Metal-free benzannulation to synthesis of 2,3-disubstituted naphthalenes: Reaction of 2-(Phenylethynyl)benzaldehyde and alkynes by Br?nsted acid

Article abstract of DOI:10.1246/bcsj.20160308

Metal-free benzannulation reaction of 2-(phenylethynyl)- benzaldehyde and alkynes proceeded in the presence of Br?nsted acid under microwave irradiation to give the 2,3- disubstituted naphthalenes.

Full text of DOI:10.1246/bcsj.20160308

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Metal-Free Benzannulation to Synthesis of 2,3-Disubstituted Naphthalenes:
Reaction of 2-(Phenylethynyl)benzaldehyde and Alkynes by Brønsted Acid
Rui Umeda,* Naoki Ikeda, Masahiro Ikeshita, Keita Sumino,
Sota Nishimura, and Yutaka Nishiyama*
Advance Publication on the web November 25, 2016
doi:10.1246/bcsj.20160308
© 2016 The Chemical Society of Japan

Short Articles
(Organic and Biological Chemistry)
Table 1. Effect of Brønsted acid
O
Metal-Free Benzannulation to
Synthesis of 2,3-Disubstituted
Naphthalenes: Reaction of
H
Brønsted acid (0.45 mmol)
Ph
Ph
Ph
+
ClCH2CH2Cl (2 mL)
Ph
Ph
80 C, 15 h
1 (0.45 mmol)
2a (0.30 mmol)
3a
2-(Phenylethynyl)benzaldehyde and
Alkynes by Brønsted Acid
entry
Brønsted acid
yield (%)a
1
2
3
4
5
6
7
8
9
CH3COOH
CH2ClCOOH
CHCl2COOH
CCl3COOH
CHF2COOH
CF3COOH
TfOH
trace
trace
1
19
4
41
18
4
Rui Umeda,* Naoki Ikeda, Masahiro Ikeshita, Keita
Sumino, Sota Nishimura, Yutaka Nishiyama*
10-camphorsulfonic acid
TsOH·H2O
Faculty of Chemistry, Materials and Bioengineering, Kansai
University, Osaka 564-8680
35
a GC yield.
Received October 12, 2004; E-mail: umeda@kansai-u.ac.jp,
nishiya@kansai-u.ac.jp,
First, the effect of various Brønsted acids (0.45 mmol) on
the benzannulation of 2-(phenylethynyl)benzaldehyde (1)
(0.45 mmol) and diphenylacetylene (2a) (0.30 mmol) was
investigated at 80 °C for 15 h (Table 1). In the cases of acetic,
chloroacetic, dichloroacetic, trichloroacetic, difluoroacetic,
trifluoromethanesulfonic, and 10-camphorsulfonic acids, only
a small amount of 2,3-diphenylnaphthalene (3a) was formed
(entries 1-5 and 7,8). On the other hand, the reaction using
trifluoroacetic acid and p-toluenesulfonic acid monohydrate
(TsOH·H2O), gave 3a in moderate yields (entries 6 and 9). 9
Metal-free
benzannulation
reaction
of
2-(phenylethynyl)benzaldehyde and alkynes proceeded in
the presence of Brønsted acid under microwave irradiation
to give the 2,3-disubstituted naphthalenes.
The multiple substituted naphthalene derivatives are
attractive from the viewpoint of biological, pharmaceutical,
and material sciences. Numerous synthetic procedures have
been reported for the preparation of multiple substituted
naphthalenes. In general, to introduce various functional
groups on naphthalene framework, transition metal-catalyzed
cross coupling reaction using organometallic or
organohalogen compounds has been developed. An alternative
approach to the preparation of them is benzannulation reaction,
which could be remarkably tolerant of bulky substituents with
high regioselectivity.1 Recently, Asao and Yamamoto group
has reported Au or Cu-catalyzed benzannulation reaction of
2-(phenylethynyl)benzaldehyde and alkynes to afford the
multiple substituted naphthalenes.2a,3b Since the Asao and
Yamamoto’s report, the synthesis of naphthalene derivatives
by the transition metal-catalyzed benzannulation reaction
using 2-(phenylethynyl)benzaldehyde has been disclosed by
various groups.2-8
Table 2. Effect of Brønsted acid under microwave
condition
O
H
Brønsted acid (0.45 mmol)
Ph
Ph
Ph
+
ClCH2CH2Cl (2 mL)
200 C, 30 min
M.W.
Ph
Ph
1 (0.45 mmol)
2a (0.30 mmol)
3a
entry
Brønsted acid
yield (%)a
1
2
3
CH3COOH
CCl3COOH
CF3COOH
N.D.
N.D.
28
4
5
6
7
CF3CF2COOH
CF3CF2CF2COOH
PhCOOH
39
42
N.D.
N.D.
35
In this paper, we report the metal-free benzannulation
reaction of 2-(phenylethynyl)benzaldehyde and alkynes in the
presence of Brønsted acid under microwave irradiation to
afford the 2,3-disubstituted naphthalenes (Scheme 1).
C6F5COOH
TfOH
8
9
10-camphorsulfonic acid
23
10
TsOH·H2O
64
O
a 1H NMR yield.
R1
R2
H
R1
Brønsted acid
To improve the yield of product, we investigated the
effect of Brønsted acid on the reaction under microwave
irradiation condition. The benzannulation of 1 (0.45 mmol)
and 2a (0.30 mmol) in the presence of various Brønsted acids
(0.45 mmol) was carried out at 200 °C for 30 min under
microwave irradiation and these results are shown in Table 2.
The treatment of acetic or trichloroacetic acids did not give 3a
+
R2
ClCH2CH2Cl
Ph
200 C, 30 min
M.W.
1
2
3
Scheme 1

O
at all (entries 1-2). The use of the fluoro-substituted carboxylic
acids, such as trifluoroacetic, pentafluoropropionic, and
heptafluorobutyric acids, led to the formation of 3a in 28-42%
yields (entries 3-5). On the other hand, the reaction did not
occur with benzoic or pentafluorobenzoic acids as Brønsted
acids (entries 6 and 7). When the reaction was carried out with
sulfonic acids as Brønsted acid, the yield of 3a was increased
up to 64% (entries 8-10).
H
Ph
Ph
TsOH·H2O (0.90 mmol)
Ph
+
Ph
solvent (2 mL)
200 C, 30 min
M.W.
Ph
1 (0.60 mmol)
2a (0.30 mmol)
3a
entry
solvent
yield (%)a
1
2
3
4
5
6
ClCH2CH2Cl
Toluene
Chlorobenzene
CH3CN
83
41
48
49
N.D.
N.D.
Table 3. Effects of reaction time and ratio of 1, 2a and
TsOH·H2O under microwave condition
O
DMF
H
Ph
Ph
TsOH·H2O
Ph
DMSO
+
a 1H NMR yield.
ClCH2CH2Cl (2 mL)
200 C, 30 min
M.W.
Ph
Ar
1
2a (0.30 mmol)
3a
Finally, we investigated the effect of solvent on the
reaction (Table 4). When aromatic solvents, toluene and
chlorobenzene, and acetonitrile were used, 3a was obtained in
moderate yields (entries 2-4). The use of DMF and DMSO
showed no formation of 3a (entries 5 and 6). On the reaction,
1,2-dichloroethane solvent gave the best yield of 3a (entry 1).
entry
Ar
1 (mmol) TsOH·H2O (mmol) yield (%)a
1
2b
3
Ph
Ph
Ph
Ph
Ph
Ph
Ph
0.45
0.45
0.60
0.75
0.30
0.60
0.60
0.60
0.60
0.60
0.45
0.45
0.45
0.45
0.45
0.60
0.90
0.90
0.90
0.90
64
49
73
4
70
Table 5. Benzannulation of 1 with various alkynes 2
5c
6
60d
77
O
R1
R2
7
8
9
83 (49)
43
75
H
R1
TsOH·H2O (0.90 mmol)
+
4-CH3OC6H4
4-CH3C6H4
4-ClC6H4
R2
ClCH2CH2Cl (2 mL)
Ph
200 C, 30 min
M.W.
10
84
1 (0.60 mmol)
2 (0.30 mmol)
3
a 1H NMR yield. The number in parenthesis shows isolated yield.
b The reaction was carried out for 60 min.
c 2a (0.45 mmol) was used.
entry
R1
R2
yield (%)a
d The yield of 3a was based on 1.
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
Ph
Ph
Ph
n-C5H11
Ph
n-C6H13
CH3
C2H5
3b, 63
3c, 37b
3d, 59
3e, 40c
3f, 56
3g, N.D.
3h, N.D.
3i, 61
4-CH3C6H4
4-CH3OC6H4
4-FC6H4
4-CNC6H4
4-NO2C6H4
n-C5H11
H
Next, with TsOH·H2O as Brønsted acid, the effects of
reaction time and the ratio of 1, 2a and TsOH·H2O on the
benzannulation were investigated and these results are shown
in Table 3. The reaction of 1 (0.45 mmol), 2a (0.30 mmol) and
TsOH·H2O (0.45 mmol) for a longer reaction time (60 min)
afforded 3a in low yield (entries 1 and 2). Although the yield
of 3a was improved by increasing of amount of 1 (0.60 mmol),
more increasing of amount of 1 (0.75 mmol) led to no
improvement of the yield of 3a (entries 3-4). In the case of the
use of an excess amount of 2a compared to 1, the yield of 3a
was slightly reduced (entry 5). The effect of the amount of
Brønsted acid was studied (entries 3 and 6-7). The use of 0.90
mmol of TsOH·H2O led to the best yield of 3a.10,11,12 Next, the
effect of substituents on the aromatic ring (Ar) of 1 was
investigated. In the case of 1 having 4-anisyl group, the yields
of 3a decreased due to the formation of unidentified products,
which would be formed by the reaction of 1 (Ar =
4-CH3OC6H4) with itself (entry 8). For both cases of 1
substituted 4-tolyl and 4-chlorophenyl groups, the
benzannulation smoothly proceeded to give 3a in good yields
(entries 9 and 10).
3j, 28
3k, 92
10
H
a Isolated yield.
b 1-Phenylbutan-1-one (36%) was formed as by-product.
c
1-Phenyl-2-(4-methoxyphenyl)ethanone (42%) was formed as
by-product.
The various alkynes 2 were allowed to react with 1 under
the same reaction conditions as that of entry 1 in Table 4 and
these results are shown in Table 5. The reaction of 1 and
1-phenyl-1-alkynes,
1-phenyl-1-propyne
and
1-phenyl-1-butyne, proceeded to form 3b and 3c in 63 and
37% yields, respectively (entries 1 and 2). The yield of 3c was
low due to the formation of the hydration product,
1-phenylbutan-1-one (36%), as by-product (entry 2). In the
cases of the use of electron-rich aryl substituted
Table 4. Effect of solvent under microwave condition
ethynylbenzenes,
such
as
1-methoxy-4-(phenylethynyl)benzene
and
1-methyl-4-(phenylethynyl)benzene, 3d and 3e were obtained
in 59 and 40% yields, respectively (entries 3 and 4). In the

O
latter case, 1-phenyl-2-(4-methoxyphenyl)ethanone as
by-product was also obtained in 42% yield. Next, the
reaction of 2 having electron-withdrawing groups on the
phenyl ring was examined. The benzannulation of
1-fluoro-4-(phenylethynyl)benzene took place to give 3f in
56% yield (entry 5). On the other hand, for the reaction of the
H
Ph
Ph
CF3COOD (0.90 mmol)
Ph
+
Ph
ClCH2CH2Cl (2 mL)
200 C, 30 min
M.W.
Ph
D(H)
1 (0.60 mmol)
2a (0.30 mmol)
70% (D : H = 64 : 36)
O
O
CF3COOD
diarylacetylenes
substituted
with
strongly
Ph
O
CF3
electron-withdrawing groups, such as cyano or nitro groups,
on the phenyl moieties, the corresponding products 3g,h were
not formed (entries 6 and 7). These results agree with those of
Re-catalyzed benzannulation.8a The reaction of dialkyl
substituted alkyne, 6-dodecyne, with 1 gave 3i in 61% yield
(entry 8). For the reaction of aromatic terminal alkyne,
phenylacetylene, the yield of 3j was low (entry 9). In contrast
to that of aromatic terminal alkyne, the benzannulation of the
alkyl substituted terminal alkyne, 1-octyne, proceeded
efficiently to give 3k in 92% yield (entry 10).13
Ph
CF3COO
O
Ph
O OCOCF3
Ph
Ph
Ph
D
Ph
D
Scheme 3.
In conclusion, the metal-free benzannulation of
2-(phenylethynyl)benzaldehyde (1) with various alkynes 2 in
the presence of TsOH·H2O as Brønsted acid under microwave
irradiation for 30 min gave the corresponding
2,3-disubstituted naphthalene derivatives 3. This protocol
allowed the preparation of multiple and sterically hindered
polycyclic aromatic hydrocarbons.
It is important to note that the double benzannulation
reaction
of
1,4-diphenylbutadiyne
and
1,4-bis(phenylethynyl)benzene with 1 proceeded to afford 4
and 5, in 39 and 70% yields, respectively (Scheme 2).
O
Acknowledgement
Ph
Ph
H
TsOH·H2O (1.80 mmol)
This is a product of research which was financially
supported in part by the Kansai University Subsidy for
Supporting Young Scholars, 2015.
+
ClCH2CH2Cl (2 mL)
200 C, 30 min
M.W.
Ph
Ph
Ph
1 (1.20 mmol)
2 (0.45 mmol)
Ph
4, 39%
References
Ph
O
H
1. For a review on benzannulation, see: S. Kotha, S. Misra,
S. Halder, Tetrahedron 2008, 64, 10775.
TsOH·H2O (1.80 mmol)
+
ClCH2CH2Cl (2 mL)
200 C, 30 min
M.W.
Ph
2. For selected gold-catalyzed reactions, see: a) N. Asao, K.
Takahashi, S. Lee, T. Kasahara, Y. Yamamoto, J. Am.
Chem. Soc. 2002, 124, 12650; b) N. Asao, H. Aikawa, Y.
Yamamoto, J. Am. Chem. Soc. 2004, 126, 7458; c) N.
Asao, K. Sato, Menggenbateer, Y. Yamamoto, J. Org.
Chem. 2005, 70, 3682.
3. For selected copper-catalyzed reactions, see: a) N. Asao,
T. Kasahara, Y. Yamamoto, Angew. Chem. Int. Ed.
2003,42, 3504; b) N. Asao, T. Nogami, S. Lee, Y.
Yamamoto, J. Am. Chem. Soc. 2003, 125, 10921; c) N. T.
Patil, Y. Yamamoto, J. Org. Chem. 2004, 69, 5139; d) N.
Asao, H. Aikawa, J. Org. Chem. 2006, 71, 5249-5253.
4. For selected palladium-catalyzed reactions, see: a) R.-Y.
Tang, J.-H. Li, Chem. Eur. J. 2010, 16, 4733.
5. For selected platinum-catalyzed reactions, see: a) H.
Kusama, H. Funami, J. Takaya, N. Iwasawa, Org. Lett.
2004, 6, 605; b) D. Hildebrandt, W. Hîggenberg, M.
Kanthak, T. Plçger, I. M. Mîller, G. Dyker, Chem.
Commun. 2006, 2260; c) H. Kusama, H. Funami, N.
Iwasawa, Synthesis 2007, 2014.
6. For selected indium-catalyzed reactions, see: a) R.
Yanada, K. Hashimoto, R. Tokizane, Y. Miwa, H.
Minami, K. Yanada, M. Ishikura, Y. Takemoto, J. Org.
Chem. 2008, 73, 5135; b) K. Sakthivel, K. Srinivasan,
Org. Biomol. Chem. 2014, 12, 269.
Ph
5, 70%
Ph
2 (0.45 mmol)
1 (1.20 mmol)
Scheme 2.
To investigate the reaction pathway, we carried out the
reaction of 2-(phenylethynyl)benzaldehyde (1) with
diphenylacetylene (2a) in the presence of trifluoroacetic
acid-d, CF3COOD, as Brønsted acid at 200 °C for 30 min
under microwave irradiation (Scheme 3). The deuterium
incorporation at the 1-position on the product was confirmed
by H NMR.14 From this result and the previous reaction
1
pathway described by Asao and Yamamoto,3b one of the
plausible reaction pathways is shown in Scheme 3. First, the
deuteration or protonation to carbon-carbon triple bond of 1
followed by the internal cyclization forms the benzopyrylium
cation. Diels-Alder type cyclization of the benzopyrylium
cation with 2a gives the cyclic adduct. Finally, the elimination
of acid anhydride from the cyclic adduct affords the
2,3-disubstituted naphthalene.
7. For selected zinc-catalyzed reactions, see: a) X.-L. Fang,
R.-Y. Tang, X.-G. Zhang, P. Zhong, C.-L. Deng, J.-H. Li,
J. Organomet. Chem. 2011, 696, 352; b) X. Zhao, X.-G.
Zhang, R.-Y. Tang, C.-L. Deng, J.-H. Li, Eur. J. Org.
Chem. 2010, 4211.
8. For rhenium-catalyzed reactions, see: a) R. Umeda, K.

Kaiba, S. Morishita, Y. Nishiyama, ChemCatChem 2011,
3, 1743; b) R. Umeda, H. Tabata, Y. Tobe, Y. Nishiyama,
Chem. Lett. 2014, 43, 883; c) R. Umeda, M. Kimura, Y.
Tobe, Y. Nishiyama, Bull. Chem. Soc. Jpn. 2016, 89,
110.
9. In all cases, the formation of 1-benzoylnaphthalenes
derivative, which could be formed by Au-catalyzed
benzannulation reaction of 1 and alkyne, as by-product
was not observed. See ref. 2a.
10. Due to the difficult separation of a small amount of
impurities, the isolated yield of 3a was low.
11. General
procedure
for
the
reaction
of
2-(phenylethynyl)benzaldehyde (1) and alkynes 2: A
solution of 2-(phenylethynyl)benzaldehyde (1) (0.60
mmol, 124 mg), alkyne 2 (0.30 mmol), and TsOH·H2O
(0.90 mmol, 171 mg) in ClCH2CH2Cl (2.0 mL) was
treated at 200 ˚C for 30 min under microwave condition
(Biotage INITIATOR; All reactions were carried out
under the temperature-constant operation). The reaction
mixture was diluted with CHCl3 and washed with
saturated NaHCO3 aq. and brine. The organic layer was
dried over MgSO4. After removal of the solvent under
reduced pressure, the residue was purified by
chromatography on SiO2 to give the naphthalene
derivatives. Further purification was carried out a
recyclable preparative HPLC, if necessary. The
structures of the products were assigned by their NMR
spectra. The product was characterized by comparing its
spectral data with previous report.8a
12. The benzannulation of 1 (0.60 mmol) and 2a (0.30
mmol) in the presence of TsOH·H2O (0.90 mmol) was
carried out at 150 °C for 2 h without microwave
irradiation to give 3a in 53% yield.
13. The 2-(phenylethynyl)benzaldehyde (1) and alkynes as
the starting materials were completely consumed in all
reactions in Table 5 and uncharacterized polymeric
materials were formed on these reactions except for
entries 2 and 4.
14. The ratio of 2,3-diphenylnaphthalene, which does not
contain the deuterium, was slightly high. It seems that
the H/D exchange between the CF3COOD and H2O
contained in the solvent would be occurred.

Metal-Free Benzannulation to Synthesis of 2,3-Disubstituted Naphthalenes: Reaction of
2-(Phenylethynyl)benzaldehyde and Alkynes using Brønsted Acid
Rui Umeda, Naoki Ikeda, Masahiro Ikeshita, Keita Sumino, Sota Nishimura and Yutaka Nishiyama
Metal-free benzannulation reaction of 2-(phenylethynyl)benzaldehyde and alkynes was assisted by Brønsted acid
under microwave irradiation to give the 2,3-disubstituted naphthalenes.