Catalytic amounts of CBr4 mediated dehydrogenative coupling of isochromans with aromatic ketones

Article abstract of DOI:10.1039/c4cc09922b

In the presence of catalytic amounts of CBr₄ (a metal-free mediator), an unexpected oxidative dehydrogenative coupling of isochromans with ketones occurred to construct new C^sp3-C^sp3 bonds. The reactions were performed und

Full text of DOI:10.1039/c4cc09922b

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DOI: 10.1039/C4CC09922B
ARTICLE TYPE
Catalytic amounts of CBr Mediated Dehydrogenative Coupling of
4
Isochromans with Aromatic Ketones
a
Congde Huo,* Mingxia Wu, Fengjuan Chen, Xiaodong Jia, Yong Yuan and Haisheng Xie
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
In the presence of catalytic amounts of CBr
4
(a metal-free
4
amounts of CBr without using any metal catalyst under air
mediator), an unexpected oxidative dehydrogenative coupling 50 atmosphere. The use of catalytic amounts of very stable metal-
sp3
of isochromans with ketones occurred to construct new C
C
-
free mediator instead of complex metal involved catalyst systems
has many advantages such as low cost and easy handling.
sp3
bond. The reactions were performed under simple
1
0
solvent-free aerobic conditions.
1
O
O
O
O
Conditions A - E
Carbon-carbon bond forming reactions are of fundamental
interest and great significance in organic synthesis. In the past
few years, oxidative dehydrogenative coupling, namely the direct
coupling of two different C−H bonds, has gained significant
attention since this strategy presented an atom-economic and
concise way to construct complex molecules from simple starting
+
R2
R2
R1
R1
3
2
DDQ (120 mol%), N2
1
2
2
3
3
4
4
5
0
5
0
5
0
5
A
2
006, Li's work
Cu(OTf)2 (5 mol%), InCl3 (5 mol%), NHPI (20 mol%), O2
009, Li's work
1
materials. Most of the oxidative dehydrogenative coupling
3
B
C
D
E
reactions involve the activation of the sp C-H bond adjacent to
2
2
the nitrogen atom. On the contrary, so far, much few catalyst
Cu(OTf)2 (10 mol%), T BF4- (120 mol%), TFA (20 mol%), H2O (10 mol%)
+
systems have been developed to the activation of corresponding
3
3,4
less reactive sp C-H bonds next to an oxygen atom. For
example, through literature, there have been only four published
cases involving the oxidative dehydrogenative coupling between
2011, Mancheno's work
MnO2 (300 mol%), CH3SO3H (excess), Air
2013, Lou's work
4
isochromans and simple ketones until now. This reaction was
first reported by Li et al in 2006 using 2,3-dichloro-5,6-
CBr4 (20 mol%), Air
dicyanobenzoquinone (DDQ, 120 mol %) as the promoter under
4
a
This work, catalytic amouts of metal-free mediator
nitrogen atmosphere. They also developed another variant of the
above reaction using Cu(OTf) (5 mol %) and InCl (5 mol %) as
2
3
Scheme 1. CDC Reaction of Isochromans with Ketones
catalysts in the presence of N-hydroxyphthalimide (NHPI, 20
4
b
mol %) under oxygen atmosphere after three years. Recently, in 55 Very recently, we discovered unprecedented auto-oxidative
2
011 and 2013, two similar approaches were developed
dehydrogenative coupling of glycine derivatives with indoles and
auto-oxidative Povarov/aromatization tandem reaction of glycine
derivatives with olefins. The reactions were performed in the
absence of any redox-active catalyst and any chemical oxidant
respectively by Mancheño et al using Cu(OTf) (10 mol %) as the
2
+
-
6
catalyst and TEMPO oxoammonium salt (T BF
4
, 120 mol %) as
the oxidant and by Lou et al using manganese dioxide (MnO2,
300 mol %) and methanesulfonic acid (CH SO
4
c
H, large excess) 60 under mild conditions and only organic solvents and atmosphere
3
3
4
d
as oxidation system under aerobic conditions . Although these
examples have achieved notable progress in this area, metal
complex involved catalyst systems and stoichiometric or more
amounts of chemical oxidants were always necessary in these
air were required. Encouraged by the above interesting results,
we evaluated the auto-oxidative transformation using benzylic
ethers as substrates because cyclic benzylic ethers, such as
isochromans, are core units of a number of bioactive compounds
methods. Therefore, the development of a simple and efficient 65 and they are structurally interesting and pharmaceutically
method only using catalytic amounts of metal-free mediator for
this reaction is highly desired.
7
valuable. However, the oxidation of corresponding less reactive
C-H bonds next to an oxygen atom were not successful under
these auto-oxidation reaction conditions. Our previous
investigations revealed that dichloroethane (DCE) was crucial for
For many years, carbon tetrabromide (CBr ) has been used for
4
5
organic transformations occasionally. In this paper, CBr
4
has
been found for the first time to show good reactivity for cross- 70 the auto-oxidative coupling of glycine derivatives. This
dehydrogenative coupling (CDC) reactions. We described a
highly efficient oxidative dehydrogenative coupling reaction
between isochromans and simple ketones mediated by catalytic
information enlightened us to screen other halogen-containing
reagents. To begin this study, we chose isochroman 1a and
acetophenone 2a as the model substrates to search for potential
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[journal], [year], [vol], 00–00 | 1

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Page 2 of 4
sp3
sp3
mediator and suitable reaction conditions. Surprisingly, C -C
coupling product 3aa was obtained in high yield (Scheme 2).
bond coupling compound 3aa was produced in high yield (75 %)
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DOI: 10.1039/C4CC09922B
when 20 mol % of CBr was used (Table 1, entry 6). Both
4
4
increasing and decreasing CBr loading resulted in lower yields
5
(Table 1, entries 10-12). No improvement of the transformation
were observed when pure oxygen gas was used instead of air
(
Table 1, entry 13). Further studies indicated that the yields
decreased with lower or higher reaction temperature (Table 1,
entries 14-16).
O
O
[Hal]
+
1
a
Ph
Ph
2a
Neat
3
aa
O
O
Entry
[Hal]
Loading
Atmosphere
Temperature
Yield [%]
1
2
3
4
5
6
7
8
9
DCE
DBE
NBS
NIS
20 mol%
20 mol%
20 mol%
20 mol%
20 mol%
20 mol%
20 mol%
20 mol%
20 mol%
5 mol%
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
O2
Air
Air
Air
100 o
100 o
100 o
100 o
100 o
100 o
100 o
100 o
100 o
100 o
100 o
100 o
100 o
r.t.
C
C
C
C
C
C
C
C
C
C
C
C
C
0
9
38
40
33
75
41
8
DBDMH
CBr4
CHBr3
CH2Br2
Br2
36
42
71
66
65
50
66
71
1
1
1
1
1
1
1
0
1
2
3
4
5
6
CBr4
CBr4
10 mol%
30 mol%
20 mol%
20 mol%
20 mol%
20 mol%
CBr4
CBr4
CBr4
CBr4
80 o
C
CBr4
120 o
C
1
0
a
b
Reaction conditions: 1a (1.5 mmol), 2a (0.5 mmol), 48 h. Yields of the
isolated product. DCE = dichloroethane. DBE = dibromoethane. NBS =
N-Bromosuccinimide. NIS = N-Iodosuccinimide. DBDMH = 1,3-
dibromo-5,5-dimethylhydantoin.
1
5
Table 1. Halogen-containing reagents mediated CDC reaction of
a,b
isochroman with acetophenone
Under the optimized conditions, we probed the scope and
generality of both isochromans and ketones for this CBr
4
mediated dehydrogenative coupling (Table 2). Initially, we
investigated different substituted aryl ketones. Various ketones
2
2
3
3
4
0
5
0
5
0
(
Table 2, 3aa-3at) with electron-donating groups or electron-
withdrawing groups were all suitable substrates in this
transformation. The ketones with ortho or meta substituents
delivered the corresponding alkylated isochromans in good yields
(Table 2, 3ag-3an), illustrating that steric hindrance played a
poor role in the reaction. The preparation of halogen atoms
bearing products makes this methodology more useful for further
transformations (Table 2, 3ad, 3ae, 3ag, 3aj-3an, 3ap).
Especially, bearing of fluorine atoms into organic compounds
could produce meaningful changes in its chemical or
a
Standard reaction conditions: 1 (1.5 mmol), 2 (0.5 mmol), CBr
4
(0.1
o
b
4
5
mmol), neat, air, 100 C, 48 h. Isolated Yields of the isolated products.
a,b
4
Table 2. CBr -Mediated CDC Reaction of Isochromans with ketones
8
pharmacological properties. The procedure was also successfully
applied for hetero aromatic ketones and polycyclic aromatic
ketones (Table 2, 3aq-3at), and their corresponding products
were obtained at good yields. Furthermore, we explored the
different cyclic benzylic ethers. 3-Methylisochroman, 4-
methylisochroman and 6,7-dimethoxyisochroman all gave the
corresponding products in high yields. It is worth noting that, ,
5
0
4
Scheme 2. CBr -Mediated Decarboxylative Alkylation of Isochromans
To investigate the mechanism of this transformation, some
control experiments were carried out. First of all, the reaction of
1a and 2a under argon atmosphere were investigated (Table 3,
Entry 2). The designed product 3aa were achieved in 28 % yield.
9
unlike Mancheño group's previous report, when -keto ester 4
were used as carbon nucleophile instead of ketones, the 55 This result indicates that CBr can initiate this oxidative coupling
4
decarboxylative alkylation of isochroman occurred under this
CBr promoted process. The corresponding decarboxylative
reaction without oxygen with lower efficiency. At the same time,
the reaction of 1a with 2a under an argon atmosphere resulted in
a significant drop in yield, thus indicating that oxygen is crucial
4
2
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for the reaction. Secondly, the reactions of 1a and 2-bromo-1-
phenylethan-1-one (A) in the presence of 0.2 equivalents of CBr
Table 3, Entry 3) and in the absence of CBr (Table 3, Entry 4)
reaction. Further application of this CBr
will be reported in due course.
4
-mediated methodology
4
View Article Online
DOI: 10.1039/C4CC09922B
(
4
were investigated respectively. The designed product 3aa was
achieved in 55% and 10 % yields. These results indicate that
Acknowledgements
5
4
5
We thank the National Natural Science Foundation of China
compound A should be an important intermediate in this CBr
4
(
(
21262029) and the Fok Ying Tong Education Foundation
141116) for financially supporting this work.
mediated process. Radical trapping experiment was also
conducted by employing TEMPO as a radical scavenger. No
designed product 3aa was obtained in the standard reaction of 1a
with 2a (Table 3, Entry 5). This result suggests that the present
reaction includes a radical process.
Notes and references
1
0
a
Key Laboratory of Eco-Environment-Related Polymer Materials
5
5
0
5
Ministry of Education; College of Chemistry and Chemical Engineering,
Northwest Normal University, Lanzhou, Gansu 730070, China. E-mail:
huocongde1978@hotmail.com
†
Electronic Supplementary Information (ESI) available: [Experimental
procedures and characterization data]. See DOI: 10.1039/b000000x/
1
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6
7
7
8
8
9
9
5
0
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0
5
Our proposed reaction mechanism for this catalytic amounts of
sp3
sp3
CBr4 induced C -C
coupling is illustrated in Scheme 3.
initially react to form 2-bromo-1-
Acetophenone 1a and CBr
4
2
2
3
0
5
0
phenylethan-1-one A. Then, a homolytic cleavage of C-Br bond
occurs under heating conditions to form radical B and bromine
radical. When the bromine radical is formed, it can abstract the
hydrogen atom from isochroman 1a to generate radical C,
coupling of radical B and C results in the desired product 3aa
(Path 1). On the other path, radical C can react with dioxygen to
provide the peroxide radical D. Peroxide radical D then abstracts
the hydrogen atom from isochroman 1a to form hydroperoxide E
and radical C. Chain propagation continues until all isochroman
a are consumed. Benzoxy cation F is then formed through an
acid catalyzed S 1 type procedure from hydroperoxide E. Finally,
benzoxy cation F can then be trapped with ketone 2a to afford the
desired product 3aa (Path 2).
2
2
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5
Scheme 3. Proposed Reaction Mechanism
Conclusions
1
00
4
In summary, we have demonstrated a novel CBr -mediated
dehydrogenative coupling between cyclic benzyl ethers and
ketones. The reactions were performed in simple solvent-free
aerobic conditions. Only catalytic amounts of CBr was used as a 105
promoter. This work also presents a new way to initiate radical
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