Synthesis of Substituted Naphthalenes by 1,4-Palladium Migration Involved Annulation with Internal Alkynes

Article abstract of DOI:10.1002/cjoc.201800169

The palladium catalyzed annulation of 1-bromo-2-vinylbenzene derivatives with internal alkynes was realized for the efficient synthesis of substituted naphthalenes. A controllable aryl to vinylic 1,4-palladium migration process is the key for success.

Full text of DOI:10.1002/cjoc.201800169

Synthesis of Substituted Naphthalenes by 1,4-Palladium Migration
Involved Annulation with Internal Alkynes†
Dong Wei,a,b Tian-Jiao Hu,b Chen-Guo Feng*,b,c and Guo-Qiang Lin*,a,b
ABSTRACT The palladium catalyzed annulation of 1-bromo-2-vinylbenzene derivatives with internal alkynes was realized for the efficient synthesis of
substituted naphthalenes. A controllable aryl to vinylic 1,4-palladium migration process is the key for success.
KEYWORDS metal migration, naphthalene, palladium, annulation, alkyne
same alkynes. In the meanwhile, the (2-aryl)vinyl metal species
Introduction
originating from oxidative addition of a vinyl halide was also
The naphthalene core exists extensively in natural products[1]
and bioactive molecules.[2] Moreover, substituted naphthalenes
have found wide application in optical and electronic materials.[3]
As a result, the development of chemoselective and regioselective
methods for their synthesis is of great importance. Owing to the
scarcity of suitable source material and the difficulty in selectivity
control, it is often unapproachable to synthesize a substituted
naphthalene by electrophilic aromatic substitution. Intense
research interest has been devoted to synthetic methods via
benzannulation of properly functionalized arenes,[4] which include
annulation via Fisher Carbenes,[5] Diels-Alder reactions,[6]
transition-metal-mediated cyclizations,[7] ring rearrangement
aromatizations,[8] and acid or base promoted cyclizations.[9]
reported by the Larock group,[11] which is limited by the difficulty
of accessing corresponding stereodefined vinyl halides, especially
for acyclic ones. Therefore, developing a practical and versatile
synthetic method by the introduction of a new generation mode
of (2-aryl)vinyl metal species is attractive.
1,4-Palladium migration is quite common in organometallic
chemistry, which can be used to metalate a remote C-H bond,
generating a new organometallic species that is difficult to acquire
by other means.[12] Recently, an efficient aryl to vinylic
1,4-palladium process was disclosed by our group.[13] We envision
the generated vinylpalladium intermediate might couple with
alkynes and provide
a new method for the synthesis of
substituted naphthalenes.
Scheme 1 Synthesis of naphthalene via benzannulation of (2-aryl)vinyl
metal species and internal alkyne
Results and Discussion
To test our hypothesis, we began our study by testing the
annulation of alkene 1a and alkyne 2a in the presence of Pd(OAc)2
and various ligands (Table 1). All the tested bis-phosphine ligands
were competent to promote the planned reaction sequence.
Interestingly, ligands bearing odd-numbered carbon chain gave
higher reaction yields than those with even-numbered ones,
which may be ascribed to a subtle conformation effect of ligand
on the reaction. The importance of ligand conformation was also
shown by the fact that DPEPhos (L6) gave 99% reaction yield
(entry 6) while conformationally rigid Xantphos (L7) gave only 66%
reaction yield (entry 7). Mono-phosphine ligand can also be used,
but was less effective. A screening of solvent found CH2Cl2 as
another optimal solvent (entry 12). Lowering the reaction
temperature to 90 oC, resulted in no product formation (entry 17)
With the optimized conditions in hand, the scope of alkenes
was first explored (Table 2). High reaction yields were observed
when the position of phenyl ring A was installed by a variety of
substituted phenyl groups (3aa-3ga), as well as naphthalenyl (3ha)
and thienyl (3ia) groups. While the phenyl ring A was replaced by
a methyl group, a substrate used recently in the coupling with
alkyne for the preparation of tetracyclic compounds,[14] the
desired naphthalene 3ja was still produced under our reaction
conditions, albeit in reduced yield. An ester group was also
compatible (3ka), which provides a useful handle for further
derivatization. Introduction of either electron-donating or
electron-withdrawing substituents to the C-5 position of phenyl
ring B furnished the desired products in high yields (3ia-3pa).
Replacing the phenyl ring B by a pyridyl group was also tolerated
From the standpoint of retrosynthetic analysis, the
naphthalene ring can be divided into a (2-aryl)vinyl metal moiety
and an alkyne, which represents an obvious but modular synthetic
strategy. Pioneered by the work of Sakakibara,[10a] the
corresponding (2-aryl)vinyl metal species can be in situ generated
via alkyne insertion and then react with a second alkyne to yield
the desired naphthalenes. This kind of transformation represents
one of the most concise synthetic methods, and now can be
promoted by a variety of transition metals.[10] However, the
resulting naphthalenes are restricted to the incorporation of two
(3qa). As expected,
a substrate bearing a C-4 methyl
a
School of Physical Science and Technology, ShanghaiTech University, Shanghai
200031, China
Key Laboratory of Synthetic Chemistry of Natural Substances, Center for
c Innovation Research Institute of Traditional Chinese Medicine, Shanghai
University of Traditional Chinese Medicine, Shanghai 201203, China
E-mail: fengcg@sioc.ac.cn, lingq@sioc.ac.cn
b
†
Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry,
University of Chinese Academy of Sciences, Chinese Academy of Sciences,
Shanghai 200032, China
Dedicated to Professor Xiyan Lu on the occasion of his 90th birthday.
This article has been accepted for publication and undergone full peer review but has not
been through the copyediting, typesetting, pagination and proofreading process, which
may lead to differences between this version and the Version of Record. Please cite this
article as doi: 10.1002/cjoc.201800169
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substituented phenyl ring B generated two regio-isomers (3ra and
3ra’) in a 1.2:1 ratio, which is in accordance with the proposed
migration mechanism.
Scheme 2 Synthesis of naphthalene via benzannulation of (2-aryl)vinyl
metal species and internal alkynea
R1
A
Table 1 Optimization of reaction conditionsa
R1
B
A
Pd(OAc)2/L6
(5 mol % Pd)
Ph
R2
B
+
R2
CsOAc, dioxane
110 oC, 3 h
Ph
Ph
Br
Ph
1
2a
3
Variation at the phenyl ring A:
Me
Me
Me
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Temp./oC
110
solvent
dioxane
yieldb /%
57
3aa, 94%
3ba, 87%
3ca, 99%
3da, 91%
entry
1
ligand
OMe
F
Cl
L1
2
3
L2
L3
L4
L5
L6
L7
L8
L9
L10
L6
L6
L6
L6
L6
L6
L6
L6
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
90
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
THF
93
82
92
85
99
66
53
36
29
64
99
34
28
62
26
nd
95
4
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
5
3ea, 84%
3fa, 81%
3ga, 80%
3ha, 83%
6
S
7
Me
CO2Me
8
Ph
Ph
Ph
9
Ph
Ph
Ph
10
11
12
13
14
15
16
17
18
3ia, 56%
3ja, 65%
3ka, 60%
Variation at the phenyl ring B:
CH2Cl2
toluene
MeCN
Me
Ph
MeO
Ph
F
Ph
Cl
Ph
Ph
Ph
3ma, 92%
Ph
Ph
3oa, 73%
Ph
DMF
3la, 89%
3na, 88%
MeOH
dioxane
dioxane
Ph
130
Me
+
Me
a Reaction condition: 1a (0.19 mmol, 1.0 equiv), 2a (0.19 mmol, 1.0 equiv),
Pd(OAc)2 (0.05 equiv), ligand (0.1 equiv for L1-L7 and 0.2 equiv for L8-L10 ),
CsOAc (2.0 equiv), solvent (1 mL). b Determined by 1H NMR spectroscopy
using CH2Br2 as an internal standard.
Ph
N
F3C
Ph
Ph
Ph
Ph
3pa, 90%
Ph
3ra'
3ra
3qa, 64%
95% (isomer ratio = 1.2:1)b
Next, the scope of alkynes was examined (Scheme 3). The
coupling with various symmetrical, internal alkynes bearing two
different aryl groups proceeded smoothly to afford 3ab-3af in
good to excellent yields. While the reaction with two
thienyl-substituted alkynes gave reduced reaction yield (3ag), only
a trace amount of product was detected by GC-MS analysis with
di-butyl substituted alkyne (3ah). Although the application of
a
Reaction condition: 1 (0.30 mmol, 1.0 equiv), 2a (0.30 mmol, 1.0 equiv),
Pd(OAc)2 (0.05 equiv), L6 (0.1 equiv), CsOAc (2.0 equiv), dioxane (1.5 mL).
Yield refers to isolated product. b Isomer ratio was determined by 1H NMR
analysis of the crude product.
Two gram-scale reactions were carried out to demonstrate the
practicability of the developed method, which offered the desired
products in comparable reaction yields to those observed on
small reaction scale (eqs 2 and 3).
A possible mechanism was proposed based on the current
experimental observations and previous reports,[13] in which
alkene 3r was used as the model substrate to elucidate the
regioselectivity in this reaction (Scheme 5). The reaction is
initiated by the oxidative addition of starting substrate 3r, and is
followed by a 1,4-palladium migration process, which may be
promoted by the generation of less sterically encumbered
vinylpalladium B. Insertion of internal alkyne produces
intermediate C and undergoes a subsequent cyclization with the
phenyl ring B from two different directions to afford 3ga and 3ga’,
non-symmetrical alkynes usually brings
a mixture of two
regioisomers, it is possible to control the regioselectivity by
applying alkynes with marked differences in the two substituents.
For example, excellent regioselectivies were observed with
1-phenyl-2-(trimethylsilyl) acetylene (>20:1) and methyl
phenylpropiolate (14:1). The structure of the corresponding major
isomers 3ak and 3al were determined by X-ray crystallographic
structure analysis (Scheme 4),[15] which can be explained by the
regioselectivity preference in the alkyne insertion step via an
alkenylpalladium intermediate,[11,16] and was further confirmed by
a control experiment with alkenyl bromide 4 as the coupling
partner (eq 1).
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Ph
Ph
respectively.
Pd(OAc)2/L6
(5 mol % Pd)
Ph
Ph
+
+
(2)
(3)
Ph
CsOAc, dioxane
110 oC, 3 h
88%
Ph
Br
Scheme 3 Scope of internal alkynesa
1a
2a
3aa
, 1.0 g
, 1.216 g
Ph
Ph
Ph
Pd(OAc)2/L6
(5 mol % Pd)
Ph
Pd(OAc)2/L6
(5 mol % Pd)
R4
Ph
+
R3
CsOAc, dioxane
110 oC, 3 h
Br
R4
TM
S
S
CsOAc, dioxane
110 oC, 3 h
70%
Ph
Br
R3
3
TMS
3ak, 0.955 g
1a
2
1a, 1.0 g
2k
WWith symmetrical internaal alkynes:
Ph
Ph
Ph
Ph
Scheme
5 Proposed mechanism for palladium-catalyzed naphthalene
synthesis
Me
Mee
OMe
F
Ph
Ph
Ph
[Pd0]
Me
1,4-Pd migration
Ph
Me
H
PdXLn
PdXLn
Me
OMe
3ad
F
Me
n
Me
3ab
3ac
3ae
, 98%
Ph
, 82%
, 82%
, 89%
Br
3r
A
B
Ph
Ph
o
i
t
a
r
e
s
n
Ph
Ph
Ph
i
e
n
y
Me
Ph
k
l
S
a
Ph
Ln Pd
Me
Ph
Ph
PdXLn
Ph
C
CF3
S
Me
Me
Ph
Pd
Ln
Me
3ah
CF3
D'
C
D
3af
3ag
, 56%
, 96%
, trace
WWith unsymmetrical inteernal alkynes:
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
+
+
Me
S
Me
Ph
Ph
Ph
Ph
Me
S
Ph
3ra
3ai
3ai'
3aj
3aj'
3ra'
58% (isomer ratio = 1.4:1)b
87%
(isomer
Ph
Ph
Ph
Ph
ratio =
6:1)b
+
+
Ph
CO2Me
3al'
Ph
TMS
CO2Me
Conclusions
TMS
Ph
Ph
3ak
3ak'
3al
In summary, wwe developed a convenient protocol for the
modular synthesis of substituted naphthalenes. A wide variety of
substituted naphthalene compounds were prepared in good to
excellent yields. The success of this transformation involves a key
1,4-palladium migration step.
72% (3ak/3ak' = >20:1)b
84%
3al 3al'
(
/
= 14:1)b
a
Reaction condition: 1a (0.30 mmol, 1.0 equiv), 2 (0.30 mmol, 1.0 equiv),
Pd(OAc)2 (0.05 equiv), L6 (0.1 equiv), CsOAc (2.0 equiv), dioxane (1.5 mL).
Yield refers to isolated product. b Isomer ratio was determined by 1H NMR
analysis of the cruude product.
Supporting Innformation
The supporting information for this article is available on the
WWW under https //doi.org/10.1002/cjoc.2018xxxxx.
::
Acknowledgement
Scheme 4 X-Ray crrystallographic structure of 3ak and 3al
Financial support from the National Natural Science
Foundation of China (21472212, 21572253, 21772216), the
Strategic Priority Research Program of the Chinese Academy of
Sciences (XDB 200020100) and The Key Research Program of
Frontier Science (QYZDY-SSW-SLH026) is acknowledged.
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(The following will be filled in by the editorial staff)
Manuscript received: XXXX, 2017
Revised manuscript received: XXXX, 2017
Accepted manuscript online: XXXX, 2017
Version of record online: XXXX, 2017
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Entry for the Table of Contents
Page No.
R1
Synthesis of Substituted Naphthalenes by
1,4-Palladium
Annulation with Internal Alkynes
Pd(OAc)2/DPEPhos
(5 mol % Pd)
R1
Br
R4
Migration
Involved
O
R2
+
R2
PPh2
R3
CsOAc, dioxane
110 oC, 3 h
29 examples
56-98% yields
PPh2
R4
R3
DPEPhos
via:
R1
R1
1,4-Pd migration
R2
R2
PdX
PdX
The palladium catalyzed annulation of 1-bromo-2-vinylbenzene derivatives with internal alkynes
was realized for the efficient synthesis of substituted naphthalenes. A controllable aryl to vinylic
1,4-palladium migration process is the key for success.
Dong Wei, Tian-Jiao Hu, Chen-Guo Feng,*
Guo-Qiang Lin*
This article is protected by copyright. All rights reserved.