Cycloaddition reactions of benzyne with olefins

Article abstract of DOI:10.1016/j.cclet.2014.09.013

Some novel cycloaddition reactions based on benzyne and olefins have been developed. These reactions were performed in the absence of a transition metal catalyst, and they displayed good yields. These cycloaddition reactions of benzyne with olefins provid

Full text of DOI:10.1016/j.cclet.2014.09.013

Chinese Chemical Letters 25 (2014) 1535–1539
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Original article
Cycloaddition reactions of benzyne with olefins
*
*
Zhao Chen, Xie Han, Jin-Hua Liang, Jun Yin, Guang-Ao Yu , Sheng-Hua Liu
Key Laboratory of Pesticide and 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:
Some novel cycloaddition reactions based on benzyne and olefins have been developed. These reactions
were performed in the absence of a transition metal catalyst, and they displayed good yields. These
cycloaddition reactions of benzyne with olefins provide effective routes for synthesizing benzocyclo-
butenes, biaryl compounds and 9,10-dihydrophenanthrene derivatives.
Received 4 June 2014
Received in revised form 27 July 2014
Accepted 26 August 2014
Available online 19 September 2014
ß 2014 Guang-Ao Yu and Sheng-Hua Liu. Published by Elsevier B.V. on behalf of Chinese Chemical
Society. All rights reserved.
Keywords:
Cycloaddition
Benzyne
Olefins
Benzocyclobutenes
Biaryl
9,10-Dihydrophenanthrene
1. Introduction
Benzyne is an extremely reactive intermediate [11], and has
been comprehensively used as
a building block in organic
Benzocyclobutenes are useful both as intermediates in the field
of organic synthesis and as structural elements in active
pharmaceutical compounds [1,2]. More importantly, they can
undergo thermal electrocyclic ring-opening to give ortho-xyly-
lenes that can then react in pericyclic reactions, such as Diels–
Alder cycloadditions [3–5]. These characteristics have been fully
exploited in the total synthesis of polycyclic natural products
[1,2]. Although benzocyclobutenes possess high synthetic value
themselves, hardly any general procedures exist for the prepara-
tion of functionalized benzocyclobutenes. This greatly restricts
their availability and their use as organic synthesis intermediates.
The biaryl structural motif and 9,10-dihydrophenanthrene
derivatives are dominant features and general structural units in
many pharmaceutically important and biologically active com-
pounds [6,7]. As a consequence, organic chemists have attempted
to exploit new and more efficient aryl–aryl bond-forming methods
for over a century [8]. Despite the variety of routes that have been
developed to synthesize aryl–aryl bonds, the most widespread
methods are transition-metal-mediated reactions [9,10]. Hence,
synthesizing biaryl compounds and 9,10-dihydrophenanthrene
derivatives in the absence of a transition metal catalyst remains an
important and significant project.
synthesis [12]. Nevertheless, its application has been limited
due to the strict reaction conditions for its preparation. With the
emergence of moderate preparation methods of arynes [13], it has
attracted a great deal of attention in the area of organic synthesis.
In this article, we report cycloaddition reactions of benzyne
with olefins. These cycloaddition reactions provide effective routes
for the synthesis of benzocyclobutenes, biaryl compounds and
9,10-dihydrophenanthrene derivatives in the absence of a transi-
tion metal catalyst. Moreover, these reactions display good yields.
2. Experimental
The benzyne precursor 1a was prepared using the known
procedures [13]. Commercially available CsF, norbornadiene,
norbornene, vinyl butyl ether, methyl acrylate, ethyl acrylate,
styrene, trans-stilbene, indene and all reagents were used without
further purification. The 1H NMR and 13C NMR spectra were
acquired on American Varian Mercury Plus 400 spectrometer
(400 MHz). The 1H NMR spectra are reported as follows: chemical
shift in ppm (d) relative to the chemical shift of TMS at 0.00 ppm,
integration, multiplicities (s = singlet, d = doublet, t = triplet,
m = multiplet), and coupling constant (Hz). 13C NMR chemical
shifts are reported in ppm (d) relative to the central line of the
triplet for CDCl3 at 77 ppm. EI-MS was obtained using a Thermo
Scientific DSQII. Elemental analyses (C, H) were performed by the
Microanalytical Services, College of Chemistry, CCNU. The X-ray
crystal-structure determinations of 1c, 8c and 9c were obtained on
*
Corresponding authors.
E-mail addresses: chshliu@mail.ccnu.edu.cn (G.-A. Yu),
yuguang@mail.ccnu.edu.cn (S.-H. Liu).
http://dx.doi.org/10.1016/j.cclet.2014.09.013
1001-8417/ß 2014 Guang-Ao Yu and Sheng-Hua Liu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.

1536
Z. Chen et al. / Chinese Chemical Letters 25 (2014) 1535–1539
a
Bruker APEX DUO CCD system. Column chromatographic
(t, 1H, J = 4 Hz), 3.73 (d, 3H, J = 8 Hz), 3.48 (d, 2H, J = 4 Hz). These
separations were carried out on silica gel (200–300 mesh). TLC
was performed using commercially prepared 100–400 mesh silica
gel plates (GF254) and visualization was effected at 254 nm.
data are in good agreement with literature values [14].
Compound 6c: Light yellow oil. 1H NMR (400 MHZ, CDCl3):
d
7.26–7.23 (m, 2H), 7.18 (d, 1H, J = 4 Hz), 7.10 (t, 1H, J = 8 Hz), 4.30
(t, 1H, J = 4 Hz), 4.22–4.17 (m, 2H), 3.47 (t, 2H, J = 4 Hz), 1.32–1.27
(m, 3H). 13C NMR (100 MHZ, CDCl3):
d 171.94, 144.01, 142.71,
2.1. General synthetic procedure for 1c
127.91, 127.09, 122.67, 122.23, 60.58, 45.74, 33.68, 14.04. EI-MS:
m/z 176 [M]+. Anal. Calcd. for C11H12O2: C, 74.98; H, 6.86. Found: C,
74.91; H, 6.91.
The mixture of o-(trimethylsilyl)phenyl triflate (3 mmol,
2.0 equiv.), norbornadiene (1.0 equiv.), and anhydrous CsF
(6.0 equiv.) was soluted in dried CH3CN (15 mL). Then, the
resulting mixture was stirred at room temperature for 12 h. After
the reaction completed, 20 mL of water was added to the mixture,
and then extracted with CH2Cl2 (3Â 20 mL), and dried over
anhydrous Na2SO4 and concentrated under reduced pressure. The
residue was purified by column chromatography on silica gel
(eluent: petroleum ether) to afford the desired product 1c.
Compound 1c: White solid, mp: 121.8–122.5 8C. 1H NMR
2.4. General synthetic procedure for 7c
The mixture of o-(trimethylsilyl)phenyl triflate (1.5 mmol,
3.0 equiv.), styrene (1.0 equiv.), and anhydrous CsF (9.0 equiv.)
was soluted in dried 1,4-dioxane (5 mL). Then, the resulting
mixture was stirred at 110 8C for 12 h. After the reaction
completed, 20 mL of water was added to the mixture and then
extracted with CH2Cl2 (3 Â 20 mL), and dried over anhydrous
Na2SO4 and concentrated under reduced pressure. The residue was
purified by column chromatography on silica gel (eluent:
petroleum ether/CH2Cl2) to afford the desired product 7c.
(400 MHZ, CDCl3): d 7.19 (t, 4H, J = 4 Hz), 7.01–6.99 (m, 4H), 3.29 (s,
4H), 2.38 (s, 2H), 0.76 (s, 2H). 13C NMR (100 MHZ, CDCl3):
d 146.36,
127.32, 121.96, 49.41, 37.28, 26.04. EI-MS: m/z 244 [M]+. Anal.
Calcd. for C19H16: C, 93.40; H, 6.60. Found: C, 93.48; H, 6.55.
Compound 7c: Light yellow oil. 1H NMR (400 MHZ, CDCl3):
7.75 (d, 2H, J = 8 Hz), 7.32–7.27 (m, 3H), 7.24 (d, 3H, J = 4 Hz), 2.89
d
2.2. General synthetic procedure for 2c
(d, 4H, J = 12 Hz). 13C NMR (100 MHZ, CDCl3):
d 137.13, 134.30,
The mixture of o-(trimethylsilyl)phenyl triflate (1 mmol,
1.0 equiv.), norbornadiene (2.0 equiv.), and anhydrous CsF
(3.0 equiv.) was soluted in dried CH3CN (15 mL). Then, the
resulting mixture was stirred at room temperature for 12 h. After
the reaction completed, 20 mL of water was added to the mixture,
and then extracted with CH2Cl2 (3Â 20 mL), and dried over
anhydrous Na2SO4 and concentrated under reduced pressure. The
residue was purified by column chromatography on silica gel
(eluent: petroleum ether) to afford the desired product 2c.
127.99, 127.22, 126.82, 123.56, 28.88. EI-MS: m/z 180 [M]+. Anal.
Calcd. for C14H12: C, 93.29; H, 6.71. Found: C, 93.25; H, 6.76.
2.5. General synthetic procedure for 8c
The mixture of o-(trimethylsilyl)phenyl triflate (3 mmol,
3.0 equiv.), trans-stilbene (1.0 equiv.), and anhydrous CsF
(9.0 equiv.) was soluted in dried CH3CN (15 mL). Then, the
resulting mixture was stirred at room temperature for 12 h. After
the reaction completed, 20 mL of water was added to the mixture,
and then extracted with CH2Cl2 (3Â 20 mL), and dried over
anhydrous Na2SO4 and concentrated under reduced pressure.
The residue was purified by column chromatography on silica
gel (eluent: petroleum ether/CH2Cl2) to afford the desired
product 8c.
Compound 2c: Colorless oil. 1H NMR (400 MHZ, CDCl3):
d 7.20–
7.15 (m, 2H), 7.09–7.05 (m, 2H), 6.24 (d, 2H, J = 12 Hz), 3.15 (t, 2H,
J = 10 Hz), 2.78 (s, 2H), 1.27 (t, 1H, J = 8 Hz), 0.87 (d, 1H, J = 8 Hz).
13C NMR (100 MHZ, CDCl3):
d 146.13, 136.66, 127.00, 121.77, 47.55,
41.54, 41.34, 29.70. EI-MS: m/z 168 [M]+. Anal. Calcd. for C13H12: C,
92.81; H, 7.19. Found: C, 92.85; H, 7.12.
Compound 8c: White solid, mp: 165.8–166.6 8C. 1H NMR
2.3. General synthetic procedures for 3c–6c
(400 MHZ, CDCl3):
d
7.91 (d, 2H, J = 8 Hz), 7.36–6.96 (m, 16 H, aryl-
143.77, 137.06,
H), 4.43 (s, 2H). 13C NMR (100 MHZ, CDCl3):
d
The mixture of o-(trimethylsilyl)phenyl triflate (3 mmol,
2.0 equiv.), olefins (1.0 equiv.), and anhydrous CsF (6.0 equiv.)
was soluted in dried CH3CN (15 mL). The resulting mixture was
stirred at room temperature for 12 h. After the reaction completed,
20 mL of water was added to the mixture, and then extracted with
CH2Cl2 (3Â 20 mL), and dried over anhydrous Na2SO4 and
concentrated under reduced pressure. The residue was purified
by column chromatography on silica gel (eluent: petroleum ether)
to afford the desired products 3c–6c.
134.25, 129.95, 128.29, 128.13, 128.03, 127.54, 126.26, 123.52,
52.59. EI-MS: m/z 332 [M]+. Anal. Calcd. for C26H20: C, 93.94; H,
6.06. Found: C, 93.99; H, 6.02.
2.6. General synthetic procedure for 9c
The mixture of o-(trimethylsilyl)phenyl triflate (3 mmol,
3.0 equiv.), indene (1.0 equiv.), and anhydrous CsF (9.0 equiv.)
was soluted in dried CH3CN (15 mL). Then, the resulting mixture
was stirred at room temperature for 12 h. After the reaction
completed, 20 mL of water was added to the mixture, and then
extracted with CH2Cl2 (3Â 20 mL) and dried over anhydrous
Na2SO4 and concentrated under reduced pressure. The residue was
purified by column chromatography on silica gel (eluent:
petroleum ether/CH2Cl2) to afford the desired product 9c.
Compound 3c: Colorless oil. 1H NMR (400 MHZ, CDCl3):
d 7.20–
7.18 (m, 2H), 7.00–6.98 (m, 2H), 3.18 (s, 2H), 2.27 (s, 2H), 1.60–1.55
(m, 2H), 1.18 (d, 2H, J = 4 Hz), 0.97–0.94 (m, 1H), 0.85 (d, 1H,
J = 8 Hz). 13C NMR (100 MHZ, CDCl3):
d
146.50, 127.11, 121.81,
50.44, 36.57, 31.92, 27.79. EI-MS: m/z = 170 [M]+. Anal. Calcd. for
C
13H14: C, 91.71; H, 8.29. Found: C, 91.65; H, 8.33.
Compound 4c: Colorless oil. 1H NMR (400 MHZ, CDCl3):
d
7.28–
Compound 9c: White solid, mp: 89.7–90.6 8C. 1H NMR
7.23 (m, 2H), 7.14 (d, 2H, J = 8 Hz), 5.04 (s, 1H), 3.66–3.57 (m, 2H),
3.48–3.44 (m, 1H), 3.12 (d, 1H, J = 12 Hz), 1.65–1.57 (m, 2H), 1.44–
(400 MHZ, CDCl3): d 7.27–7.18 (m, 4H), 7.13–7.06 (m, 4H), 6.41–
6.37 (m, 1H), 6.11 (d, 1H, J = 8 Hz), 5.98–5.95 (m, 1H), 5.88 (d, 1H,
J = 8 Hz), 3.34 (d, 2H, J = 20 Hz), 1.83 (d, 1H, J = 8 Hz), 1.64–1.61 (m,
1H). 13C NMR (100 MHZ, CDCl3):
d 148.56, 145.94, 143.91, 142.76,
131.37, 128.24, 127.80, 127.69, 127.57, 125.88, 125.00, 124.32,
122.01, 121.59, 121.43, 120.95, 60.21, 52.79, 52.51, 45.68,
45.44. EI-MS: m/z = 268 [M]+. Anal. Calcd. for C21H16: C, 93.99;
H, 6.01. Found: C, 93.91; H, 6.06.
1.39 (m, 2H), 0.94 (t, 3H, J = 6 Hz). 13C NMR (100 MHZ, CDCl3):
d
146.30, 142.54, 129.18, 126.91, 123.44, 122.70, 68.63, 38.63, 31.95,
19.37, 13.90. EI-MS: m/z 176 [M]+. Anal. Calcd. for C12H16O: C,
81.77; H, 9.15. Found: C, 81.81; H, 9.09.
Compound 5c: Light yellow oil. 1H NMR (400 MHZ, CDCl3):
d
7.26–7.24 (m, 2H), 7.18 (d, 1H, J = 4 Hz), 7.11 (d, 1H, J = 4 Hz), 4.32

Z. Chen et al. / Chinese Chemical Letters 25 (2014) 1535–1539
1537
Table 1
Optimization of [2 + 2] cycloaddition reaction of benzyne with norbornadienea
Table 2
[2 + 2] Cycloaddition reaction products of benzyne with olefins.a
Entry
1
Olefin
Product
Yield (%)b
TMS
OTf
CsF, CH3CN
12 h
+
75
.
1b
1c
1b
1a
1c
2c
3c
Entry
Molar ratio of 1a/1b/CsF
Temp (oC)
Yieldb
2
3
73c
85
1
2
3
4
5
6
2/2/2
2/1/2
2/1/4
2/1/6
2/1/6
2/1/6
25
25
25
25
50
90
17%
43%
71%
75%
61%
21%
1b
2b
4
78
a
Reactions performed on 0.5 mmol scale, 5 mL of the solvent.
Isolated yield.
b
O
O
3b
4b
4c
5c
5
6
81
83
O
O
3. Results and discussion
O
O
O
O
O
We initially examined the [2 + 2] cycloaddition reaction of
benzyne and norbornadiene using 2.0 equiv. of compound 1a,
2.0 equiv. of 1b and 2.0 equiv. of CsF at 25 8C in anhydrous
acetonitrile (see Table 1, entry 1), the desired [2 + 2] cycloaddition
product 1c was obtained in a yield of 17%. In addition, we were able
to grow a single crystal of 1c, and its structure was confirmed by X-
ray crystallography (Fig. 1a). Subsequently, we altered the molar
ratio of the reactants and, as shown in Table 1, a higher yield was
observed when the proportion of 1b was reduced from 2.0 to
1.0 equiv. (Table 1, entry 2). Increasing yields were also obtained
when we increased the amount of CsF (Table 1, entries 3–4).
Further studies concentrated on the effect of temperature. Data in
Table 1 (entries 5 and 6) show that the reaction is less effective at
higher temperatures. Therefore, the best result (75% yield of [2 + 2]
cycloaddition reaction product 1c) was obtained using 1a
(2.0 equiv.), 1.0 equiv. of 1b, 6.0 equiv. of CsF in acetonitrile at
25 8C for 12 h.
O
5b
6c
a
Reaction conditions: o-(trimethylsilyl)phenyl triflate (2.0 equiv., 3.0 mmol),
olefin (1.0 equiv.), CsF (6.0 equiv.), CH3CN, 25 8C, 12 h.
b
Isolated yields.
c
o-(Trimethylsilyl)phenyl triflate (1.0 equiv., 1.0 mmol), olefin (2.0 equiv.), CsF
(3.0 equiv.), CH3CN, 25 8C, 12 h.
Scheme 1. Cycloaddition reactions of benzyne with trans-stilbene.
Using this optimized set of reaction conditions, we then tested
other [2 + 2] cycloaddition reactions of benzyne and olefins
(Table 2). It was determined that other olefin substrates, including
norbornene 2b, vinyl butyl ether 3b, methyl acrylate 4b, ethyl
acrylate 5b, could also smoothly undergo a [2 + 2] cycloaddition
reaction with yields ranging from 78% to 85% (Table 2, entries 3–6).
In addition, we obtained the product 2c involving a single double
bond [2 + 2] cycloaddition reaction of benzyne and norbornadiene
in a yield of 73% using 1.0 equiv. 1a, 2.0 equiv. 1b and 3.0 equiv. CsF
at 25 8C in anhydrous acetonitrile (Table 2, entry 2).
3.0 equiv. of 6b and 9.0 equiv. of CsF at 25 8C in anhydrous
acetonitrile (Table 3, entry 1). Subsequently, we attempted to
optimize the molar ratios of the reactants. As can be seen in Table 3,
increasing yields were observed as the quantity of 1b was reduced
from 3.0 equiv. to 1.5 equiv., then to 1.0 equiv. under the same
conditions (Table 3, entries 2–3). Subsequent studies focused on
the effects of solvent and temperature. Entries 4–7 of Table 3
demonstrate that the best reaction condition used dioxane as
solvent. Simultaneously, we also noticed that higher temperatures
produced increasing yields (Table 3, entries 8–9). According to the
above optimizations, the best result (87% yield of the biaryl
Next, biaryl compound 7c was obtained when we carried out
the reaction of benzyne with styrene using 3.0 equiv. of 1a,
Fig. 1. The single crystal structure of compound 1c (a), 8c (b) and 9c (c) (hydrogen atoms are omitted for clarity).

1538
Z. Chen et al. / Chinese Chemical Letters 25 (2014) 1535–1539
Scheme 2. Proposed mechanism of the reaction.
1.0 equiv. of 8b and 9.0 equiv. of CsF at 25 8C in anhydrous
acetonitrile (Scheme 3). The synthesis of product 9c is the result of
a [2 + 4] cycloaddition and then [2 + 2] cycloaddition reaction of
benzyne. The structure of compound 9c has also been determined
by X-ray crystallography (Fig. 1c).
4. Conclusion
In summary, some novel and significant cycloaddition reactions
and products based on the reactions of benzyne and olefins have
been developed. These cycloaddition reactions display good yields,
even in the absence of a transition metal catalyst. These reactions
of benzyne with olefins provide efficient methods for the synthesis
of benzocyclobutenes, biaryl compounds and 9,10-dihydrophe-
nanthrene derivatives.
Scheme 3. Cycloaddition reactions of benzyne with indene.
compound 7c) was obtained using 1a (3.0 equiv.), 1.0 equiv. of 6b,
9.0 equiv. of CsF at 110 8C in anhydrous dioxane.
In later work, we obtained the remarkable cycloaddition
product 8c in 62% yield when we examined the reaction of
benzyne and trans-stilbene using 3.0 equiv. of 1a, 1.0 equiv. of 7b
and 9.0 equiv. of CsF at 25 8C in anhydrous acetonitrile (Scheme 1).
The possible mechanism for this reaction is shown in Scheme
2. The [2 + 4] cycloaddition reaction of trans-stilbene with benzyne
generated from o-(trimethylsilyl)phenyl triflate resulted in the
generation of intermediate 1, which can add to another molecule of
electrophilic benzyne in a concerted-ene reaction leading to the
formation of the target product. However, the [2 + 4] cycloaddition
reaction of cis-stilbene with benzyne can not be carried out due to
the presence of the space steric hindrance. Therefore, we were not
able to obtain the corresponding cycloaddition product under the
same reaction conditions using cis-stilbene as substrate. The
structure of compound 8c was determined by X-ray crystallogra-
phy (Fig. 1b).
Acknowledgments
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).
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Reactions performed on 0.5 mmol scale, 5 mL of the solvent.
b
c
Isolated yield.
NR: No reaction.

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1539
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