Selective cyclization of alkynols and alkynylamines catalyzed by potassium tert-butoxide

Article abstract of DOI:10.1016/j.tet.2014.06.078

Potassium tert-butoxide (t-BuOK) was found to be an effective catalyst for the cyclization of aromatic alkynols and alkynylamines. In the presence of 10 mol % t-BuOK, a range of alkynols were converted to the corresponding exo-cyclic enol ethers as pure Z

Full text of DOI:10.1016/j.tet.2014.06.078

Tetrahedron 70 (2014) 7022e7031
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Tetrahedron
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Selective cyclization of alkynols and alkynylamines catalyzed by
potassium tert-butoxide
*
Deng Yuan Li, Ke Ji Shi, Xiao Feng Mao, Zheng Le Zhao, Xin Yan Wu, Pei Nian Liu
Shanghai Key Laboratory of Functional Materials Chemistry, Key Lab for Advanced Materials and Institute of Fine Chemicals, East China University
of Science and Technology, Meilong Road 130, Shanghai, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 19 April 2014
Received in revised form 12 June 2014
Accepted 19 June 2014
Available online 24 June 2014
Potassium tert-butoxide (t-BuOK) was found to be an effective catalyst for the cyclization of aromatic
alkynols and alkynylamines. In the presence of 10 mol % t-BuOK, a range of alkynols were converted to
the corresponding exo-cyclic enol ethers as pure Z-stereoisomers with 100% selectivity and moderate to
excellent yields. Moreover, the cyclization of alkynylamines was also achieved to afford indoles and
isoindolin-1-ones in good yields.
Crown Copyright Ó 2014 Published by Elsevier Ltd. All rights reserved.
Keywords:
Alkynols
Alkynylamines
Potassium tert-butoxide
exo-Cyclic enol ethers
Indoles
Isoindolin-1-ones
1. Introduction
catalysts. Recently, endo-iodocyclization of alcohols has also been
developed in the presence of I2/NaHCO3.9 endo-Cyclization of
Heteroatom-containing compounds are useful building blocks
for synthesizing a diverse range of natural products with biological
activity.1 The intramolecular addition of heteroatomehydrogen
bonds across the carbonecarbon triple bond provides a straight-
forward approach to heterocyclics with 100% atom efficiency, ful-
filling the requirements of green chemistry.2 For example, alkynols
and alkynylamines, which are important synthons for numerous
structurally fascinating heterocyclic compounds,3 can undergo
cycloisomerization to yield exo- or endo-heterocycles containing O
or N (Scheme 1).4 endo-Cyclization of alkynols has been achieved
using Mo, W,5 Ru,6 Rh,7 Ag, Pd and Au complexes or salts8 as
alkynylamines generating indoles, dihydroisoquinolines and dihy-
droquinolines has also been achieved with diverse catalysts: Cr, Mo,
W,10 Rh,11 Pd,12 Ru13 Cu,14 Hg(OTf)2,15 Pt,16 Et2Zn,17 Ir.18
Cyclization of alkynols giving exo-cyclic enol ethers was first
achieved by the use of HgO and BF3$Et2O as the catalysts.19 Several
more catalysts were later found to work well in this reaction:
organolanthanide complexes of the form Ln[N(SiMe3)2]3, where Ln
refers to La, Sm, Y, Lu, Nd;20 heavier alkaline earth bis(-
trimethylsilyl)amides;21 Bu4NF;22 and transition metal catalysts,
26
such as Pd(OAc)2,23 Ag2CO3,24 AuCl,25 Cu(OTf)2
and the
Cu(NHC)(Me) complex.27 Tandem exo-cyclization/isomerization
reactions of alkynols, which firstly generate exo-intermediates and
then undergo the isomerization to give the endo products, produce
endo-cyclic enol ethers or furans in the presence of RuCl2(PPh3)(p-
30
cymene)28 or palladium catalysts, such as PdCl2,29 Pd(OAc)2 and
K2PdI4.31 exo-Cyclization of aromatic alkynols promoted by stoi-
chiometric NaH has been described,32 although the same reaction
with catalytic amount base as the catalyst has not been reported
yet.
Scheme 1. Alkyne nucleophile endo- or exo-cycloisomerization.
As the applications of cyclization of alkynols, recently we ap-
plied exo-cyclic enol ethers to the reaction with imines, and dihy-
droisobenzofuran derivatives were obtained in THF and
isoquinolin-1(2H)-one products were obtained in DMSO.33 More-
over, the tandem reaction involving DielseAlder reaction and an
* Corresponding author. E-mail address: liupn@ecust.edu.cn (P.N. Liu).
http://dx.doi.org/10.1016/j.tet.2014.06.078
0040-4020/Crown Copyright Ó 2014 Published by Elsevier Ltd. All rights reserved.

D.Y. Li et al. / Tetrahedron 70 (2014) 7022e7031
7023
intermolecular nucleophilic addition reaction for exo-cyclic enol
ether with benzyne was achieved to afford phenanthro[10.1-bc]
furan.34
Changing the cyclization catalyst from t-BuOK to weaker bases,
such as K2CO3 or KOH decreased yields to 64% and 45%, respectively
(entries 11 and 12). Similarly, decreasing the loading of t-BuOK to
5 mol % or lowering the reaction temperature to 70 ꢀC substantially
reduced yields (entries 14 and 15). Note that the organic base
triethylamine was ineffective as a catalyst (entry 13).
Cyclization of alkynylamines to form exo-cyclic products has
been developed as the efficient method to construct N-heterocy-
clics,17,35 and the effective catalysts include phase transfer cata-
lysts,36 I2,37 or Pd.35d,38 Recently, stoichiometric KH, t-BuOK39 or t-
BuONa40 catalyzed cyclization of alkynylamines has been de-
veloped to afford indoles or isoindolin-1-ones. To date, however,
the same cyclization reaction with catalytic amount base as catalyst
has not been reported.
Thus the transition-metal-free cyclization reactions of both
alkynylamines and alkynols using commercially available, less ex-
pensive catalysts are still highly desirable. Here we report potas-
sium tert-butoxide (t-BuOK) as the effective catalyst for the exo-
cycloisomerization of alkynols and alkynylamines. For the alkynols,
catalytic reactions exhibit 100% regioselectivity, giving exo-cyclic
enol ethers in good to excellent yields. The alkynylamines could
also do the transformation to give indoles and isoindolin-1-ones in
good yields.
Next we analyzed the cyclization of various alkynols in DMSO at
80 ꢀC (oil bath temperature), using 10 mol % t-BuOK as the catalyst
(Table 2). After 5 h, the cyclic enol ether products were obtained
with 100% exo-selectivity, and their structures were fully consistent
with published data for 1H and 13C{1H} NMR and mass spectrom-
etry. 1H NMR analysis of the products, together with single-crystal
X-ray diffraction analysis of product 2j (Fig. 1), indicated that all
cyclic enol ether products were pure Z-stereoisomers except 2z.
NOESY experiments with 2w showed that H1 was close to H2 and
H3, confirming the Z-configuration of the cyclic enol ether products.
Cyclization of both the terminal alkynol 1a and the internal
alkynol bearing a phenyl group on the alkynyl group gave product
2b in similarly high yield around 94%. Alkynols 2c,e,f,h and i,
bearing electron-donating functional groups like NH2, NHBoc, OMe
or Me at ortho-, meta- or para-positions on the aromatic rings gave
the corresponding exo-cyclic enol ethers in excellent isolated yields
of 88e97%. Similar results were observed with alkynols 2d,g and
2jel bearing electron-withdrawing groups like Cl, F or CF3 at ortho-,
meta- or para-positions on the aromatic rings. These results suggest
that neither the nature nor position of electron-donating or
electron-withdrawing functional groups on the aromatic ring sig-
nificantly affect substrate cyclization.
An alkynol with an ester group gave 2m in slightly lower yield of
83%, demonstrating the tolerance of the ester group under these
strongly basic catalytic reaction conditions. The presence of a pyr-
idyl heterocyclic ring on the end of the alkynyl group inhibited
cyclization, giving product 2n in 61% yield. In contrast, the presence
of cyclopropyl at the end of the alkynyl group produced the cor-
responding cyclic enol ether 2o in 95% yield. The presence of an
aliphatic hexyl substituent on the end of the alkynyl group led to
complex cyclization results under these reaction conditions.
In the cyclization process, we also investigated the substituent
effect of the methylene carbon in the benzyl alcohol. Alkynols with
methyl or n-butyl substitutions gave products 2p and 2q in excel-
lent yields of 97% and 95%, respectively. However, attaching a tert-
butyl group to the methylene of the benzyl alcohol created so much
steric hindrance that cyclization could not proceed. Modifying the
aromatic ring of the benzyl alcohol with electron-withdrawing
groups, such as F or Cl or with electron-donating groups, such as
Me or OMe led to the corresponding products 2reu in yields of
88e98%. Multisubstituted alkynols were tolerated in the reaction,
giving rise to the cyclization products 2vex in yields of 80e95%.
Although these results demonstrate the flexibility of the catalytic
system, the highly alkaline conditions may prevent the use of more
complicated substrates with base-sensitive functional groups. In
addition, cyclization of aliphatic alkynols does not proceed effi-
ciently under these conditions.
2. Results and discussion
First we explored the catalytic activity of t-BuOK (10 mol %) in
alkynol cyclization using (2-ethynylphenyl)methanol 1a as the
model substrate; we tested the reaction in various solvents at 80 ꢀC
(Table 1). Reaction products were analyzed after 5 h by 1H NMR,
using PhSiMe3 as the internal standard. The cyclization of 1a did
not proceed in toluene or 1,2-dichloroethane (DCE), and the same
reaction in 1,4-dioxane or acetone gave low yields (Table 1, entries
1e4). When the reaction was carried out in THF, 1a cyclized with
61% yield (entry 5). Yields of cyclic enol ether 2a were 70e79%
when the solvents were acetonitrile, dimethylformamide (DMF),
methanol or N-methyl-2-pyrrolidone (NMP) (entries 6e9). Sur-
prisingly, when the solvent was dimethyl sulfoxide (DMSO), the
reaction produced the cyclized product 2a exclusively in 94% yield
and 100% exo-selectivity (entry 10). We suggest that this significant
solvent effect is because polar aprotic DMSO stabilizes the anionic
reaction intermediate.
Table 1
Cyclization of (2-ethynylphenyl)methanol 1a under various conditionsa
Entry
Solvent
Catalyst
Yieldb (%)
1
2
3
4
5
6
7
8
Toluene
DCE
1,4-Dioxane
Acetone
THF
Acetonitrile
DMF
Methanol
NMP
DMSO
DMSO
DMSO
DMSO
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
K2CO3
0
<5
30
44
61
70
73
74
79
94
64
45
0
To demonstrate the potential usefulness of the alkynol cycliza-
tion for generating derivatives of natural products, we focused on
an alkynol modified with cholesterol. Cholesterol is an essential
structural component of mammalian cell membranes and it serves
as a precursor for the biosynthesis of steroid, bile acids and vitamin
D.41 Incubating an alkynol modified with cholesterol 1y with
10 mol % of t-BuOK in THF at 80 ꢀC gave the desired cyclization
product 2y in 94% yield. This reaction did not proceed in DMSO,
because the substrate showed poor solubility in that solvent.
To test whether ethynylphenol would react in our cyclization
procedure, we incubated 2-((4-methoxyphenyl)ethynyl)phenol
with 10 mol % of t-BuOK in DMSO at 80 ꢀC. The desired product, 2-
(4-methoxyphenyl)benzofuran 2z, was obtained in 90% yield. This
9
10
11
12
13
14c
15d
KOH
Et3N
t-BuOK
t-BuOK
DMSO
DMSO
60
45
a
Reaction conditions: catalyst (0.1 mmol), 1a (1.0 mmol), solvent (2 mL), 80 ꢀC,
5 h, unless otherwise noted.
b
Determined by 1H NMR integration using PhSiMe3 as the internal standard.
t-BuOK (0.05 mmol).
At 70 ꢀC.
c
d

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D.Y. Li et al. / Tetrahedron 70 (2014) 7022e7031
Table 2
Cyclization of various alkynols using t-BuOK as catalysta
were obtained when the aniline aromatic ring was substituted with
an electron-withdrawing chlorine or an electron-donating methyl
group, giving the indoles 4c and 4d in 91% and 98% yields, re-
spectively (entries 3 and 4). The results indicate that such sub-
stituents exert negligible electronic effects on the reaction.
Interestingly, cyclization of the benzamide derivatives 3eei led to
isoindolin-1-ones 4eei in good yields with 100% exo-selectivity.
However, products 4fei were E-stereoisomers, opposite to the
configuration obtained in alkynol cyclization, which were fully
consistent with published data for 1H and 13C{1H} NMR and mass
spectrometry.42 We ascribe the different selectivity of N-atom at-
tack to the alkyne moiety to the steric effect derived from the
substituted groups linked with N-atom. The cyclization reaction
tolerated alkyl substituents on the benzamide including Me and
dodecyl groups, leading to isoindolin-1-ones 4eeg in yields of
67e94% (entries 5e7). Aryl or benzyl substituents on the benza-
mide led to slightly lower yields of 67% for product 4h and 56% for
4i, respectively (entries 8 and 9).
Fig. 1. The ORTEP diagram of product 2j.
result indicates that the phenolate is sufficiently nucleophilic to
attack the alkyne moiety under current catalytic conditions.
To explore whether our alkynols cyclization procedure would
also promote the reaction of alkynylamines, which would possesses
greater synthetic potential, we incubated a wide range of alkynyl-
amines in DMSO at 80 ꢀC in the presence of 10 mol % of t-BuOK
catalyst (Table 3). First we tested 2-(phenylethynyl)aniline 3a and
3b, which bear the nucleophilic moieties NTs and NBn, and we
obtained the indoles 4a and 4b as the cyclization products in 92%
and 93% yields, respectively (entries 1 and 2). Similar good results
Before speculating on the mechanism of our t-BuOK-catalyzed
cyclization, we wanted to eliminate the possibility that trace
transition metals in our t-BuOK were catalyzing the reaction. ICP-
AES analysis of t-BuOK, which we purchased from TCI, showed
that levels of Pd, Ni, Au, Pt, Ru and Rh were below the detection
limit of 2 ppm, and that the level of Cu was below the detection

D.Y. Li et al. / Tetrahedron 70 (2014) 7022e7031
7025
Table 3
Cyclization of alkynylamines using t-BuOK as catalysta
Entry
Substrate
Product
Yield (%)
Entry
Substrate
Product
Yield (%)
1
93
6
79
2
3
4
93
7
8
9
67
67
56
91
98
5
94
a
Reaction conditions: alkynamide (0.5 mmol), t-BuOK (0.05 mmol), 80 ꢀC, 5 h, 1.5 mL DMSO, unless otherwise noted. Isolated yields are reported.
limit of 5 ppm. This suggests that our results reflect cyclization
catalyzed by t-BuOK instead of by transition metals.
Based on the transition metal-catalyzed cyclization of alky-
nols,25,26 we propose a mechanism for t-BuOK-catalyzed cyclization
of alkynols and alkynylamines (Scheme 2). The t-BuOK deproto-
nates the XeH bond of the alkynol or alkynylamine, leading to
anion intermediate A, the alkynyl moiety of which undergoes nu-
cleophilic attack to form alkene anion B. Protolysis then generates
the cyclic product and regenerates t-BuOK, completing the catalytic
cycle.
3. Conclusion
In summary, we describe for the first time that commercially
available t-BuOK effectively catalyzes the exo-cyclization of alky-
nols and alkynylamines to generate exo-cyclic enol ethers, indoles
Scheme 2. Proposed reaction mechanism for t-BuOK-catalyzed cyclization of alkynols
or alkynylamines.

7026
D.Y. Li et al. / Tetrahedron 70 (2014) 7022e7031
and isoindolin-1-ones in high yields. This approach offers a flexible,
robust and efficient alternative to transition metal-catalyzed
cyclization.
(1.96 g, 7.5 mmol), and diisopropyl azodicarboxylate (2.02 g,
10 mmol). Then, ((4-iodophenyl)ethynyl)trimethylsilane (1.45 g,
5.5 mmol) was added. The reaction mixture was stirred at room
temperature for 2 days. The reaction mixture was concentrated
under vacuum to give the crude product, which was purified by
column chromatography on silica gel using 50:1 hexane/EtOAc as
eluent. Then the obtained product was dissolved in THF (30 mL) at
0 ꢀC and stirred for 30 min. The reaction mixture was concentrated
under vacuum to give the crude product, which was purified by
column chromatography on silica gel using 50:1 hexane/EtOAc as
4. Experimental section
4.1. General
All manipulations were carried out under nitrogen atmosphere
using standard Schlenk techniques, unless otherwise stated. Sol-
vents were distilled under nitrogen from sodiumebenzophenone
(hexane, diethyl ether, THF, benzene) or calcium hydride
(dichloromethane, DMSO, DMF). The organic alkynols9a,22,26,43 and
alkynylamines11,13b,22 were prepared according to the reported lit-
erature methods. Potassium tert-butoxide (1 M in THF) used in the
catalytic reactions was purchased from TCI. Other commercially
eluent to afford 4-(3R)-5-cholesten-3
b-oxybenzylethynyl as
a white solid in 70% yield (1.70 g). 1H NMR (400 MHz, CDCl3, 25 ꢀC):
d
7.39 (d, J¼8.72 Hz, 2H), 6.83 (d, J¼8.72 Hz, 2H), 5.24 (t, J¼2.60 Hz,
1H), 4.54 (t, J¼2.40 Hz, 1H), 2.98 (s, 1H), 2.50e2.54 (m, 1H),
2.31e2.35 (m, 1H), 0.86e2.04 (m, 38H), 0.69 (s, 3H); 13C NMR
(100.6 MHz, CDCl3, 25 ꢀC):
d 158.3, 138.4, 133.6, 122.5, 116.5, 114.0,
available chemicals were used as received. Chemical shifts (
d
, ppm)
84.0, 75.7, 73.1, 56.9, 56.3, 50.0, 42.4, 39.9, 39.6, 37.1, 36.3, 36.0, 33.2,
32.0, 29.8, 28.4, 28.1, 25.9, 24.4, 24.0, 23.0, 22.7, 20.9,18.8, 14.3,12.0;
HRMS (ESI, TOF) calcd for C35H51Oþ [MþH]þ: 487.3934, found:
487.3944.
in the 1H NMR spectra were recorded using TMS as internal stan-
dard or referenced to the deuterated solvents. Chemical shifts in 13
{1H} NMR spectra were referenced to the deuterated solvents.
C
4.2. General procedure for the preparation of alkynols
4.2.4. (2-(4-(3R)-5-Cholesten-3
nol (1y). The compound was prepared from 2-iodobenzyl alcohol
(468.1 mg, 2 mmol) and 4-(3R)-5-cholesten-3 -oxybenzylethynyl
b-oxybenzylethynyl)phenyl)-metha-
To a mixture of the 2-iodobenzyl alcohol (1.16 g, 5.0 mmol) in
DMF (30 mL) were added PdCl2(PPh3)2 (0.70 g, 0.10 mmol), and
CuI (0.19 g, 0.10 mmol) under nitrogen. After the reaction mixture
was stirred for 5 min at room temperature, N,N-diisopropylamine
(2.02 g, 4.0 equiv) was added by a syringe. The reaction mixture
was then heated at 70 ꢀC. A solution of the alkynes (1.2 equiv)
in DMF (5 mL) was added dropwise over 10 min, and the mixture
was allowed to stir at 70 ꢀC for 2 h. After cooling, the reaction
mixture was washed with saturated aq NH4Cl and water, and
then extracted with EtOAc (3ꢁ25 mL). The combined
organic extracts were dried over MgSO4 and concentrated under
vacuum to give the crude product, which was purified by column
chromatography on silica gel using 9:1 to 4:1 hexane/EtOAc as
eluent.
b
(973.5 mg, 2.4 mmol) following the typical procedure. The product
1y was obtained in 75% yield (888 mg) as white solid after column
chromatography (eluent¼petroleum ether/ethyl acetate 10:1 v/v).
Mp: 154e156 ꢀC; 1H NMR (400 MHz, CDCl3, 25 ꢀC):
d 7.50e7.52 (m,
1H), 7.41e7.46 (m, 3H), 7.25e7.34 (m, 2H), 6.88 (d, J¼8.76 Hz, 2H),
5.25 (t, J¼2.64 Hz, 1H), 4.89 (d, J¼5.88 Hz, 2H), 4,56 (s, 1H), 2.53 (d,
J¼15.00 Hz, 1H), 2.35 (d, J¼15.08 Hz, 1H), 2.21 (t, J¼6.28 Hz, 1H),
0.86e2.03 (m, 38H), 0.69 (s, 3H); 13C NMR (100.6 MHz, CDCl3,
25 ꢀC):
d 158.2, 142.4, 138.4, 133.0, 132.1, 128.5, 127.6, 127.4, 122.6,
121.9, 116.7, 114.8, 94.6, 85.4, 73.2, 64.3, 56.9, 56.3, 50.0, 22.4, 39.9,
39.6, 37.1, 36.3, 36.0, 33.2, 32.0, 28.4, 28.2, 25.9, 24.4, 24.0, 23.0, 22.7,
20.9, 19.2, 18.8, 12.0; HRMS (ESI, TOF) calcd for C42H57O2þ [MþH]þ:
593.4353, found: 593.4360.
4.2.1. Ethyl
4-((2-(hydroxymethyl)phenyl)ethynyl)benzoate
4.3. Typical procedure for the cyclization of alkynols
(1m). The compound was prepared from 2-iodobenzyl alcohol
(1.17 g, 5 mmol) and ethyl 4-ethynylbenzoate44 (1.04 g, 6 mmol)
following typical procedure. The product 1m was obtained as
a white solid in 67% yield (1.40 g) as white solid after column
chromatography (eluent¼petroleum ether/ethyl acetate 10:1 v/v).
To a solution of alkynol (1, 1.0 mmol) in DMSO (2 mL) was added
t-BuOK (0.1 mmol, 100 mL, 1 M in THF). The resulting solution was
stirred at 80 ꢀC for 5 h. The reaction mixture was then cooled to
room temperature and extracted from brine water (10 mL) with
diethyl ether (3ꢁ5 mL). The combined organic extracts were dried
with anhydrous Na2SO4, filtered and evaporated in vacuo. The
residue was purified by flash column chromatography on silica gel
to afford the desired product. 2deg, 2jem, 2o, 2p, 2rew, 2y and 2z
are new compounds and the other products are known compounds.
Note that the yield of 2a in the optimization of the reaction con-
ditions was determined by 1H NMR integration using PhSiMe3 as
the internal standard.
Mp: 85e87 ꢀC; 1H NMR (400 MHz, CDCl3, 25 ꢀC):
d 8.04 (d,
J¼7.96 Hz, 2H), 7.50e7.59 (m, 4H), 7.40 (t, J¼7.56 Hz, 1H), 7.29e7.33
(m, 1H), 4.93 (d, J¼6.32 Hz, 2H), 4.39 (q, J¼7.08 Hz, 2H), 2.07 (t,
J¼6.32 Hz, 1H), 1.41 (t, J¼7.08 Hz, 3H); 13C NMR (100.6 MHz, CDCl3,
25 ꢀC):
d 166.2, 143.0, 132.4, 131.5, 130.1, 129.6, 129.3, 127.6, 127.5,
127.2, 120.7, 93.4, 89.7, 63.8, 61.3, 14.4; HRMS (ESI, TOF) calcd for
þ
C
18H17O3 [MþH]þ: 281.1172, found: 281.1175.
4.2.2. (2-(Cyclopropylethynyl)phenyl)methanol (1o). The com-
pound was prepared from 2-iodobenzyl alcohol (1.17 g, 5 mmol)
and ethynylcyclopropane (0.40 g, 6 mmol) following typical pro-
cedure. The product 1o was obtained in 85% yield (0.86 g) as a pale
yellow oil after column chromatography (eluent¼petroleum ether/
4.3.1. 1-Methylene-1,3-dihydroisobenzofuran (2a).22 The compound
was prepared from 1a (132.2 mg, 1.0 mmol) following typical
procedure. The reaction mixture was cooled to room temperature
and extracted by n-hexane (3ꢁ5 mL). The combined organic ex-
tracts were evaporated in vacuo to obtain the 2a (124 mg, 94%) as
ethyl acetate 10:1 v/v). 1H NMR (400 MHz, C6D6, 25 ꢀC):
d 7.36e7.39
(m, 2H), 7.27e7.29 (m, 1H), 7.19e7.22 (m, 1H), 4.77 (d, J¼6.52 Hz,
a pale yellow oil. 1H NMR (400 MHz, DMSO-d6, 25 ꢀC):
d 7.64 (d,
2H), 2.14 (t, J¼6.56 Hz, 1H), 1.45e1.52 (m, 1H), 0.80e0.93 (m, 4H);
J¼6.68 Hz, 1H), 7.36e7.43 (m, 3H), 5.30 (s, 2H), 4.59 (d, J¼1.84 Hz,
13C NMR (100.6 MHz, CDCl3, 25 ꢀC):
d 142.7, 132.4, 128.0, 127.5,
1H), 4.35 (d, J¼1.72 Hz, 1H); 13C NMR (100.6 MHz, DMSO-d6, 25 ꢀC):
127.3, 122.1, 98.7, 73.4, 64.2, 9.0, 0.5; HRMS (ESI, TOF) calcd for
d 161.4, 140.2, 132.9, 129.2, 128.0, 121.7, 120.6, 77.8, 73.3; HRMS (ESI,
C
12H13Oþ [MþH]þ: 173.0961, found: 173.0960.
TOF) calcd for C9H9Oþ [MþH]þ: 133.0647, found: 133.0650.
4.2.3. 4-(3R)-5-Cholesten-3
b
-oxybenzylethynyl. To
a
mixture of
4.3.2. (Z)-1-Benzylidene-1,3-dihydroisobenzofuran
(2b).45,46 The
cholesterol (1.93 g, 5.0 mmol) in THF (50 mL) were added PPh3
compound was prepared from 1b (208.3 mg, 1.0 mmol) following

D.Y. Li et al. / Tetrahedron 70 (2014) 7022e7031
7027
typical procedure.196 mg (94% yield) of product 2b was obtained as
a white solid after column chromatography (eluent¼petroleum
ether/ethyl acetate 50:1 v/v). Mp: 100e102 ꢀC; 1H NMR (400 MHz,
1H NMR (400 MHz, CDCl3, 25 ꢀC):
d
7.81 (s, 1H), 7.55e7.57 (m,
1H), 7.53 (d, J¼8.04 Hz, 1H), 7.35e7.38 (m, 3H), 7.21e7.25 (m, 1H),
7.10 (d, J¼8.04 Hz, 1H), 5.87 (s, 1H), 5.52 (s, 2H); 13C NMR
C6D6, 25 ꢀC):
d
8.00 (d, J¼7.44 Hz, 2H), 7.34 (t, J¼7.84 Hz, 2H),
7.09e7.21 (m, 2H), 6.94e7.02 (m, 2H), 6.69 (d, J¼6.92 Hz, 1H), 6.02
(s, 1H), 4.85 (s, 2H); 13C NMR (100.6 MHz, C6D6, 25 ꢀC):
156.6,
(100.6 MHz, CDCl3, 25 ꢀC):
d 157.5, 139.6, 138.4, 134.6, 134.3,
129.6, 129.3, 128.3, 127.5, 125.9, 125.2, 121.4, 120.3, 95.1, 75.3;
HRMS (EI, TOF) calcd for C15H11ClO [M]þ: 242.0498, found:
242.0497.
d
139.6, 137.1, 135.3, 128.7, 128.6, 128.5, 125.7, 121.2, 120.2, 97.1, 74.8;
HRMS (ESI, TOF) calcd for C15H13Oþ [MþH]þ: 209.0960, found:
209.0967.
4.3.8. (Z)-1-(4-Methoxybenzylidene)-1,3-dihydroisobenzo-furan
(2h).26 The compound was prepared from 1h (238.3 mg, 1.0 mmol)
following typical procedure. 231 mg (97% yield) of product 2h was
4.3.3. (Z)-1-(2-Methoxybenzylidene)-1,3-dihydroisobenzo-furan
(2c).32a The compound was prepared from 1c (119.1 mg, 0.5 mmol)
following typical procedure. 111 mg (93% yield) of product 2c was
obtained as a pale yellow solid after column chromatography
(eluent¼petroleum ether/ethyl acetate 30:1 v/v). Mp: 136e138 ꢀC;
obtained as
a
brown oil after column chromatography
(eluent¼petroleum ether/ethyl acetate 50:1 v/v). Mp: 118e129 ꢀC;
1H NMR (400 MHz, C6D6, 25 ꢀC):
d
7.96 (d, J¼8.76 Hz, 2H), 7.25 (d,
J¼7.44 Hz, 1H), 6.96e7.02 (m, 4H), 6.71 (d, J¼7.40 Hz, 1H), 6.03 (s,
1H NMR (400 MHz, acetone-d6, 25 ꢀC):
d
8.22 (d, J¼7.68 Hz, 1H),
1H), 4.90 (s, 2H), 3.35 (s, 3H); C NMR (100.6 MHz, C6D6, 25 ꢀC):
13
7.66e7.68 (m, 1H), 7.46e7.48 (m, 1H), 7.40e7.42 (m, 2H), 7.10e7.14
(m,1H), 6.91e6.96 (m, 2H), 6.44 (s,1H), 5.54 (s, 2H), 3.87 (s, 3H); 13
NMR (100.6 MHz, acetone-d6, 25 ꢀC):
157.0, 156.5, 140.3, 135.8,
d
158.3, 155.0, 139.3, 135.6, 129.9, 129.7, 128.2, 121.3, 119.9, 114.3,
þ
C
96.9, 74.6, 54.8; HRMS (ESI, TOF) calcd for C16H15O2 [MþH]þ:
d
239.1066, found: 239.1070.
129.6, 129.4, 129.0, 127.1, 126.0, 122.4, 121.1, 120.6, 111.0, 89.8, 75.5,
55.8; HRMS (EI, TOF) calcd for C16H14O2 [M]þ: 238.0994, found:
238.0998.
4.3.9. (Z)-1-(4-Methylbenzylidene)-1,3-dihydroisobenzofuran
(2i).26 The compound was prepared from 1i (222.3 mg, 1.0 mmol)
following typical procedure. 204 mg (92% yield) of product 2i was
4.3.4. (Z)-1-(2-Chlorobenzylidene)-1,3-dihydroisobenzofuran
(2d). The compound was prepared from 1d (121.4 mg, 0.5 mmol)
following typical procedure. 108 mg (89% yield) of product 2d
was obtained as a white solid after column chromatography
(eluent¼petroleum ether/ethyl acetate 40:1 v/v). Mp:
obtained as
a white solid after column chromatography
(eluent¼petroleum ether/ethyl acetate 50:1 v/v). Mp: 95e97 ꢀC; 1H
NMR (400 MHz, C6D6, 25 ꢀC):
d
7.96 (d, J¼8.12 Hz, 2H), 7.16e7.24 (m,
3H), 6.96e7.02 (m, 2H), 6.69 (d, J¼7.40 Hz, 1H), 6.05 (s, 1H), 4.88 (s,
2H), 2.20 (s, 3H); 13C NMR (100.6 MHz, acetone-d6, 25 ꢀC):
d
156.6,
102e104 ꢀC; 1H NMR (400 MHz, acetone-d6, 25 ꢀC):
d
8.35 (d,
140.3,135.6,135.3,134.7,129.7,129.6,128.9,128.6,122.4,120.6, 96.7,
75.6, 21.2; HRMS (ESI, TOF) calcd for C16H15Oþ [MþH]þ: 223.1117,
found: 223.1127.
J¼7.96 Hz, 1H), 7.77e7.79 (m, 1H), 7.46e7.52 (m, 3H), 7.41 (d,
J¼8.04 Hz, 1H), 7.29e7.33 (m, 1H), 7.11e7.15 (m, 1H), 6.41 (s, 1H),
5.59 (s, 2H); 13C NMR (100.6 MHz, acetone-d6, 25 ꢀC):
d 159.0,
140.8, 135.1, 134.9, 131.8, 130.4, 130.0, 129.1, 127.6, 127.1, 122.5,
121.1, 91.4, 76.0; HRMS (EI, TOF) calcd for C15H11ClO [M]þ:
242.0498, found: 242.0495.
4.3.10. (Z)-1-(4-Fluorobenzylidene)-1,3-dihydroisobenzofuran
(2j). The compound was prepared from 1j (226.2 mg, 1.0 mmol)
following typical procedure. 217 mg (96% yield) of product 2j was
obtained as
a white solid after column chromatography
4.3.5. (Z)-3-(Isobenzofuran-1(3H)-ylidenemethyl)aniline (2e). The
compound was prepared from 1e (223.3 mg, 1.0 mmol) following
typical procedure. 217 mg (97% yield) of product 2e was obtained as
a white solid after column chromatography (eluent¼petroleum
ether/ethyl acetate 5:1 v/v). Mp: 113e115 ꢀC; 1H NMR (400 MHz,
(eluent¼petroleum ether/ethyl acetate 50:1 v/v). Mp: 114e115 ꢀC;
1H NMR (400 MHz, acetone-d6, 25 ꢀC):
d
7.76 (dd, J1¼8.84 Hz,
J2¼5.64 Hz, 2H), 7.68e7.70 (m, 1H), 7.47e7.49 (m, 1H), 7.40e7.43
(m, 2H), 7.08 (t, J¼8.96 Hz, 2H), 6.10 (s, 1H), 5.55 (s, 2H); 13C NMR
(100.6 MHz, acetone-d6, 25 ꢀC):
d
161.3 (d, JCeF¼227.96 Hz),
acetone-d6, 25 ꢀC):
d
7.66e7.68 (m, 1H), 7.45e7.46 (m, 1H),
156.9, 140.4, 135.3, 134.0 (d, JCeF¼3.36 Hz), 130.1 (d, JCeF¼7.58 Hz),
129.8, 129.0, 122.4, 120.7, 115.7 (d, JCeF¼21.35 Hz), 95.5, 75.7;
HRMS (ESI, TOF) calcd for C15H12OFþ [MþH]þ: 227.0866, found:
227.0871.
7.38e7.40 (m, 2H), 7.12 (s, 1H), 6.98e7.03 (m, 2H), 6.47e6.49 (m,
1H), 5.95 (s, 1H), 5.52 (s, 2H), 4.54 (br, NH2); 13C NMR (100.6 MHz,
acetone-d6, 25 ꢀC):
d 156.6, 149.0, 140.3, 138.0, 135.7, 129.5, 128.9,
122.4, 120.6, 118.1, 114.6, 112.8, 97.5, 75.5; HRMS (ESI, TOF) calcd for
C
15H14NOþ [MþH]þ: 224.1070, found: 224.1076.
4.3.11. (Z)-1-(4-Chlorobenzylidene)-1,3-dihydroisobenzofuran
(2k). The compound was prepared from 1k (242.7 mg, 1.0 mmol)
following typical procedure. 226 mg (93% yield) of product 2k was
4.3.6. (Z)-tert-Butyl(3-(isobenzofuran-1(3H)-ylidenemethyl)-phenyl)
carbamate (2f). The compound was prepared from 1f (323.4 mg,
1.0 mmol) following typical procedure. 285 mg (88% yield) of
product 2f was obtained as a white solid after column chroma-
tography (eluent¼petroleum ether/ethyl acetate 15:1 v/v). Mp:
obtained as
a white solid after column chromatography
(eluent¼petroleum ether/ethyl acetate 50:1 v/v). Mp: 113e115 ꢀC;
1H NMR (400 MHz, CDCl3, 25 ꢀC):
7.55e7.58 (m, 1H), 7.34e7.39 (m, 3H), 7.28 (d, J¼8.56 Hz, 2H), 5.90
d
7.67 (d, J¼8.60 Hz, 2H),
164e166 ꢀC; 1H NMR (400 MHz, acetone-d6, 25 ꢀC):
d
8.34 (br, 1H),
(s, 1H), 5.52 (s, 2H); 13C NMR (100.6 MHz, CDCl3, 25 ꢀC):
d
156.9,
7.85 (s,1H), 7.73e7.75 (m,1H), 7.40e7.48 (m, 4H), 7.36 (d, J¼7.44 Hz,
139.4, 135.0, 134.7, 130.6, 129.1, 129.0, 128.5, 128.3, 121.4, 120.1, 95.2,
75.1; HRMS (EI, TOF) calcd for C15H11ClO [M]þ: 2423.0498, found:
242.0497.
1H), 7.21 (t, J¼7.88 Hz, 1H), 6.05 (s, 1H) 5.55 (s, 2H), 1.50 (s, 9H); 13
C
NMR (100.6 MHz, acetone-d6, 25 ꢀC):
d 157.3, 153.8, 140.5, 138.0,
135.5, 129.8, 129.2, 129.0, 122.9, 122.4, 120.8, 118.5, 116.3, 96.9, 79.7,
þ
75.7, 28.6; HRMS (ESI, TOF) calcd for C20H22NO3 [MþH]þ:
4.3.12. (Z)-1-(4-(Trifluoromethyl)benzylidene)-1,3-dihydroiso-ben-
zofuran (2l). The compound was prepared from 1l (276.3 mg,
1.0 mmol) following typical procedure. 257 mg (93% yield) of
product 2l was obtained as a pale yellow solid after column
chromatography (eluent¼petroleum ether/ethyl acetate 50:1 v/v).
324.1594, found: 324.1596.
4.3.7. (Z)-1-(3-Chlorobenzylidene)-1,3-dihydroisobenzofuran
(2g). The compound was prepared from 1g (242.7 mg, 1.0 mmol)
following typical procedure. 216 mg (89% yield) of product
2g was obtained as a white solid after column chromatography
(eluent¼petroleum ether/ethyl acetate 50:1 v/v). Mp: 70e73 ꢀC;
Mp: 138e140 ꢀC; 1H NMR (400 MHz, C6D6, 25 ꢀC):
d 7.77 (d,
J¼8.20 Hz, 2H), 7.54 (d, J¼8.28 Hz, 2H), 7.18e7.20 (m, 1H),
6.95e7.02 (m, 2H), 6.68 (d, J¼6.48 Hz, 1H), 5.83 (s, 1H), 4.78 (s,

7028
D.Y. Li et al. / Tetrahedron 70 (2014) 7022e7031
2H); 13C NMR (100.6 MHz, C6D6, 25 ꢀC):
d
158.6, 140.7, 139.9,
1.38e1.47 (m, 2H), 0.92 (t, J¼7.12 Hz, 3H); 13C NMR (100.6 MHz,
134.6, 129.3, 128.2, 127.9, 126.9 (q, JCeF¼32.19 Hz), 125.5 (q,
acetone-d6, 25 ꢀC):
d 156.4, 143.6, 137.8, 135.6, 129.7, 129.1,
JCeF¼271.36 Hz), 125.2 (q, JCeF¼3.86 Hz), 121.3, 120.4, 95.5, 75.1;
129.0, 128.6, 125.8, 122.3, 120.7, 96.4, 86.9, 36.3, 27.9, 23.2, 14.3;
HRMS (ESI, TOF) calcd for C19H21Oþ [MþH]þ: 265.1587, found:
265.1592.
þ
HRMS (ESI, TOF) calcd for C16H12OF3 [MþH]þ: 277.0835, found:
277.0849.
4.3.13. (Z)-Ethyl 4-(isobenzofuran-1(3H)-ylidenemethyl)-benzoate
(2m). The compound was prepared from 1m (280.3 mg,
1.0 mmol) following typical procedure. 233 mg (83% yield) of
product 2m was obtained as a pale yellow solid after column
chromatography (eluent¼petroleum ether/ethyl acetate 20:1 v/v).
4.3.18. (Z)-1-Benzylidene-6-fluoro-1,3-dihydroisobenzofuran
(2r). The compound was prepared from 1r (226.3 mg, 1.0 mmol)
following typical procedure. 222 mg (98% yield) of product 2r was
obtained as
a white solid after column chromatography
(eluent¼petroleum ether/ethyl acetate 30:1 v/v). Mp: 77e79 ꢀC; 1H
Mp: 133e135 ꢀC; 1H NMR (400 MHz, CDCl3, 25 ꢀC):
d
8.00 (d,
NMR (400 MHz, acetone-d6, 25 ꢀC):
d
7.73 (d, J¼7.40 Hz, 2H),
J¼8.44 Hz, 2H), 7.78 (d, J¼8.48 Hz, 2H), 7.59e7.79 (m, 1H),
7.48e7.52 (m, 2H), 7.30e7.34 (m, 2H), 7.12e7.21 (m, 2H), 6.14 (s,
7.35e7.42 (m, 3H), 5.99 (s, 1H), 5.56 (s, 2H), 4.37 (q, J¼7.12 Hz, 2H),
1H), 5.54 (s, 2H); 13C NMR (100.6 MHz, acetone-d6, 25 ꢀC):
d
164.0
1.40 (t, J¼7.12 Hz, 3H); 13C NMR (100.6 MHz, CDCl3, 25 ꢀC):
d
166.9,
(d, JCeF¼242.86 Hz), 156.4 (d, JCeF¼4.39 Hz), 137.9 (d, JCeF¼9.68 Hz),
137.2, 136.2 (d, JCeF¼1.99 Hz), 129.1, 128.7, 126.3, 124.2 (d,
JCeF¼9.36 Hz), 117.0 (d, JCeF¼24.07 Hz), 107.3 (d, JCeF¼24.66 Hz),
97.9, 75.5; HRMS (ESI, TOF) calcd for C15H12OFþ [MþH]þ: 227.0866,
found: 227.0868.
158.5, 141.3, 139.8, 134.6, 129.8, 129.5, 128.4, 127.4, 126.7, 121.4,
þ
120.4, 95.7, 75.4, 60.8, 14.5; HRMS (ESI, TOF) calcd for C18H17O3
[MþH]þ: 281.1172, found: 281.1172.
4.3.14. (Z)-2-(Isobenzofuran-1(3H)-ylidenemethyl)pyridine
(2n).26,47 The compound was prepared from 1n (209.2 mg,
1.0 mmol) following typical procedure. 128 mg (61% yield) of
product 2n was obtained as a yellow oil after column chromatog-
raphy (eluent¼petroleum ether/ethyl acetate 2:1 v/v). 1H NMR
4.3.19. (Z)-1-Benzylidene-6-chloro-1,3-dihydroisobenzofuran
(2s). The compound was prepared from 1s (226.3 mg, 1.0 mmol)
following typical procedure. 226 mg (93% yield) of product 2s
was obtained as a white solid after column chromatography
(eluent¼petroleum ether/ethyl acetate 50:1 v/v). Mp: 113e115 ꢀC;
(400 MHz, acetone-d6, 25 ꢀC):
d 8.47e8.48 (m, 1H), 8.13 (d,
J¼8.16 Hz, 1H), 7.78e7.80 (m, 1H), 7.66e7.71 (m, 1H), 7.45e7.54 (m,
1H NMR (400 MHz, CDCl3, 25 ꢀC):
d
7.71 (d, J¼7.96 Hz, 2H), 7.52 (s,
3H), 7.03e7.60 (m, 1H), 6.24 (s, 1H), 5.61 (s, 2H); 13C NMR
1H), 7.29e7.35 (m, 3H), 7.24 (d, J¼8.28 Hz, 1H), 7.14e7.18 (m, 1H),
(100.6 MHz, acetone-d6, 25 ꢀC):
d
159.8, 156.8, 150.0, 141.0, 136.4,
5.91 (s, 1H), 5.47 (s, 2H); 13C NMR (100.6 MHz, CDCl3, 25 ꢀC):
d
155.1,
135.0, 130.5, 129.2, 123.1, 122.5, 121.3, 120.5, 98.4, 76.2; HRMS (ESI,
137.6, 137.0, 136.0,134.4,129.0,128.5,128.0,125.8, 122.5, 120.2, 97.6,
74.7; HRMS (EI, TOF) calcd for C15H11ClO [M]þ: 242.0498, found:
242.0499.
TOF) calcd for C14H12NOþ [MþH]þ: 210.0913, found: 210.0914.
4.3.15. (Z)-1-(Cyclopropylmethylene)-1,3-dihydroisobenzo-furan
(2o). The compound was prepared from 1o (172.2 mg, 1.0 mmol)
following typical procedure. The reaction mixture was cooled
room temperature and extracted by n-hexane (3ꢁ5 mL). The
combined organic extracts were evaporated in vacuo to obtain the
2o (164 mg, 95%) as a pale yellow oil. 1H NMR (400 MHz, DMSO-d6,
4.3.20. (Z)-1-Benzylidene-6-methyl-1,3-dihydroisobenzofuran
(2t). The compound was prepared from 1t (222.3 mg, 1.0 mmol)
following typical procedure. 200 mg (90% yield) of product 2t
was obtained as a white solid after column chromatography
(eluent¼petroleum ether/ethyl acetate 50:1 v/v). Mp: 106e109 ꢀC;
25 ꢀC):
d
7.43e7.46 (m, 1H), 7.37e7.39 (m, 1H), 7.29e7.32 (m, 2H),
1H NMR (400 MHz, CDCl3, 25 ꢀC):
d
7.73 (d, J¼7.28 Hz, 2H), 7.39 (s,
5.33 (s, 2H), 4.60 (d, J¼9.44 Hz, 1H), 1.64e1.73 (m, 1H), 0.73e0.77
1H), 7.31e7.35 (m, 2H), 7.22 (d, J¼7.84 Hz, 1H), 7.12e7.17 (m, 2H),
(m, 2H), 0.36e0.40 (m, 2H); 13C NMR (100.6 MHz, DMSO-d6,
5.92 (s, 1H), 5.48 (s, 2H), 2.42 (s, 3H); 13C NMR (100.6 MHz, CDCl3,
25 ꢀC):
d
154.5, 138.8, 133.3, 128.0, 127.8, 121.6, 119.1, 99.2, 73.1, 8.1,
25 ꢀC):
d 156.5, 138.0, 136.7, 136.6, 135.2, 130.0, 128.5, 127.8, 125.3,
7.0; HRMS (ESI, TOF) calcd for C12H13Oþ [MþH]þ: 173.0960, found:
121.0, 120.4, 96.0, 74.9, 21.6; HRMS (EI, TOF) calcd for C16H14O [M]þ:
222.1045, found: 222.1044.
173.0961.
4.3.16. (Z)-1-Benzylidene-3-methyl-1,3-dihydroisobenzofuran
(2p). The compound was prepared from 1p (222.3 mg, 1.0 mmol)
following typical procedure. 229 mg (97% yield) of product 2p
was obtained as a brown oil after column chromatography
(eluent¼petroleum ether/ethyl acetate 50:1 v/v). 1H NMR
4.3.21. (Z)-1-Benzylidene-5-methoxy-1,3-dihydroisobenzo-furan
(2u). The compound was prepared from 1u (238.3 mg, 1.0 mmol)
following typical procedure. 210 mg (88% yield) of product 2u
was obtained as a white solid after column chromatography
(eluent¼petroleum ether/ethyl acetate 25:1 v/v). Mp: 118e121 ꢀC;
(400 MHz, acetone-d6, 25 ꢀC):
d
7.75 (d, J¼7.32 Hz, 2H), 7.69e7.71
1H NMR (400 MHz, CDCl3, 25 ꢀC):
d
7.70 (d, J¼7.24 Hz, 2H), 7.47 (d,
(m, 1H), 7.40e7.46 (m, 3H), 7.28e7.32 (m, 2H), 7.11 (t, J¼7.40 Hz,
J¼8.52 Hz, 1H), 7.30e7.33 (m, 2H), 7.09e7.13 (m, 1H), 6.92 (dd,
1H), 6.05 (s, 1H), 5.81 (q, J¼6.52 Hz, 1H), 1.62 (d, J¼6.52 Hz, 3H);
J1¼8.52 Hz, J2¼2.24 Hz,1H), 6.83 (d, J¼1.52 Hz,1H), 5.81 (s,1H), 5.47
13C NMR (100.6 MHz, acetone-d6, 25 ꢀC):
d
156.2, 144.9, 137.7,
(s, 2H), 3.84 (s, 3H); C NMR (100.6 MHz, CDCl3, 25 ꢀC):
d
160.9,
13
135.3, 129.8, 129.1, 129.0, 128.6, 125.8, 122.2, 120.8, 96.5, 83.2, 22.0;
HRMS (ESI, TOF) calcd for C16H15Oþ [MþH]þ: 223.1117, found:
223.1120.
156.4, 141.3, 136.8, 128.4, 127.6, 127.5, 125.0, 121.2, 115.3, 105.8, 94.7,
74.7, 55.7; HRMS (EI, TOF) calcd for C16H14O2 [M]þ: 238.0994,
found: 238.0995.
4.3.17. (Z)-1-Benzylidene-3-butyl-1,3-dihydroisobenzofuran
(2q).25 The compound was prepared from 1q (264.4 mg,
1.0 mmol) following typical procedure. 251 mg (95% yield) of
product 2q was obtained as a yellow oil after column chroma-
tography (eluent¼petroleum ether/ethyl acetate 50:1 v/v). 1H
4.3.22. (Z)-1-Benzylidene-5,6-dimethoxy-1,3-dihydroisobenzo-furan
(2v). The compound was prepared from 1v (268.3 mg, 1.0 mmol)
following typical procedure. 215 mg (80% yield) of product 2v was
obtained as
a white solid after column chromatography
(eluent¼petroleum ether/ethyl acetate 5:1 v/v). Mp: 115e117 ꢀC;
NMR (400 MHz, acetone-d6, 25 ꢀC):
d
7.76 (d, J¼7.32 Hz, 2H),
1H NMR (400 MHz, acetone-d6, 25 ꢀC):
d
7.68 (d, J¼7.28 Hz, 2H),
7.68e7.72 (m, 1H), 7.40e7.46 (m, 3H), 7.31 (t, J¼7.92 Hz, 2H), 7.11
(t, J¼7.40 Hz, 1H), 6.05 (s, 1H), 5.73 (dd, J1¼3.80 Hz, J2¼7.68 Hz,
1H), 2.08e2.14 (m, 1H), 1.73e1.82 (m, 1H), 1.48e1.59 (m, 2H),
7.09e7.29 (m, 3H), 7.05e7.09 (m, 2H), 5.94 (s, 1H), 5.46 (s, 2H), 3.90
(s, 3H), 3.86 (s, 3H); 13C NMR (100.6 MHz, acetone-d6, 25 ꢀC):
d
158.1, 152.3, 151.2, 138.1, 133.2, 129.0, 128.2, 127.5, 125.4, 105.1,

D.Y. Li et al. / Tetrahedron 70 (2014) 7022e7031
7029
103.5, 94.9, 75.6, 56.3; HRMS (EI, TOF) calcd for C17H16O3 [M]þ:
268.1099, found: 268.1100.
4.4.1. 2-Phenyl-1-tosyl-1H-indole (4a).48 The compound was pre-
pared from 3a (173.7 mg, 0.5 mmol) following typical procedure
but using DMSO (1.5 mL) as solvent. 160 mg (92% yield) of product
4a was obtained as a white solid after column chromatography
(eluent¼petroleum ether/ethyl acetate 10:1 v/v). Mp: 145e147 ꢀC;
4.3.23. (Z)-5,6-Dimethoxy-1-(4-methylbenzylidene)-1,3-
dihydroisobenzofuran (2w). The compound was prepared from 1w
(282.3 mg, 1.0 mmol) following typical procedure. 268 mg (95%
yield) of product 2w was obtained as a white solid after column
chromatography (eluent¼petroleum ether/ethyl acetate 5:1 v/v).
1H NMR (400 MHz, C6D6, 25 ꢀC):
d
8.31 (d, J¼8.36 Hz,1H), 7.48e7.50
(m, 2H), 7.42e7.45 (m, 4H), 7.33e8.37 (m, 1H), 7.24e7.28 (m, 3H),
7.04 (d, J¼8.08 Hz, 2H), 6.54 (s, 1H), 2.28 (s, 3H); 13C NMR
Mp: 196e198 ꢀC; 1H NMR (400 MHz, acetone-d6, 25 ꢀC):
d
7.58 (d,
(100.6 MHz, C6D6, 25 ꢀC):
d 144.6, 142.3, 138.4, 134.8, 132.6, 130.7,
J¼8.16 Hz, 2H), 7.24 (s, 1H), 7.09 (d, J¼8.00 Hz, 2H), 7.04 (s, 1H), 5.90
130.5, 129.3, 128.8, 127.6, 126.9, 124.9, 124.4,120.8, 116.8, 113.7, 21.6;
HRMS (EI, TOF) calcd for C21H17NO2S [M]þ: 347.0980, found:
347.0985.
(s, 1H), 5.44 (s, 2H), 3.89 (s, 3H), 3.86 (s, 3H), 2.28 (s, 3H); 13C NMR
(100.6 MHz, CDCl3, 25 ꢀC):
d 156.3, 150.7, 149.8, 134.6, 133.8, 132.0,
129.2, 127.4, 127.2, 103.6, 102.1, 94.5, 74.8, 56.3, 56.2, 21.3; HRMS
þ
(ESI, TOF) calcd for C18H19O3 [MþH]þ: 283.1328, found: 283.1331.
4.4.2. 1-Benzyl-2-phenyl-1H-indole (4b).49 The compound was
prepared from 3b (141.7 mg, 0.5 mmol) following typical procedure
but using DMSO (1.5 mL) as solvent. 132 mg (93% yield) of product
4b was obtained as a white solid after column chromatography
(eluent¼petroleum ether/ethyl acetate 100:1 v/v). Mp: 89e91 ꢀC;
4.3.24. (Z)-5-Benzylidene-5,7-dihydro-[1,3]dioxolo[4,5-f]iso-
benzofuran (2x).26 The compound was prepared from 1x (126.1 mg,
1.0 mmol) following typical procedure. 107 mg (85% yield) of
product 2x was obtained as a white solid after column chroma-
1H NMR (400 MHz, C6D6, 25 ꢀC):
d
7.67 (d, J¼5.12 Hz, 1H), 7.43 (d,
tography (eluent¼petroleum ether/ethyl acetate 5:1 v/v). Mp:
J¼5.96 Hz, 2H), 7.36e7.37 (m, 3H), 7.22e7.28 (m, 3H), 7.13e7.17 (m,
1
83e85 ꢀC; H NMR (400 MHz, CDCl3, 25 ꢀC):
d
7.69 (d, J¼7.28 Hz,
3H), 7.02 (d, J¼7.08 Hz, 2H), 6.65 (s, 1H), 5.36 (s, 2H); 13C NMR
2H), 7.29e7.33 (m, 2H), 7.10e7.13 (m, 1H), 6.96 (s, 1H), 6.74 (s, 1H),
(100.6 MHz, C6D6, 25 ꢀC):
d 142.0, 138.3, 138.1, 132.8, 129.4, 128.9,
6.04 (s, 2H), 5.73 (s, 1H), 5.41 (s, 2H); 13C NMR (100.6 MHz, CDCl3,
128.7, 128.4, 128.2, 127.3, 126.1, 122.0, 120.7, 120.3, 110.7, 102.5, 47.9;
HRMS (ESI, TOF) calcd for C21H18Nþ [MþH]þ: 284.1434, found:
284.1435.
25 ꢀC):
d 156.6, 149.4, 148.6, 136.6, 133.6, 128.6, 128.5, 127.5, 125.1,
102.0, 101.5, 100.2, 94.8, 74.8; HRMS (EI, TOF) calcd for C16H12O3
[M]þ: 252.0786, found: 252.0784.
4.4.3. 1-Benzyl-5-chloro-2-phenyl-1H-indole (4c). The compound
was prepared from 3c (158.9 mg, 0.5 mmol) following typical
procedure but using DMSO (1.5 mL) as solvent. 145 mg (91% yield)
of product 4c was obtained as a white solid after column chroma-
tography (eluent¼petroleum ether/ethyl acetate 100:1 v/v). Mp:
4.3.25. (Z)-1-(4-(3R)-5-Cholesten-3b-oxybenzylidene)-1,3-
dihydroisobenzofuran (2y). The compound was prepared from 1y
(118.6 mg, 0.2 mmol) following typical procedure but using THF
(1 mL) as solvent. 112 mg (94% yield) of product 2y was obtained as
a white solid after column chromatography (eluent¼petroleum
ether/ethyl acetate 5:1 v/v). Mp: 179e181 ꢀC; 1H NMR (400 MHz,
102e104 ꢀC; 1H NMR (400 MHz, C6D6, 25 ꢀC):
d 7.62 (s, 1H),
7.37e7.43 (m, 5H), 7.22e7.30 (m, 3H), 7.05e7.10 (m, 2H), 6.98 (d,
C6D6, 25 ꢀC):
d
7.97 (d, J¼8.68 Hz, 2H), 7.24 (d, J¼7.52 Hz, 1H), 7.08
J¼7.04 Hz, 2H), 6.58 (s, 1H), 5.34 (s, 2H); 13C NMR (100.6 MHz, C6D6,
(d, J¼8.68 Hz, 2H), 6.95e7.04 (m, 2H), 6.71 (d, J¼7.36 Hz, 1H), 6.04
(s, 1H), 5.39 (t, J¼2.48 Hz, 1H), 4.91 (s, 2H), 4.35 (s, 1H), 2.48 (d,
J¼14.88 Hz, 1H), 2.34 (d, J¼14.88 Hz, 1H), 0.93e2.08 (m, 38H), 0.71
25 ꢀC):
d 143.3, 137.9, 136.4, 132.3, 129.4, 129.3, 129.0, 128.8, 128.5,
127.5, 126.0, 125.9, 122.2, 120.0, 111.7, 102.0, 48.0; HRMS (EI, TOF)
calcd for C21H16ClNþ [M]þ: 317.0971, found: 317.0970.
(s, 3H); 13C NMR (100.6 MHz, C6D6, 25 ꢀC):
d 156.4, 155.0, 139.3,
138.8, 135.7, 129.8, 128.2, 127.9, 122.6, 121.3, 119.9, 116.8, 97.0, 74.6,
72.8, 57.0, 56.6, 50.2, 42.6, 40.2, 40.0, 37.3, 36.7, 36.3, 33.6, 32.3, 28.7,
28.4, 26.2, 24.6, 24.5, 23.1, 22.8, 21.2, 19.2, 19.1, 12.2; HRMS (ESI,
4.4.4. 1-Benzyl-5-methyl-2-phenyl-1H-indole (4d).50 The com-
pound was prepared from 3d (148.7 mg, 0.5 mmol) following
typical procedure but using DMSO (1.5 mL) as solvent. 146 mg (98%
yield) of product 4d was obtained as a white solid after column
chromatography (eluent¼petroleum ether/ethyl acetate 100:1 v/v).
þ
TOF) calcd for C42H57O2 [MþH]þ: 593.4353, found: 593.4362.
4.3.26. 2-(4-Methoxyphenyl)benzofuran (2z). The compound was
prepared from 1z (224.2 mg,1.0 mmol) following typical procedure.
213 mg (95% yield) of product 2z was obtained as a yellow oil after
column chromatography (eluent¼petroleum ether/ethyl acetate
Mp: 125e127 ꢀC; 1H NMR (400 MHz, C6D6, 25 ꢀC):
d 7.45 (s, 1H),
7.41e7.44 (m, 2H), 7.32e7.39 (m, 3H), 7.20e7.28 (m, 3H), 7.06 (d,
J¼8.36 Hz, 1H), 7.02 (d, J¼7.20 Hz, 2H), 6.97 (d, J¼8.32 Hz, 1H), 6.57
(s, 1H), 5.34 (s, 2H), 2.45 (s, 3H); 13C NMR (100.6 MHz, C6D6, 25 ꢀC):
25:1 v/v). Mp: 144e146 ꢀC; 1H NMR (400 MHz, CDCl3, 25 ꢀC):
d
7.78
d 142.0, 138.5, 136.6, 133.0, 129.5, 129.3, 128.8, 128.7, 128.6, 128.0,
(d, J¼8.80 Hz, 2H), 7.54 (d, J¼7.08 Hz, 1H), 7.49 (d, J¼7.84 Hz, 1H),
127.2, 126.1, 123.6, 120.4, 110.4, 102.0, 47.09, 21.6; HRMS (EI, TOF)
7.18e7.26 (m, 2H), 6.96 (d, J¼8.80 Hz, 2H), 6.87 (s, 1H), 3.84 (s, 3H);
calcd for C22H19Nþ [M]þ: 297.1517, found: 297.1518.
13C NMR (100.6 MHz, CDCl3, 25 ꢀC):
d 160.1, 156.2, 154.8, 129.6,
126.5, 123.8, 123.4, 122.9, 120.7, 114.3, 111.1, 99.8, 55.4; HRMS (EI,
4.4.5. 2-Methyl-3-methyleneisoindolin-1-one (4e).51 The com-
pound was prepared from 3e (79.6 mg, 0.5 mmol) following typical
procedure but using DMSO (1.5 mL) as solvent. 75 mg (94% yield) of
product 4e was obtained as a white solid after column chroma-
tography (eluent¼petroleum ether/ethyl acetate 25:1 v/v). Mp:
TOF) calcd for C15H12O2 [M]þ: 224.0837, found: 224.0839.
4.4. Typical procedure for the cyclization of alkynylamines
68e70 ꢀC; 1H NMR (400 MHz, C6D6, 25 ꢀC):
d
7.82 (d, J¼7.52 Hz,1H),
To a solution of alkynylamines (3, 0.5 mmol) in DMSO (1.5 mL)
was added t-BuOK (0.1 mmol, 100 mL, 1 M in THF). The resulting
7.68 (d, J¼7.64 Hz,1H), 7.55e7.59 (m, 1H), 7.47e7.51 (m, 1H), 5.18 (d,
J¼1.60 Hz, 1H), 4.85 (d, J¼1.60 Hz, 1H), 3.29 (s, 3H); 13C NMR
solution was stirred at 80 ꢀC for 5 h. The reaction mixture was then
cooled to room temperature and extracted from brine water
(10 mL) with diethyl ether (3ꢁ5 mL). The combined organic ex-
tracts were dried with anhydrous Na2SO4, filtered and evaporated
in vacuo. The residue was purified by flash column chromatography
on silica gel to afford the desired product. 4c and 4gei are new
compounds and the other products are known compounds.
(100.6 MHz, C6D6, 25 ꢀC):
d 167.2, 143.0, 136.2, 133.9, 131.9, 129.5,
123.1, 119.8, 88.6, 25.8; HRMS (EI, TOF) calcd for C10H9NO [MþH]þ:
159.0684, found: 159.0685.
4.4.6. (E)-3-Benzylidene-2-methylisoindolin-1-one (4f).42 The com-
pound was prepared from 3f (117.6 mg, 0.5 mmol) following typical
procedure but using DMSO (1.5 mL) as solvent. 93 mg (79% yield) of

7030
D.Y. Li et al. / Tetrahedron 70 (2014) 7022e7031
product 4f was obtained as a white solid after column chroma-
References and notes
tography (eluent¼petroleum ether/ethyl acetate 5:1 v/v). Mp:
1
1. (a) Elliot, M. C.; Williams, E. J. Chem. Soc., Perkin Trans. 1 2001, 2303e2340; (b)
Elliot, M. C. J. Chem. Soc., Perkin Trans. 1 2000, 1291e1318; (c) Mitchinson, A.;
Nadin, A. J. Chem. Soc., Perkin Trans. 1 2000, 2862e2892.
114e116 ꢀC; H NMR (400 MHz, C6D6, 25 ꢀC):
d
7.83 (d, J¼7.52 Hz,
1H), 7.36e7.46 (m, 6H), 7.29e7.32 (m, 2H), 6.51 (s, 1H), 3.39 (s, 3H);
13C NMR (100.6 MHz, C6D6, 25 ꢀC):
d
166.7, 137.6, 135.3, 135.0, 131.5,
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130.7, 129.6, 129.3, 128.8, 127.9, 123.2, 123.1, 110.3, 26.2; HRMS (EI,
TOF) calcd for C16H13NO [M]þ: 235.0997, found: 235.0998.
4.4.7. (E)-3-Benzylidene-2-dodecylisoindolin-1-one (4g). The com-
pound was prepared from 3g (155.7 mg, 0.5 mmol) following
typical procedure but using DMSO (1.5 mL) as solvent. 104 mg (67%
yield) of product 4g was obtained as a white solid after column
chromatography (eluent¼petroleum ether/ethyl acetate 10:1 v/v).
Mp: 45e47 ꢀC; 1H NMR (400 MHz, C6D6, 25 ꢀC):
d
7.83 (d, J¼7.48 Hz,
ꢀ
ꢀ
4235e4238; (c) Varela-Fernandez, A.; Gonzalez-Rodríguez, C.; Varela, J. A.;
1H), 7.38e7.45 (m, 6H), 7.28e7.31 (m, 2H), 6.54 (s, 1H), 3.88 (t,
J¼7.36 Hz, 2H), 1.71e1.78 (m, 2H), 1.34e1.42 (m, 5H), 1.25 (br, 13H),
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Castedo, L.; Saa, C. Org. Lett. 2009, 11, 5350e5353; (d) Liu, P. N.; Su, F. H.; Wen, T.
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0.87 (t, J¼6.36 Hz, 3H); 13C NMR (100.6 MHz, C6D6, 25 ꢀC):
d 166.7,
136.4, 135.5, 135.2, 131.4, 130.6, 129.7, 129.3, 128.8, 127.9, 123.2,
110.2, 39.7, 32.0, 29.8, 29.7, 29.5, 28.5, 27.2, 22.8, 14.2; HRMS (EI,
TOF) calcd for C27H35NO [M]þ: 389.2719, found: 3890.2722.
7. Trost, B. M.; Rhee, Y. H. J. Am. Chem. Soc. 2003, 125, 7482e7483.
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5523e5527; (c) Martínez, C.; Alvarez, R.; Aurrecoechea, J. M. Org. Lett. 2009, 11,
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4.4.8. (E)-3-Benzylidene-2-(p-tolyl)isoindolin-1-one (4h). The com-
pound was prepared from 3h (155.7 mg, 0.5 mmol) following
typical procedure but using DMSO (1.5 mL) as solvent. 104 mg (67%
yield) of product 4h was obtained as a white solid after column
chromatography (eluent¼petroleum ether/ethyl acetate 5:1 v/v).
Mp: 124e126 ꢀC; 1H NMR (400 MHz, C6D6, 25 ꢀC):
d 7.93 (d,
J¼7.56 Hz, 1H), 7.46e7.50 (m, 1H), 7.40e7.44 (m, 5H), 7.30e7.37 (m,
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6H), 6.35 (s, 1H), 2.44 (s, 3H); C NMR (100.6 MHz, C6D6, 25 ꢀC):
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d
166.5, 138.5, 138.3, 135.3, 135.0, 132.1, 131.9, 130.3, 130.2, 129.6,
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129.5, 128.8, 128.7, 127.9, 123.7, 123.2, 112.3, 21.4; HRMS (ESI, TOF)
calcd for C22H18NOþ [MþH]þ: 312.1383, found: 312.1385.
4.4.9. (E)-2-Benzyl-3-benzylideneisoindolin-1-one (4i). The com-
pound was prepared from 3i (155.7 mg, 0.5 mmol) following typical
procedure but using DMSO (1.5 mL) as solvent. 87 mg (56% yield) of
product 4i was obtained as a white solid after column chroma-
tography (eluent¼petroleum ether/ethyl acetate v/v). Mp:
118e120 ꢀC; 1H NMR (400 MHz, CDCl3, 25 ꢀC):
d
7.95 (d, J¼7.52 Hz,
1H), 7.43e7.47 (m, 1H), 7.31e7.40 (m, 11H), 7.25e7.28 (m, 1H), 6.46
(s, 1H), 5.13 (s, 2H); 13C NMR (100.6 MHz, CDCl3, 25 ꢀC):
d
166.9,
22. Hiroya, K.; Jouka, R.; Kameda, M.; Yasuhara, A.; Sakamoto, T. Tetrahedron 2001,
57, 9697e9710.
136.9,136.1,135.2,135.1,131.8,130.3,129.6,129.4,128.8,128.7,127.9,
127.5, 127.1, 123.5, 123.3, 111.7, 43.4; HRMS (EI, TOF) calcd for
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C
22H17NO [M]þ: 311.1310, found: 311.1313.
Acknowledgements
We thank Prof. Guochen Jia in the Hong Kong University of
Science & Technology for the generous helps and discussions. This
work was supported by the National Natural Science Foundation of
China (Project Nos. 21172069, 21190033 and 21372072), the In-
novation Program of Shanghai Municipal Education Commission
(Project No. 12ZZ050), the Basic Research Program of the Shanghai
Committee of Sci. & Tech. (Project No.13NM1400802), NCET (NCET-
13-0798) and the Fundamental Research Funds for the Central
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Supplementary data
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The X-ray crystallographic data of 2j, the copies of 1H spectra for
products 2aez and 4aei, 13C NMR spectra for new compounds
2deg, 2jem, 2o, 2p, 2rew, 2y, 2z, 4c and 4gei. Supplementary data
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j.tet.2014.06.078.
€
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