Palladium-Catalyzed Domino Reaction of Two Aryl Iodides involving C–H Activation Processes: Efficient Synthesis of Fused Polycycles

Article abstract of DOI:10.1002/ejoc.201601051

The palladium-catalyzed domino intermolecular C(sp²)–H activation reaction of two aryl iodides was explored. This simple palladium catalytic system showed good activity.

Full text of DOI:10.1002/ejoc.201601051

A Journal of
Accepted Article
Title: Palladium-Catalyzed Domino Reaction of Two Aryl Iodides Involving C-H Acti-
vation Processes: An Efficient Synthesis of Fused Polycycles
Authors: Haiyu He; Wei Wang; Xiaojun Yu; Jin Huang; Lei Jian; Haiyan Fu; Xueli
Zheng; Hua Chen; Ruixiang Li
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201601051
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European Journal of Organic Chemistry
10.1002/ejoc.201601051
SHORT COMMUNICATION
Palladium-Catalyzed Domino Reaction of Two Aryl Iodides
Involving C-H Activation Processes: An Efficient Synthesis of
Fused Polycycles
Hai-Yu He,[a] Wei Wang,[b] Xiao-Jun Yu,[a] Jin Huang,[a] Lei Jian,[a] Hai-Yan Fu,[a] Xue-Li Zheng,[a] Hua
Chen,[a] and Rui-Xiang Li*[a]
Dedication ((optional))
Abstract: A palladium-catalyzed domino intermolecular C(sp2)-H
activation reaction of two aryl iodides is reported. This simple
palladium catalytic system shows good activity.
Introduction
The rapid construction of complex heteroatom-containing
molecular skeletons has become an attractive challenge in the
past years. Transition metal-catalyzed domino C-H activation
reactions represent a highly efficient strategy for the rapid
formation of multiple bonds in one-pot reactions.[1] In particular,
palladium-catalyzed C-H activation has received substantial
attention in recent years. And indeed, significant progress has
been achieved in this field.[2] For example, Lautens,[3] Catellani,[4]
and Cámpora[5] have reported some interesting transformations
that proceed through alkyl or aryl palladacycle intermediates. To
our knowledge, only a few examples of complete alkyl to aryl
Scheme 1. Precedent in alkyl to aryl palladium rearrangement via C-H
activation.
palladium rearrangement via intramolecular C-H activation have
been reported.[3d,6]
Larock[6a] used Pd(OAc)2-bis(diphenylphosphino)methane
(dppm) as catalyst and carried out the synthesis of fused biaryls
cardiovascular drugs.[10] Both 9,10-dihydrophenanthrene and
B (Scheme 1a) by an intramolecular Heck reaction of compound
chroman are vital pharmacophores, so their hybrid frame is
A, and then 1,4-palladium alkyl to aryl migrations through a
also valuable in medicinal chemistry.[11]
sequence of C-H activations. More recently, Lautens[3d]
Inspired by earlier studies[3,6] and in continuation with our
illustrated an intermolecular domino reaction of two aryl iodides
research interest in the area of palladium-catalyzed domino C-H
involving two C-H functionalizations (Scheme 1b). The complex
activation sequence,[12] herein we report a simple and efficient
fused biaryls F was obtained through substrate C processing a
palladium-catalyzed C-H activation reaction of two aryl iodides
as shown in Scheme 2. A noteworthy advantage of our method
five-membered palladacycle D intermediate to react with another
aryl iodide E. In this system, complex Pd-1, Pd-2 and Pd-3
(Scheme 1b) must be added.
Structurally, compound 3 (Scheme 2) is a hybrid between 9,
was that this palladium-catalyzed C-H activation reactions can
be achieved by using simple palladium catalytic system.[12,13]
We began our investigation with the 2-iodo-1-(3-methylbut-3-
enyloxy)benzene (1a) as a model substrate. Our initial efforts
were focused on the influence of bases. The screening of bases
were carried out by reacting 0.25 mmol of 1a with 2 mol% of
10-dihydrophenanthrene and chroman motifs. The former is an
important unit in sedative-hypnotic drugs[7] and antifungal
drugs,[8] the latter is widely found in natural dyes[9] and
[Pd(COD)Cl2], 2 equiv of base and 1 equiv of (nBu)4NBr
o
(TBAB) in dimethylacetamide (DMA) at 120 C under nitrogen
for 24 h. Product 4a was separated as a crystalline solid and its
structure was confirmed by single-crystal X-ray diffraction.[14]
When Na2CO3, NaHCO3 and NaOAc were used, the yields were
not satisfying (0-26 % yields; Table1, entries 1-3). K2CO3 and
K3PO4 were found to be most suitable for the reaction (Table
1, entries 5 and 6). Cs2CO3 was also efficient though gave a little
lower yield of the cross-coupling product 4a (Table 1, entry 4).
However, the yield of 4a did not continue to increase when using
stronger bases, such as CsF, KOH, NaOH, KOtBu and LiOtBu
(Table 1, entries 7-11).
[a]
[b]
H.-Y. He, X.-J. Yu, J. Huang, L. Jian, H.-Y. Fu, X.-L. Zheng, H.
Chen, Prof. Dr. R.-X. Li
Key lab of Green Chemistry and Technology, Ministry of Education;
College of Chemistry, Sichuan University, Chengdu 610064 (China)
Fax: (+86)-28-8541-2904
E-mail: liruixiang@scu.edu.cn
W. Wang
State Key Laboratory of Biotherapy and Cancer Center, West China
Hospital, West China Medical School, Sichuan University, Chengdu,
610064 (China)
Supporting information for this article is given via a link at the end of
the document.
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European Journal of Organic Chemistry
10.1002/ejoc.201601051
SHORT COMMUNICATION
Table 1. Optimization of palladium-catalyzed domino reaction of 1a[a]
.
Scheme 2. Palladium-catalyzed C-H activation reaction of two aryl iodides
(this work).
Entry
1
Base
Solvent
DMA
Temp [oC]
120
120
120
120
120
120
120
120
120
120
120
120
120
120
100
100
100
100
130
140
Yield [%][b]
0
Next, a wide range of solvents, including toluene, ortho-xylene,
1,4-dioxane, dimethylacetamide (DMA), dimethylformamide
(DMF), 1-methyl-2-pyrrolidinone (NMP), and n-butanol were
tested. NMP was found to be the most efficient (Table 1, entry
14), DMA and DMF gave comparable yields (Table 1, entries 5
and 12), and n-butanol was not a suitable solvent for this
reaction (Table 1, entry 17).
NaOAc
NaHCO3
Na2CO3
Cs2CO3
K2CO3
K3PO4
CsF
2
DMA
0
3
DMA
26
4
DMA
57
o
Besides, best fitting temperature for this reaction was 120 C.
5
DMA
70
When the temperature dropped to 100 oC, 1a did not convert
completely, and 59 % yield was obtained (Table 1, entry 18).
Raising temperature to 130 oC or 140 oC, more byproducts were
generated, so the yield of 4a decreased obviously (18-41 %;
Table 1, entries 19 and 20).
6
DMA
70
7
DMA
64
8
KOH
DMA
55
With K2CO3 as a base, NMP as a solvent, we went on to
exmine the effect of palladium precursors on the reaction (Table
2). It was found that different sources of palladium showed
significant effect on the yield. When Pd(dba)2 was used as the
catalyst, the yield of the desired cross-dehydrogenative-coupling
product 4a was only 32 % (Table 2, entry 3). However,
[Pd(COD)Cl2] showed the best activity to give product 4a in the
best yield (73 %; Table 2, entry 5). It is worth mentioning that
this reaction barely proceeded without TBAB (Table 2, entry 8).
We have previously reported that the active palladium species is
Pd(0) in this kind of catalytic system and it is present in the form
of nanoparticles,[12,13] TBAB played a key role to stabilize the Pd
nanoparticles or maintain the lifetime of Pd species.
9
NaOH
KOtBu
LiOtBu
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
DMA
58
10
11
12
13
14
15
16
17
18
19
20
DMA
38
DMA
Trace
69
DMF
Ortho-xylene
NMP
40
73
Toluene
1,4-dioxane
n-butanol
NMP
24
64
Based on the optimization of reaction condition, the following
reactions were performed with [Pd(COD)Cl2] (2-4 mol%) as
catalyst, K3PO4 or K2CO3 (2 equiv) as base and TBAB (1 equiv)
Trace
59
o
as additive under nitrogen at 120 C. The scope of this one-pot
NMP
41
reaction was explored under the optimized reaction condition. At
first, the reaction of double molecular 2-methyl-1-butenyl ethers
was tested (Scheme 3). For the substrate without substituent on
the aromatic ring, the desired product 4a was formed in up to 62 %
yield. Obviously, chloro group on the aromatic ring had a
negative effect and led to the low yields of desired products.
Moreover, the use of para-substituted aryl iodide resulted in a
little higher yield (4b) than meta-substituted aryl iodide (4c).
Next, the cross-coupling reaction between two different aryl
iodides was evaluated (Table 3). To our delight, when the 2-
iodo-1-(3-methylbut-3-enyloxy)benzene was used as substrate
1a, electron-donating (Me, OMe) and electron-withdrawing (F)
substituents on the aromatic ring of iodobenzene could drive the
reaction to form the desired products in good yields (Table 3,
entries 1-6). In general, electron-donating substituents, such as
methoxy and methyl groups, played the stronger promotional
role and caused higher yields (3b, 3c) than electron-withdrawing
counterparts (3e, 3f). Similarly, it was found that
NMP
18
[a] Reaction conditions: 1a (0.25 mmol), TBAB (0.25 mmol), Base (0.5 mmol),
Solvent (1 mL), [Pd(COD)Cl2] (2 mol%) under nitrogen for 24 h. [b] Yields are
determined by GC.
para-substituted and ortho-substituted aryl iodides gave higher
yields (3b, 3c, 3d) than meta-substituted aryl iodides (3h). In
addition, multi-substituted aryl iodide was also tolerated in this
system although a poor yield of 32 % was given (3g). In order to
further expand the scope, we turned our attention to variations
on the aromatic ring of the 2-methyl-1-butenyl ether. The
reactions of chloro-substituted 2-methyl-1- butenyl ether with
para-substituted iodobenzene recovered that the introduction of
a chloro group on the aromatic ring of 2-methyl-1-butenyl
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European Journal of Organic Chemistry
10.1002/ejoc.201601051
SHORT COMMUNICATION
Table 2. Effect of catalyst precursors on this domino reaction[a]
.
Entry
[Pd]
TBAB [equiv]
Yield [%][b]
1
2
3
4
5
6
7
8
PdCl2
1.0
1.0
1.0
1.0
1.0
1.0
1.0
0
49
Pd(OAc)2
Pd(dba)2
[Pd(C3H5)Cl]2
[Pd(COD)Cl2]
[Pd(PhCN)2Cl2]
no
68
32
43
73
53
0
[Pd(COD)Cl2]
Trace
[a] Reaction conditions: 1a (0.25 mmol), TBAB (0.25 mmol), K2CO3 (0.5
mmol), NMP (1 mL), [Pd] (2 mol%) at 120 oC under nitrogen for 24 h. [b]
Yields are determined by GC.
ether led to the sharply decreased yield of desired product
(Table 3, entries 9-13).
Scheme 3. Scope of the palladium-catalyzed C-H activation reaction of the
same substrates. Yields of isolated products.
So far, the exact reaction mechanism is not yet clear.
However, on the basis of these preliminary results and literature
reports,[3d,7,15,16] a possible pathway for this domino reaction was
depicted as shown in Scheme 4. The Pd(0) catalyst went
Table 3. Scope of the palladium-catalyzed C-H activation reaction of different
substrates[a]
.
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European Journal of Organic Chemistry
10.1002/ejoc.201601051
SHORT COMMUNICATION
Representative procedure for the synthesis of 3a: [Pd(COD)Cl2] (5.7 mg,
0.02 mmol), K3PO4 (2.0 mmol), TBAB (161 mg, 0.5 mmol) were added
into dried Schlenk tube with a magnetic bar and the tube was flushed
with dry nitrogen five times. Then, 1a (0.5 mmol), 2a (1.0 mmol) and
NMP (4 mL) were added successively into it. The mixture was stirred at
120 °C for 24 h. After standard workup procedures (see the Supporting
Information), the crude product was purified by silica gel chromatography,
and 3a was isolated as white solid (81.2 mg, 0.344 mmol, 69 %).
Acknowledgements
We gratefully acknowledge support from the Natural Science
Foundation of China (No. 21572137).
[a] Reaction conditions: Substrate 1 (0.5 mmol), Substrate 2 (1.0 mmol),
TBAB (0.5 mmol), K3PO4 (2.0 mmol), NMP (4.0 mL), [Pd(COD)Cl2] (4 mol%)
at 120 °C under nitrogen for 24 h. [b] Isolated yields. [c] Combined yield.
Regioisomeric ratio=1.1:1.
Keywords: C-H activation • Carbopalladation • Domino
reactions • Fused polycycles • Palladium
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Conclusions
In conclusion, we have reported
a simple and efficient
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palladium-catalyzed intermolecular domino reaction involving a
sequence of C-H activations. In this transformation, three new
C-C bonds were formed. This reaction provides an efficient way
to synthesize fused polycycles from simple starting materials. In
addition, this protocol avoided the application of phosphorus
ligands which are not friendly to the environment.
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12, 480; c) J. Zhou, J. He, B. Wang, W. Yang, H. Ren, J. Am. Chem.
Soc. 2011, 133, 6868; d) A. Bunescu, Org. Lett . 2015, 17, 334.
Experimental Section
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European Journal of Organic Chemistry
10.1002/ejoc.201601051
SHORT COMMUNICATION
SHORT COMMUNICATION
C-H activation
Hai-Yu He, Wei Wang, Xiao-Jun Yu, Jin
Huang, Lei Jian, Hai-Yan Fu, Xue-Li
Zheng, Hua Chen, and Rui-Xiang Li*
Page No.1 – Page No.5
A palladium-catalyzed intermolecular domino reaction involving a sequence of C-H
activations is reported. This reaction provides a simple and efficient method for the
synthesis of fused polycycles from simple starting materials.
Palladium-Catalyzed Domino
Reaction of Two Aryl Iodides
Involving C-H Activation Processes:
An Efficient Synthesis of Fused
Polycycles
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