Palladium(II)-catalyzed synthesis of functionalized indenes from o -alkynylbenzylidene ketones

Article abstract of DOI:10.1021/jo1023574

An efficient method for the synthesis of functionalized indenes from o-alkynylbenzylidene ketones under palladium(II) catalysis was developed. The reaction is initiated by trans-nucleopalladation of alkynes, followed by conjugate addition and quenched by

Full text of DOI:10.1021/jo1023574

pubs.acs.org/joc
SCHEME 1. Cyclization of o-Alkynylbenzylidene Ketones
Catalyzed by Pd(II)
Palladium(II)-Catalyzed Synthesis of Functionalized
Indenes from o-Alkynylbenzylidene Ketones
Feng Zhou, Xiuling Han, and Xiyan Lu*
State Key Laboratory of Organometallic Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 345 Lingling Road, Shanghai 200032, China
to the synthesis of the indene ring system have been devel-
oped, embodying the annulation of phenyl-substituted
allylic alcohols,4 the ring expansion of substituted cyclo-
propenes,5 and the reduction/dehydration of the indanones.6
Although the methods mentioned above are quite effective in
synthesizing simple indenes, certain drawbacks are unavoid-
able in the preparation of highly substituted indenes, namely
lengthy reaction sequences, strong acid conditions, and the
low tolerance for sensitive organic functionality. Tandem
cyclization reactions catalyzed by transition metals have
been proven highly useful especially when the highly sub-
stituted indene derivatives and their yields are concerned,7,8
whereas there are only limited reports for the synthesis of
acetoxyindenes or haloindenes.9 On the basis of the advance-
ment of acetoxypalladation and halopalladation chemistry,10
we conceived if 3-functionalized indenes could be obtained
via the tandem reaction of o-alkynylbenzylidene ketone
initiated by nucleopalladation of the triple bond (Scheme 1).
Herein we report our results of the successful synthesis of this
class of indene compounds.
xylu@mail.sioc.ac.cn
Received November 27, 2010
An efficient method for the synthesis of functionalized
indenes from o-alkynylbenzylidene ketones under palla-
dium(II) catalysis was developed. The reaction is initiated
by trans-nucleopalladation of alkynes, followed by con-
jugate addition and quenched by protonolysis of the
carbon-palladium bond. With acetate and halide ions
as nucleophiles, 3-acetoxy- and 3-halogen-substituted in-
denes could be obtained in high yields.
With the hypothesis mentioned above, initial studies were
focused on using o-alkynylbenzylidene ketone 1a as a model
substrate. Gratifyingly, the tandem cyclized product 2a was
formed in 85% yield in HOAc (Table 1, entry 1). Other
solvents such as HOAc/CH3CN (1/1), HOAc/DCE (1/1),
Molecules containing the indene core have been attractive
as drug candidates possessing remarkable biological
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as well as precursors of metallocene complexes3 for catalysts
of polymerization processes. Consequently, some approaches
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DOI: 10.1021/jo1023574
r
Published on Web 01/20/2011
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2011 American Chemical Society

Zhou et al.
JOCNote
TABLE 1. Optimization of the Palladium-Catalyzed Synthesis of
3-Acetoxy Indene from 1aa
TABLE 2. Palladium-Catalyzed Synthesis of 3-Acetoxy Indenesa,b
entry
ligand
bpyc
bpy
bpy
bpy
bpy
—
bpy
solvent (v/v)
HOAc
HOAc/CH3CN (1/1)
HOAc/DCE (1/1)
time (h)
yield (%)b
1
2
3
4
5
30
40
40
30
20
24
24
20
36
36
24
36
24
50
24
85
53
36
85
85
0
HOAc/toluene (1/1)
HOAc/dioxane (1/1)
HOAc/dioxane (1/1)
HOAc/dioxane (1/1)
HOAc/dioxane (1/1)
HOAc/dioxane (1/1)
HOAc/dioxane (1/1)
HOAc/dioxane (1/1)
HOAc/dioxane (1/1)
HOAc/dioxane (1/1)
HOAc/dioxane (1/1)
HOAc/dioxane (1/1)
6
7d
8e
9f
0
bpy
83
29
87
92
78
0
NO2-bpyc
MeO-bpyc
Phen.H2Oc
Phenc
PPh3
10
11
12
13
14
15h
bpy/H2Og
bpy
87
73
aReaction conditions: 1a (0.15 mmol), Pd(OAc)2 (10 mol %), ligand
(12 mol %), solvent (2 mL), 90 °C. bIsolated yield. bpy = 2,20-
c
aReactions were carried out at 90 °C with 1 (0.15 mmol), Pd(OAc)2
bipyridine; NO2-bpy = 4,40-dinitro-2,20-bipyridine; MeO-bpy = 4,40-
dimethoxy-2,20-bipyridine; Phen = 1,10-phenanthroline. dNo Pd(OAc)2
was used. ePd(OAc)2/ligand (1/2). f53% of 1a was recovered. gH2O (12
mol %) was added. h1 equiv of LiOAc was added.
(10 mol %), Phen H2O (12 mol %) in HOAc/dioxane (1/1, 2 mL).
bIsolated yield. cThe reaction was carried out at 80 °C. dNo cyclized
product was obtained. eThe reaction was carried out at 60 °C.
3
HOAc/toluene (1/1), and HOAc/dioxane (1/1) were also
examined (Table 1, entries 2-5). Finally, the HOAc/dioxane
(1/1) system was chosen as the solvent because of the highest
yield obtained and the shortest time required. Control experi-
ments demonstrated that no reaction occurred in the absence
of the palladium catalyst or the ligand (Table 1, entries 6 and
7). When the ratio of catalyst and ligand was changed from 1/
1.2 to 1/2, the yield slightly declined to 83% (Table 1, entry 8).
Next, several ligands including nitrogen-containing ligands
with electron-withdrawing or -donating group and triphe-
nylphosphine were screened. 1,10-Phenanthroline monohy-
drate gave the best yield (92%), while a lower yield was
obtained by using 1,10-phenanthroline (Table 1, entries
9-13). The reaction yield incredibly reduced to 73% with
the addition of LiOAc (Table 1, entry 15). Thus, 1a (0.15
mmol), Pd(OAc)2 (10 mol %), 1,10-phenanthroline mono-
hydrate (12 mol %), and HOAc/dioxane (1/1) at 90 °C were
chosen as the optimized conditions.
Under these optimized reaction conditions, the scope of
the tandem reaction was investigated. The results are shown
in Table 2. The substrates, 1a-c and 1e with an alkoxy or
alkyl group on one side of the alkyne, reacted smoothly to
give corresponding cyclized products in good to excellent
yields (Table 2, 2a-c and 2e). The reaction of 1d with an
electron-withdrawing group on one side of the alkyne could
also proceed successfully to give the product with the yield of
68% (Table 2, 2d). In the case of phenyl-substituted alkyne
1f, the reaction was completed in 72 h and the yield was
declined dramatically to 54% (Table 2, 2f). Similar reactivity
was observed in the ketones with different substituents
(Table 2, 2a and 2g). When the ketone group in 1a was
changed to an ester group 1h, no annulation product was
detected (Table 2, 2h). The effect of the substituents on the
aromatic ring of the o-alkynylbenzylidene ketone was also
TABLE 3. Optimization of the Palladium-Catalyzed Synthesis of
3-Halogen-Substituted Indenesa
yield (%)b
entry
LiX
temp (°C)
time (h)
3
4
1
2
3
4
LiBr
LiBr
LiBr
LiCl
80
60
50
50
4.5
6.0
8.5
7.0
3a (52)
3a (70)
3a (75)
3m (80)
4a (39)
4a (8)
4a (0)
4m (0)
aReaction conditions: 1a (0.15 mmol), Pd(OAc)2 (5 mol %), LiX (4.0
equiv), HOAc (2 mL). bIsolated yield.
examined. The reactions gave good to excellent yields
(Table 2, 2i-k). However, only a 55% yield of the product
was obtained with the naphthalene ring as a substitute for the
benzene ring (Table 2, 2l).
After the reaction initiated by acetoxypalladation was well
developed, the halide ion was chosen as the nucleophile instead
of the acetoxy anion to perform the reaction. First, 1a was
still chosen as the model substrate. On the basis of our
previous works,10d the reaction was initially conducted at
80 °C by using Pd(OAc)2 as the catalyst in the presence of
LiBr and HOAc. The desired 3-bromoindene derivative 3a
was generated in 52% yield together with a byproduct 4a
(Table 3, entry 1). Comparing 3a with 4a, it is obvious that
the group OMe in 3a was replaced by the group OAc in 4a.
Control experiments revealed that 4a could be formed by
only heating 3a in the presence of LiBr/HOAc at 80 °C,
indicating that the byproduct 4a might be formed from the
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Zhou et al.
JOCNote
TABLE 4. Palladium-Catalyzed Synthesis of 3-Halogen-Substituted
Indenesa,b
SCHEME 2
SCHEME 3. Hydrolysis of 3-Acetoxy Indene
SCHEME 4. Proposed Mechanism for the Annulation Reaction
aReactions were carried out at 50 °C with 1 (0.15 mmol), Pd(OAc)2
(5 mol %), LiX (4 equiv), and HOAc (1 mL). bIsolated yield. cThe
reaction was carried out at 70 °C. dNo cyclized product was obtained.
eThe reaction was carried out at 90 °C.
product 3a. It was proposed in literature11 that the reaction
involves the formation of an oxonium intermediate by the
coordination of the oxygen atom of the ether in product 3a to
the lithium ion. The reaction is then driven to completion by
nucleophilic attack of the acetate ion in the presence of acetic
acid. Then it was observed that a higher yield of 3a (70%)
could be obtained at a lower temperature (60 °C) (Table 3,
entry 2). When the temperature was further lowered to 50 °C,
the reaction afforded 3a in 75% isolated yield without the
formation of 4a (Table 3, entry 3). Moreover, the yield could
be increased to 80% when LiCl was used as the nucleophile
instead of LiBr (Table 3, entry 4). Then, LiBr was chosen
as the nucleophile for easier transformation to other deriva-
tives.
Then a variety of other substrates are readily accessed with
this methodology as outlined in Table 4. The substrates 1a-c
and 1e with an alkoxy or alkyl group on one side of the
alkyne reacted smoothly to give corresponding cyclized
products in good to excellent yields (Table 4, 3a-c and 3e).
Cyclization of 1d with an electron-withdrawing group oc-
curred providing 3d with a yield of 89%, which was higher
than the yield of the corresponding 3-acetoxy product 2d.
The annulation of substrate 1f was completed in 50 h with a
84% yield of the product (Table 4, 3f). Similar results were
achieved in the ketones with different substituents (Table 4,
3a and 3g). In the case of an ester group (1h), no cyclized
product was found (Table 4, 3h). It is worth noting that the
reaction of the substrates 1i and 1j with electron-donating
groups in the benzene ring gave the products 4i and 4j, in
which the group OMe was completely replaced by the group
OAc as shown in Scheme 2, probably due to the further
conversion of the initial products similar to the transforma-
tion of 3a to 4a. On the other hand, the reaction of 1k with a
chlorine atom in the benzene ring provided 3k in 93% yield in
a normal way (Table 4, 3k). Surprisingly, no product was
detected when the benzene ring was changed to the naphtha-
lene ring even at 90 °C with the extension of the reaction time
to 50 h (Table 4, 3l).
The possibility of further conversion of the 3-acetoxy
indenes to other products was studied. Treatment of 2c with
HCl (1 mol/L) in dioxane at 90 °C afforded the hydrolysis
product 5c in 85% yield with the formation of exocyclic
double bond (Scheme 3). Compound 5c could be transferred
further to the spirocyclic skeletons,12 which occurred widely
in a large number of natural products.13
A plausible mechanism involving trans-nucleopalladation
and conjugate addition is proposed as shown in Scheme 4.
The first step involves π-coordination of the carbon-carbon
(12) Muthusamy, S.; Krishnamurthi, J.; Nethaji, M. Chem. Commun.
2005, 3862.
(13) For reviews of spirocyclic compounds, see: (a) Martin, J. D. In
Studies in Natural Products Chemistry; Rahman, A. U., Ed.; Elsevier:
Amsterdam, The Netherlands, 1990; Vol. 6, p 59. (b) Sannigrahi, M.
Tetrahedron 1999, 55, 9007 and references cited therein.
(11) (a) Burwell, R. L. Chem. Rev. 1954, 54, 615. (b) Bajwa, J. S.;
Anderson, R. C. Tetrahedron Lett. 1991, 32, 3021.
J. Org. Chem. Vol. 76, No. 5, 2011 1493

Zhou et al.
JOCNote
multiple bond of 1 to the Pd(II) species followed by trans-
nucleopalladation of the carbon-carbon triple bond of I to
afford vinylpalladium species II. Then, conjugate addition of
the vinylpalladium species to the double bond of the benzy-
lidene ketone occurs to yield III or IV. Protonolysis of IV
gives the products 2 in the presence of an acid with regenera-
tion of the palladium(II) species to complete the catalytic
cycle.10a It is also worth mentioning that the bidentate
nitrogen-containing ligands or halide ions play a crucial role
in inhibiting the β-H elimination of intermediate III and
promoting the protonolysis of the carbon-palladium bond
making the catalytic cycles possible.10a,d,g,h
In conclusion, we have developed a palladium-catalyzed
synthesis of functionalized indenes from o-alkynylbenzyli-
dene ketones. A variety of 3-acetoxy- and 3-halogen-sub-
stituted indenes can be easily obtained from this method.
Further studies on the asymmetric version and application of
this reaction are underway.
(1 mL) was stirred at 50 °C for 2-50 h. Then the solvent was
removed under reduced pressure and the residue was purified by
flash chromatography (petroleum ether:ethyl acetate = 20:1 to
3:1) to afford the product 3a in 75% yield as an oil. IR (neat) ν
3070, 2984, 2926, 2893, 2822, 1719, 1610, 1461, 1361, 1261, 1190,
1161, 1093, 1021, 928, 761, 736, 536 cm-1; 1H NMR (300 MHz,
CDCl3) δ 7.42-7.33 (m, 3H), 7.28-7.23 (m, 1H), 4.37 (d, J =
12.0 Hz, 1H), 4.30 (d, J = 12.0 Hz, 1H), 4.15 (t, J = 6.3 Hz, 1H),
3.32 (s, 3H), 2.99 (dd, J = 17.4, 6.3 Hz, 1H), 2.65 (dd, J = 17.4,
6.6 Hz, 1H), 2.18 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 206.7,
145.4, 143.3, 141.9, 127.3, 126.7, 122.9, 121.1, 120.6, 68.0, 58.0,
45.6, 44.1, 30.2; MS (70 eV, EI) m/z (%) 296 [Mþ, 81Br], 294 [Mþ,
79Br], 264, 262, 238, 236, 221 (100), 219, 207, 183, 171, 155, 141,
139, 128, 127, 115, 101, 89, 77, 63, 43; HRMS calcd for
C14H1579BrO2 294.0255, found 294.0253. Characterization data
for other products in Table 4 were shown in the Supporting
Information.
Hydrolysis of 3-Acetoxy Indene 2c. 3-Acetoxy indene 2c (0.24
mmol) was dissolved in 1 mL of dioxane. Then the HCl (1 mL, 1
mol/L) was added and the mixture was heated at 90 °C for 40
min. The reaction mixture was diluted with diethyl ether (25 mL)
and washed with saturated NaHCO3. The aqueous layer was re-
extracted with diethyl ether (25 mL) twice. The organic layers
were combined, dried (Na2SO4), and filtered, and the solvent
was removed in vacuo. The residue was purified by flash
chromatography (petroleum ether:ethyl acetate = 4:1) to give
the product 5c in 85% yield as an oil. IR (neat) ν 2956, 2924,
2852, 1708, 1643, 1607, 1467, 1363, 1302, 1205, 1160, 1099, 985,
757 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 7.8 Hz,
1H), 7.62 (t, J = 7.8 Hz, 1H), 7.49-7.40 (m, 2H), 6.35 (s, 1H),
5.63 (s, 1H), 4.44 (t, J = 6.3 Hz, 1H), 2.96-2.93 (m, 2H), 2.22 (s,
3H); 13C NMR(100 MHz, CDCl3) δ 206.5, 192.8, 153.2, 147.9,
137.3, 135.3, 128.1, 125.5, 124.4, 120.0, 50.0, 37.1, 30.4; MS (70
eV, EI) m/z (%) 200 [Mþ], 191, 169, 158, 143, 128, 115, 99, 86, 84,
57, 49 (100); HRMS calcd for C13H12O2 200.0837, found 200.0836.
Experimental Section
Typical Procedure for the Palladium-Catalyzed Synthesis of
3-Acetoxy Indenes. To a solvent mixture of HOAc/dioxane (1/1,
2 mL) containing Pd(OAc)2 (10 mol %) and 1,10-phenanthro-
line monohydrate (12 mol %) was added substrate 1a (0.15 mmol)
at 90 °C under nitrogen atmosphere. The mixture was stirred
until 1a disappeared as monitored by TLC. On cooling, the
solvent was removed under reduced pressure and the residue was
purified by flash chromatography (petroleum ether:ethyl acet-
ate = 20:1 to 4:1) to give the product 2a in 92% yield as an oil.
IR (neat) ν 2991, 2937, 2890, 2824, 1770, 1717, 1648, 1464, 1362,
1203, 1162, 1121, 1089, 1012, 949, 896, 755, 538 cm-1; 1H NMR
(400 MHz, CDCl3) δ 7.36 (dd, J = 7.2, 0.4 Hz, 1H), 7.29-7.19
(m, 2H), 7.12 (d, J = 6.8 Hz, 1H), 4.20-4.11 (m, 3H), 3.27 (s,
3H), 2.98 (dd, J = 17.6, 6.4 Hz, 1H), 2.70 (dd, J = 17.2, 6.8 Hz,
1H), 2.36 (s, 3H), 2.17 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
207.0, 168.1, 146.7, 145.0, 137.8, 130.4, 126.8, 126.2, 123.4,
118.4, 65.3, 57.9, 44.4, 42.2, 30.2, 20.5; MS (70 eV, EI) m/z
(%) 274 [Mþ], 242, 216, 200, 174, 157 (100), 143, 128, 115, 103,
89, 77, 58, 43; HRMS calcd for C16H18O4 274.1205, found
274.1202. Characterization data for other products in Table 2
were shown in the Supporting Information.
Acknowledgment. The Major State Basic Research Pro-
gram (2006CB806105) is acknowledged. We also thank the
National Natural Science Foundation of China (20732005,
20872158) and the Chinese Academy of Sciences for financial
support.
Supporting Information Available: Experimental proce-
dures and characterization data of new compounds. This ma-
terial is available free of charge via the Internet at http://pubs.
acs.org.
Typical Procedure for the Palladium-Catalyzed Synthesis of
3-Halogen-Substituted Indenes. Under nitrogen, a solution of 1a
(0.15 mmol), Pd(OAc)2 (5 mol %), and LiBr (4 equiv) in HOAc
1494 J. Org. Chem. Vol. 76, No. 5, 2011