Palladium(II)-catalyzed C-C and C-O bond formation for the synthesis of C1-benzoyl isoquinolines from isoquinoline: N -oxides and nitroalkenes

Article abstract of DOI:10.1039/c6cc03530b

C₁-Benzoyl isoquinolines can be generated via a palladium(ii)-catalyzed C-C and C-O coupling of isoquinoline N-oxides with aromatic nitroalkenes. The reaction proceeds through remote C-H bond activation and subsequent intramolecular oxygen atom transfer (OAT). In this reaction, the N-O bond was designed as a directing group in the C-H bond activation as well as the source of an oxygen atom.

Full text of DOI:10.1039/c6cc03530b

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DOI: 10.1039/C6CC03530B
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COMMUNICATION
Palladium(II)‐Catalyzed C‐C and C‐O Bonds Formation for the
Synthesis of C1‐Benzoyl Isoquinolines from Isoquinoline N‐Oxides
and Nitro Alkenes
Received 00th January 20xx,
Accepted 00th January 20xx
Jiu‐ling Li,a† Wei‐ze Li,a†Ying‐chun Wang,ab Qiu Ren,a Heng‐shan Wang,*a and Ying‐ming Pan*a
DOI: 10.1039/x0xx00000x
www.rsc.org/
C1‐Benzoyl isoquinolines can be generated via a palladium(II)‐ system independently, which integrates C‐H activation with OAT in
catalyzed C‐C and C‐O coupling of isoquinoline N‐oxides with coupling reaction of quinoline N‐oxides with alkynes (Scheme 1b).
aromatic nitro alkenes. The reaction proceeds through remote However, to the best our knowledge, there were no papers about
C−H bond acꢀvaꢀon and subsequent intramolecular oxygen atom developing coupling of N‐oxides with alkenes by combination of C‐H
transfer (OAT). In this reaction, the N‐O bond was designed as a activation with OAT assisted by an oxidizing N‐O directing group.
directing group in the C‐H bond activation as well as the source of Herein, we report that C1‐benzoyl isoquinolines can be generated
an oxygen atom.
via a palladium(II)‐catalyzed C‐C and C‐O coupling of isoquinoline N‐
Oxides with aromatic nitro alkenes (Scheme 1c). The reaction
proceeds through remote C−H bond activation and subsequent
intramolecular oxygen atom transfer (OAT). In this reaction, the N‐
O bond was designed as a directing group in the C‐H bond
activation as well as the source of an oxygen atom. Furthermore,
the reaction does not need to add any additives or ligands apart
from palladium(II) catalyst to produce C1‐benzoyl isoquinolines in
good to excellent yields.
Metal‐catalyzed activation of C‐H bonds bears great potential,
which has been widely recognized as a simple synthetic scheme to
construct carbon‐carbon and carbon‐hetero bonds.1 Therefore, a
tremendously large number of synthetic methods have been
established. In these reports, Fagnou’s work is impressive for
pioneering a new strategy to achieve C–H bond activation, which
designs a built‐in oxidizing N‐O as the directing group existing in
multiple C‐H bonds functionalization reactions.1h Owing to its
predictable site‐selectivity, the built‐in oxidizing N‐O directing group
has been widely applied in C‐H activation to achieve polyfunctional
heteroaromatic ring.2 Despite the fast‐paced development of this
field, the N‐O directing group only plays a role in locating activation
of C‐H bonds and the O‐atom from N‐O bond is not utilized to
participate in the transformations. As a result, only one heteroatom
was incorporated into the product in most intermolecular coupling
reactions with releasing a small molecule.2,3 Besides, participation
of additional agents, including ligand,2d oxidant or additive2a,b and
acid or base,2c,e is necessary to reach the goal of C‐H activation.
Recently, it is exciting that the N‐O bond in tertiary amine N‐
oxides can readily undergo O‐atom transfer (OAT) to alkynes to
build heteroaromatic compounds when ruthenium(II)4, gold and
iridium(III) complexes5 as a catalyst (Scheme 1a). In addition, Li6 and
Chang7 groups discovered Rh(III) complexes/additive mediated
Scheme 1 Combination of C‐H activation with OAT.
Firstly, we initiated our research on the model reaction of
isoquinoline N‐oxides 1a with aryl nitro‐olefin 2a for screening
optimum reaction conditions (Table 1). No reaction was
observed when In(OTf)3 was employed as the catalyst or
without any catalysts (Table 1, entries 1 and 2). Whereas other
metal catalysts, such as Sm(OTf)3, Ce(OTf)2 and RuCl2(PPh3)3,
were not productive for the reactions (Table 1, entries 3‐5). To
our delighted, Pd(OAc)2 was added to the reaction
demonstrating good catalytic activity, but PdCl2 was found to
a. State Key Laboratory for Chemistry and Molecular Engineering of Medicinal
Resources, School of Chemistry and Pharmaceutical Sciences of Guangxi Normal
University, Guilin 541004, People’s Republic of China.
b. College of Chemistry and Chemical Engineering, Jishou University, Jishou 416000,
People’s Republic of China.
† These authors contributed equally to this work.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1‐3 | 1
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Journal Name
be less effective (Table 1, entries 6 and 7). Then, different (Figure 1). It is noted that the quinoline N‐oxiVdieewsArwticalesOnnlionet
DOI: 10.1039/C6CC03530B
solvents were evaluated, and the reactions were inhibited applicable in this reaction.
visibly when they were handled in chlorobenzene, DMF or DCE
(Table 1, entries 8‐10). A 25% decrease in the yield was
Table 2 Substrate scope for the benzoylation of isoquinolines a,b
observed upon performing the reaction at
a lower
temperature of 90 oC . The yield was not improved distinctly at
o
higher temperature (130 C). Compared with 10 mol % of the
Pd(OAc)2, the yield of 3a was raised slightly when 1 equiv of
Pd(OAc)2 was employed (Table 1, entry 7 vs. entry 13). It did
not affect the yield of 3a, that the reaction mixture was
conducted in dry DMSO under argon (Table 1, entry 15), which
confirmed that the reaction was not determined by O2 or H2O.
N
O
N
O
N
O
N
O
N
O
MeO
MeO
OMe
OMe
3d (70%)
3e (72%)
3a (80%)
3b (75%)
3c (73%)
Table 1 Optimization of reaction conditionsa
N
N
O
N
O
N
O
N
O
O
Cl
Cl
Cl
3h (73%)
Br
3j (76%)
3f (78%)
3g (68%)
3i (86%)
Temp
Entry
Catalyst (mol%)
Solvent
Yieldb (%, 3a)
(oC)
110
110
110
110
110
110
110
110
110
110
90
N
N
O
N
O
N
O
N
O
1
2
3
4
5
6
7
8
9
10
11
12
13
14c
none
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
PhCl
DMF
DCE
DMSO
DMSO
DMSO
DMSOd
n. d.
n. d.
<5
<5
<5
42
80
36
28
32
55
83
82
O
I
In(OTf)3 (10)
Sm(OTf)3 (10)
Ce(OTf)2 (10)
RuCl2(PPh3)3 (10)
PdCl2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (100)
Pd(OAc)2 (10)
Br
F
NC
3k (65%)
3l (62%)
3o (75%)
3m (83%)
3n (80%)
OMe
Cl
NO2
Br
N
N
O
N
N
O
N
O
N
Ph
O
Ph
3r (78%)
Ph
3s (78%)
O
Ph
Ph
Ph
O
3t (70%)
3q (86%)
3u(76%)
3p (80%)
a Reaction conditions: 1 (0.6 mmol), 2 (0.5 mmol), and Pd(OAc)2 (0.05 mmol)
in DMSO (1.5 mL) at 110 oC for 12‐16 h. Isolated yield of pure product
b
130
110
110
based on 2.
79
a General conditions: isoquinoline N‐oxides 1a (0.6 mmol, 1.2 equiv),
aromatic nitro alkenes 2a (0.5 mmol, 1 equiv) in solvent (1.5 mL) for
12 h. b Yield of isolated. c Under Ar atmosphere. d Dried solvent.
With the optimum reaction conditions (Table 1, entry 7), we
explored the scope of this reaction firstly by investigating
isoquinoline N‐oxides with multiple nitro alkenes 2. As shown
Figure. 1 X‐ray crystal structure of C1‐ benzoyl isoquinoline 3r
.
in Table 2, mono‐substituted aryl nitro alkenes derivatives
bearing electron‐donating and ‐withdrawing functional groups
including methyl, methoxy, isopropyl, halo and cyano were
Some control experiments were carried out to probe
possible paths of the reaction in Scheme 3. We experimented
with different types of aryl nitro‐olefins substrates to explore
harmonious in the catalytic system (3b, 3c and 3e‐3n). In
addition, di‐substituted aryl (3d) and fused ring (3o) nitro
alkenes also proceeded smoothly with good yields. Aromatic
nitro alkenes electron‐withdrawing substituents on the aryl
ring promoted the reaction with better yield. Regrettably,
aliphatic nitro alkenes were not applicable in this reaction. The
isoquinoline N‐oxides derivatives were tolerated in this
transformation, and whether electron donating groups or
electron withdrawing groups could get good yields (3p‐3u).
the reaction. Initially, the reaction of 1a and
4 (1‐phenyl‐2‐
nitropropene) under the optimum reaction conditions
generated product 3a in 78% isolated yield (Scheme 3a, the
structure was determined by 1HNMR and HRMS, see the ESI†).
The structure of
a
representative product 3r8 was
Scheme 3 Controlled Reactions
unambiguously confirmed by X‐ray crystallographic analysis
2 | J. Name., 2012, 00, 1‐3
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Scheme 4 A plausible mechanism for the coupling reaction of N‐
View Article Online
DOI: 10.1039/C6CC03530B
Oxides with alkenes.
3a
CH3NO2
OAc
N
HOAc
[PdOAc]
H
Ph
O
1a
NO2
E
[PdOAc]
HOAc
N
O
N
O
PdOAc
HPdOAc
D
Ph
A
NO2
Ph
OAT
2a
NO2
N
O
N
O
NO2
Ph
Ph
NO2
C
PdOAc
B
Pd(OAc)2
OAc
+
[PdOAc]
Then the compound
5 ((Z)‐(1‐nitroethene‐1,2‐diyl)dibenzene)
and 1a were stirred under the standard conditions and the
product 3a was observed in 10% isolated yield (Scheme 3b).
In summary, we have developed
a palladium(II)‐catalyzed
Besides, the compound
6 (the structure was determined by coupling reaction of isoquinoline N‐oxides with aromatic nitro
1HNMR and 1HRMS, see the ESI†) was generated in this
transformation. Whether the model reaction was conducted
under 18O2 or the H218O was added in the reaction, no product
18O‐3a was found by HRMS (Scheme 3c and 3d), which
confirmed the O atom of product 3a was from the N‐O bond of
isoquinoline N‐oxides. Moreover, when 1 equivalent of 2,6‐di‐
tert‐butyl‐4‐methylphenol (BHT) was added, the yield of 3a
didn’t change significantly, which might exclude the possibility
of the radical mechanism (Scheme 3e). The experimental
results suggested a possible mechanism.
alkenes by combination of C‐H activation with OAT to prepare fully
substituted C1‐benzoyl isoquinoline in good yields. This method
represents a new strategy to synthesize C1‐benzoyl isoquinoline. In
addition, the products of the reaction can be transformed into
biologically active oxidation aporphine through the previously
reported method.14 Further investigations on the synthetic
applications of this reaction are ongoing in our laboratory.
We would like to thank National Natural Science Foundation of
China (21362002 and 81260472), Guangxi Natural Science
Foundation of China (2014GXNSFDA118007), State Key Laboratory
On the basis of our mechanistic studies, a viable approach is
shown in Scheme 4. First, aryl‐Pd complex
A is formed via for Chemistry and Molecular Engineering of Medicinal Resources
coordination of the palladium atom to 1a and subsequent
electrophilic attack at the 1‐position carbon atom and leaving
(CMEMR2014‐A02 and CMEMR2012‐A20), Guangxi’s Medicine
Talented Persons Small Highland Foundation (1306), and The Fund
of Guangxi Key Laboratory of Functional Phytochemicals Research
and Utilization (FPRU2015‐2) for financial support.
acetic acid. Then, coordination of the palladium complex
with aryl nitro‐ alkene 2a followed by syn insertion gives
intermediate B 9d
‐Hydride elimination of forms palladium
hydride and intermediate C.9 The reaction of OAT happened in
intermediate Then the structure of
frames intermediate D 10
contains nitro‐oxirane which is unstable in the role of
palladium hydride and undergos C‐O bond cleavage leading to
intermediate E 10,11
The reverse Aldol condensation of the
intermediate Meanwhile the acetic acid
gives product 3a 12
A
.
β
B
C
.
Notes and references
D
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possible intermediates in the proposed mechanism. A mixture of
1a (0.6 mmol), 2a (0.5 mmol) and Pd(OAc)2 (0.05 mmol) in DMSO
(1.5 mL) was reacted at 110 oC for 4 h and 50 μL of the mixture was
used for the ESI analysis in CH3OH. The ESI/MS analyses showed a
peak at m/z 293.0918, which was identified as the intermediate E
(see the Supporting Information).
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