ZnCl2-catalyzed [4 + 2] benzannulation of 2-ethynylbenzaldehydes with alkynes: Selective synthesis of naphthalene derivatives

Article abstract of DOI:10.1016/j.jorganchem.2010.09.062

Zn-catalyzed [4 + 2] benzannulation of 2-ethynylbenzaldehydes with alkynes is described for the selective synthesis of naphthalene derivatives. In the presence of ZnCl₂, a variety of 2-ethynylbenzaldehydes underwent the [4 + 2] benzannulation reactions with alkynes to selectively afford the corresponding naphthalene derivatives in moderate to good yields.

Full text of DOI:10.1016/j.jorganchem.2010.09.062

Journal of Organometallic Chemistry 696 (2011) 352e356
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Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
ZnCl2-catalyzed [4 þ 2] benzannulation of 2-ethynylbenzaldehydes with alkynes:
Selective synthesis of naphthalene derivatives
,
,
a
a,b,
*
Xiao-Li Fang a, Ri-Yuan Tang a, Xing-Guo Zhang a b, Ping Zhong a , Chen-Liang Deng , Jin-Heng Li
*
a College of Chemistry and Materials Science, Wenzhou University, Wenzhou 325035, China
b Key Laboratory of Chemical Biology & Traditional Chinese Medicine Research (Ministry of Education), Hunan Normal University, Changsha 410081, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Zn-catalyzed [4 þ 2] benzannulation of 2-ethynylbenzaldehydes with alkynes is described for the selective
synthesis of naphthalene derivatives. In the presence of ZnCl2, a variety of 2-ethynylbenzaldehydes
underwent the [4 þ 2] benzannulation reactions with alkynes to selectively afford the corresponding
naphthalene derivatives in moderate to good yields.
Received 26 July 2010
Received in revised form
26 September 2010
Accepted 27 September 2010
Available online 7 October 2010
Ó 2010 Elsevier B.V. All rights reserved.
Keywords:
ZnCl2
[4 þ 2] Benzannulation
Alkynylbenzaldehyde
Alkyne
Naphthalene
1. Introduction
o-alkynylbenzaldehydes with alkynes (Scheme 1) [51e53]. Subse-
quently, they found that with the aid of CF2HCOOH Cu(OTf)2 was an
The synthesis of naphthalene rings is of continuingly interesting
in the field of organic chemistry because these compounds play
important roles in materials science and pharmaceutical industries
[1e21]. Although diverse synthetic approaches toward naphthalene
compounds have been developed [1e54], versatile and efficient
methodologies to construct these compounds with selective control
of substitution patterns using readily accessible building blocks are
still needed. Recently, Lewis acid-catalyzed [4 þ 2] benzannulations
of 2-ethynylbenzaldehydes with unsaturated compounds (alkynes,
alkenes and enols) have been proven as a powerful alternative to
naphthalenes [45e54]. However, only a few papers have been
reported on these benzannulation transformations, particularly
benzannulation between 2-ethynylbenzaldehydes and alkynes
[51e54]. Moreover, the catalysts are restricted to some highly
expensive Lewis acids, such as AuCl3 and Cu(OTf)3 [45e54]. In 2002,
Asao and Yamamoto firstly described an efficient route to naphthyl
ketone derivatives through gold-catalyzed [4 þ 2] cycloaddition of
effective catalyst for this [4 þ 2] benzannulation and shifted the
selectivity toward the debenzoylated naphthalenes through
the cleavage of a carbonecarbon triple bond [54]. However, both the
debenzoylated naphthalenes (major) and naphthyl ketones (minor)
were observed in the presence of the other additives (such as
H2O, MeOH, HCO2H, CH3CO2H or CF3CO2H) or without additives
[54]. Thus, the development of some new routes, including the
use of inexpensive Lewis acids under additive-free conditions for
the [4 þ 2] benzannulation is interesting. Here, we report a practical
protocol for the synthesis of the debenzoylated naphthalenes
by Zn-catalyzed benzannulation of 2-ethynylbenzaldehydes
with alkynes without the requirement of additives (Scheme 1)
[50,55e64].
2. Experimental
2.1. General remarks
NMR spectroscopy was performed on a Bruker-300 spectrom-
eter operating at 300 MHz (1H NMR) and 75 MHz (13C NMR). TMS
(tetramethylsilane) was used an internal standard and CD3Cl was
used as the solvent. Mass spectrometric analysis was performed on
GCeMS analysis (SHIMADZU GCMS-QP2010).
* Corresponding authors. College of Chemistry and Materials Science, Wenzhou
University, Wenzhou 325035, China. Tel.: þ86731 8887 2101; fax: þ86731 8887
2531.
E-mail address: jhli@hunnu.edu.cn (J.-H. Li).
0022-328X/$ e see front matter Ó 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2010.09.062

X.-L. Fang et al. / Journal of Organometallic Chemistry 696 (2011) 352e356
353
Refs. 51-53
Ref. 54
R
O
R
Cu(OTf)2
CF2HCO2H
ClCH2CH2Cl
AuCl3
+
R'
ClCH2CH2Cl
100 o
C
100 o
C
O
2
R'
This work
1
R
R2
R2
R3
ZnCl2 (10 mol %)
ClCH2CH2Cl
+
H
R1
R1
80 o
C
R3
2
O
1
Scheme 1. Lewis acids-catalyzed [4 þ 2] benzannulations of 2-ethynylbenzaldehydes with alkynes.
2.2. Typical experimental procedure for the ZnCl2-catalyzed [4 þ 2]
with 2-(2-phenylethynyl)benzaldehyde (1a) in the presence of
ZnCl2. To our delight, internal alkynes 2be2e, bearing aryl or/and
aliphatic groups, successfully underwent the annulation reaction
with 1a and ZnCl2 in moderate to good yields (entries 1e4). For
instance, substrate 2d with a thiophen-2-yl and a n-hexyl group
was treated with 1a and ZnCl2 in 60% yield (entry 3). It was
surprised to observe that phenyl(2-phenylethynyl)sulfane (2e)
reacted with 1a did not yield the expected 2-phenyl-3-phenyl-
sulfanylnaphthelene [45], but the dephenylsulfanyl 2-phenyl-
naphthalene 7 in 84% yield (entry 4). However, electron-poor
alkyne 2f was not suitable under the same conditions (entry 5). We
were interesting to disclose that terminal alkynes displayed higher
activity than internal alkynes in term of yields. Among terminal
alkynes 2ge2j, substituents, such as phenyl, 4-NO2C6H4, n-hexyl
and t-butyl groups, were perfectly tolerated (entries 6e9).
benzannulation of 2-alkynylbenzaldehyde with alkynes
To
a Schlenk tube were added 2-alkynylbenzaldehyde 1
(0.2 mmol), alkyne 2 (1 equiv), ZnCl2 (10 mol%), and ClCH2CH2Cl
(3 mL). Then the tube was charged with argon, and was stirred at
80 ꢀC (oil bath temperature) for the indicated time until complete
consumption of starting material as monitored by TLC and GCeMS
analysis. After the reaction was finished, the reaction mixture was
cooled to room temperature, diluted in diethyl ether, and washed
with brine. The aqueous phase was re-extracted with EtOAc. The
combined organic extracts were dried over Na2SO4 and concen-
trated in vacuo. The resulting residue was purified by silica gel
column chromatography (hexane/ethyl acetate) to afford the
desired product.
3. Results and discussion
Table 1
The [4 þ 2] benzannulation reaction of 2-(phenylethynyl)benzaldehyde (1a) with
The reaction between 2-(2-phenylethynyl)benzaldehyde (1a)
and 1-phenylpropyne (2a) was chosen as a model reaction to
optimize the reaction conditions, and the results are summarized in
Table 1. Initially, a series of zinc salts, including ZnF2, ZnCl2, ZnBr2,
ZnI2 and Zn(acac)2, were investigated (entries 1e5). We found that
ZnF2 had no effect on the reaction of aldehyde 1a with alkyne 2a
(entry 1). To our delight, the reaction was carried out successfully
using ZnCl2, ZnBr2 or ZnI2 Lewis acids, and ZnCl2 was the most
effective in terms of yields (entries 2e4). However, Zn(acac)2 was
inert for the benzannulation reaction (entry 5). It was disclosed that
the yields of the desired product 3 were reduced when the loading
of ZnCl2 was increased to 20 mol% or decreased to 5 mol% (entries 6
and 7). Subsequently, three other solvents, DMF, dioxane and
toluene, were evaluated, and they were found to disfavor this
benzannulation reaction: a trace amount of the desired product 3
was observed in either DMF or dioxane, and in toluene only 35%
yield was isolated (entries 8e10). Among the effect of the reaction
temperature examined, it turned out that at room temperature the
activities of substrates 1 and 2 were lowered (entry 11), and the
reaction at 100 ꢀC provided the identical results to those of 80 ꢀC
(entry 12). Other Lewis acids, including YbCl3, Yb(OTf)3, InCl3 and
GaCl3, were tested; however, they displayed less efficiency for the
reaction (enries 13e16).
prop-1-ynylbenzene (2a)a
CHO
Me
Ph
[Zn]
+
Ph
Me
2a
Ph
3
1a
.
Entry
[Zn]
Solvent
T (ꢀC)
Isolated yield (%)
1
2
3
4
ZnF2
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
DMF
80
80
80
80
80
80
80
80
80
80
rt
100
80
80
80
80
trace
86
81
79
trace
77
ZnCl2
ZnBr2
ZnI2
5
Zn(acac)2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
YbCl3
Yb(OTf)3
InCl3
6b
7c
8
65
trace
trace
35
50
83
trace
6
11
9
dioxane
toluene
10
11
12
13
14
15
16
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
GaCl3
10
With the optimal reaction conditions in hand, the scopes of both
2-alkynylbenzaldehydes and alkynes for the benzannulation
reaction were explored (Table 2). A variety of alkynes 2be2j, either
internal or terminal alkynes, were initially investigated by reaction
a
Reaction conditions: 1a (0.2 mmol), 2a (0.2 mmol), and [Zn] (10 mol %) in
solvent (3 mL) for 36 h.
b
ZnCl2 (20 mol%).
ZnCl2 (5 mol%) for 48 h.
c

354
X.-L. Fang et al. / Journal of Organometallic Chemistry 696 (2011) 352e356
Table 2
ZnCl2-catalyzed benzannulation of 2-ethynylbenzaldehydes (1) with alkynes (2)a
R2
CHO
R2
R3
ZnCl2 (10 mol %)
R1
R1
+
ClCH2CH2Cl, 80 o
C
R3
2
R
1
.
Entry
1
Substrate 1
Alkyne 2
Time (h)
20
Isolated yield (%)
CHO
Ph
Ph
(2b)
54 (4)
Ph
(1a)
(1a)
(1a)
(1a)
(1a)
(1a)
(1a)
(1a)
(1a)
CHO
(2c)
(2d)
2
3
4
5
6
7
8
9
20
20
11
24
12
16
12
12
51 (5)
Ph
CHO
n
C6H13
60 (6)
S
Ph
CHO
Ph
S Ph
(2e)
84 (7)
Ph
CHO
MeO2C
CO2Me
(2f)
trace (8)
Ph
CHO
Ph
(2g)
81 (7)
Ph
CHO
O2N
70 (9)
(2h)
Ph
CHO
(2i)
61 (10)
53 (11)
Ph
CHO
(2j)
Ph

X.-L. Fang et al. / Journal of Organometallic Chemistry 696 (2011) 352e356
355
Table 2 (continued )
Entry
Substrate 1
CHO
Alkyne 2
Time (h)
Isolated yield (%)
Ph
Ph
Ph
(2a)
(2a)
(2a)
10
10
45 (3)
OMe (1b)
CHO
11
8
86 (3)
O
(1c)
CHO
12
20
31 (3)
N
(1d)
CHO
Ph
Ph
Ph
(2a)
(2a)
(2a)
13
14
15
11
20
10
70 (3)
15 (3)
87 (12)
(1e)
CHO
(1f)
F
CHO
CHO
Ph
(1g)
(1h)
Ph
(2a)
16
9
89 (13)
Ph
a
Reaction conditions: 1 (0.2 mmol), 2 (0.2 mmol), ZnCl2 (10 mol%), in ClCH2CH2Cl (3 mL) at 80 ꢀC.
Subsequently, a number of 2-alkynylbenzaldehydes 1be1h were
examined for the reaction with alkyne 2a under the optimal
conditions (entries 10e16). Substituents, 4-MeOC6H4, 4-CH3CO
C6H4, and n-hexyl groups, at the terminal alkyne on the 2-ethy-
nylbenzaldehyde moiety were consistent with the optimal condi-
tions (entries 10,11, and 13). The desired product 3 was still isolated
in 31% from the reaction of pyridin-3-yl-containing substrate
1d with alkyne 2a and ZnCl2 (entry 12). However, 2-ethy-
nylbenzaldehyde (1f) was less active for the reaction (entry 14).
Gratifyingly, the optimal conditions were compatible with both F-
and Me-substituted benzaldehydes 1g and 1h, providing the cor-
responding product 12 and 13 in good yields (entries 15 and 16).
A possible mechanism as outlined in Scheme 2 was proposed on
the base of the earlier reported mechanism [45e54]. The coordi-
nation of the triple bond of 2-ethynylbenzaldehyde 1 to ZnCl2
enhances the electrophilicity of alkyne (intermediate A), followed
by the nucleophilic attack of the carbonyl oxygen to the electron-
deficient alkyne among intermediate A affords intermediate B. The
DielseAlder reaction of B with an alkyne 2 takes place leading to
intermediate D [54]. Finally, the bond rearrangement of interme-
diate D yields the decarbonylated naphthalenes and regenerates
the active Zn catalyst species. The activity of Zn salts is
ZnCl2 > ZnBr2, ZnI2 > ZnF2, Zn(acac)2 in terms of yields, and the
reason is that ZnCl2 is more acidic than the other Zn salts.

356
X.-L. Fang et al. / Journal of Organometallic Chemistry 696 (2011) 352e356
R
Cl2Zn
R
ZnCl2
R
1
CHO
ZnCl2
O
CHO
A
B
2
O
R
ZnCl2
R
Cl2Zn
O
C
D
Scheme 2. Possible mechanism.
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4. Conclusion
Insummary, we have developedapracticalZnCl2-catalyzed[4þ 2]
benzannulation method for the synthesis of the decarbonylated
naphthalenes. In the presence of ZnCl2, a variety of 2-ethynyl-
benzaldehydes underwent the [4 þ 2] benzannulation reactions with
numerous alkynes to selectively afford the corresponding naphtha-
lene derivatives in moderate to good yields. Compared with the
earlier report [54], two features were established: (1) This reaction is
practical and regiospecific; and (2) this reactionwas carried out using
inexpensive Lewis acid catalyst under additive-free conditions.
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Acknowledgments
We thank the National Natural Science Foundation of China
(Nos. 20872112 and 20972114), and Zhejiang Provincial Natural
Science Foundation of China (No. Y407116) for financial support.
Appendix. Supplementary material
Supplementary data related to this article can be found online at
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