Alder-ene reaction of aryne with olefins

Article abstract of DOI:10.1016/j.tetlet.2013.08.049

A novel intermolecular Alder-ene reaction based on aryne and olefins was developed. We performed this transformation under mild conditions such as at room temperature, and this reaction displayed high selectivity and good yields only in the presence of CsF. Hence, the intermolecular Alder-ene reaction of aryne with olefins provides an effective route to synthesize derivatives of olefins.

Full text of DOI:10.1016/j.tetlet.2013.08.049

Tetrahedron Letters 54 (2013) 5785–5787
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Tetrahedron Letters
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Alder-ene reaction of aryne with olefins
⇑
⇑
Zhao Chen, Jinhua Liang, Jun Yin , Guang-Ao Yu, Sheng Hua Liu
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, Wuhan 430079, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel intermolecular Alder-ene reaction based on aryne and olefins was developed. We performed this
transformation under mild conditions such as at room temperature, and this reaction displayed high
selectivity and good yields only in the presence of CsF. Hence, the intermolecular Alder-ene reaction of
aryne with olefins provides an effective route to synthesize derivatives of olefins.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 7 June 2013
Revised 23 July 2013
Accepted 15 August 2013
Available online 22 August 2013
Keywords:
Intermolecular
Alder-ene reaction
Aryne
Olefins
Derivatives
Olefins and derivatives of olefins play a very important role in
the synthesis of functional organic molecules.1–4 The substituted
allylarenes as one type of key synthetic intermediate have been
widely applied in the synthesis of biological drugs, natural prod-
ucts and functional molecules.5–7 Therefore, the exploration of effi-
cient strategies and methods to synthesize the allylarenes has been
an important topic. At present, some approaches have been re-
ported to synthesize the allylarene derivatives such as Friedel–
Crafts allylation, Heck coupling reaction of olefins with aryl ha-
lides, metal-mediated allylation of aryl nucleophiles, metal-pro-
moted cross coupling reaction of aryl halides with allyl
nucleophiles, and selective cross-coupling of organic halides with
allylic acetates.8 Although these methods could efficiently synthe-
size allylarenes and some functional derivatives, they usually suf-
fer from the expensive metal catalysts and higher temperature.
Hence, the development of a simple and mild reaction condition
and economic reaction is still significant and a challenging project.
Arynes are highly reactive intermediates,9 and have been com-
prehensively utilized as building blocks in organic synthesis.10
However, the rigorous reaction conditions for their preparation
greatly limited their application. With the emergence of moderate
preparation methods of arynes,11 they have attracted considerable
attentions in the field of synthetic application. Alder-ene reaction
is a kind of classic reaction to construct the carbon–carbon
bonds.12 Many reports based on Alder-ene reaction have been pub-
lished until now.
R
OTf
CsF
R
R
TMS
Scheme 1. The intermolecular ene reaction of aryne with olefins.
However, there are a few examples of aryne ene reactions, for
instance, the intramolecular aryne ene reactions13–15 and the inter-
molecular ene reaction of aryne and alkynes.16 To the best of our
knowledge, the intermolecular ene reaction of aryne with olefins
is still rather rare so far. Therefore, we were quite curious to clear
the situation of the reaction of olefin and aryne. Herein, we report
one type of intermolecular aryne ene reaction providing a straight-
forward access to some allylarene derivatives under mild reaction
conditions such as at room temperature, and this synthetic ap-
proach also revealed high selectivity and good yields. More impor-
tantly, this method is a catalyst-free reaction only in the presence
of CsF, moreover, it also displays a wide scope of substrates.
As shown in Scheme 1, the benzyne was formed using the 2-
(trimethylsilyl)phenyl trifluoromethanesulfonate as
a starting
material in the presence of CsF, which was subjected to Alder-
ene reaction with olefins to generate allylarene. In the initial stud-
ies, o-(trimethylsilyl)phenyl triflate 1a and cyclohexene 1b were
selected as substrates of model reaction in the presence of CsF. In
consideration of the easy formation of benzyne in CH3CN, we firstly
investigated this reaction under the condition of 1.0 equiv 1a,
1.0 equiv 1b, and 1.0 equiv CsF at 25 °C in anhydrous acetonitrile
⇑
Corresponding authors. Tel./fax: +86 027 67867725.
E-mail addresses: yinj@mail.ccnu.edu.cn (J. Yin), chshliu@mail.ccnu.edu.cn
(S.H. Liu).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.08.049

5786
Z. Chen et al. / Tetrahedron Letters 54 (2013) 5785–5787
Table 1
Table 2
Optimization of the intermolecular aryne ene reaction of olefinsa
Substrate scope for the intermolecular aryne ene reaction of olefinsa
OTf
CsF
+
TMS
Entry
1
Olefin
Product
Yieldb (%)
80
12 h
1a
1b
1c
1c
1b
2b
Entry
Molar ratio of 1a/1b/CsF
Temp (°C)
Solvent
1c
b
yield (%)
2
3
85
86
2c
3c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
1/1/1
2/1/1
3/1/1
1/2/1
1/3/1
1/4/1
1/4/2
1/4/3
1/4/4
1/4/4
1/4/4
1/4/4
1/4/4
1/4/4
1/4/4
1/4/4
25
25
25
25
25
25
25
25
25
25
25
25
50
70
90
110
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
THF
25
21
15
28
33
36
56
76
80
NRc
NRc
NRc
71
55
50
37
3b
4
77
4c
4b
5b
DCM
Dioxane
CH3CN
CH3CN
CH3CN
CH3CN
5
6
7
75
80
73
5c
6c
6b
7b
a
b
c
Reactions performed on 0.5 mmol scale, 5 mL of the solvent.
Isolated yield.
NR: no reaction.
7c
(Table 1, entry (1). Fortunately, the target molecule 3-phenyl-
cyclohexene (1c) was obtained in yield of 25%. Subsequently, we
tried to change the molar ratio of reactants. As can be observed
in Table 1, the decreasing yields were observed along with the
increasing of 1a from 1.0 equiv to 2.0 or 3.0 equiv under the same
condition. Simultaneously, a further Aldel-ene reaction between
excessive benzyne and product 1c was observed, to generate more
than once ene reaction products. Unfortunately, the reaction sys-
tem was so intricate that we could not obtain pure multiple ene
reaction products. Next, a higher yield (36%) was obtained when
the 4.0 equiv cyclohexene was used (Table 1, entries 4–6) com-
pared with entry 1. From these reactions, we found that 1) the
amount of benzyne is less than olefins; 2) the amount of cyclohex-
ene can obviously affect the yield of reaction. Subsequently, further
investigation was performed by changing the amount of CsF (en-
tries 7–9). An inspiring result that the yields were increasing along
with the increasing amount of CsF was observed, and the highest
yield of 80% can be afforded when 4.0 equiv were used in this sys-
tem, which indicated that a large amount of cesium fluoride is
8
9
75
76
8b
8c
9c
9b
10
88
10b
10c
a
Reaction conditions: o-(trimethylsilyl)aryl triflate (1.0 equiv, 1.0 mmol), olefin
(4.0 equiv), CsF (4.0 equiv), CH3CN, 25 °C, 12 h.
b
Isolated yields.
be compatible with this reaction and obtain products with rela-
tively good yields (73–80%, entries 5–8). Besides, 1-phenylcyclo-
hexene 9b, as a kind of substituted cyclic olefin, exhibited good
reactivity and afforded the expected ene reaction product in yield
of 76% (entry 9). It was worth noting that the perfect regioselectiv-
ity was observed with forming only a type of ene reaction product
when we used 2-methyl-2-butene 8b (entry 8) or 1-phenyl-
cyclohexene 9b (entry 9) as the reaction substrate. Finally, we
made use of 1,5-cyclooctadiene 10b, a type of dialkene, as the
substrate to test the reaction, and we were surprised to realize that
intermolecular ene reaction occurred at two olefin function groups
to provide product 10c in yield of 88% (entry 10). Furthermore, we
still gained the same product 10c when the benzyne precursor 1a
was excess.
In addition to the o-(trimethylsilyl)phenyl triflate 1a, other
substituted aryne precursors could undergo the intermolecular ar-
yne ene reaction of olefins in this methodology favorably as well
(Table 3). The 4,5-dimethylbenzyne precursor 2a, and the 1,3-ben-
zodioxole derivative 3a have all been examined under our optimal
condition. They formed the expected ene reaction products 11c,
12c, 13c, and 14c, respectively with yields ranging from 70–74%
indispensable. From these investigations, we found that
a
1:4:4 M ratio of the reactants 1a, 1b, and cesium fluoride was
the best stoichiometric ratio.
Subsequent studies focused on the effects of solvent and tem-
perature. From entries 10–12, the reaction can not work when
THF, dichloromethane, and dioxane were utilized as solvents.
Meanwhile, we also found that higher temperature will result in
the decrease of yields. According to the above studies, the best re-
sult (80% yield of 3-phenylcyclohexene 1c) was obtained by using
1a (1.0 equiv), 4.0 equiv of 1b, 4.0 equiv of CsF, 15 mL of acetoni-
trile at 25 °C for 12 h.
Followed the optimized condition, we then tested the scope of
this reaction using a variety of cyclic olefins and alkyl-olefins (Ta-
ble 2). It was found, except for cyclohexene, substrates of other
cyclic olefins, including cyclopentene 2b, cycloheptene 3b, and
cyclooctene 4b, could also occur this reaction smoothly in yields
ranging from 77% to 86% (entries 2–4). Additionally, under opti-
mized reaction conditions, the substituted chain olefins, including
methylene-cyclopentane 5b, 2,3-dimethyl-2-butene 6b, 2,3,3-
trimethylbutene 7b, and 2-methyl-2-butene 8b, were also able to

Z. Chen et al. / Tetrahedron Letters 54 (2013) 5785–5787
5787
Table 3
under moderate condition of reaction. The work provides an effi-
cient approach for the preparation of some allylarene derivatives.
Investigation of different arynes in the intermolecular aryne ene reaction of olefinsa
Entry
Benzyne
Olefin
Productb
Acknowledgments
OTf
The authors acknowledge financial support from the National
Natural Science Foundation of China (Nos. 20931006, 21072070,
21072071, 21272088), and the Program for Academic Leader in
Wuhan Municipality (No. 201271130441).
1
TMS
1b
2a
11c
, 71%
O
TMS
OTf
O
O
O
2
1b
5b
5b
Supplementary data
3a
12c
, 70%
OTf
TMS
TMS
OTf
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.
2013.08.049.
3
4
13c
, 73%
2a
O
O
O
O
References and notes
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14c
, 74%
3a
a
Reaction conditions: o-(trimethylsilyl)aryl triflate (1.0 equiv, 1.0 mmol), olefin
(4.0 equiv), CsF (4.0 equiv.), CH3CN, 25 °C, 12 h.
b
Isolated yields.
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H
R'
H
R'
R
R
R
+
R'
Scheme 2. The mechanism of intermolecular Alder-ene reaction based on aryne
and olefins.
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(entries 1–4). The mechanism of ene reaction of aryne with olefins
is similar to that of general ene reaction (Scheme 2).
In summary, a significant and selective procedure for the inter-
molecular ene reaction of aryne with olefins has been developed,
and this method has been shown to be tolerant of a wide variety
of substituted chain olefins and cyclic olefins with excellent yields
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