumed that re-aromatization or retro-Claisen
reaction,21,22 which might serve as the driving force for the C-
C bond cleavage in this process,20,23 was assisted by water and
Cu(II) salt.
2) When the reactions were conducted in the absence of
Cu(II) salt under lower temperature, with the assistance of
primary amines, regioselective aryl Csp2-H oxidative Heck
reaction took place, which followed by condensation and
oxidative aromatization to give the desired fused azepines
products 6.24
AUTHOR INFORMATION
Corresponding Author
*Email: xwli@gdu.edu.cn
Notes
The authors declare no competing financial interest.
ASSOCIATED CONTENT
The Supporting Information is available free of charge on the
ACS Publications website at DOI:
Experimental procedures and spectra data for all new
compounds (PDF)
On the other hand, while under acidic conditions, oxidative
hydroxylation of benzylic C-H bond with molecular oxygen
led to hydroxylated fused pyridine intermediate (which was
isolated as 7a’ when R1 = R = Me). Upon further dehydration,
C-C double bonds were formed, which underwent oxidative
cleavage under Rh(III)-catalyzed aerobic oxidation,17
affording to azafluorenone products 7.
ACKNOWLEDGMENT
We are grateful for the financial supported by the National
Natural Science Foundation of China (21602032), the One
Hundred Young Talent program of Guangdong University of
Technology and GDUT Analysis and Test Center for the HRMS
analysis. We also appreciated Dr. Zihang Qiu, Dr. Dianhu Zhu
and Dr. Yu-Feng Liang and Prof. Chao-Jun Li at McGill
University for helpful comments and discussions.
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Page 6 of 9
Pyridines. Tetrahedron 2004, 60, 6043. c) Hill, M. D. Recent
Strategies for the Synthesis of Pyridine Derivatives. Chem. Eur. J.
2010, 16, 12052.
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ACS Catalysis
R
Sequential C-H and C-C activation cascade:
N
1
C1-C(O) cleavage
R1
2
3
4
5
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R3
OEt
NH
R
Ha
R1
NH2
C1
N
C-Ha/N-H cleavage
O
Rh(III)
30 min
R
O
R1
R1
C2
OH
R2
R2
R
R3
R2
OH
R3
R3
isolatable intermediates
N
C2-C(R3) and C-C(O) cleavage
R1
O2
O
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