Copper-catalyzed intramolecular aryl-bicyclization of diynes with diaryliodonium salts: Via vinyl cations

Article abstract of DOI:10.1039/c6cc05735g

A novel protocol for the synthesis of polycyclic compounds from linear diynes and diaryliodonium salts has been realized. The reaction proceeded through Cu-catalyzed arylation of alkynes to generate two vinyl carbocation intermediates that subsequently reacted with arene groups to form fused rings containing diene moieties.

Full text of DOI:10.1039/c6cc05735g

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DOI: 10.1039/C6CC05735G
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Copper‐catalyzed intramolecular aryl‐bicyclization of diynes with
diaryliodonium salts via vinyl cations
fReceived 00th January 20xx,
Accepted 00th January 20xx
Guohua Wang, Chao Chen*, and Jing Peng
DOI: 10.1039/x0xx00000x
www.rsc.org/
A novel protocol for synthesis of polycyclic compounds from linear
diynes and diaryliodonium salts has been realized. The reaction
proceeded through Cu‐catalyzed arylation of alkyne to generate
vinyl carbocation intermediates twice that subsequently reacted
with arene group to form fused ring containing diene moiety.
Ring‐fused backbones widely exist in natural products,
pharmaceuticals and opto‐electronic materials (Fig. 1).1 Thus
the methodology of constructing ring‐fused backbones are
very worthy of being studied. Various cyclization reactions,
such as Diels‐Alder reaction with alkenes or alkynes, transition‐
metal catalyzed single or multiple carbometallation reactions
have been well established to synthesize polycyclic
compounds.2 In the past few decades the electrophilic
cyclization has proven to be most efficient ways to build up
3,4
polycyclic compounds.
As a result, various electrophiles
were applied for the synthesis of cyclic compounds. This
electrophiles triggered reaction featured mild reaction
conditions, simple operation and easily available linear
substrates. Nevertheless, the electrophiles used to initiate the
cyclization were narrowly limited to H+, Lewis acids, halogen
and phosphine derivatives.3a,4 By utilizing linear diynes,
previous works showed various ways to construct ring‐fused
backbones such as metal‐promoted cycloaddition (Scheme
1a).5 Recently, cyclization using highly reactive boron reagents
has also received much attention (Scheme 1b, c). 6,1c
Scheme 1 Synthesis of specified ring‐fused backbones.
However, the employment of C‐electrophiles to promote
poly‐cyclization is rarely reported, but undoubtedly important.
Herein, we would like to report a poly‐cyclization initiated by
C‐electrophiles, generated from diaryliodonium salts (Scheme
1d). The diaryliodonium salts, as environmentally friendly
benign C‐electrophiles, are often used to react with alkenes
and alkynes to form functionalized or complex carbocations,
which underpin a wide range of chemical transformations.7,8
The progress disclose a novel and efficient pathway to
construct polycyclic molecules with diaryliodonium salts.
Based on precedent studies of cyclization reactions
triggered by diaryliodonium salts,9,10 we envisioned that the
Fig. 1 Significance of ring‐fused backbones.
a. Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology (Ministry
of Education), Department of Chemistry, Tsinghua University, Beijing, 100084,
China. E‐mail: chenchao01@mails.tsinghua.edu.cn
†Electronic Supplementary Information (ESI) available: Experimental procedures,
full characterization including 1H NMR and 13C NMR datas and spectras for all new
compounds and X‐ray crystal structure of 3ae. CCDC 1471734. For ESI and
linear diyne substrates
1 could form the vinyl carbocation
twice during the electrophilic cyclization which consequently
gives possibility to construct ring‐fused backbones. The ring‐
crystallographic
data
in
CIF
or
other
electronic
format
See
fused backbone of desired product
3 was found in natural
DOI: 10.1039/x0xx00000x
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products such as insecticidal agent.11 We developed a novel
and simple protocol to synthesize such polycyclic
hydrocarbons by using the benign C‐electrophile: Ar2IOTf. It is
notable that the designed substrates could be extended to 1,7‐
diyne which results in azulene derivatives and the target
With the optimal reaction condition in hand,VtiehweAsrtcicolepOenlionef
diaryliodonium salts with different substit
ring were explored. As shown in Scheme 2, the aromatic rings
bearing electron‐withdrawing groups such as F, Cl, Br were
tolerated well in the process (3ab‐3ad), and these untouched
halogen substituents render the cyclic‐products for further
transformations. Likewise, substrates containing electron‐
D
O
u
I:
e
1
n
0
t
.1
s
0
o
39
n
/C
t
6
h
C
e
C
p
0
h
57
enyl
3
5
G
product 3 is aryl‐functionalized (Scheme 1d).
Initially, we attempted to perform the reaction by treating
1,8‐di‐p‐tolyl‐1,7‐octadiyne 1a and diaryliodonium triflate 2a
with CuBr (10 mol%) in dry dichloromethane at 80 oC for 12 h.
The reaction solution colour turned from colorless to yellow
and then black. The desired product was found trace in GC‐MS
(Table 1, entry 1). When additive Li2CO3 (1.2 eq.) was added to
the reaction, to our delight, the desired product azulene
derivative 3aa was observed in 65% yield (entry 2). In the
following trials, different solvents were applied to this
hydrocarbon cyclization reaction (entry 3‐7), and 3aa was
formed in a comparative higher yield of 73% (isolated 66%)
when dichloroethane (DCE) was used (entry 7). Prolonging
reaction time didn’t give any better results (entry 8). In
addition, several other additives were investigated in this
study (entry 9‐14), but most of them didn’t produce the
expected product. The results indicate that the base Li2CO3
could possibly promote the cyclization or neutralize the acid
generated in the reaction. Different copper salts were
screened for this reaction and CuBr proved to be the best one
(entry 15‐17). The product yield was not improved when
temperature altered (entry 18, 19). So far as we tried, the
optimal reaction condition is listed as entry 7 showed.
withdrawing groups such as trifluoromethyl (2h) and ester (2i
)
group were effectively converted to the expected products in
moderate yields. Moreover, substrates with electron‐donating
groups were tried. It turned out that substrate with the methyl
group (2a) was transformed smoothly under the standard
condition and substrate with methoxy group (2f) led to a low
yield which might be attributed to electronic effect. In the case
of para‐substitued bulky isobutyl group of the substrate (2g),
the yield was reduced to 40% (3ag). For substrates with meta‐
substitued methyl (2j), the product yield was reduced to 50%
(
3aj) compared to 3aa. Similarly, if substrate with ortho‐
substitued fluorine (2k) was used, the yield was dramatically
reduced to 29% (3ak). The results indicated that the steric
hindrance showed great effects on the outcome of the
cyclization products. To further confirm the structure of the
product, a single crystal of product 3ae was characterized by
XRD (Fig.2 CCDC 1471734).
Encouraged by the above study, the scope of diynes were
further explored by varying the substituents on the phenyl
moities. Under the optimized conditions for the amazing
intramolecular aryl‐bicyclization, other analogues of 1a with 4‐
Table 1 Optimization of reaction conditionsa
p-Tol
catalyst
additive
CH3
CH3
OTf
Tol
+
CH3
I
Tol
solvent
temp.
time
Tol
3aa
1a
entry
2a
temp(oC)
yield(%)b
catalyst
additive
solvent
time(h)
1
2
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
Cu(OTf)2
CuI
DCM
DCM
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
70
90
12
12
12
12
12
12
12
64
12
12
12
12
12
12
12
12
12
12
12
trace
65
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
t-BuOLi
LiPF6
3
CH2BrCH2Br
CHCl3
37
4
50
Mixed solventc
1,4-dioxane
5
58
6
trace
73(66)d
68
7
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
8
9
trace
trace
0
10
11
12
13
14
15
16
17
18
19
LiCl
LiBr
0
Cs2CO3
Na2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
trace
NRe
20
51
CuCl
CuBr
CuBr
56
61
Standard conditions: 1a (0.2 mmol), 2 (1.2 eq.), CuBr (10 mol%), Li2CO3 (1.2 eq.),
in the dichloroethane (2 mL) at 80 °C, 12 h under N2 atmosphere. Yields provided
above were isolated.
25
aUnless noted, reaction were performed with 1a (0.2 mmol), 2a (1.2 eq.),
catalyst (10 mol%), additive (1.2 eq.), in the solvent (2 mL) at the preceding
temperature. bNMR yield using trichloroethylene as an internal standard. c1
mL DCM and 1 mL DCE. disolated yield. eno reaction.
Scheme 2 Scope of copper‐catalyzed electrophilic cyclization of 1a with diaryliodonium
salts.
2 | J. Name., 2012, 00, 1‐3
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the target product 3la was obtained in 65% yield. VFioewrAdrtiiyclneeOn1limne
with two ester groups substituted on the 10th39/Cyi ldC0 73th5G
D
c
O
h
I:
a
1
i
0
n
.
,
e
6
e
C
o
5
f
e
product 3ma is very low on account of the ester groups
inhibiting the formation of the six‐membered cycles.
Interestingly, When diyne (n=1) with 4‐MeO‐substituent on
the phenyl ring (1n) was conducted under the optimal reaction
condition (Scheme 3), the corresponding product of 3na was
trace. Insteadly, a new product of 4na, arylated by one more
toluene group of 3na, was obtained in 22% yield or 61% yield
when more Ar2IOTf was used. When diyne with a weaker
electron‐donating group on the phenyl ring (1b) was studied,
4ba was also formed in 10% yield besides the main product
3ba. Likewise, when more Ar2IOTf was used, 4ba was
increased to 54% yield and 3ba was decreased to 43% yield.
The structure of 4ba was confirmed by COSY, HMQC, HMBC
spectroscopy (see supporting information). The arylation site
selectivity is in accordance with the reported literature. 12 the
reactivity of unsymmetrical diyne 1o was also designed. The
reaction 1o and 2a mainly afforded product 3oa in 72% yield,
which showed great site selectivity. When 2a was increased to
2.4 equivalent, product 4oa was formed in 25% yield.
Fig.2 Crystal structure of 3ae (CCDC No.: 1471734) .
CH3‐, 4‐F‐, 4‐Cl‐, and 4‐Br‐substituents on the phenyl ring also
worked well to give products 3ba
Moreover, the diynes with three carbons aliphatic chain such
as 1b 1d 1f 1h (n=1) were transformed to give the desired
product 3ba 3da 3fa 3ha in higher yields compared with 3aa
3ca 3ea 3ga (n=2). It was a delightful result that the product
‐3ha, respectively (Table 2).
,
,
,
,
,
,
,
,
,
yield of 3fa was greatly improved to 85% when Ar2IOTf was
increased to 2.4 equivalent. Diynes 1i and 1j proceeded the
reaction to form 3ia and 3ja in low yields, which was due to
the electronic and steric effect. When diyne 1k with 3‐Br‐
substituent on phenyl ring was conducted, both isomers of 3ka
and 3ka’ were formed by different reaction site during the
intramolecular cyclization. It didn’t make any difference to the
ratio of 3ka and 3ka’ by increasing the quantity of Ar2IOTf. It is
hard to isolate the two isomers. On the other hand, when the
aliphatic chain of the diyne was inserted by heteroatom (1l),
According to the above results, the final structure of
4 the
products were greatly affected by the electronic effect
because the fused benzene ring with electron‐donating group
was easier to be arylated by the Ar2IOTf.
It is precedented that the diaryliodonium salts could be
catalyzed by copper salt to generate reactive electrophilic
species Ar‐Cu(III) in situ, which is regarded as carbocation
equivalents that could easily be attacked by nucleophiles.7,13
Based on the above results, a plausible mechanism is proposed
for the intramolecular bicyclization reaction (Scheme 4,
exemplified with 1b). Ar‐Cu(III) is formed through electrophilic
addition of Cu(I) species by Ar2IOTf. Then Ar‐Cu(III) is attacked
Table 2 The scope investigation of diynea.
R1
R1
Cu[I] (10 mol%)
OTf
Tol
Li2CO3 (1.2 equiv)
+
I
Tol
DCE, 80 o
12 h, N2
C
R2
Tol
R2
by the alkynyl group of diyne to form intermediate I (favoured
n = 1 or 2
3
1b-m
2a
Substrate 1
Product 3 (yield b
)
Substrate 1
Product 3 (yield b
)
p-Tol
4-COOMe-Ph
CH3
CH3
COOMe
COOMe
Tol
Tol
CH3
COOMe
2-F-Ph
3ia, 19% c
3ba, 80% c
1b
1i
F
4-F-Ph
F
F
Tol
Tol
F
F
1c, n = 2
1d, n = 1
3ca, n = 2, 42%
3da, n = 1, 85% c
F
3ja, 36% c, d
1j
p-Tol
4-Cl-Ph
Cl
Cl
Tol
Tol
O
Tol
Tol
CH3
Cl
1e, n = 2
1f, n = 1
3ea, n = 2, 38%
3fa, n = 1, 66% (85% c, d
1l
3la, 65%
)
MeOOC
MeOOC
4-Br-Ph
p-Tol
Br
Br
Tol
Tol
MeOOC
MeOOC
Tol
Tol
Br
CH3
1g, n = 2
1h, n = 1
3ga, n = 2, 36%
3ha, n = 1, 64% c
1m
3ma, 19%
Br
Br
3-Br-Ph
Standard conditions: 1 (0.2 mmol), 2a, CuCl (10 mol%), Li2CO3 (In accordance with
2a), in the dichloroethane (2 mL) at 80 °C, 12 h under N2 atmosphere. Yields
provided above were isolated.
3-Br-Ph
Br
+
2a
Tol
Tol
3ka'
3ka
Br
1k
1.2 equiv 2a 3ka: 19% 3ka': 11% c
2.4 equiv 2a 3ka: 34% 3ka': 22% c
Scheme 3 New product 4 generated under standard condition.
a standard condition, b isolated yield, c CuCl was used instead of CuBr, d 2.4 eq.
diaryliodonium salts and Li2CO3 were used.
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3
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and easily attacked by the other alkynyl group in the same
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Friedel‐Crafts type reaction to produce the final product 3.
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,
When the fused benzene ring of
donating groups, a new product
further electrophilic substitution of product
3
4
is substituted by electron‐
would be formed through
. The additive
3
Li2CO3 might neutralize the acid generated in the reaction and
have some coordination effect during the cyclization.
According to the mechanism, the design of the diyne is artful
to proceed such intramolecular bicyclization.
In summary, with a properly designed substrate diyne, we
have developed a simple and efficient method to build up ring‐
fused backbones with diaryliodonium triflate reagents. This
aryl‐bicyclization was catalyzed by Cu(I) and the aryl group of
the diaryliodonium triflate reagents served as the electrophilic
agent. This strategy gave hint on the synthesis of complex
polycyclic compounds by consecutively forming several vinyl
cations.
This work was supported by National Natural Science
Foundation of China (21102080, 21372138, 21290194,
21221002 and 21032004) and the Fok Ying‐Tong Education
Foundation, China (Grant No. 151014).
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