Pd(PPh3)4/AgOAc-catalyzed one-pot synthesis of substituted 3,4-dihydronaphthalen-1(2H)-ones

Article abstract of DOI:10.1007/s00706-011-0681-5

A novel and efficient one-pot synthesis of 3,4-dihydronaphthalen-1(2/7)- ones by employing 2-iodocyclo-hex-2-enones, 1-alkynes, and a Pd[(C ₆H₅)₃P]₄/AgOAc catalytic system is described. The attractive features o

Full text of DOI:10.1007/s00706-011-0681-5

Monatsh Chem (2012) 143:1055–1059
DOI 10.1007/s00706-011-0681-5
ORIGINAL PAPER
Pd(PPh3)4/AgOAc-catalyzed one-pot synthesis
of substituted 3,4-dihydronaphthalen-1(2H)-ones
•
Hui Liu Peiyun Yan Yan Li Jinliang Liu
•
•
•
•
Qian Sun Xingbin Wang Cunde Wang
•
Received: 2 July 2011 / Accepted: 31 October 2011 / Published online: 29 November 2011
Ó Springer-Verlag 2011
Abstract A novel and efficient one-pot synthesis of 3,4-
dihydronaphthalen-1(2H)-ones by employing 2-iodocyclo-
hex-2-enones, 1-alkynes, and a Pd[(C6H5)3P]4/AgOAc
catalytic system is described. The attractive features of this
method, which enables the facile preparation of 3,4-di-
hydronaphthalen-1(2H)-one derivatives, are its very simple
and straightforward procedure, mild reaction conditions,
and good yields (65–87%).
1-alkynes to give the corresponding 3,4-dihydronaphthalen-
1(2H)-ones [12].
Silver salts can be used as stoichiometric oxidants for
the oxidation of various organic or inorganic substrates.
Recently some reports have shown that silver salt catalysts
or co-catalysts efficiently promoted organic reactions
[13, 14]. Significant development of palladium(0)/silver
salt catalyzed cross-coupling reactions has occurred only in
the past decade. This fact encouraged us to perform a
detailed investigation into the use of combined catalysts
comprising a Pd complex and silver salts for our research
purposes. In continuation of our interest in the preparation
of structurally complex natural molecules, we needed a key
building block with a 3,4-dihydronaphthalen-1(2H)-one
core. Initially the coupling reaction was studied with the
PdCl2(PPh3)2/Et3N catalyst system by Pal and coauthors
[15]. Recent studies have shown that silver acetate exhibits
interesting catalytic activities functioning as a transition
metal catalyst; however, to the best of our knowledge, there
have been no reports on the palladium/silver acetate-cata-
lyzed one-pot synthesis of the 3,4-dihydronaphthalen-
1(2H)-ones from 2-iodo-2-cyclohexenones and 1-alkynes.
In this article, we report a mild coupling reaction and
cycloaddition catalyzed by a new combination of catalysts,
Pd(PPh3)4 and AgOAc, to prepare 3,4-dihydronaphthalen-
1(2H)-ones (Scheme 1).
Keywords Alkynes ꢀ Carbocycles ꢀ Catalysis ꢀ
Cycloadditions ꢀ One-pot synthesis
Introduction
Many natural products containing 3,4-dihydronaphthalen-
1(2H)-ones exhibit interesting biological profiles due to their
unique molecular structure, mode of action, and high
potency [1–10]. 3,4-Dihydronaphthalen-1(2H)-one and its
substituted derivatives are also important synthetic inter-
mediates [7, 11]. Therefore, the efficient synthesis of these
compounds has attracted the interest of synthetic organic
chemists. Many methods can be used for the synthesis of 3,4-
dihydronaphthalen-1(2H)-ones. For example, conjugated
enynes, which are readily obtained by the Sonogashira–
Linstrumelle reaction, undergo Diels–Alder reactions with
Electronic supplementary material The online version of this
article (doi:10.1007/s00706-011-0681-5) contains supplementary
material, which is available to authorized users.
Results and discussion
Initially, the published methods which were used for the
preparation of 2-iodo-2-cyclohexenones from 2-cyclohex-
enones were screened using 2a as a model compound.
Reagents and solvents investigated for the reaction were I2/
4-dimethylaminopyridine (DMAP)/K2CO3/tetrahydrofuran
H. Liu ꢀ P. Yan ꢀ Y. Li ꢀ J. Liu ꢀ Q. Sun ꢀ X. Wang ꢀ
C. Wang (&)
School of Chemistry and Chemical Engineering,
Yangzhou University, Yangzhou, People’s Republic of China
e-mail: wangcd@yzu.edu.cn; cundeyz@hotmail.com
123

1056
H. Liu et al.
Scheme 1
O
O
O
Pd(PPh3)4, AgOAc, DIPEA,
1-alkyne, DMF, 100 °C, 12 h
I2, DMAP, K2CO3,
THF-H2O, r.t., 2 h
I
R'
98-99%
65-87%
R
R
R
R
R
R
R'
1a
2a
, R = H
1b, R = CH3
, R = H
2b, R = CH3
3-9
(THF)-H2O [16] and I2/pyridine/CCl4 [17]. The results
showed that the reaction was mild at ambient temperature
while using I2/DMAP/K2CO3/THF-H2O or I2/pyridine/
CCl4. Although the reaction conditions were different the
yields were excellent (96–99% yield, Scheme 1; Table 1).
Our proposed one-pot synthesis of 3,4-dihydronaphthalen-
1(2H)-ones from 2-iodo-2-cyclohexenones and 1-alkynes
involves two steps: the formation of a conjugated enyne by
coupling of a vinyl iodide and 1-alkyne and subsequent
thermal Diels–Alder cycloaddition ofthe resultant conjugated
enyne and 1-alkyne.. The construction of conjugated enynes
via palladium-catalyzed coupling reaction of 1-alkynes with
1-haloalkenes or alkenyl triflates has been used widely [18,
19]. Among them, the palladium-catalyzed cross-coupling
reaction of 1-alkynes with a-halo-a,b-unsaturated ketones is
convenient. Typically these coupling reactions are carried out
using a palladium catalyst such as Pd(PPh3)2Cl2, Pd(PPh3)4,
Pd(OAc)2 and a copper salt as a co-catalyst in the presence of
an amine base. However, the conventional Sonogashira sp2–
sp coupling reaction of vinyl iodide with 1-alkynes catalyzed
by palladium catalysts in the presence of copper iodide under
Aror N2 atmosphere has some weak points such as the Glaser-
type oxidative dimerization of 1-alkynes and low yield.
However, studies indicate that the Glaser-type oxidative
dimerization of 1-alkynes is avoided by the replacement of
copper iodide by silver halides [20].
We initially tested a combination of PdCl2(PPh3)2 and
AgI as the catalyst system. In agreement with our expec-
tation, when the reaction of 2-iodocyclohex-2-enone and
1-ethynylcyclohexanol was carried out in the presence of
i-Pr2NEt using PdCl2(PPh3)2 and AgI as a combined catalyst
in N,N-dimethylformamide (DMF) for 12 h, the desired
product 3,4-dihydro-5,7-bis(1-hydroxycyclohexyl)naph-
thalen-1(2H)-one (3) was obtained in 81% yield (Table 2,
entry 1). Furthermore, the replacement of AgI by AgOAc
achieved a high yield of 85% for the product 3 (Table 2,
entry 2), because silver acetate has a better solubility than
silver halide in organic solvents. Various other palladium
catalysts were screened. These reactions worked well
with 2-iodocyclohex-2-enone and 1-ethynylcyclohexanol
(2.5 equiv), forming the desired product 3, when the
reaction was carried out using commercially available
AgOAc (20 mol%) as a co-catalyst in the presence of
PdCl2 or Pd(PPh3)4 (5 mol%) and i-Pr2NEt (1.5 equiv) in
DMF at 100 °C for 12 h (78% yield, Table 2, entry 3; and
87% yield, Table 2, entry 4). The reaction was also
Table 1 Preparation of a-iodo-a,b-unsaturated carbonyl compounds
2a, 2b
Entry
Product
R
Reaction conditions
Yield/%
1
2
3
4
2a
2a
2b
2b
H
I2/DMAP/K2CO3/THF-H2O
I2/pyridine/CCl4
99
97
96
98
H
Me
Me
I2/DMAP/K2CO3/THF-H2O
I2/pyridine/CCl4
Table 2 Pd/Ag salt-catalyzed
one-pot synthesis of
3,4-dihydro-5,7-bis
(1-hydroxycyclohexyl)
naphthalen-1(2H)-one (3)
Entry
Reaction conditionsa
Yield/%
1
PdCl2(PPh3)2/AgI/i-Pr2NEt/DMF/100 °C/12 h
PdCl2(PPh3)2/AgOAc/i-Pr2NEt/DMF/100 °C/12 h
PdCl2/AgOAc/i-Pr2NEt/DMF/100 °C/12 h
Pd(PPh3)4/AgOAc/i-Pr2NEt/DMF/100 °C/12 h
Pd(PPh3)4/AgOAc/i-Pr2NEt/THF/90 °C/12 h
Pd(PPh3)4/AgOAc/i-Pr2NEt/DMF/90 °C/18 h
Pd(PPh3)4/AgOAc/i-Pr2NEt/DMF/110 °C/12 h
Pd(PPh3)4/AgOAc/K2CO3/DMF/100 °C/12 h
Pd(PPh3)4/AgOAc/Et3N/DMF/100 °C/12 h
Pd(PPh3)4(2.5 mol%)/AgOAc/i-Pr2NEt/DMF/100 °C/12 h
Pd(PPh3)4(7.5 mol%)/AgOAc/i-Pr2NEt/DMF/100 °C/12 h
Pd(PPh3)4/AgOAc(15 mol%)/i-Pr2NEt/DMF/100 °C/12 h
Pd(PPh3)4/AgOAc(25 mol%)/i-Pr2NEt/DMF/100 °C/12 h
81
85
78
87
75
78
85
58
84
75
86
81
85
2
3
4
5
6
7
a
Reaction conditions
8
2-iodocyclohex-2-enones/1-
cyclohexyl-1-hydroxyacetylene/
base = 1:2.5:1.5, Pd catalyst
(5 mol%)/Ag salt (20 mol%);
100 °C, 12 h, nitrogen. Isolated
yield based on 2-iodocyclohex-
2-enone
9
10
11
12
13
123

Pd(PPh3)4/AgOAc-catalyzed one-pot synthesis
1057
performed at 90 or 110 °C in the presence of Pd(PPh3)4/
AgOAc in DMF or THF. As shown in Table 2, the reaction
at 90 °C gave a low yield (Table 2, entry 5). The yield of
the product 3 was not significantly improved by prolonging
the reaction time (Table 2, entry 6). When the reaction was
carried out at 110 °C, the desired product 3 was obtained in
85% yield (Table 2, entry 7), less than the yield of the
product at 100 °C. Therefore 100 °C is recommended as
the optimum temperature and the best solvent for
the reaction was DMF. We also examined various bases
(i-Pr2NEt, Et3N, and K2CO3) (Table 2, entries 4, 8, 9).
Among the conditions tested, i-Pr2NEt and Et3N efficiently
promoted this reaction in DMF as solvent in high yield,
whereas the weak base sodium carbonate afforded lower
yields (Table 2, entry 8). Thus i-Pr2NEt and Et3N were the
bases of choice.
Table 3 Pd(PPh3)4/AgOAc-catalyzed synthesis of 3,4-dihydro-
naphthalen-1(2H)-ones
1, 2
R
H
R0
Product
Yield/%
87
a
3
4
5
82
83
6
7
68
79
The results showed that the Pd(PPh3)4/AgOAc catalyst
system in the presence of i-Pr2NEt gave product 3 in a
high yield (87%, Table 2, entry 4). Subsequently we
examined this reaction in the presence of different
amounts of Pd(PPh3)4 and AgOAc. In the presence of
AgOAc (20 mol%) and i-Pr2NEt as base, both decreasing
and increasing the amount of Pd(PPh3)4 (Table 2, entries
10 and 11) somewhat decreased the product yield. Then
in the presence of Pd(PPh3)4 and i-Pr2NEt as base, both
decreasing and increasing the amount of AgOAc
(Table 2, entries 12 and 13) somewhat decreased the
product yield. The use of a further excess amount of
AgOAc (25 mol%) did not improve the yield (85%,
Table 2, entry 13).
b
Me
8
9
73
65
Reaction conditions 2-iodocyclohex-2-enones/1-alkyne/base = 1:2.5:1.5,
Pd(PPh3)4 (5 mol%)/AgOAc (20 mol%); 100 °C, 12 h, nitrogen. Isolated
yield based on 2-iodocyclohex-2-enone
These results showed that the experimental procedure
for this one-pot synthesis of 3,4-dihydro-5,7-bis(1-hy-
droxycyclohexyl)naphthalen-1(2H)-one was very simple
and straightforward. A mixture of 2-iodocyclohex-2-enone
(1 mmol), 1-ethynylcyclohexanol (2.5 mmol), and i-Pr2NEt
(DIPEA; 1.5 mmol) in 10 cm3 DMF was stirred at 100 °C
in the presence of 5 mol% Pd[(C6H5)3P]4 and 20 mol%
AgOAc for 12 h under nitrogen. Then after a simple
workup the product was directly purified using column
chromatography. Following the general reaction condi-
tions, we next examined the scope of this reaction with
various 2-iodocyclohex-2-enones and 1-alkynes, and the
results are summarized in Table 3. In general the reaction
proceeded efficiently for various 2-iodocyclohex-2-enones
and 1-alkynes to produce the desired 3,4-dihydronaphthalen-
1(2H)-ones in good yields (65–87%).
biologically important naphthalen-1(2H)-ones and struc-
turally related natural products.
Experimental
All reactions were run under nitrogen. All melting points
were determined on a Yanaco melting point apparatus. IR
spectra were recorded on a Nicolet FT-IR 5DX spectrom-
1
eter. The H NMR (300 MHz) and 13C NMR (75 MHz)
spectra were recorded on a Bruker ACF-300 spectrometer
with TMS as internal reference in CDCl3 solutions. The
J values are given in hertz. Elemental analyses were per-
In summary, we have successfully developed a novel
and operationally simple one-pot reaction for highly effi-
cient synthesis of 3,4-dihydronaphthalen-1(2H)-ones by
employing 2-iodocyclohex-2-enones, 1-alkynes, and a new
Pd[(C6H5)3P]4/AgOAc system. This general method pro-
vides high yields of 3,4-dihydronaphthalen-1(2H)-ones
which are key intermediates for the preparation of some
formed on
a Perkin-Elmer 240C instrument. Flash
chromatography was performed on silica gel (230–400
mesh) eluting with ethyl acetate–hexane mixtures.
2-Iodocyclohex-2-enone (2a) was prepared using Krafft
and Cran’s method [16]; 2-iodo-4,4-dimethylcyclohex-2-
enone (2b) was prepared using Felpin’s method [17].
123

1058
H. Liu et al.
General procedure for the one-pot synthesis
of 3,4-dihydronaphthalen-1(2H)-ones 3–9
144.88, 138.76, 137.80, 137.00, 136.50, 135.80, 135.20,
130.20, 129.88, 129.02, 128.60, 128.32 (2C), 127.70 (2C),
126.20, 125.78, 40.98 (O=C–CH2), 28.80 (C=C–CH2),
23.24 (3CH2) ppm; IR (NaCl, film): vꢀ = 1,672, 1,610,
To a mixture of 2-iodocyclohex-2-enone or 2-iodo-4,4-
dimethylcyclohex-2-enone (1.0 mmol), 34 mg AgOAc
(0.20 mmol), 58 mg Pd[(C6H5)3P]4 (0.05 mmol), and
200 mg DIPEA (1.5 mmol) in 10 cm3 DMF was added the
appropriate 1-alkyne (2.5 mmol) at room temperature
under nitrogen. The resultant mixture was stirred at 100 °C
for 12 h under nitrogen. TLC showed the starting material
disappeared. The mixture was diluted with 15 cm3
dichloromethane (DCM) and the solid was removed by
filtration, the filtrate was then concentrated in vacuo and
purified by flash chromatography (silica gel, EtOAc/hex-
anes, 1:1) providing the desired products 3–9.
1,550, 1,458, 1,430, 1,320 cm-1
.
3,4-Dihydro-5,7-bis(1-hydroxycyclohexyl)-4,4-
dimethylnaphthalen-1(2H)-one (8, C24H34O3)
Yield: 73%; m.p.: 98–100 °C (EtOAc); 1H NMR
8
(300 MHz, CDCl3): d = 8.10 (d, J = 2.1 Hz, 1H, C–H),
6
7.95 (d, J = 2.1 Hz, 1H, C–H), 2.63 (t, J = 6.6 Hz, 2H,
O=C–CH2), 2.25 (bs, 2H, 2 OH), 2.10–1.23 (m, 22H, 3CH2
and 2 cyclohexyl), 1.20 (s, 6H, 2 CH3) ppm; 13C NMR
(75 MHz, CDCl3): d = 198.27 (1C=O), 146.88 (CH=C–C),
146.10 (CH=C–C), 142.56 (CH=C–C), 135.04 (CH=C–C),
127.36 (CH=C–C), 123.12 (CH=C–C), 74.86 (C–OH),
73.98 (C–OH), 39.42 (O=C–CH2), 38.94 (2C), 38.08 (2C),
31.82 (2C, 2 CH3), 28.78 (C=C–CH2), 26.12, 25.68, 23.78
(3CH2), 22.30 (4C) ppm; IR (NaCl, film): vꢀ = 3,450,
3,4-Dihydro-5,7-bis(1-hydroxycyclohexyl)-
naphthalen-1(2H)-one (3)
Yield: 87%; light brown solid; m.p.: 175–176 °C
(EtOAc/hexanes) (174–176 °C [15]).
1,665, 1,600, 1,510, 1,450, 735 cm-1
.
3,4-Dihydro-5,7-bis(1-hydroxy-1-methylethyl)-
naphthalen-1(2H)-one (4)
3,4-Dihydro-5,7-bis(1-hydroxy-1-methylethyl)-4,4-
dimethylnaphthalen-1(2H)-one (9, C18H26O3)
1
Yield: 82%; light brown solid; m.p.: 109–111 °C
(EtOAc/hexanes) (108–110 °C [15]).
Yield: 65%; m.p.: 81–83 °C (EtOAc/hexanes); H NMR
8
(300 MHz, CDCl3): d = 7.96 (d, J = 2.1 Hz, 1H, C–H),
7.80 (d, J = 2.1 Hz, 1H, C–H), 2.53 (t, J = 6.0 Hz, 2H,
6
3,4-Dihydro-5,7-bis(1-hydroxyethyl)naphthalen-1(2H)-one
(5)
Yield: 83%; oil (brown gum [15]).
O=C–CH2), 2.13 (bs, 2H, 2 OH), 1.90 (t, J = 6.0 Hz, 2H,
3CH2), 1.61 (s, 6H, 2 CH3), 1.49 (s, 6H, 2 CH3), 1.37 (s,
6H, 2 CH3) ppm; 13C NMR (75 MHz, CDCl3): d = 198.20
(1C=O), 146.42 (CH=C–C), 145.38 (CH=C–C), 141.60
(CH=C–C), 126.75 (CH=C–C), 124.12 (CH=C–C), 123.24
(CH=C–C), 74.20 (C–OH), 72.52 (C–OH), 39.10 (O=C–
CH2), 31.64 (2C, 2 CH3), 31.56 (2C, 2 CH3), 30.18 (2C, 2
CH3), 28.46 (C=C–CH2), 23.46 (3CH2) ppm; IR (NaCl,
film): vꢀ = 3,405, 1,665, 1,618, 1,578, 1,460, 1,378, 1,205,
3,4-Dihydro-5,7-diisobutylnaphthalen-1(2H)-one
(6, C18H26O)
Yield: 68%; oil; 1H NMR (300 MHz, CDCl3): d = 7.90 (d,
J = 2.1 Hz, 1H, = C–H), 7.82 (d, J = 2.1 Hz, 1H, = C–
8
6
2
H), 3.18 (t, J = 6.0 Hz, 2H, CH2), 2.62 (d, J = 6.6 Hz,
2H, =C–CH2), 2.51 (d, J = 6.6 Hz, 2H, =C–CH2), 2.50 (t,
4
3
J = 6.0 Hz, 2H, CH2), 2.08 (m, 2H, CH2), 2.02 (m, 1H,
CH), 1.86 (m, 1H, CH), 1.12 (d, J = 6.6 Hz, 6H, 2 CH3),
1.00 (d, J = 6.6 Hz, 6H, 2 CH3) ppm; 13C NMR (75 MHz,
CDCl3): d = 198.82 (1C=O), 147.24 (CH=C–C), 144.88
(CH=C–C), 138.76 (CH=C–C), 128.32 (CH=C–C), 127.70
(CH=C–C), 122.90 (CH=C–C), 42.86 (CH=C–CH2), 40.98
(CH=C–CH2), 39.02 (O=C–2CH2), 31.10 (CH), 29.68
(CH), 28.80 (C=C–4CH2), 23.24 (CH2–3CH2–CH2), 22.64
(2C, 2 CH3), 22.13 (2C, 2 CH3) ppm; IR (NaCl, film):
920, 738 cm-1
.
Acknowledgments We are grateful to the NSF of Jiangsu Province
(Grant BK2008216) for financial support.
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