Synthesis of Isoquinoline Derivatives via Palladium-Catalyzed C?H/C?N Bond Activation of N-Acyl Hydrazones with α-Substituted Vinyl Azides

Article abstract of DOI:10.1002/adsc.201901394

A palladium-catalyzed cyclization of N-acetyl hydrazones with vinyl azides has been developed. Various substituted isoquinolines, including diverse fused isoquinolines can be prepared via this protocol in moderate to good yields. Mechanistic studies suggest that α-substituted vinyl azide serves as an internal nitrogen source. Also, C?H bond activation and C?N bond cleavage have been realized using hydrazone as directing group. (Figure presented.).

Full text of DOI:10.1002/adsc.201901394

Title: Synthesis of Isoquinoline Derivatives via Palladium-Catalyzed C-
H/C-N Bond Activation of N-Acyl Hydrazones with α-Substituted
Vinyl Azides
Authors: Huanfeng Jiang, Biao Nie, Wanqing Wu, Wei Zeng, Qingyun
Ren, Ji Zhang, and Yingjun Zhang
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201901394
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10.1002/adsc.201901394
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Synthesis of Isoquinoline Derivatives via Palladium-Catalyzed
C-H/C-N Bond Activation of N-Acyl Hydrazones with α-
Substituted Vinyl Azides
Biao Niea, Wanqing Wua, Wei Zenga, Qingyun Renb, Ji Zhangb, Yingjun Zhangb* and
Huanfeng Jianga,c*
a
Key Laboratory of Functional Molecular Engineering of Guangdong Province, School of Chemistry and Chemical
Engineering, South China University of Technology, Guangzhou, 510640, China
Fax: (+86)-020-87112906; phone: (+86)-020-87112906; E-mail: jianghf@scut.edu.cn
State Key Laboratory of Anti-Infective Drug Development, Dongguan 523871, China
b
E-mail: zhangyingjun@hec.cn
State Key Laboratory of Applied Organic Chemistry (Lanzhou University), Lanzhou 730000, China
c
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. A palladium-catalyzed cyclization of N-acetyl
hydrazones with vinyl azides has been developed. Various
substituted isoquinolines, including diverse fused
isoquinolines can be prepared via this protocol in moderate
to good yields. Mechanistic studies suggest that α-substituted
vinyl azide serves as an internal nitrogen source. Also, C-H
bond activation and C-N bond cleavage have been realized
using hydrazone as directing group.
Keywords: C-H activation; N-acyl hydrazones; directing
group; isoquinoline
of our knowledge, palladium-catalyzed C-H
functionalization using aryl ketone hydrazones as
directing groups for the synthesis of isoquinolines
have never been reported to date. In addition, N-acetyl
hydrazone as the directing group has not been studied
in C−H activation yet. Inspired by our previous studies
on palladium-catalyzed reactions,[14] we envisaged that
the N-acetyl hydrazone as the building block could be
applied to this synthetic protocol. Herein, we present a
new strategy via Pd-PEPPSI-IPr catalyzed C-H/C-N
bond activation employing N-acetyl hydrazones,
which could act as a novel traceless directing group by
C-N bond cleavage to afford substituted isoquinolines
(Scheme 1b).
Introduction
Isoquinolines are useful N-heterocyclic structures
found in natural products, pharmaceutical molecules,
[1]
PET imaging agents, catalyst ligands, and OLED
materials (Figure 1).[2] Traditionally, syntheses of
isoquinolines using classical protocol such as Bichler-
Napieralski,[3] Pomeranz-Fritsch[4] and Pictet-Spengle
rreactions,[5] often suffer from multistep process and
harsh reaction conditions. To avoid the limitations of
the above reactions, various synthetic approaches for
isoquinolines have been developed. Recently,
transition-metal-catalyzed direct C-H functionalization
has emerged as a novel strategy to construct
isoquinoline skeleton by C-H/N-N bond activation or
C-H/N-O bond activation with nitrogen-containing
directing groups including aromatic hydrazines,
imines, azines oximes, etc.[6-9] In most cases, internal
nitrogen source of isoquinolines was also provided by
directing groups.
In recent years, several aromatic hydrazones (N-Tos,
N-Cbz, N-Boc, and N-pyridine, etc.) have been
explored in rhodium(III),[10] cobalt(III),[11] cobalt(II),
[12]
and ruthenium(II)[13] -catalyzed annulations with
alkynes through C-H/N-N bond activation to afford
1,3,4-trisubstituted isoquinolines, along with N-N
bond cleavage of hydrazones (Scheme 1a). To the best
1
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10.1002/adsc.201901394
Advanced Synthesis & Catalysis
Figure 1. Representative useful molecules with
isoquinoline scaffold
3
4
5
6
7
8
9
Pd(OPiv)2 (10)
NaOAc
NaOAc
KOAc
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
toluene
toluene
toluene
toluene
toluene
toluene
80
80
80
80
80
90
27
56
45
50
34
66
PEPPSI-IPr (10)c
PEPPSI-IPr (10)
PEPPSI-IPr (10)
PEPPSI-IPr (10)
PEPPSI-IPr (10)
PEPPSI-IPr (10)
AgOAc
CsOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
Cu2O
BQ
toluene
toluene
toluene
toluene
TFE
100
100
100
100
100
81
50
10 PEPPSI-IPr (10)
11 PEPPSI-IPr (10)
12 PEPPSI-IPr (10)
13 PEPPSI-IPr (10)
K2S2O8
DDQ
Cu2O
41
NR
35
Scheme 1. Synthesis of isoquinolines via C-H activation
using aryl hydrazone as directing group
14 PEPPSI-IPr (10)
15 PEPPSI-IPr (10)
16 PEPPSI-IPr (10)
17 PEPPSI-IPr (10)
18 ---
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
---
CH3CN
DMSO
DMF
100
100
100
trace
trace
trace
37
Results and Discussion
1,4-dioxane 100
We initiated our studies by utilizing acetophenone-
N-acetylhydrazone (1a) and (1-azidovinyl) benzene
(2a) as the model substrates to optimize the reaction
parameters (Table 1). When 1a was reacted with 2a in
the presence of Pd(OAc)2 (10 mol %), NaOAc (1.0
toluene
100
NR
19d PEPPSI-IPr (100)
toluene
100
trace
a.Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol),
catalyst (10 mol %), NaOAc (1.0 equiv), Cu2O (2.0 equiv)
in the solvent (2 mL) under air atmosphere for 12 h, unless
otherwise noted. b.Isolated yield. TFE = trifluoroethanol
c.the corresponding structure:
o
equiv), Cu2O (2.0 equiv) in toluene at 80 C for 12 h,
the desired product 3aa was obtained in 30% yield
(Table 1, entry 1). During further screening of the
catalysts, PEPPSI-IPr was indicated the most effective
(Table1, entries 2-4). It was found that other acetate
additives such as KOAc, AgOAc, CsOAc could not
promote the reaction (Table1, entries 5-7). Further
o
increasing the temperature to 100 C led to the best
yield of the product up to 81% (Table1, entry 9). The
examination of different solvents suggested that
toluene was the most effective solvent for this
transformation, while other solvents such as TFE,
MeCN, DMSO, DMF, and 1,4-dioxane failed to
facilitate the reaction (Table 1, entries 13-17). Control
experiment indicated that the reaction did not occur in
the absence of Pd catalysts (Table1, entry 18). When
the reaction was carried out in the presence of a
stoichiometric amount of Pd without Cu2O, only trace
amount of the product was obtained (Table 1, entry
19). Finally, we found PEPPSI-IPr-NaOAc-Cu2O
catalytic system with toluene as solvent resulted in the
formation 3aa in best yields at 100 oC.
d.
the amount of PEPPSI-IPr was 100 mol % in the absence
of Cu2O.
With the optimized reaction condition in hand, the
substrate scope of the reaction was then investigated.
Firstly, a broad range of N-acetyl hydrazones were
screened to couple with (1-azidovinyl)benzene (2a) as
shown in Scheme 2. To our delight, variation from
alkyl aryl ketones to benzophenone and cycloalkyl
aryl ketones hydrazones reacted smoothly with 2a to
afford isoquinolines 3aa-3ia in 60-81% yields.
Especially, cyclohexyl, cyclopentyl, cyclobutyl and
cyclopropyl substituted hydrazones were compatible
in this transformation (3fa-3ia). The substrate bearing
a methyl group at the ortho-position of N-acetyl
hydrazone showed the lowest reactivity and the
corresponding product 3ja was just obtained in a trace
isolated yield, presumably due to the steric hindrance
of ortho substitution.
Table 1. Optimization of reaction conditionsa
The C-H functionalization occurred regioselectively
at the less hindered site for meta-substituted substrate
(Me, 1k), yielding a mixture of isomers 3ka as the
temp
Entry Catalyst (mol %)
Additive 1
NaOAc
Additive 2
Cu2O
Solvent
toluene
toluene
yieldb (%)
(oC)
1
2
Pd(OAc)2 (10)
Pd(TFA)2 (10)
80
30
41
target
product.
Diverse
mono-substituted
NaOAc
Cu2O
80
acetophenone N-acetyl hydrazones with either
electron-donating (Me, Bu, Ph, OMe, OPh) or
2
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10.1002/adsc.201901394
Advanced Synthesis & Catalysis
electron-withdrawing (F, Br, Cl, CN) group on the
para-position of the phenyl ring proceeded well in
this reaction and transformed to the desired products
in moderate yields (3la-3ra, 3sa-3va). 1-
Acetylnaphthalene hydrazone was also reactive for the
transformation, yielding the corresponding product
3wa. Furthermore, this method was suitable for
disubstituted N-acetyl hydrazones, and the desired
products could be isolated in good yields with
exclusive regioselectivity (3xa-3ya). The reaction of
3,4-methylenedioxy acetophenonehydrazone 1z with
2a afforded a 1:1 mixture of two regio isomer 3za in
74% total yield.
corresponding product 3al in moderate yield. More
importantly, the alkyl and alkoxycarbonyl vinyl azides
were also compatible in this transformation, giving the
corresponding products 3am, 3an, and 3ao,
respectively. Furthermore, the heteroarene vinyl azide
was tolerable, converting to the desired product 3ap in
63% yield.
Table 3. Substrate scope of vinyl azides[a], [b]
Table 2. Substrate scope of N-acetyl hydrazonesa,b
a.Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol),
catalyst (10 mol %), NaOAc (1.0 equiv), Cu2O (2.0 equiv)
o
in the solvent (2 mL) at 100 C under air atmosphere for 12
h, unless otherwise noted. b.Isolated yield.
a.Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol),
Interestingly, fused isoquinolines could be obtained
by this protocol in moderate to good yields (Scheme
4). The transformations of 1-tetralone, 1-
benzosuberone hydrazone proceeded smoothly to give
the desired polycyclic product 5aa, 5ba in moderate
yields. Moreover, chroman-4-one, thiochroman-4-one-
hydrazone substrates could be converted to
polyheterocyclic products 5ca and 5da in 88% and
91% yields respectively, which could be further
applied to the synthesis of structurally related natural
products.
catalyst (10 mol %), NaOAc (1.0 equiv), Cu2O (2.0 equiv)
o
in the solvent (2 mL) at 100 C under air atmosphere for 12
h, unless otherwise noted. b.Isolated yield.
Next, the scope of the vinyl azide in the coupling
with N-acetyl hydrazones 1a under the standard
reaction conditions was examined (Table 3). Various
substituted vinyl azides could react well with 1a,
leading to the corresponding isoquinoline products in
moderate to good yields. The steric effect significantly
affected this transformation. meta- and para-Methyl-
substituted substrates proceeded smoothly (3ab, 3ac),
Table 4. Synthesis of fused isoquinolinesa,b
while
ortho-methyl-substituted
substrate
was
converted to the isoquinoline product 3ad in low yield.
Substitution of aryl group of vinyl azides with
electron-withdrawing groups, such as fluoride and
trifluoromethyl, led to isoquinoline products in 74%
and 71% yields respectively (3ae, 3ah). In addition, 1-
naphthyl vinyl azide could transfer to the
3
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10.1002/adsc.201901394
Advanced Synthesis & Catalysis
Scheme 3e).
a.Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol),
catalyst (10 mol %), NaOAc (1.0 equiv), Cu2O (2.0 equiv)
o
in the solvent (2 mL) at 100 C under air atmosphere for 12
h, unless otherwise noted. b.Isolated yield.
As an exploration of the application of this protocol,
the synthetic transformation is shown in Scheme 2. 7-
Methoxyflavanone 6, a flavonoid natural product with
a variety of biological activities,[15] could be easily
converted to hydrazone 7 and reacted with vinyl azide
2a to provide desired isoquinoline product 8 in 51%
yield.
Scheme 3. Mechanistic studies
Based on these experimental results and previous
reports,[16] a plausible mechanism is shown in Scheme
4. The thermal decomposition of vinyl azide 2a gave
2H-azirines 10, which could be reduced by the Cu(I)
species to afford the Cu(II) aza-enolate A via single-
electron-transfer (SET) process. The removal and
exchange the ligand from Pd-PEPPSI-IPr with NaOAc
formed the active Pd(II) species. Then, coordination of
the nitrogen atom to the Pd(II) center, followed by
cleavage of arene ortho C-H bond afforded five-
a.Reaction conditions: 6 (0.2 mmol), 2a (0.3 mmol), catalyst
(10 mol %), NaOAc (1.0 equiv), Cu2O (2.0 equiv) in the
o
solvent (2 mL) at 100 C under air atmosphere for 12 h,
unless otherwise noted. b.Isolated yield.
membered palladacycle intermediate
B
and
Scheme
methoxyflavanone
2.
Synthetic
transformations
of
7-
accompanied by a release of one equivalent of HOAc.
Protonolysis of A was proposed to offer iminyl copper
species C. [17] The transmetalation of C with complex
B gave iminyl palladium species D. Subsequently,
tautomerization of D to its enamine form afforded E,
which was in equilibrium with its C-bound Pd(II)
complex F. Then, F underwent reductive elimination
to provide G with generation of Pd(0) species. Finally,
intramolecular condensation of G led to H, followed
by elimination of NH2NHAc delivered compound 3
and a redox reaction between Pd(0) and Cu(II) species
regenerated the Pd(II) and Cu(I) catalyst
concomitantly.
Several experiments were performed to explore the
reaction mechanism. The product 3aa could not be
obtained by reaction of ketone 9 with 2a under the
standard conditions (Scheme 3a), while ary-2H-azirine
10 could react with 1a to afford 3aa in 62% isolated
yield under the same conditions (Scheme 3b),
suggesting that ary-2H-azirine 10 was an important
intermediate involved in the reaction process.
Furthermore, when the 15N-labeld hydrazone was
added to react with vinyl azide 2a under the standard
condition, the corresponding 15N-labeled product
could not be found (Scheme 3c). Comparatively, when
using 15N-labeled vinyl azide as the substrate, the 15N-
labeled product could be obtained (Scheme 3d). These
results revealed that vinyl azide 2a provided the sole
nitrogen source to the formation of product 3aa. In
order to detect kinetic isotope effect, 1a and deuterated
N-acetyl hydrazones 1a-d5 were added in an
intermolecular competition reaction, and the result
suggested that C-H activation of 1a was probably
involved in the rate-determining step (kH/kD 3.35,
=
4
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10.1002/adsc.201901394
Advanced Synthesis & Catalysis
Laboratory of Anti-Infective Drug Development (SKLAID201803)
for financial support.
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Conclusion
In summary, we have developed a Pd(II)-catalyzed
C-H activation/C-N cyclization reaction of N-acyl
hydrazones with α-substituted vinyl azide. C-H bond
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General Procedure for the Synthesis of Isoquinolines
Hydrazone 1 (0.2 mmol), vinyl azide 2 (0.3 mmol), Pd-
PEPPSI-IPr (0.02 mmol, 10 mol %), NaOAc (16.4 mg, 0.2
mmol, 1.0 equiv), Cu2O (57.2 mg, 0.4 mmol, 2.0 equiv).
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purified by flash column chromatography to afford the
isoquinoline products (silica gel, petroleum ether/ethyl
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5
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10.1002/adsc.201901394
Advanced Synthesis & Catalysis
FULL PAPER
Synthesis of Isoquinoline Derivatives via
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