Palladium-Catalyzed Isoquinoline Synthesis by Tandem C-H Allylation and Oxidative Cyclization of Benzylamines with Allyl Acetate

Article abstract of DOI:10.1021/acs.orglett.1c01153

A novel approach to synthesize 3-methylisoquinolines via a one-pot, two-step, palladium(II)-catalyzed tandem C-H allylation/intermolecular amination and aromatization is reported. A wide series of 3-methylisoquinoline derivatives were obtained directly using this method in moderate to good yields, and we highlight the synthetic importance of this new transformation.

Full text of DOI:10.1021/acs.orglett.1c01153

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Letter
Palladium-Catalyzed Isoquinoline Synthesis by Tandem C−H
Allylation and Oxidative Cyclization of Benzylamines with Allyl
Acetate
Yujie Chen, Zhibin Huang,* Chenyang Dai, Shan Yang, Da-Qing Shi,* and Yingsheng Zhao*
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ABSTRACT: A novel approach to synthesize 3-methylisoquino-
lines via a one-pot, two-step, palladium(II)-catalyzed tandem C−H
allylation/intermolecular amination and aromatization is reported.
A wide series of 3-methylisoquinoline derivatives were obtained
directly using this method in moderate to good yields, and we
highlight the synthetic importance of this new transformation.
Subsequently, Hua’s group developed a convenient one-pot
synthesis of isoquinolines using a three-component reaction
mixture of aryl ketones, hydroxylamine, and alkynes.6 In 2015,
Ackermann’s group also developed a synthesis of isoquinoline
skeletons via a Co catalyst.11b Although these C−H activation
strategies have provided effective methodologies for the
preparation of isoquinolines, the skeleton of isoquinolines is
usually limited to 1,3,4-substituted products as another
coupling partner is the 1,2-disubstituted alkynes. The
construction of unsubstituted or monosubstituted isoquino-
lines is still difficult. What is more, the magic methyl effect is
well acknowledged in medicinal chemistry. This seemingly
simple exchange of a C−H for a C−CH3 can affect important
drug properties. Therefore, the construction of methyl-
substituted isoquinolines has potential application value. We
herein report a palladium-catalyzed oxalylamide-assisted, one-
pot approach for the synthesis of isoquinolines from readily
available benzylamines and allyl acetate, which can be
transformed further into isoquinolines by direct treatment
with sodium hydroxide. A wide variety of 3-methylisoquinoline
derivatives were obtained directly from this one-pot, two-step
synthetic method. A preliminary mechanistic study showed the
reaction proceeded via a palladium(II) acetate catalyzed,
tandem C−H allylation, and intermolecular amination reaction
to afford these isoquinolines.
soquinoline, as an important structural framework, is
Iencountered frequently in biologically active natural
products, organic materials, drugs, and some important ligands
and possesses unique activities and functionalities.1 Over the
past few decades, various approaches to construct isoquinoline
skeletons have been extensively explored. Traditionally, the
Bischler−Napieralski, Pomeranz−Fritsch, and Pictet−Gams
reactions2 have provided practical methods for the synthesis of
isoquinolines. However, these methods usually suffer from
harsh reaction conditions or limited substrate scope.
Transition-metal-catalyzed C−H functionalizations have re-
ceived significant attention3 and have become an effective
pathway to realize important synthetic skeleton construction.4
Several groups such as the Miura,5 Hua,6 Li,7 Yang,8 Wang,9
Zhu,10 and Ackermann groups11 have successfully demon-
strated the isoquinolines can be easily prepared by C−H
functionalizations and developed transition-metal (Rh, Pd, Co,
Ru, Mn)-catalyzed formation of isoquinolines with assistance
from directing groups such as aromatic imines, oxime,
hydrazones, azide, etc. (Figure 1).12 For example, Miura’s
group disclosed a highly efficient rhodium-catalyzed C−H
bond cleavage and oxidative coupling reaction of aromatic
imines with alkynes to produce isoquinoline derivatives.5
Our group has reported the oxalylamide directing group is
an effective N,O-bidentate directing group for assisted remote
C−H activation of aromatic alkylamines.13 In addition, allyl
acetate is an effective agent in the synthesis of heterocyclic
Received: April 3, 2021
Published: May 17, 2021
Figure 1. Transition-metal-catalyzed C−H activation to synthesize
isoquinoline derivatives
https://doi.org/10.1021/acs.orglett.1c01153
© 2021 American Chemical Society
Org. Lett. 2021, 23, 4209−4213
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Letter
compounds via tandem reactions.14 On the basis of these
results, we speculated that isoquinolines may be directly
obtained by treating the oxalylamide-protected benzylamine
with allyl acetate via a C−H allylation followed by an
intermolecular amination reaction.
With the optimal conditions in hand, the functional group
tolerance of this transformation was investigated as shown in
Scheme 1. Generally, the ortho-substituted oxalylamide-
a
Scheme 1. Scope of OA-Protected Benzylamines
With these conditions in mind, we examined the reaction of
oxalylamide-protected benzylamine 1a (0.1 mmol) and allyl
acetate 2a (0.2 mmol) in the presence of Pd(OAc)2 (5 mol %)
as the catalyst and AgOAc (2 equiv) as the oxidant in tert-
amyl−OH at 120 °C for 36 h. To our delight, the desired
product 3a was obtained in 17% yield, along with a recovery of
1a (Table 1, entry 1). Next, we investigated additives such as
a
Table 1. Optimization of the Reaction Conditions
b
entry
oxidants
additive
AcOH
PivOH
1-AdOH
yield (%)
1
2
3
4
5
6
7
8
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
Ag2CO3
Ag2O
17
23
56
36
51
67
70
73
65
55
81
trace
trace
trace
none
Ac-Gly-OH
(BnO)2PO2H
(EtO)2PO2H
(n-BuO)2PO2H
(PhO)2PO2H
BNDHP
(n-BuO)2PO2H
(n-BuO)2PO2H
(n-BuO)2PO2H
(n-BuO)2PO2H
(n-BuO)2PO2H
9
10
11
12
13
14
a
Conditions: 1 (0.2 mmol), 2a (0.4 mmol), Pd(OAc)2 (5 mol %),
Ag2CO3 (0.4 mmol), and (n-BuO)2PO2H (0.3 equiv) in DCE (0.3
b
mL) at 120 °C in an oil bath for 36 h; isolated yields. Pd(OAc)2 (10
Cu(OAc)2
PhI(OAc)2
Ag2CO3
c
mol %). 140 °C.
c
15
a
protected benzylamines performed well. Functional groups
such as methyl, methoxy, fluoride, chloride, and bromide were
all well-tolerated, leading to the corresponding products in
moderate to good yields. The meta- or para-substituted
benzylamines were all compatible with this transformation,
yielding the corresponding products in moderate to good
yields as well. It is worth noting that when benzylamines with
strong electron-withdrawing groups such as F and CF3 were
examined, the reaction achieves good results by increasing the
catalyst amount (3o−3p). Meanwhile, para-substituted benzyl-
amines with isopropyl, tert-butyl, and phenyl substituents also
could proceed, but yields were lower (3l−3n). Disubstituted
substrates have also been converted successfully, including
methyl- and halogen-substituted benzylamines, to obtain the
target product in moderate to good yields (3q−3u).
Interestingly, when 2-methylallylamine was used, the reaction
yielded pyridine derivative in 30% yield (3v) and suggested a
potentially powerful tool for the synthesis of pyridine.
To demonstrate the practicality of this method, we tried to
remove the directing group under basic conditions. Gratify-
ingly, oxalylamide was readily removed when 3a dissolved in
ethanol and heated at 80 °C for 24 h. It was surprising that the
product underwent aromatization while removing the directing
group without adding any other oxidant, directly generating
isoquinoline 4 in excellent yield (see the Supporting
Information). We then attempted to synthesize isoquinoline
derivatives by direct addition of NaOH and ethanol to the
reaction and heating at 80 °C for 24 h. The isoquinolines were
Reaction conditions: 1a (0.1 mmol), 2a (0.2 mmol), Pd(OAc)2 (5
mol %), oxidant (2 equiv), and additive (0.3 equiv) in the solvent at
120 °C in an oil bath for 36 h under air in a sealed tube. Yields were
based on GC analysis using tridecane as an internal standard. No
b
c
Pd(OAc)2.
AcOH, PivOH, 1-AdOH, Ac-Gly-OH, and (BnO)2PO2H
(Table 1, entries 2−6), well-known for promoting C−H
activation, to improve the efficiency of this transformation.
Those results showed that additives PivOH, Ac-Gly-OH, and
(BnO)2PO2H all showed a good promoting effect; 3a was
obtained in yields up to 67% when (BnO)2PO2H was used as
the additive (Table 1, entry 6). We explored several other
phosphates including (EtO)2PO2H, (n-BuO)2PO2H,
(PhO)2PO2H, and (BNDHP) to improve the yield of 3a
(Table 1, entries 7−10). Encouragingly, 3a was obtained when
(n-BuO)2PO2H was used as the additive (Table 1, entry 8).15
Although the role of (n-BuO)2PO2H remained unclear, it
probably took part in proton transfer and in stabilization of
Pd(0) during the catalytic cycle. What is more, organic
phosphoric acids might work as a solid-to-solution phase-
transfer catalyst (PTC), slowly bringing Ag+ ions into the
solution phase.16 A series of oxidants were also screened; after
adding commonly used oxidants such as Ag2CO3, Ag2O,
Cu(OAc)2, and PhI(OAc)2 (Table 1, entries 11−14), Ag2CO3
provided the target product in 81% yield (Table 1, entry 11). A
control experiment showed the Pd(OAc)2 catalyst was
essential for this tandem reaction (Table 1, entry 15).
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Letter
obtained in 68% yield with oxalylamide-protected benzylamine
as the product (4a). We evaluated a large group of substrates
for this one-pot, two-step method (Scheme 2). As before, a
tetrachloride, the bromomethylisoquinoline 5 was achieved in
60% yield,17 which was converted to 6 in short order.18 2-((4-
(Aminomethyl)phenyl)amino)-2-oxoacetic acid is considered
to be a bioactive molecule.19 Its derivative 9, which contained
an isoquinoline backbone, could also be easily synthesized
from p-aminobenzylamine (Scheme 3c).
a
Scheme 2. One-Pot Approach to Isoquinoline Synthesis
Some control experiments were performed to understand
the reaction pathway (Scheme 4). We used the allylation
Scheme 4. Preliminary Mechanistic Studies
product of oxalylamide-protected benzylamine as the starting
material; under standard reaction conditions, a 72% yield was
obtained for the target compound, this indicated the reaction
went through an allylation and might show β-OAc elimination
as reported in previous literature (Scheme 4a).20 In the
absence of Pd(OAc)2, no target product was formed, indicating
the palladium catalyst was crucial for the formation of C−C
and C−N bonds. Subsequently, we conducted deuterium
labeling experiments by adding acetic acid-d4 under standard
conditions; those results indicated that ortho C−H bond
might undergo reversible activation.
a
Conditions: 1 (0.2 mmol), 2a (0.4 mmol), Pd(OAc)2 (5 mol %),
oxidant (0.4 mmol), and additive (0.3 equiv) in DCE (0.3 mL) at 120
°C in an oil bath for 36 h. Followed by NaOH (25 equiv) and EtOH
(1.5 mL); isolated yields.
series of 3-methylisoquinoline derivatives were successfully
synthesized in moderate to good yields. Various substituted
benzylamines, such as methyl, methoxy, tert-butyl, isopropyl,
fluorine, chlorine, and bromine all resulted in good yields.
Substitutions at any position were all compatible. Interestingly,
when we used the fluorine-substituted benzylamine substrate,
the resulting fluorine-containing isoquinoline products reacted
with the ethanol solvent to yield ethoxy-substituted isoquino-
line products (4o, 4p).
Based on these results and previous literature,13,21 a possible
mechanism is proposed (Scheme 5): A palladacycle
Scheme 5. Plausible Catalytic Cycle
A gram-scale reaction was carried out to demonstrate the
synthetic value of this new strategy (Scheme 3a); the target
product was obtained in 65% yield. Next we explored the
transformation of 4a to further demonstrate the synthetic value
of this process in the synthesis of 3-methylisoquinolines
(Scheme 3b). When 4a was subjected to NBS/AIBN in carbon
Scheme 3. Synthetic Approach
intermediate II was initially formed by oxalylamide-directing
ortho-C−H bond activation; intermediate II then underwent
migratory alkene insertion to form a new seven-membered
cyclic intermediate III, which then underwent β-OAc
elimination to generate a new olefin-containing Pd complex
IV.20 The next step involved palladium-catalyzed amino-
palladation of IV via an intramolecular cyclization to generate
intermediate V.22 Finally, the target product 3a was formed by
β-hydride elimination and double bond isomerization.
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Letter
In conclusion, we have developed an efficient synthesis of
dihydroisoquinoline derivatives by a Pd(OAc)2 catalyzed
tandem of C−H allylation and intermolecular amination
reactions, which are further transformed into isoquinolines
by direct treatment with sodium hydroxide. A series of 3-
methylisoquinoline derivatives were obtained from this one-
pot, two-step method in moderate to good yields, highlighting
the synthetic importance of this new transformation.
Scientific and Technologic Infrastructure of Suzhou
(SZS20170), and the PAPD Project. The project was also
supported by the Open Research Fund of the School of
Chemistry and Chemical Engineering, Henan Normal
University.
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ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01153.
Experimental procedures, new compound character-
ization data, and NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Zhibin Huang − Key Laboratory of Organic Synthesis of
Jiangsu Province, College of Chemistry, Chemical Engineering
and Materials Science, Soochow University, Suzhou 215123,
P. R. China; Email: zbhuang@suda.edu.cn
Da-Qing Shi − Key Laboratory of Organic Synthesis of Jiangsu
Province, College of Chemistry, Chemical Engineering and
Materials Science, Soochow University, Suzhou 215123, P. R.
China; orcid.org/0000-0003-2262-8491; Email: dqshi@
suda.edu.cn, yszhao@suda.edu.cn
Yingsheng Zhao − Key Laboratory of Organic Synthesis of
Jiangsu Province, College of Chemistry, Chemical Engineering
and Materials Science, Soochow University, Suzhou 215123,
P. R. China; School of Chemistry and Chemical Engineering,
Henan Normal University, Xinxiang 453000, P.R.China;
orcid.org/0000-0002-6142-7839; Email: yszhao@
suda.edu.cn
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Authors
Yujie Chen − Key Laboratory of Organic Synthesis of Jiangsu
Province, College of Chemistry, Chemical Engineering and
Materials Science, Soochow University, Suzhou 215123, P. R.
China
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Chenyang Dai − Key Laboratory of Organic Synthesis of
Jiangsu Province, College of Chemistry, Chemical Engineering
and Materials Science, Soochow University, Suzhou 215123,
P. R. China
Shan Yang − Key Laboratory of Organic Synthesis of Jiangsu
Province, College of Chemistry, Chemical Engineering and
Materials Science, Soochow University, Suzhou 215123, P. R.
China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01153
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the financial support from the
Natural Science Foundation of China (Nos. 21772139), the
Major Basic Research Project of the natural Science
Foundation of Jiangsu Higher Education Institutions
(17KJA150006), the Jiangsu Province Natural Science Found
for Distinguished Young Scholars (BK20180041), Project of
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