Gold catalyzed carbocyclization of phenyl substituted allylic acetates to synthesize benzocycle derivatives

Article abstract of DOI:10.1016/j.tetlet.2011.03.142

An efficient and environmentally benign method was developed to synthesize the benzocycles from phenyl substituted allylic acetates through gold catalyzed Friedel-Crafts type carbocyclization reaction. Different substitution patterns were investigated, wh

Full text of DOI:10.1016/j.tetlet.2011.03.142

Tetrahedron Letters 52 (2011) 2990–2993
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Gold catalyzed carbocyclization of phenyl substituted allylic acetates to
synthesize benzocycle derivatives
Heng Liu a, Ya-Hui Wang b, Li-Li Zhu b, Xiao-Xiao Li b, Wen Zhou b, Zili Chen b,c, , Wen-Xiang Hu a,
⇑
⇑
a Capital Normal University, Beijing 100048, PR China
b Department of Chemistry, Renmin University of China, Beijing 100872, PR China
c Beijing National Laboratory of Molecular Sciences, CAS Key Laboratory of Molecular Recognition and Function, Institute of Chemistry,
Chinese Academy of Sciences, Beijing 100190, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient and environmentally benign method was developed to synthesize the benzocycles from phe-
nyl substituted allylic acetates through gold catalyzed Friedel–Crafts type carbocyclization reaction. Dif-
ferent substitution patterns were investigated, which gave a series of benzocyclohexane derivatives in
moderate to excellent yields.
Received 26 January 2011
Revised 21 March 2011
Accepted 30 March 2011
Available online 5 April 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Gold catalyzed reaction
Benzocycle
Friedel–Crafts reaction
Allylic acetate
Utilizing gold complexes in homogeneous organic catalysis has
achieved great progress in recent years. In this regard, most of the
reported reactions started from the activation of the substrate’s C–
reaction of the allylic acetates with propargylic alcohols to give
multifunctionalized oxygen hetereocycles (Scheme 1, Eq. 3).6b It
was proposed that an allylic cation intermediate was formed as
the key intermediate from allylic acetate in the condition of gold
catalyst, which was then trapped by the intra- or intermolecular
nucleophiles to give the desired products. We envisioned that the
C multiple bonds via forming auric
p-complexes, and focused on
the transformations involving alkyne-, allene-, or olefin-containing
derivatives.1 In the process, the gold complex was usually used as
the p-acid catalyst.
Allylic esters are important building blocks in organic synthesis.
These substrates have been widely utilized in transition metal
(especially later transition metal, such as: Ni, Pd, Ir, Rh etc.) cata-
lyzed allyl coupling reactions to provide alkene-containing prod-
ucts of variable structural characteristics and diversities.2
However, the study of employing gold complexes in the reaction
of allylic esters, to our knowledge, is very limited.34 This is very
notable as compared with the extensive research of propargylic es-
ters in gold chemistry.5
O
O
O
RO
RO
Au(I) or
Au(III)
OAc
(Eq. 1)
ROOC
O
O
R1 R2
O
Au(I) or
Au(III)
OAc
Ph
Ph
or
MeOOC
(Eq. 2)
X
X
X=NTs or C(COOMe)2
R1, R2=H or OH
We have recently investigated the gold catalyzed reactions of
the allylic acetates.6 In our previous results, it was found that gold
catalyzed intramolecular nucleophilic addition of the esters onto
Ph
OAc
R5
Au(I)
Oxygen
Hetereocycles
the allylic acetates would give
c-vinyl butyrolactones with high
+
(Eq. 3)
R4
R2
R3
diastereoselectivities (Scheme 1, Eq. 1).6a As an extension of this
reaction, carbocyclization of the dienyl acetates via gold catalysis
provided 3-vinyl cyclohexanols and their bicyclic derivatives
(Scheme 1, Eq. 2).6c And then, we reported the inter-molecular
R1
OH
CO2R
CO2R
OAc
RO2C
Gold catalyst
RO2C
⇑
Corresponding authors. Fax: +86 10 62516660 (Z.L.C.); fax: +8610 68904750
(W.-X.H.).
E-mail addresses: zilichen@ruc.edu.cn (Z.L. Chen), huwx66@163.com (W.-X. Hu).
Scheme 1. Gold catalyzed reactions of the allylic acetate derivatives.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.03.142

H. Liu et al. / Tetrahedron Letters 52 (2011) 2990–2993
2991
Table 1
classical routes to prepare these compounds have recourse to the
cyclic radical addition and carbopalladation of the 2-alkenyl/alky-
nyl aryl halides, in which, the tedious preparation of the aryl halide
reactants was needed.8a In 2002, Ma and Zhang reported the acid
catalyzed cyclic Friedel–Crafts reaction of 6-acetoxy-4-alkenyl are-
nes to construct the benzocycle derivatives.8 However, the syn-
thetic utility of this reaction was dwarfed by the high reaction
temperature and the use of the acidic solvent (TFA/HOAc = 3:1).
In this Letter, we will report an efficient and environmentally be-
nign method to synthesize these important structural entities via
gold catalyzed carbocyclization of the phenyl substituted allylic
acetates. In this reaction, gold complex was used as the strong le-
wis acid catalyst.
The readily available 4-acetoxy-2-isopentene substituted ben-
zylmalonate 1a was chosen as the model system for our initial
investigation. When compound 1a was treated with 5% mol equiv
of AuPPh3Cl/AgOTf or AuPPh3Cl/AgBF4 in DCM at rt, no product was
obtained (Table 1, entries 1 and 2). To enhance the catalyst’s lewis
acidity, the silver source was changed from AgOTf and AgBF4 to
AgPF6 and AgSbF6. To our delight, the reaction occurred when 5%
mol equiv of AuPPh3Cl/AgPF6 was employed, giving product 2a in
32% yield (Table 1, entry 3), while combination of AuPPh3Cl/AgSbF6
(5% mol equiv) afforded the desired product in nearly quantitative
yield (Table 1, entry 4).
The effect of the catalyst loading on the reaction yield was then
tested. 2% mol equiv of catalyst also gave a high reaction yield,
though with a long reaction time (Table 1, entry 5). However, fur-
ther reducing the gold catalyst amount to 1% led to a much less
yield (Table 1, entry 6). In solvent screening experiments, no reac-
tion occurred in CH3CN. The effect of dichloroethane (DCE) was
similar to DCM (Table 1, entries 7 and 8). AuPPh3Cl or AgSbF6 alone
failed to catalyze the reaction at all. (Table 1, entries 9 and 10).
Among the non-phosphine-ligated gold catalysts, AuCl3 had the
highest catalytic activity (Table 1, entry 12). Lewis acids such as
BF3ÁEt2O, Cu(OTf)2, AlCl3, FeCl3 were also examined. BF3ÁEt2O, and
Carbocyclization of 1a to provide benzocycle 2aa
E
E
CO2Et
CO2Et
catalyst
Solvent
OAc
E=CO2Et
1a
2a
Catalyst (loading %)
Solvent
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
AuPPh3Cl/AgOTf (5)
AuPPh3Cl/AgBF4(5)
AuPPh3Cl/AgPF6(5)
AuPPh3Cl/AgSbF6(5)
AuPPh3Cl/AgSbF6(2)
AuPPh3Cl/AgSbF6(1)
AuPPh3Cl/AgSbF6(2)
AuPPh3Cl/AgSbF6(2)
AuPPh3Cl
AgSbF6
AuCl
AuCl3
AlCl3
DCM
DCM
DCM
DCM
DCM
DCM
DCE
CH3CN
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
6
6
6
6
0
0
32
99
95
72
91
0
0
0
0
12
12
12
12
6
9
10
11
12
13
14
15
16
17
18
6
6
3
4
4
4
3
4
93
31
0
FeCl3
Cu(OTf)2
0
BF3ÁEt2O
67
Trace
61
TsOH
AuPPh3Cl/AgSbF6(2)
1 equiv K2CO3
24
a
Unless noted, all reactions were carried out at 0.5 mmol scale in solvent (1 mL)
at room temperature.
b
Isolated yields.
presence of the allylic cation intermediate might also promote the
intramolecular C–C bond formation between phenyl group and
allylic acetates to provide the benzocycle derivatives (Scheme 1).
Benzocycles appear frequently as common structural units in
natural and unnatural products with biological potentials.7 The
Table 2
Gold catalyzed carbocyclization of phenyl substituted allylic acetates 1 to synthesize benzocycle derivatives 2a
R1
R2 R3
CO2Et
CO2Et
E
E
catalyst
Solvent
OAc
R2
E=CO2Et or CO2Me
R3
R1
1
2
Entry
1
Substrate
% Cat.
2
Time (h)
Product
Yield (%)b
95
CO2Et
CO2Et
OAc
OAc
EtO2C
EtO2C
12
1a
2a
E
E
2
3
2
5
2
6
87
23
1b, R= tBu
1c, R= F
2b, R= tBu
2c, R= F
MeO2C
MeO2C
R
R
E=CO2Me
CO2Me
CO2Me
OAc
MeO2C
MeO2C
4
2
4
95
2d
1d
Ph
E
5
6
2
2
4
2
99
97
E
1e, R = H
OAc
2e, R = H
2f, R = tBu
E=CO2Me
MeO2C
MeO2C
1f, R = tBu
R
R
Ph
(continued on next page)

2992
H. Liu et al. / Tetrahedron Letters 52 (2011) 2990–2993
Table 2 (continued)
Entry
Substrate
% Cat.
Time (h)
0.5
Product
Yield (%)b
Ph
CO2Me
CO2Me
OAc
MeO2C
MeO2C
7
2
99
Ph
2g
1g
Ph
OAc
MeO2C
MeO2C
8
9
2
2
1
2
91
75
CO2Me
CO2Me
2h
1h
Ph
E
E
MeO2C CO2Me
OAc
E=CO2Me
1i
2i
E
E
CO2Me
CO2Me
OAc
MeO2C
MeO2C
E=CO2Me
OAc
1j
2j
10
2
2
4
65
72
anti/syn = 1/1
EE
NTs
OAc
TsN
11
24
2k
1k
a
Unless noted, all reactions were carried out at 0.5 mmol scale in 1 mL DCM at room temperature with the addition of 2% mol equiv of Ph3PAuCl/AgSbF6.
Isolated yields.
b
AlCl3 gave 2a in moderate yields, together with a mixture of elim-
To determine the effect of the substrate’s stereochemistry on
the reaction yield, we turned to investigate the reactions of com-
ination products (Table 1, entries 13 and 16). In the control exper-
iments, TsOH afforded trace amount of 2a. Treating 1a in the basic
condition gave 2a in 61% yield after a prolonged reaction time (Ta-
ble 1, entry 18).
pound 3 (regioisomer of 1e) and trans-1h. Treating
3 with
Ph3PAuCl/AgSbF6 in DCM gave 2e in 97% yield (Scheme 2, Eq. 4),
while the reaction of trans-1h afforded 2h in 79% yield (Scheme 2,
Eq. 5). These results were similar to those of 1e, 1h (Table 2, entry
5, 9). Nevertheless, when the alcoholic analogue 4 underwent the
same transformation in the condition of gold catalyst, the corre-
sponding product 2e was obtained only in 56% yield, which is con-
siderably lower than that of 1e. A plausible mechanism started
from the formation of an allylic cation intermediate, which was
then trapped by the intramolecular electrophilic substitution reac-
tion to give the desired product. This conforms to the similar reac-
tivities exhibited by compound 3 (regioisomer of 1e) and trans-1h.
By using the condition from entry 5 in Table 1, the scope and
limitations of this reaction were then explored.9 A number of cyclic
and linear substrates with different substitution patterns at the
phenyl group as well as at the allylic acetate moiety were prepared
from the simple starting materials by utilizing –C(COOMe) or TsN–
as the linker group. Table 2 showed some representative examples
for the preparation of the benzocycle derivatives 2 using a variety
of differently substituted substrates 1a–1k. The influence of the
substituent R1 on the phenyl group (Table 2’s Scheme) was first
studied by using terminal 4-acetoxy-2-isopentene as the electro-
phile. It was found that substrates 1b and 1d, bearing an electro-
rich phenyl group (Table 2, entries 2 and 4), worked better than
their electro-deficient analogue 1c. Compound 2c was obtained
only in 23% yield, even in the condition of 5% mol equiv of gold cat-
alyst. Compound 2d was formed as the para-selective product,
without formation of the ortho isomer. The substituents at the dou-
ble bond and at the ally carbon also affected the reaction yield. As
compared with the results of 2a, 2b, and 2d, product 2e, 2f, and 2g
can be obtained in slightly higher reaction yields (Table 2, entries
5–7). In the reaction of naphthyl containing substrate 1h, only
ortho-selective product 2h was separated in 91% yield (Table 2, en-
try 8). This means the electric effect is more favored. The cyclic
substrate 1i can be transformed into tricyclic product 2i, with a
slightly lower yield (75%, Table 2, entry 9). Substrate 1j, which con-
tained two allylic acetate units, was also investigated. It provided
the corresponding tricyclic product 2j in 65% yield with a ratio of
anti/syn = 1:1 (Table 2, entry 10). Substrate with –NTs as the linker
group was then studied. As compared with the result obtained
from 1a, TsN– containing substrate 1k gave the desired products
in relative low yield (72%, Table 2, entry 11).
CO2Me
CO2Me
Ph
OAc
Ph3PAuCl/
AgSbF6 (2%)
MeO2C
MeO2C
(Eq. 4)
DCM, rt
Ph
3
2e, 97%
MeO2C CO2Me
MeO2C CO2Me
Ph3PAuCl/
AgSbF6 (2%)
(Eq. 5)
(Eq. 6)
OAc
DCM, rt
Trans-1h
Ph
2h, 79%
CO2Me
CO2Me
MeO2C CO2Me
Ph3PAuCl/
AgSbF6 (2%)
OH
DCM, rt
Ph
4
2e, 56%
Scheme 2. Investigation of the reaction of compound 3, trans-1h, and compound 4.

H. Liu et al. / Tetrahedron Letters 52 (2011) 2990–2993
2993
Fleming, I., Eds.; Pergamon: Oxford, 1991; pp 585–661. Vol. 4; (c) Hegedus, L. S.
In Organometallics in Synthesis; Schlosser, M., Ed.; Wiley: Chichester, 1994; pp
427–444; (d) Hegedus, L. S. Organische Synthesemit übergangsmetallen; VCH:
Weinhein, 1995.
Eq. 6’s result means that the presence of the acetate would favor
the formation of the allylic cation intermediate.
In summary, we herein have developed an efficient and envi-
ronmentally benign new method for the preparation of the benzo-
cycles via a gold catalyzed carbocyclization. Different substitution
patterns were investigated, which gave a series of benzocyclohex-
ane derivatives in moderate to excellent yields. The reaction pro-
ceeded via a Friedel–Crafts type carbocyclization process, in
which, the gold catalyst exhibited high lewis acidity.
3. (a) Marion, N.; Gealageas, R.; Nolan, S. P. Org. Lett. 2007, 9, 2653; (b) Gourlaouen,
C.; Marion, N.; Nolan, S. P.; Maseras, F. Org. Lett. 2009, 11, 81; (c) Porcel, S.;
9
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López-Carrillo, V.; Garc
2008, 47, 1883.
a-Yebra, C.; Echavarren, A. M. Angew. Chem., Int. Ed.
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M.; Gagosz, F. Org. Lett. 2007, 9, 985; (b) Aponick, A.; Li, C.-Y.; Biannic, B. Org.
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Lett. 2010, 12, 3468; (c) Zhu, L.-L.; Wang, Y.-H.; Zhang, Y.-X.; Li, X.-X.; Liu, H.;
Chen, Z. J. Org. Chem. 2011, 76, 441.
7. (a) Kuramoto, M.; Yamada, K.; Shikano, M.; Yazawa, K.; Arimoto, H.; Okamura,
T.; Uemura, D. Chem. Lett. 1997, 885; (b) Buckingham, J., Ed. Dictionary of Natural
Products; Chapman & Hall, London, 1994, Vol. 1, pp. 812–813.; (c) Palmer, D. C.;
Strauss, M. J. Chem. Rev. 1977, 77, 1–36; (d) Shiotani, S.; Kometani, T.;
Mitsuhashi, K.; Nozawa, T.; Kurobe, A.; Futsukaichi, O. J. Med. Chem. 1976, 19,
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Acknowledgment
Support of this work by the grant from the National Sciences
Foundation of China (Nos. 20872176 and Nos. 21072224) is grate-
fully acknowledged.
Supplementary data
8. (a) Ma, S.; Zhang, J. Tetrahedron Lett. 2002, 43, 3435. and references therein; (b)
Ma, S.; Zhang, J. Tetrahedron 2003, 59, 6273.
Supplementary data (a brief experimental details and the spec-
tra data for all the products) associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2011.03.142.
9. General Procedure for the gold catalyzed Friedel–Crafts type carbocyclization
reaction of allylic acetate: The gold catalyst was generated in a oven-dried
schlenk tube containing a magnetic stir bar under N2 by addition of AgSbF6
(0.02 equiv), AuPPh3Cl (0.02 equiv), and 0.5 mL CH2Cl2. After stirring the catalyst
mixture at room temperature for 2 min, a solution of substrate 1a (0.5 mmol) in
0.5 mL CH2Cl2 was added. The resulting mixture was allowed to stand at room
temperature until complete consumption of starting material monitored by TLC
analysis, then the solvent was removed by rotary evaporation, and the residue
was purified by column chromatography on silica gel to afford the described
compound 2a in 95% yield. The spectral data of diethyl 3,4-dihydro-4-methyl-4-
vinylnaphthalene-2,2(1H)-dicarboxylate 2a: 1H NMR (400 MHz, CDCl3): d 7.18–
7.15 (m, 4H), 5.85 (dd, J = 17.3,10.5 Hz, 1H), 4.93 (d, J = 10.6 Hz, 1H), 4.63 (d,
J = 17.2 Hz, 1H), 4.17 (q, J = 7.1 Hz, 2H), 4.08 (q, J = 7.1 Hz, 2H), 3.33 (d,
J = 16.0 Hz, 1H), 3.12 (d, J = 16.1 Hz, 1H), 2.52 (d, J = 14.3 Hz, 1H), 2.38 (d,
J = 14.2 Hz, 1H), 1.39 (s, 3H), 1.23 (t, J = 7.1 Hz, 3H), 1.20 (t, J = 7.1 Hz, 3H); 13C
NMR (100 MHz, CDCl3): d 171.9, 170.9, 147.0, 139.7, 133.7, 128.8, 127.7, 126.4,
126.1, 112.5, 61.4, 61.1, 52.3, 40.8, 40.5, 35.0, 29.3, 14.0, 13.8.
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