Ligand-Free and Solvent-Free Synthesis of 1,3-Disubstituted Naphthalenes through Stille Coupling

Article abstract of DOI:10.1055/s-0039-1690850

A variety of 1,3-disubstituted naphthalenes have been prepared by palladium-catalyzed annulation of (o-ethynylphenyl)acetyl chloride with design of a new synthetic strategy by Stille coupling using functionalized organostannanes. The method affords excellent yields of the substituted naphthalenes and accommodates a wide variety of functional groups under mild conditions. Mechanistic studies show intramolecular cyclization as a major step following C-C bond coupling.

Full text of DOI:10.1055/s-0039-1690850

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2020, 31, A–D
letter
A
en
S. Sbi et al.
Letter
Synlett
Ligand-Free and Solvent-Free Synthesis of 1,3-Disubstituted
Naphthalenes through Stille Coupling
Sanae Sbia
R1SnBu3
R1
Victor Mkpenieb
Kiyoshi Tanemurac
Taoufik Rohand*a
Cl
R2SnBu3
Pd(0)
O
60 °C
0
0
0
0-0
0
0
2-7
3
7
0-9
3
5
8
22 Examples of
R1 and R2
functionalized moieties
yield: 50–91%
CH
a Laboratory of Analytical and Molecular Chemistry, Department of
Chemistry, University Cadi Ayyad, Faculty Polydisciplinaire of Safi,
Sidi Bouzid 46000 Safi, Morocco
R2
double Stille coupling reactions plus cyclization
taoufik.rohand@uca.ac.ma
b Department of Chemistry, University of Uyo, P. M. B. 1017, Uyo,
Nigeria
c Chemical Laboratory, School of Life Dentistry at Niigata, Nippon
Dental University, Hamaura-cho, Niigata 951-8580, Japan
Received: 14.01.2020
Accepted after revision: 18.02.2020
Published online: 20.03.2020
hydes and alkynes catalyzed by gold and copper,17,18 the re-
action of diaryl buta-1,3-diynes with cyclic amines cata-
lyzed by copper(I),19 and reactions between 2-bromobenz-
aldehydes and functionalized alkenes catalyzed by
palladium.20
DOI: 10.1055/s-0039-1690850; Art ID: st-2020-u0028-l
Abstract A variety of 1,3-disubstituted naphthalenes have been pre-
pared by palladium-catalyzed annulation of (o-ethynylphenyl)acetyl
chloride with design of a new synthetic strategy by Stille coupling using
functionalized organostannanes. The method affords excellent yields of
the substituted naphthalenes and accommodates a wide variety of
functional groups under mild conditions. Mechanistic studies show in-
tramolecular cyclization as a major step following C–C bond coupling.
The aryl substrate functionalized with an alkynyl frag-
ment at the ortho position has recently attracted attention
because of the ease of cyclization.21 For example, the
benzannulation between ortho-(phenylethynyl)benzalde-
hyde and alkyne by Asao and Yamamoto affords 2,3-disub-
stituted naphthalene (Scheme 1a) with outstanding toler-
ance.22 Huang and Larock prepared a variety of substituted
naphthalenes using internal alkynes and o-(2-alkenyl)aryl
halides through palladium-catalyzed annulation (Scheme
1b).23 This method affords carbon–carbon bonds in a single
step and accommodates a variety of functional groups in
excellent yields. Palladium-catalyzed annulation methods
are very effective and have been employed for various syn-
theses including those of indoles, isoquinolines, benzofu-
rans, and PAHs.24–27
Key words ethynylbenzene, organostannanes, 1,3-disubstituted
naphthalenes, Stille coupling, palladium(0) catalysis
The versatility of naphthalene derivatives as polycyclic
hydrocarbons (PAHs) in areas including synthetic organo-
metallic chemistry,1 materials science,2 organic photovolta-
ic devices,3 bioactive molecules,4 light-emitting diodes,5
field effect transistors,6 molecular recognition and fluores-
cent sensors,7,8 has been known for many years.
The efficient and regioselective construction of a naph-
thalene framework has been successful in synthetic organic
chemistry. Among the many methods employed in the syn-
thesis of naphthalene derivatives (polysubstituted naphtha-
lene), metal-catalyzed annulation of functionalized aromat-
ic substrates has gained significant attention, probably be-
cause of the straightforward approach and the use of mild
conditions in the preparation.9–14
In the metal-catalyzed annulation reaction, the starting
substrates, functional groups on the substrates, and metal
catalyst used depend on the design, the type of the involved
reaction, and utilized synthetic protocol. Some of such syn-
thetic procedures include the use of arylindium reagents
and alkynes catalyzed by iron,15 the reaction of phenylacet-
aldehyde dimethylacetal with 1-phenyl-1-butyne catalyzed
by rhenium,16 benzannulation between o-alkynylbenzalde-
Because of the abundance of naphthalene skeletal
frameworks in many biologically important natural prod-
ucts,28–32 the desire for a new synthetic strategy towards
the construction of polysubstituted naphthalene is still
highly anticipated. Inspired by these developments, we de-
signed a new route to construct the 1,3-disubstituted naph-
thalene core through palladium(0)-catalyzed Stille coupling
reaction of (o-ethynylphenyl)acetyl chloride and organos-
tannanes functionalized with different organic moieties.
Stille coupling for the construction of naphthalene deriva-
tives has rarely been reported. The success of this new syn-
thetic approach is demonstrated by the widespread toler-
ance for various functional groups.
We started the synthesis of 1,3-diphenylnaphthalene
derivatives 3–22 with the reaction of (o-ethynylphenyl)ace-
tyl chloride (1) and substituted organostannanes 2 in the
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–D
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
S. Sbi et al.
Letter
Synlett
presence of a catalytic amount of Pd(PPh3)4 catalyst under
solvent-free conditions without any ligands. The 1,3-disub-
stituted naphthalenes were obtained in moderate to high
yields (Scheme 1c, Table 1).
Initially, the effect of substituents was investigated by
evaluating the reactivity of para-, meta-, and ortho-tolyltin.
The obtained results revealed that the reaction is signifi-
cantly influenced by the type and position of the substitu-
ents as indicated by the different yields of products. The re-
action of 1 with para-tolyltin furnished 6 in 86% yield,
whereas ortho- and meta-tolyltin afforded the desired
products with diminished yields of 68 and 79% (4 and 5),
respectively.
O
R1
R2
R1
R2
R3
H
[Cu] or [Zn]
(a)
(b)
+
+
R3
R1
Ph
Y
[Pd0]
Y
X
R2
R2
R1
X = Br, I; Y = COOEt, CN, Ar
This work
(c)
R1SnBu3
R2SnBu3
Cl
R1
2
Pd(0)
O
CH
1
60 °C, 8 h
R2
3–22
As shown in Table 1, electron-donating groups, such as
methyl (4–6), and trifluoromethoxy (7), as well as electron-
withdrawing groups, such as fluoro (8), chloro (9), bromo
(10), and iodo (11) on the phenyl ring of the aryltins, were
Scheme 1 Synthesis of polysubstituted naphthalene derivatives
Table 1 Synthesis of 1,3-Disubstituted Naphthalene Derivatives with Various Functionalized Aryltinsa
Product
R1
R2
Yield (%)b
59
Product
R1
R2
Yield (%)b
70
3
13
Ph
Ph
4
5
68
79
14
15
67
79
CH3
CH3
CH3
CH3
CH3
6
86
16
89
CH3
CH3
CH3
7
8
9
88
76
91
17
18
19
85
88
81
CH3
OCF3
OCF3
F
F
F
Br
Cl
Cl
10
11
12
75
61
50
20
21
22
75
78
68
CF3
Br
Br
OCH3
I
I
OCH3
OCH3
a Reagents and conditions: Alkyne 1 (0.2 mmol), R1SnBu3 (0.4 mmol), R2SnBu3 (0.4 mmol), Pd(PPh3)4 (5 mol%, 0.01 mmol), 8 h, 60 °C.
b Yields of isolated products.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–D

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S. Sbi et al.
Letter
Synlett
accommodated in this transformation. Biaryltins, such as 4-
phenylphenyltin and 2-naphthyltin also gave the desired
products 13 and 14 in 70 and 67% yield, respectively. It
therefore appeared that electron-donating groups at the
para position seem to achieve better yields relative to elec-
tron-withdrawing groups at the same position. By modify-
ing the substituents on the phenyl ring of aryltin, it became
obvious that para-, meta-, and even sterically hindered or-
tho-substituted tins (products 15–17, 79–89% yield) can be
effectively accommodated in this one-pot synthetic proto-
col. The procedure tolerates a broad range of aryltins bear-
ing both electron-donating substituents (–Me, –OMe, prod-
ucts 16, 17, and 21) and electron-withdrawing substituents
(–F, –Br, –CF3, products 18–20).
A plausible mechanism for the formation of products 3–
22 is shown in Scheme 2. In this Stille coupling, the first
step is the oxidative addition of (2-ethynylphenyl)acetyl
chloride onto the Pd(0) catalyst and this is followed by
transmetalation of R1 through organostannane. The reactiv-
ity of the alkynyl fragment leads to the coupling of R2 and
subsequent removal of a molecule of water in the last step.
The removal of water affords rearrangement of the double
bond leading to the formation of disubstituted naphtha-
lenes 3–22 as the desired products.
Funding Information
T.R. is grateful to the University Cadi Ayyad, especially the Faculty
Polydisciplinaire of Safi, for the financial support given to the Labora-
tory of Analytical and Molecular Chemistry. K.T. thanks Nippon Den-
tal University for the financial support to the Chemical Laboratory.()()()
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1690850.
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References and Notes
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L2Pd
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O
CH
L
Cl Pd
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L2Pd
O
R1
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H2C
R2
R1SnBu3
ClSnBu3
CH
HSnBu3
PdL2
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R2SnBu3
O
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Scheme 2 Plausible mechanism for the Pd-catalyzed synthesis of 1,3-
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In summary, a new method for the one-pot synthesis of
1,3-naphthalene and its derivatives in good yields has been
developed with use of a palladium-catalyzed reaction of
alkynes, acylchloride, and aryltins without any solvent.32
The use of a ligand became unnecessary because of the ac-
tivation by heating and also facilitated stabilization of the
arylpalladium species for the nucleophilic addition and
coupling of the alkyne carbon bond. Mechanistic studies
show intramolecular cyclization as a major step following
C–C bond coupling. The excellent result obtained from this
work will inspire the application of this method in the
preparation of other fused heteroaromatic ring systems
such as anthracenes and xanthrenes.
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© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–D

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Letter
Synlett
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washed with sat. aq NaHCO3 solution (2×10 mL) and distilled
water (10 mL), and then poured into ethyl acetate. The aqueous
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rated under vacuum.
Product 3 was obtained by flash column chromatography (hep-
tane/ethyl acetate). Identification of 3 was carried out by com-
parison with the data reported in the literature33 (see Sup-
porting Information).
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(32) One-Pot Synthesis of Naphthalenes 3–22; General Procedure
A Schlenk reaction tube was successively charged with alkyne 1
(0.2 mmol), R1SnBu3 (0.4 mmol), R2SnBu3 (0.4 mmol), and
Pd(PPh3)4 (5 mol%, 0.01 mmol). The reaction mixture was
stirred and heated at 60 °C for 8 h. The reaction was monitored
by TLC and the absence of any trace of the starting material
indicated completion of the reaction. The reaction mixture was
(33) Jagdale, A. R.; Park, J. H.; Youn, S. W. J. Org. Chem. 2011, 76, 7204.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–D