Coupling/cyclization of 1,6-enynes with aryl halides: An efficient and general route for the synthesis of functionalized hexahydroindole and hexahydrobenzofuran derivatives

Article abstract of DOI:10.1016/j.tet.2010.09.029

An efficient and general route for the synthesis of functionalized hexahydroindole and hexahydrobenzofuran derivatives has been developed via the palladium-catalyzed domino coupling/cyclization reaction of 1,6-enynes and aryl halides. The results indicate

Full text of DOI:10.1016/j.tet.2010.09.029

Tetrahedron 66 (2010) 8648e8653
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Coupling/cyclization of 1,6-enynes with aryl halides: an efficient and general
route for the synthesis of functionalized hexahydroindole and
hexahydrobenzofuran derivatives
,
a
a
a,b,
Tuan-jie Meng a, Yi-min Hu a , Yong-jie Sun , Tao Zhu , Shaowu Wang
*
*
a College of Chemistry and Materials Science, Anhui Normal University, Eastern Beijing Road 1, Wuhu, Anhui 241000, PR China
b State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Shanghai 200032, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 15 June 2010
Received in revised form 10 August 2010
Accepted 8 September 2010
Available online 21 September 2010
An efficient and general route for the synthesis of functionalized hexahydroindole and hexahy-
drobenzofuran derivatives has been developed via the palladium-catalyzed domino coupling/cyclization
reaction of 1,6-enynes and aryl halides. The results indicated that the electronic properties of the aryl
halides strongly affect the reaction yields.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Coupling
Palladium
Hexahydroindole
Hexahydrobenzofuran
1,6-Enynes
1. Introduction
halides for the synthesis of substituted hexahydroindoles and
hexahydrobenzofurans.
Indole and benzofuran rings are important components of many
natural products and medicinally relevant compounds.1 As such,
they are also key intermediates in the process for the preparation of
natural products and clinical medicines.2 Because the availability of
these building blocks can contribute to the production of more
complex target molecules, many methods have been studied for the
preparation of indole and benzofuran systems, ranging from clas-
sical techniques to recently discovered methods.3e5 However, only
a few examples of the synthesis of hexahydroindole and the hexa-
2. Results and discussion
Optimal parameters in the reaction of N-(3-phenylprop-2-ynyl)-
N-(cyclohex-2-enyl)-4-methylbenzenesulfonamide (4) with methyl
4-bromobenzoate are listed inTable 1. The effect of temperature was
initially surveyed in the presence of 2 mol % Pd(OAc)2/4 mol % PPh3
and 2 equiv of base (n-Bu)3N in DMF. No desired product was ob-
served when the reaction was performed at 100 ꢀC, and most of the
staring material remained unchanged (Table 1, entry 1). Product 4b
was obtained in 66% yield when the reaction temperature was
raised to 120 ꢀC. However, no significant increase in the yield of
product 4b was observed when the reaction temperature was raised
from 120 to 130 ꢀC (Table 1, entries 2 and 3). Solvents frequently
used in Heck reactions, such as CH3CN, toluene, and DMF, were
employed as the reaction media under the conditions indicated in
Table 1. The best results were obtained in DMF (Table 1, entries 2, 4,
and 5). Attempts to improve the yield of the domino coupling/cy-
clization reaction by utilizing other inorganic bases, such as K2CO3,
NaCO3, and NaHCO3, were unsuccessful (Table 1, entries 8e10), and
(n-Bu)3N was found to be more effective than those of inorganic
bases. When the catalyst loading was less than 1.5 mol %, the
product yield was lower (Table 1, entry 6). A high yield of 66% was
hydrobenzofuran derivatives have been demonstrated. Yeh and
6
€
Backvall reported the synthesis of hexahydroindole and hexahy-
drobenzofuran7 through intramolecular 1,4-nucleophilic additions
of cyclic 1,3-dienes with amines or alcohols as nucleophiles.
€
Brase et al. synthesized hexahydroindole by an intramolecular
DielseAlder reaction.8 Meanwhile, palladium-catalyzed cyclization
reactions have been employed for the synthesis of different het-
erocycles.9,10 This study aims to investigate the potential of palla-
dium-catalyzed domino coupling/cyclization of enynes with aryl
* Corresponding authors. Tel.: þ86 553 386 9310; fax: þ86 553 388 3517; e-mail
addresses: yiminhu@mail.ahnu.edu.cn (Y.-m. Hu), swwang@mail.ahnu.edu.cn
(S. Wang).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.09.029

T.-jie Meng et al. / Tetrahedron 66 (2010) 8648e8653
8649
Table 1
the steric effects on the carbopalladationprocess. Noticeably, N-(but-
2-ynyl)-N-(cyclopent-2-enyl)-4-methylbenzenesulfonamide and
Optimization of Cyclization Conditionsa
N-(but-2-ynyl)-N-(cyclohept-2-enyl)-4-methylbenzenesulfonamide
had been tested and lead to complex products, probably the reason is
the high torsional strain of the cycloalkenyl group (cyclopentenyl or
cyclohepenyl).
Table 2
Synthesis of hexahydroindole and hexahydrobenzofurana
Entrya [Pd]/PPh3 (mol %)
Base (equiv) Solvent
T (ꢀC)b Yieldc (%)
1
2
3
4
Pd(OAc)2/PPh3 (2:4)
Pd(OAc)2/PPh3 (2:4)
Pd(OAc)2/PPh3 (2:4)
Pd(OAc)2/PPh3 (2:4)
Pd(OAc)2/PPh3 (2:4)
(n-Bu)3N
(n-Bu)3N
(n-Bu)3N
(n-Bu)3N
(n-Bu)3N
DMF
DMF
DMF
CH3CN
100
120
130
100
Trace
66
65
Trace
29
5
Toluene 120
6
7
8
9
10
11
12
13
Pd(OAc)2/PPh3 (1.5:3) (n-Bu)3N
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
120
120
120
120
120
120
120
120
51
66
21
14
16
Trace
38
Pd(OAc)2/PPh3 (3:6)
Pd(OAc)2/PPh3 (2:4)
Pd(OAc)2/PPh3 (2:4)
Pd(OAc)2/PPh3 (2:4)
PdCl2/PPh3 (2:4)
Pd(dba)2
(n-Bu)3N
K2CO3
Na2CO3
NaHCO3
(n-Bu)3N
(n-Bu)3N
(n-Bu)3N
Entry
Enyne
R1
Product
Yieldb (%)
1
2
3
4
5
6
7
8
1
1
1
1
1
1
2
2
2
2
2
2
2
2
3
3
3
3
4
4
4
4
4-COMe
3-Cl
4-Cl
1a
1b
1c
1d
1e
1f
2a
2b
2c
2d
2e
2f
2g
2h
3a
3b
3c
3d
4a
4b
4c
4d
73
72
76
81
74
75
78
85
60
83
74
83
81
40
67
57
70
61
27
66
40
63
Pd(PPh3)4
44
4-CN
a
All reactions were carried out under argon for 16 h by using enyne (1.0 equiv),
methyl 4-bromobenzoate (1.2 equiv), Pd(OAc)2, PPh3, base, and solvent (5 mL)
under the indicated conditions.
4-CO2Et
4-CHO
4-COMe
4-CN
H
4-Cl
b
Oil bath temperature.
Isolated yield.
c
9
10
11
12
13
14
15
16
17
18
19
20
21
22
3-Cl
4-CO2Me
4-CO2Et
4-OMe
4-Cl
obtained when 2 mol % Pd(OAc)2 was applied (Table 1, entry 2), and
no apparent improvement was observed on the yield when the Pd
(OAc)2 loading was more than 2 mol % (Table 1, entry 7). Other
palladium catalysts, such as Pd(dba)2, Pd(PPh3)4, and PdCl2,
exhibited lower catalytic activity than Pd(OAc)2, based on the iso-
lated yields of the product (Table 1, entries 11e13). Thus, the opti-
mized reaction conditions included 2 mol % Pd(OAc)2 as the catalyst,
4 mol % PPh3 as the ligand, tributylamine as a base, DMF as the
solvent, 16 h of reaction time, and a reaction temperature of 120 ꢀC.
To establish the scope of this methodology, reactions of enyne
substrates 1, 2, 3, and 4 with a number of aryl halides were in-
vestigated (Table 2). Under the optimized reaction conditions, vari-
ous substituted aryl bromides reacted with the substrates smoothly
and produced the corresponding functionalized hexahydroindole
and hexahydrobenzofuran derivatives. Yields of the hexahy-
droindole and hexahydrobenzofuran derivatives varied significantly
with the substituents of the aryl halides. Reactions of enynes with
aryl halides bearing electron-withdrawing groups produced better
yields of products than those of reactions of enynes with aryl halides
bearing electron-donating groups. For example, the reaction of N-
(but-2-ynyl)-N-(cyclohex-2-enyl)-4-methylbenzenesulfonamide (2)
with methyl 4-bromobenzoate resulted in 83% yield (Table 2, entry
12), whereas the reaction of 1-(3-(cyclohex-2-enyloxy)prop-1-ynyl)
benzene (3) with 1-bromo-4-methoxybenzene gave the corre-
sponding product in 40% yield (Table 2, entry 14), similar results
were observed for N-(3-phenylprop-2-ynyl)-N-(cyclohex-2-enyl)-4-
methylbenzenesulfonamide (4) with methyl 4-bromobenzoate and
1-bromo-4-methoxybenzene (Table 2, entries 19 and 20). In-
terestingly, the CeBr bond reacted selectively with the enyne when
the aryl ring bears both bromo and chloro substituents (Table 2,
entries 2, 3, 10, and 11). Differences in the enyne substrates have
influence on the domino coupling/cyclization reaction. The outputs
of reactions of substrates 3 or 4 with aryl halides were slightly lower
than those of the reactions of 1 and 2 with the corresponding aryl
halides. For example, the reaction of ethyl 4-bromobenzoate with
enyne 1 gave the desired products in 74% yield (Table 2, entry 5),
while the reaction of ethyl 4-bromobenzoate with enynes 3 gave the
corresponding products in 61% yield (Table 2, entry 18), indicating
3-Cl
4-SO2Me
4-CO2Et
4-OMe
4-CO2Me
H
4-COMe
a
Enyne (1.0 equiv), aryl bromide (1.2 equiv), Pd(OAc)2 (2 mol %), PPh3, (n-Bu3)N
(2.0 equiv), and DMF (5 mL).
b
Isolated yield.
In order to better understand the mechanism for the domino
reaction, enyne 4 was treated with palladium catalyst without aryl
halide under the same conditions for the above reaction, the self-
cyclization product 5 was isolated in a very low yield (<5%).
However, changing the conditions by adding acetic acid to the re-
action of 4 with palladium catalyst (without aryl halides), the yield
of the self-cyclization product 5 can be increased to 50%. When the
self-cyclization product 5 was treated with aryl halide, for example,
ethyl 4-bromobenzoate, no coupling product 6 was observed, in-
stead, an aryl coupling product 7 was isolated (Scheme 1). This
Scheme 1. Pathway of the cross cyclization reaction.

8650
T.-jie Meng et al. / Tetrahedron 66 (2010) 8648e8653
result suggested that coupling of the aryl group with triple bond
will occur at first in our domino/cyclization reaction, not after the
cyclization.
yields. Further exploration of the reaction scope and other types of
coupling/cyclizations of enynes is currently being done in our lab.
All new products were fully characterized by various spectro-
scopic techniques and high-resolution masss pectrometry. The
molecular structure of 2e (Fig. 1) was confirmed by single-crystal
X-ray analysis.
4. Experimental
4.1. General experiment
All the catalytic reactions were performed under an argon at-
mosphere using the oven-dried Schlenk flask. All solvents and
materials were pre-dried, redistilled or recrystallized before use.
The 1H and 13C NMR spectra were recorded at 300 and 75 MHz,
respectively. Column chromatography was performed on silica gel
300e400 mesh. Melting points were uncorrected. Infrared spectra
were recorded on FT-IR spectrometer as KBr pellets or thin film
from CHCl3 on the NaCl window. All HRMS spectra were record
using EI at 70 eV. X-ray crystallography diffraction data of 2e were
collected at room temperature with a Bruker SMART Apex CCD
diffractometer with Mo-K
monochromator using the
a
radiation (
l
¼0.71073 Å) with a graphite
u
-scan mode. Enynes, 3-(but-2-yny-
loxy)cyclohex-1-ene (1),12 N-(but-2-ynyl)-N-(cyclohex-2-enyl)-4-
methylbenzenesulfon amide (2),12 1-(3-(cyclohex-2-enyloxy)
prop-1-ynyl)benzene (3),13 and N-(3-phenylprop-2-ynyl)-N-
(cyclohex-2-enyl)-4-methylbenzenesulfon amide (4)13 were pre-
pared by published procedures.
Fig. 1. Molecular structure of 2e.
On the basis of the above results, a possible reaction mechanism
is shown in Scheme 2. The oxidative addition of aryl halides to
palladium(0) afforded arylpalladium species 8. syn Carbopallada-
tion of the arylpalladium species 8 with the carbonecarbon triple
bond generated the alkenylpalladium intermediate 9, which reac-
ted with the carbonecarbon double bond through further carbo-
4.2. Synthesis
A typical procedure for the coupling/cyclization of 1,6-enynes
with aryl halides: enyne (1.0 equiv), aryl halides (1.2 equiv), Pd
(OAc)2 (2 mol %), and PPh3 (4 mol %) were added to a degassed
solution of (n-Bu)3 (2 equiv) in DMF (5 mL), and the mixture was
stirred at room temperature for half an hour and then heated at
120 ꢀC for 16 h. The reaction mixture was then cooled, quenched
with water, and extracted with ethylacetate (30 mL). The combined
organic layers were washed with hydrochloric acid (5%), sodium
carbonate (5%), and saturated sodium chloride solution, dried over
MgSO4, and concentrated. The residue was purified by flash column
chromatography to give final product.
palladation reaction to afford 10. Afterward, syn b-elimination of 10
produced HPdBr and the desired product 11. A base assisted
reduction regenerated the active palladium species, Pd(0).2b,11
4.2.1. 1-(4-((1E)-1-(7,7a-Dihydrobenzofuran-3(2H,3aH,6H)-ylidene)
ethyl) phenyl)ethanone (1a). Viscous liquid; 1H NMR (300 MHz,
CDCl3):
d
7.94 (d, J¼7.2 Hz, 2H), 7.35 (d, J¼7.2 Hz, 2H), 5.61 (s, 1H),
5.04e5.01 (m, 1H), 4.56 (d, J¼13.5 Hz, 1H), 4.41 (d, J¼13.5 Hz, 1H),
4.22 (s, 1H), 3.27 (s, 1H), 2.61 (s, 3H), 2.13e1.91 (m, 6H), 1.60e1.56
(m,1H); 13C NMR (75 MHz, CDCl3):
d 197.7,148.6,139.8, 135.3, 128.5,
127.8, 127.3, 126.9, 124.8, 77.2, 69.6, 41.2, 26.5, 24.3, 21.1, 19.0; FT-IR
(neat): nmax 3024, 2922, 2852, 1681, 1602, 1267, 1083, 839 cmꢁ1
HRMS (EI) m/z: calcd for C18H20O2: 268.1463; found: 268.1457.
;
4.2.2. (3E)-3-(1-(3-Chlorophenyl)ethylidene)-2,3,3a,6,7,7a-hexahy-
drobenzo-furan (1b). Viscous liquid; 1H NMR (300 MHz, CDCl3):
d
7.28e7.24 (m, 3H), 7.15e7.12 (m, 1H), 5.63 (s, 1H), 5.09e5.05 (m,
1H), 4.60 (d, J¼13.2 Hz,1H), 4.41 (d, J¼13.2 Hz,1H), 4.22 (s, 1H), 3.26
(s, 1H), 2.15e1.89 (m, 6H), 1.63e1.59 (m, 1H); 13C NMR (75 MHz,
CDCl3):
d 145.4, 139.4, 134.1, 129.7, 127.7, 127.4, 126.8, 126.7, 125.9,
Scheme 2. Proposed mechanism of the reaction.
125.1, 77.2, 69.6, 41.3, 24.4, 21.3, 19.0; FT-IR (neat): nmax 3024, 2924,
2850, 1593, 1562, 1440, 1082, 786 cmꢁ1; HRMS (EI) m/z: calcd for
C16H17ClO: 260.0968; found: 260.0961.
3. Conclusions
An efficient and direct approach for constructing functionalized
hexahydroindole and hexahydrobenzofuran derivatives from read-
ily available 1,6-enynes and aryl halides was developed. Multiple
new carbonecarbon bonds were formed in one step via palladium-
catalyzed domino coupling/cyclization of 1,6-enynes and aryl ha-
lides. Results indicate that the electronic effects of the aryl halides
and the steric effects of the substrates influenced the reaction
4.2.3. (3E)-3-(1-(4-Chlorophenyl)ethylidene)-2,3,3a,6,7,7a-hexahy-
drobenzo-furan (1c). Viscous liquid; 1H NMR (300 MHz, CDCl3):
d
7.32 (d, J¼7.8 Hz, 2H), 7.19 (d, J¼7.8 Hz, 2H), 5.62 (s, 1H), 5.06e5.05
(m, 1H), 4.55 (d, J¼13.5 Hz, 1H), 4.41 (d, J¼13.5 Hz, 1H), 4.21 (s, 1H),
3.24 (s, 1H), 2.14e1.86 (m, 6H), 1.62e1.58 (m, 1H); 13C NMR
(75 MHz, CDCl3):
d 142.0, 139.2, 132.3, 129.0, 128.7, 128.6, 126.8,
125.1, 77.2, 69.6, 41.3, 24.4, 21.4, 19.1; FT-IR (neat): nmax 3026, 2922,

T.-jie Meng et al. / Tetrahedron 66 (2010) 8648e8653
8651
2850, 1593, 1489, 1440, 1082, 831 cmꢁ1; HRMS (EI) m/z: calcd for
1346, 1163, 815, 769, 705 cmꢁ1
;
HRMS (EI) m/z: calcd for
C16H17ClO: 260.0968; found: 260.0962.
C23H25NO2S: 379.1606; found: 379.1601.
4.2.4. 4-((1E)-1-(7,7a-Dihydrobenzofuran-3(2H,3aH,6H)-ylidene)
4.2.10. (3E)-3-(1-(4-Chlorophenyl)ethylidene)-2,3,3a,6,7,7a-hexahy-
ethyl)benzo-nitrile (1d). Viscous liquid; 1H NMR (300 MHz, CDCl3):
dro-1-tosyl-1H-indole (2d). Colorless solid; mp 151e152 ꢀC; 1H NMR
d
7.65 (d, J¼7.5 Hz, 2H), 7.37 (d, J¼7.5 Hz, 2H), 5.64 (s,1H), 5.00e4.97
(300 MHz, CDCl3):
d
7.76 (d, J¼6.0 Hz, 2H), 7.37 (d, J¼6.3 Hz, 2H), 7.25
(m, 1H), 4.57 (d, J¼12.6 Hz, 1H), 4.42 (d, J¼12.6 Hz, 1H), 4.23 (s, 1H),
(d, J¼6.9 Hz, 2H), 6.90 (d, J¼6.6 Hz, 2H), 5.67 (s, 1H), 5.01e4.99 (m,
1H), 4.10 (d, J¼14.7 Hz,1H), 4.00 (d, J¼14.4 Hz,1H), 3.61 (s,1H), 3.09 (s,
1H), 2.47 (s, 3H), 2.25 (m, 2H), 1.92e1.82 (m, 4H), 1.60 (m, 1H); 13C
3.23 (s, 1H), 2.14e1.84 (m, 6H), 1.62e1.58 (m, 1H); 13C NMR
(75 MHz, CDCl3):
d 148.4, 140.7, 132.3, 128.4, 127.3, 126.3, 124.5,
118.9, 110.4, 77.2, 69.7, 41.3, 24.3, 21.0, 19.2; FT-IR (neat): nmax 3024,
2922, 2854, 2227, 1604, 1504, 1440, 1082, 842 cmꢁ1; HRMS (EI) m/z:
calcd for C17H17NO: 251.1310; found: 251.1301.
NMR (75 MHz, CDCl3): d 143.6, 141.1, 134.0, 133.6, 132.6, 129.7, 128.8,
128.6, 128.4, 127.8, 125.0, 59.0, 51.4, 42.3, 25.1, 21.7, 21.6, 20.1; FT-IR
(KBr): nmax 3028, 2920, 2854,1597,1489,1438, 1336,1155, 815 cmꢁ1
HRMS (EI) m/z: calcd for C23H24ClNO2S: 413.1216; found: 413.1209.
;
4.2.5. Ethyl 4-((1E)-1-(7,7a-Dihydrobenzofuran-3(2H,3aH,6H)-ylidene)
ethyl) benzoate (1e). Viscous liquid; 1H NMR (300 MHz, CDCl3):
d
8.03
4.2.11. (3E)-3-(1-(3-Chlorophenyl)ethylidene)-2,3,3a,6,7,7a-hexahy-
(d, J¼6.9 Hz, 2H), 7.32 (d, J¼7.2 Hz, 2H), 5.60 (s,1H), 5.04e5.01 (m,1H),
4.57 (d, J¼12.9 Hz, 1H), 4.45e4.37 (m, 3H), 4.22 (s, 1H), 3.27 (s, 1H),
2.13e1.82 (m, 6H), 1.57 (m, 1H), 1.40 (t, J¼6.0 Hz, 3H); 13C NMR
dro-1-tosyl-1H-indole (2e). Colorless solid; mp 123e124 ꢀC; 1H NMR
(300 MHz, CDCl3):
d
7.76 (d, J¼7.8 Hz, 2H), 7.38 (d, J¼7.2 Hz, 2H), 7.20
(s, 2H), 6.86 (s,1H), 5.68 (s,1H), 5.01e4.98 (m,1H), 4.10 (d, J¼15.0 Hz,
1H), 4.03 (d, J¼15.0 Hz, 1H), 3.64 (s, 1H), 3.07 (s, 1H), 2.49 (s, 3H),
2.25e2.23 (m, 2H), 1.93e1.82 (m, 4H), 1.61 (m, 1H); 13C NMR
(75 MHz, CDCl3): d 166.5, 148.4, 139.6, 130.2, 129.7, 128.7, 127.6, 126.9,
125.0, 77.3, 69.7, 60.9, 41.3, 24.4, 21.2, 19.1, 14.4; FT-IR (neat): nmax
3026, 2922, 2850, 1716, 1276, 1105, 1082, 823 cmꢁ1; HRMS (EI) m/z:
calcd for C19H22O3: 298.1569; found: 298.1565.
(75 MHz, CDCl3):
127.5, 126.9, 125.6, 125.0, 58.9, 51.2, 42.1, 25.2, 21.7, 21.6, 20.2; FT-IR
(KBr): nmax 3026, 2908, 2841,1593,1492,1444,1340,1161, 815 cmꢁ1
d 144.5,143.7,134.1,134.0,129.7,128.7,128.3,127.8,
;
4.2.6. 4-((1E)-1-(7,7a-Dihydrobenzofuran-3(2H,3aH,6H)-ylidene)
HRMS (EI) m/z: calcd for C23H24ClNO2S: 413.1216; found: 413.1210.
ethyl) benzaldehyde (1f). Viscous liquid; 1H NMR (300 MHz, CDCl3):
d
10.01 (s, 1H), 7.87 (d, J¼6.3 Hz, 2H), 7.43 (d, J¼6.9 Hz, 2H), 5.61 (s,
4.2.12. Methyl 4-((1E)-1-(1,2,7,7a-tetrahydro-1-tosyl-3aH-indol-3(6H)-
1H), 5.03e5.00 (m, 1H), 4.58 (d, J¼13.2 Hz, 1H), 4.43 (d, J¼13.2 Hz,
ylidene) ethyl)benzoate (2f). Colorless solid; mp 110e112 ꢀC; 1H NMR
1H), 4.23 (s, 1H), 3.28 (s, 1H), 2.13e1.83 (m, 6H), 1.61e1.57 (m, 1H);
(300 MHz, CDCl3):
d
7.95 (d, J¼8.1 Hz, 2H), 7.76 (d, J¼7.2 Hz, 2H), 7.37
13C NMR (75 MHz, CDCl3):
d
191.8, 150.1, 140.3, 134.8, 130.0, 128.3,
(d, J¼7.2 Hz, 2H), 7.04 (d, J¼7.8 Hz, 2H), 5.64 (s,1H), 4.98e4.94 (m,1H),
4.12 (d, J¼15.0 Hz, 1H), 4.03 (d, J¼15.0 Hz,1H), 3.62 (s, 1H), 3.09 (s, 1H),
2.48 (s, 3H), 2.26e2.22 (m, 2H), 1.91e1.85 (m, 4H), 1.64e1.55 (m, 1H);
127.1, 126.9, 124.8, 77.2, 69.7, 41.3, 24.3, 21.1, 19.0; FT-IR (neat): nmax
3026, 2920, 2850, 1698, 1602, 1504, 1440, 1082, 837 cmꢁ1; HRMS
(EI) m/z: calcd for C17H18O2: 254.1307; found: 254.1297.
13C NMR (75 MHz, CDCl3):
d 166.8, 147.5, 143.6, 134.1, 133.9, 129.7,
129.1, 128.6, 128.3, 127.8, 127.5, 124.9, 58.9, 52.1, 51.4, 42.2, 25.1, 21.6,
21.5, 20.1; FT-IR (KBr): nmax 3026, 2916, 2860, 1720, 1606, 1492, 1435,
1346, 1282, 1159, 813 cmꢁ1; HRMS (EI) m/z: calcd for C25H27NO4S:
437.1661; found: 437.1656.
4.2.7. 1-(4-((1E)-1-(1,2,7,7a-Tetrahydro-1-tosyl-3aH-indol-3(6H)-
ylidene)
ethyl)phenyl)ethanone
(2a). Colorless
solid;
mp
145e147 ꢀC; 1H NMR (300 MHz, CDCl3):
d
7.88 (d, J¼7.8 Hz, 2H), 7.76
(d, J¼7.8 Hz, 2H), 7.37 (d, J¼7.8 Hz, 2H), 7.07 (d, J¼7.8 Hz, 2H), 5.65
(s,1H), 4.99e4.96 (m,1H), 4.12 (d, J¼15.0 Hz,1H), 4.02 (d, J¼15.0 Hz,
1H), 3.62 (s, 1H), 3.11 (s, 1H), 2.58 (s, 3H), 2.48 (s, 3H), 2.27e2.24 (m,
2H), 1.90e1.85 (m, 4H), 1.58 (m, 1H); 13C NMR (75 MHz, CDCl3):
4.2.13. Ethyl
(6H)-ylidene)ethyl)benzoate (2g). Colorless solid; mp 127e128 ꢀC;
1H NMR (300 MHz, CDCl3):
4-((1E)-1-(1,2,7,7a-tetrahydro-1-tosyl-3aH-indol-3
d
7.96 (d, J¼7.8 Hz, 2H), 7.76 (d, J¼7.8 Hz,
d
197.6, 147.8, 143.6, 135.6, 134.1, 133.8, 129.7, 129.0, 128.5, 128.4,
2H), 7.37 (d, J¼7.8 Hz, 2H), 7.04 (d, J¼7.5 Hz, 2H), 5.65 (s, 1H),
4.98e4.95 (m, 1H), 4.34 (q, J¼7.2 Hz, 2H), 4.12 (d, J¼14.4 Hz, 1H),
4.03 (d, J¼14.7 Hz, 1H), 3.62 (s, 1H), 3.09 (s, 1H), 2.48 (s, 3H),
2.26e2.23 (m, 2H), 1.91e1.85 (m, 4H), 1.60e1.55 (m, 1H), 1.39 (t,
127.8, 127.7, 124.8, 59.0, 51.4, 42.3, 26.6, 25.1, 21.6, 21.5, 20.1; FT-IR
(KBr): nmax 3022, 2854,1681,1604,1336,1155, 817, 704 cmꢁ1; HRMS
(EI) m/z: calcd for C25H27NO3S: 421.1712; found: 421.1710.
J¼7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3):
d 166.3, 147.4, 143.6, 134.0,
4.2.8. 4-((1E)-1-(1,2,7,7a-Tetrahydro-1-tosyl-3aH-indol-3(6H)-yli-
129.7, 129.6, 129.1, 128.9, 128.2, 127.8, 127.5, 124.9, 61.0, 59.0, 51.4,
42.3, 25.1, 21.6, 21.5, 20.1, 14.3; FT-IR (KBr): nmax 3026, 2860, 1714,
1606, 1492, 1336, 1267, 1155, 812 cmꢁ1; HRMS (EI) m/z: calcd for
C26H29NO4S: 451.1817; found: 451.1816.
dene)ethyl) benzo-nitrile (2b). Colorless solid; mp 137e139 ꢀC; 1H
NMR (300 MHz, CDCl3):
d
7.75 (d, J¼6.9 Hz, 2H), 7.58 (d, J¼6.9 Hz,
2H), 7.37 (d, J¼6.6 Hz, 2H), 7.10 (d, J¼6.9 Hz, 2H), 5.67 (s, 1H),
4.94e4.91 (m, 1H), 4.12 (d, J¼15.0 Hz, 1H), 4.01 (d, J¼15.0 Hz, 1H),
3.61 (s, 1H), 3.07 (s, 1H), 2.47 (s, 3H), 2.26e2.24 (m, 2H), 1.92e1.85
4.2.14. (3E)-2,3,3a,6,7,7a-Hexahydro-3-(1-(4-methoxyphenyl) ethyl-
(m, 4H), 1.62e1.59 (m, 1H); 13C NMR (75 MHz, CDCl3):
d
147.5, 143.7,
idene)-1-tosyl-1H-indole (2h). Colorless solid; mp 156e158 ꢀC; 1H
135.0, 133.8, 132.3, 129.7, 128.7, 128.3, 127.8, 124.4, 118.7, 110.7, 58.9,
51.4, 42.3, 25.0, 21.6, 21.4, 20.1; FT-IR (KBr): nmax 3024, 2854, 2229,
1604, 1336, 1155, 817, 704 cmꢁ1; HRMS (EI) m/z: calcd for
C24H24N2O2S: 404.1558; found: 404.1553.
NMR (300 MHz, CDCl3):
d
7.76 (d, J¼8.1 Hz, 2H), 7.36 (d, J¼7.5 Hz,
2H), 6.90 (d, J¼7.8 Hz, 2H), 6.81 (d, J¼8.1 Hz, 2H), 5.65 (s, 1H),
5.08e5.05 (m, 1H), 4.10 (d, J¼14.4 Hz, 1H), 4.02 (d, J¼15.0 Hz, 1H),
3.79 (s, 3H), 3.61 (s, 1H), 3.14 (s, 1H), 2.47 (s, 3H), 2.27e2.25 (m, 2H),
1.92e1.82 (m, 4H), 1.60 (m, 1H); 13C NMR (75 MHz, CDCl3):
d 158.3,
4.2.9. (3E)-2,3,3a,6,7,7a-Hexahydro-3-(1-phenylethylidene)-1-tosyl-
143.5, 135.1,134.1,132.5, 129.6, 129.5,128.4, 127.9, 127.8, 125.5, 113.7,
59.0, 55.2, 51.4, 42.3, 25.2, 21.9, 21.6, 20.1; FT-IR (KBr): nmax 3022,
2906, 2845, 1608, 1510, 1456, 1338, 1242,1159, 813 cmꢁ1; HRMS (EI)
m/z: calcd for C24H27NO3S: 409.1712; found: 409.1708.
1H-indole (2c). Colorless solid; mp 126e127 ꢀC; 1H NMR (300 MHz,
CDCl3):
d
7.77 (d, J¼6.9 Hz, 2H), 7.37 (d, J¼7.5 Hz, 2H), 7.28e7.21 (m,
3H), 6.96 (d, J¼6.9 Hz, 2H), 5.66 (s, 1H), 5.06e5.03 (m, 1H), 4.12 (d,
J¼14.7 Hz, 1H), 4.03 (d, J¼14.4 Hz, 1H), 3.62 (s, 1H), 3.13 (s, 1H), 2.48
(s, 3H), 2.28e2.25 (m, 2H), 1.91e1.84 (m, 4H), 1.63e1.59 (m, 1H); 13C
4.2.15. (3E)-3-((4-Chlorophenyl)(phenyl)methylene)-2,3,3a,6,7,7a-
NMR (75 MHz, CDCl3):
d
143.5, 142.7, 134.0, 132.8, 130.0, 129.7,
hexahydrobenzofuran (3a). Viscous liquid; 1H NMR (300 MHz,
128.3, 128.0, 127.8, 127.4, 126.8, 125.4, 59.0, 51.4, 42.3, 25.2, 21.8,
CDCl3):
d 7.34e7.08 (m, 9H), 5.73 (s, 1H), 5.21e5.18 (m, 1H), 4.72 (d,
21.6, 20.1; FT-IR (KBr): nmax 3024, 2910, 2870, 1597, 1490, 1440,
J¼13.5 Hz, 1H), 4.26e4.24 (m, 2H), 3.48 (s, 1H), 2.18 (m, 1H),

8652
T.-jie Meng et al. / Tetrahedron 66 (2010) 8648e8653
2.04e1.88 (m, 2H), 1.62 (m, 1H); 13C NMR (75 MHz, CDCl3):
d
142.2,
CDCl3):
d
7.54 (d, J¼7.8 Hz, 2H), 7.26e7.22 (m, 8H), 6.89 (d, J¼7.2 Hz,
141.1, 140.5, 133.0,130.5, 128.7, 128.4, 128.3, 128.0, 127.8, 127.1,124.4,
76.2, 69.5, 42.4, 24.5,19.3; FT-IR (neat): nmax 3022, 2924, 2852,1600,
1504, 1440, 1074, 827, 702 cmꢁ1; HRMS (EI) m/z: calcd for
C21H19ClO: 322.1124; found: 322.1116.
2H), 6.75 (d, J¼6.9 Hz, 2H), 5.76 (s, 1H), 5.11e5.08 (m, 1H), 4.23 (d,
J¼15.6 Hz, 1H), 4.02 (d, J¼15.6 Hz, 1H), 3.83 (s, 1H), 3.28 (s, 1H), 2.45
(s, 3H), 2.27e2.16 (m, 2H), 1.97e1.90 (m, 1H), 1.67e1.60 (m, 1H); 13C
NMR (75 MHz, CDCl3):
d 143.3, 140.9, 140.8, 136.0, 135.9, 134.6,
129.6, 128.8, 128.6, 128.3, 128.1, 127.6, 127.3, 126.9, 125.0, 58.1, 51.5,
42.5, 25.9, 21.5, 20.1; FT-IR (KBr): nmax 3024, 2866, 1692, 1346, 1161,
816, 754, 702 cmꢁ1; HRMS (EI) m/z: calcd for C28H27NO2S: 441.1762;
found: 441.1765.
4.2.16. (3E)-3-((3-Chlorophenyl)(phenyl)methylene)-2,3,3a,6,7,7a-
hexahydrobenzofuran (3b). Viscous liquid; 1H NMR (300 MHz,
CDCl3): d 7.31e7.05 (m, 9H), 5.74 (s, 1H), 5.22e5.19 (m, 1H), 4.72 (d,
J¼13.5 Hz, 1H), 4.30e4.24 (m, 2H), 3.48 (s, 1H), 2.19e2.15 (m, 1H),
2.06e1.88 (m, 2H), 1.65e1.60 (m, 1H); 13C NMR (75 MHz, CDCl3):
4.2.22. 1-(4-((1E)-(1,2,7,7a-Tetrahydro-1-tosyl-3aH-indol-3(6H)-yli-
d
143.7, 142.4, 140.9, 134.3, 132.9, 129.8, 129.1, 128.4, 128.3, 127.8,
dene) (phenyl)methyl)phenyl)ethanone (4d). Colorless solid; mp
127.4, 127.1, 127.0, 124.4, 76.2, 69.5, 42.4, 24.5, 19.2; FT-IR (neat):
nmax 3022, 2924, 2850, 1602, 1504, 1440, 1074, 827 cmꢁ1; HRMS (EI)
m/z: calcd for C21H19ClO: 322.1124; found: 322.1121.
161e163 ꢀC; 1H NMR (300 MHz, CDCl3):
d
7.83 (d, J¼7.2 Hz, 2H), 7.54
(d, J¼7.5 Hz, 2H), 7.28e7.25 (m, 5H), 6.87e6.85 (m, 4H), 5.76 (s, 1H),
5.05e5.02 (m, 1H), 4.23 (d, J¼15.6 Hz, 1H), 4.02 (d, J¼15.6 Hz, 1H),
3.84 (s, 1H), 3.24 (s, 1H), 2.56 (s, 3H), 2.46 (s, 3H), 2.24e2.15 (m, 2H),
4.2.17. (3E)-2,3,3a,6,7,7a-Hexahydro-3-((4-(methylsulfonyl) phenyl)
1.97e1.90 (m, 1H), 1.63 (m, 1H); 13C NMR (75 MHz, CDCl3):
d 197.6,
(phenyl) methylene)benzofuran (3c). Viscous liquid; 1H NMR
145.8, 143.4, 140.2, 137.1, 135.7, 135.0, 134.5, 129.6, 129.2, 129.1,
128.9, 128.6, 128.5, 128.1, 127.6, 124.5, 58.1, 51.5, 42.5, 26.5, 25.8,
21.5, 20.1; FT-IR (KBr): nmax 3026, 2866, 1682, 1346, 1161, 815, 761,
705 cmꢁ1; HRMS (EI) m/z: calcd for C30H29NO3S: 483.1868; found:
483.1876.
(300 MHz, CDCl3):
d
7.93 (d, J¼7.5 Hz, 2H), 7.49 (d, J¼8.1 Hz, 2H),
7.32e7.27 (m, 3H), 7.09 (d, J¼6.9 Hz, 2H), 5.74 (s, 1H), 5.14e5.11 (m,
1H), 4.73 (d, J¼14.1 Hz, 1H), 4.32e4.25 (m, 2H), 3.46 (s, 1H), 3.09 (s,
3H), 2.18e2.14 (m, 1H), 2.05e1.88 (m, 2H), 1.65e1.62 (m, 1H); 13C
NMR (75 MHz, CDCl3): d 147.7, 143.5, 140.4, 138.9, 132.5, 130.1, 128.5,
128.4, 128.3,127.7, 127.4, 123.9, 76.3, 69.6, 44.5, 42.3, 24.4,19.2; FT-IR
4.2.23. (3Z)-3-Benzylidene-2,3,3a,6,7,7a-hexahydro-1-tosyl-1H-in-
(neat): nmax 3024, 2920, 2850,1602,1444,1320,1138,1072, 702 cmꢁ1
HRMS (EI) m/z: calcd for C22H22O3S: 366.1290; found: 366.1286.
;
dole (5). Colorless solid; mp 131e132 ꢀC; 1H NMR (300 MHz,
CDCl3):
d
7.75 (d, J¼7.8 Hz, 2H), 7.37e7.22 (m, 5H), 7.14 (d, J¼7.2 Hz,
2H), 6.22 (s, 1H), 5.88 (d, J¼9.3 Hz, 1H), 5.74 (d, J¼9.6 Hz, 1H), 4.32
(d, J¼15.3 Hz, 1H), 4.22 (d, J¼14.7 Hz, 1H), 3.89 (s, 1H), 2.97 (s, 1H),
2.42 (s, 3H), 2.21e2.16 (m, 2H), 1.94e1.89 (m, 1H), 1.69e1.57 (m,
4.2.18. Ethyl 4-((1E)-(7,7a-dihydrobenzofuran-3(2H,3aH,6H)-ylidene)
(phenyl) methyl)benzoate (3d). Viscous liquid; 1H NMR (300 MHz,
CDCl3):
d
8.04 (d, J¼8.1 Hz, 2H), 7.37e7.23 (m, 5H), 7.10 (d, J¼6.9 Hz,
1H); 13C NMR (75 MHz, CDCl3):
d 143.4, 139.9, 136.5, 135.4, 129.8,
2H), 5.71 (s, 1H), 5.18e5.14 (m, 1H), 4.74 (d, J¼14.1 Hz, 1H), 4.39 (q,
J¼7.2 Hz,1H), 4.30e4.26 (m, 2H), 3.49 (s,1H), 2.18 (m, 1H), 2.05e1.87
(m, 2H), 1.65e1.61 (m, 1H), 1.40 (t, J¼7.2 Hz, 3H); 13C NMR (75 MHz,
129.2, 128.5, 128.2, 127.3, 127.1, 124.1, 123.9, 57.6, 49.9, 44.2, 26.1,
23.4, 21.5; FT-IR (KBr): nmax 3030, 2862, 1492, 1336, 1166, 821, 763,
700 cmꢁ1; HRMS (EI) m/z: calcd for C22H23NO2S: 365.1449; found:
365.1445.
CDCl3):
d 166.5, 145.6, 142.4, 140.7, 133.5, 129.8, 129.1, 128.9, 128.5,
128.3, 127.8, 127.2, 124.3, 76.3, 69.5, 60.9, 42.4, 24.5, 19.2, 14.4; FT-IR
(neat): nmax 3024, 2920, 2850, 1716, 1606, 1444, 1276, 1103, 1072,
702 cmꢁ1; HRMS (EI) m/z: calcd for C24H24O3: 360.1725; found:
360.1724.
4.2.24. Diethyl biphenyl-4,40-dicarboxylate(7). Colorless solid; mp
113e114 ꢀC; 1H NMR (300 MHz, CDCl3):
d
8.13 (d, J¼8.4 Hz, 4H), 7.68
(d, J¼8.1 Hz, 4H), 4.41 (q, J¼7.1 Hz, 4H), 1.42 (t, J¼7.1 Hz, 6H); 13C
NMR (75 MHz, CDCl3):
d 166.3, 144.3, 130.2, 130.0, 127.2, 61.1, 14.4;
4.2.19. (3E)-2,3,3a,6,7,7a-Hexahydro-3-((4-methoxyphenyl) (phenyl)
FT-IR (KBr): nmax 2993, 1705, 1607, 1556, 1278, 1180, 1113, 1024,
877 cmꢁ1; HRMS (EI) m/z: calcd for C18H18O4: 298.1205; found:
298.1202.
methylene)-1-tosyl-1H-indole (4a). Colorless solid; mp 136e138 ꢀC;
1H NMR (300 MHz, CDCl3):
d
7.55 (d, J¼7.5Hz, 2H), 7.27 (s, 5H), 6.89(d,
J¼6.3 Hz, 2H), 6.77 (d, J¼7.8 Hz, 2H), 6.68 (d, J¼8.4 Hz, 2H), 5.77 (s,1H),
5.15e5.12 (m,1H), 4.22 (d, J¼15.3 Hz,1H), 4.00 (d, J¼15.3 Hz,1H), 3.84
(s, 1H), 3.78 (s, 3H), 3.32 (s, 1H), 2.46 (s, 3H), 2.23e2.17 (m, 2H),
1.97e1.92 (m, 1H), 1.69e1.58 (m, 1H); 13C NMR (75 MHz, CDCl3):
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (20872002, 20832001) and Anhui Province
(TD 200707).
d
158.5, 143.3, 141.4, 135.7, 135.6, 134.6, 133.3, 129.9, 129.6, 128.6, 128.1,
127.7, 127.3, 125.1, 113.7, 58.2, 55.2, 51.6, 42.5, 26.0, 21.5, 20.3; FT-IR
(KBr): nmax 3014, 2864, 1647, 1336, 1244, 1153, 821, 765, 704 cmꢁ1
HRMS (EI) m/z: calcd for C29H29NO3S: 471.1868; found: 471.1867.
;
Supplementary data
4.2.20. Methyl 4-((1E)-(1,2,7,7a-tetrahydro-1-tosyl-3aH-indol-3(6H)-
CCDC-775882 (2e) contains the supplementary crystallographic
data for this paper. This data can be obtained free of charge from The
Cambridge Crystallographic Data Centre at www.ccdc.cam.ac.uk/
data_request/cif. Copies of 1H NMR, 13C NMR spectra of all com-
pounds are provided. Supplementary data associated with this
article can be found in the online version, at doi:10.1016/
j.tet.2010.09.029. These data include MOL files and InChIKeys of the
most important compounds described in this article.
ylidene) (phenyl)methyl)benzoate (4b). Colorless solid; mp
128e130 ꢀC; 1H NMR (300 MHz, CDCl3):
d
7.92 (d, J¼7.2 Hz, 2H), 7.56
(d, J¼7.5 Hz, 2H), 7.29e7.26 (m, 5H), 6.89e6.83 (m, 4H), 5.79e5.76 (m,
1H), 5.06e5.02(m,1H), 4.25(d, J¼15.6 Hz,1H), 4.03 (d, J¼15.3 Hz, 1H),
3.90 (s, 3H), 3.86 (s, 1H), 3.24 (s, 1H), 2.47 (s, 3H), 2.30e2.16 (m, 2H),
1.97e1.92 (m, 1H), 1.69e1.66 (m, 1H); 13C NMR (75 MHz, CDCl3):
d166.7, 145.6, 143.4, 140.2, 137.1, 135.1, 134.5, 129.7, 129.1, 128.9, 128.8,
128.7,128.5,128.3,127.7,124.6,58.1, 52.1, 51.5, 42.5, 25.9, 21.5, 20.2;FT-
IR (KBr): nmax 3026, 2866, 1720, 1346, 1278, 1161, 1101, 815, 761,
705 cmꢁ1; HRMS (EI) m/z: calcd for C30H29NO4S: 499.1817; found:
499.1816.
References and notes
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tritzky, A. R., Taylor, R. J. K., Ramsden, C. A., Scriven, E. F. V., Eds.; Elsevier:
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indole (4c). Colorless solid; mp 133e135 ꢀC; 1H NMR (300 MHz,

T.-jie Meng et al. / Tetrahedron 66 (2010) 8648e8653
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