Regio- and stereoselective intramolecular hydroalkoxylation of aromatic alkynols: an access to dihydroisobenzofurans under transition-metal-free conditions

Article abstract of DOI:10.1007/s11696-020-01159-5

An efficient, transition-metal-free method to synthesize dihydroisobenzofuran derivatives via intramolecular hydroalkoxylation of aromatic alkynols with the promotion of cesium carbonate has been developed. The reaction proceeds regioselectively with exclusive formation of 5-exo-dig product, and only Z-isomer of the new generated double bond is observed. This new protocol features with milder reaction conditions, more convenient operation and satisfactory selectivities.

Full text of DOI:10.1007/s11696-020-01159-5

Chemical Papers
https://doi.org/10.1007/s11696-020-01159-5
ORIGINAL PAPER
Regio‑ and stereoselective intramolecular hydroalkoxylation
of aromatic alkynols: an access to dihydroisobenzofurans
under transition‑metal‑free conditions
Shu‑Yan Yu1 · Li‑Hong Gao1 · Jing‑Xin Wu1 · Hong‑Bing Lan1 · Yi Ma1 · Zhi‑Gang Yin1
Received: 10 February 2020 / Accepted: 4 April 2020
© Institute of Chemistry, Slovak Academy of Sciences 2020
Abstract
An efcient, transition-metal-free method to synthesize dihydroisobenzofuran derivatives via intramolecular hydroalkoxyla-
tion of aromatic alkynols with the promotion of cesium carbonate has been developed. The reaction proceeds regioselectively
with exclusive formation of 5-exo-dig product, and only Z-isomer of the new generated double bond is observed. This new
protocol features with milder reaction conditions, more convenient operation and satisfactory selectivities.
Keywords Cesium carbonate · Intramolecular hydroalkoxylation · Dihydroisobenzofurans · Transition-metal-free
Introduction
exo-cyclization with mercury salt as the catalyst (Riediker
and Schwartz 1982), several more transition metal catalysts
were later found to work well with dihydroisobenzofuran as
main or only product, such as copper (Praveen et al. 2010;
Pouy et al. 2012), palladium (Buxaderas et al. 2014) and
palladium nanoparticles (Chahdoura et al. 2015; Mandali
et al. 2017), silver (Praveen et al. 2012), rhodium (Sarba-
jna et al. 2017), gold (Dorel and Echavarren 2015) or even
lanthanide and actinide complexes (Seo et al. 2009; Wobser
and Marks 2013). However, the cyclization regioselectivity
has not been fully resolved as many factors afecting the out-
come of selectivity, including catalyst choices, ligands, steric
environment and even additives (Costello and Ferreira 2019;
Doherty et al. 2016; Goodwin and Aponick 2015). Besides,
these transition metals-catalyzed reactions sufered some
drawbacks such as being expensive, sensitive to oxygen and
moisture and mostly violent. Given the prevalence of dihy-
droisobenzofurans in natural products and bioactive mol-
ecules, more practical catalytic system towards the construc-
tion of these entities under transition metal-free conditions
is still highly required (Krishna Reddy and Satyanarayana
2017; Mancuso et al. 2010).
Dihydroisobenzofurans skeletons are widespread in both
natural products and biologically and pharmaceutically
active compounds (Shang et al. 2015; Shishkina et al. 2016;
Yang et al. 2017). Moreover, they are useful intermedi-
ates for the synthesis of important biomolecules subunits
(Alcaide et al. 2011). Therefore, efficient and versatile
methods to form such entities from readily available start-
ing materials have been of particular interest (Aronica
et al. 2015; Kobayashi et al. 2008; Karmakar et al. 2014;
Albano and Aronica 2017,2018; Brinkmann et al. 2012;
Fairley et al. 2019). Among these developed methods,
intramolecular hydroalkoxylation of aromatic alkynols
via 5-exo-dig annulation pathway represents a straight and
atom-economical alternative to construct such oxygenated
heterocycles (Scheme 1, path A). Followed the frst report on
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s11696-020-01159-5) contains
supplementary material, which is available to authorized users.
As interest in the synthesis of heterocyclic compounds
through alkynes functionalization (Yu et al. 2018, 2020), we
realized that a base-promoted intramolecular cyclization of
aromatic alkynols would provide an alternative methodology
(Vandavasi et al, 2014). However, base-mediated cyclization
is much more difcult owing to the absence of activation of
alkyne moiety. The reported reactions are mostly restricted
* Shu-Yan Yu
yushuyan_zzuli@163.com
* Zhi-Gang Yin
yinck@zzuli.edu.cn
1
Material and Chemical Engineering College, Zhengzhou
University of Light Industry, Zhengzhou 450002,
Henan Province, People’s Republic of China
Vol.:(0123456789)
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Chemical Papers
Scheme 1 The two regioselec-
tive cyclization pathways of
aromatic alkynols
to excess use of base or harsh conditions (Berg et al. 2006;
Hiroya et al. 2001; Jean et al. 2019; Li et al. 2014; Weingar-
ten and Padwa 1995). Herein we want to report our recent
fnding that cesium carbonate could serve as an efective cat-
alyst for the intramolecular cyclization of aromatic alkynols,
afording the desired dihydroisobenzofuran compounds with
satisfactory yields and excellent regioselectivities and stere-
oselectivities in more fexible reaction conditions.
NaBH4 (5 mmol) was added in portions, and the solution
was stirred for additional 20 min. The reaction was quenched
with saturated ammonium chloride solution (30 mL).
Methanol was removed under vacuum, and the residue was
extracted by EtOAc (2×30 mL). The combined organic layer
was dried over anhydrous Na2SO4. After the solvent was
removed under reduced pressure, (2-(phenylethynyl)phenyl)
methanol 1a was obtained (1.76 g) in 95% yield, which was
used directly for the next cyclization without purifcation.
Experimental
General procedure for intramolecular hydroalkoxy-
lation of aromatic alkynols
Materials and methods
To a solution of aromatic alkynol 1 (1 mmol) in DMF (4 mL)
was added cesium carbonate (20 mol%) at room temperature.
The mixture was heated to 80 °C and stirred for 12 h. After
completion, the reaction mixture was diluted with EtOAc
(15 mL) and washed with water (3× 20 mL). The organic
layer was dried over Na2SO4, which was further purifed via
column chromatography on silica gel with the mixture of
petroleum ether and EtOAc as elute to aford the correspond-
ing dihydroisobenzofuran 2.
All reactions were carried out under air atmosphere con-
dition. Aromatic alkynols were prepared according to the
published procedure. Solvents were purchased from Alfa
Aesar or J&K, which were used directly without purifca-
tion. Column chromatography was performed on silica gel
(300–400 mesh). 1H and 13C NMR were recorded on a 600
or 400 MHz Bruker NMR spectrometer in CDCl3 or DMSO-
d6 using tetramethylsilane (TMS) as the internal standard.
General procedure for the synthesis of aromatic
alkynols
Characterization of products
Compounds 2a–2j, 2l and 2n are known compounds, only
1HNMR spectra and melting points were collected which
were consistent with previous studies. Unknown compounds
2k and 2m were fully characterized.
Aromatic alkynols were prepared through a two-step pro-
cedure including Sonogashira coupling and reduction with
the corresponding o-bromobenzaldehyde or o-bromoaceto-
phenone and alkyne as starting materials. The synthesis of
(2-(phenylethynyl) phenyl) methanol 1a was illustrated as a
representative example.
(Z)‑1‑benzylidene‑1, 3‑dihydroisobenzofuran (2a)
Under nitrogen conditions, 2-bromobenzaldehyde
(10 mmol), phenylacetylene (12 mmol), Pd(PPh3)2Cl2
(0.2 mmol) and CuI (0.1 mmol) were successively intro-
duced into a 100-mL two-neck fask equipped with Et3N
(40 mL). The resulting mixture was stirred at 50 °C for 12 h
and monitored with TLC. After completion, the crude mix-
ture was fltered through celite and Et3N was removed under
vacuum. The residue was diluted with EtOAc (60 mL) and
washed with water (2×50 mL). The organic layer was dried
over Na2SO4, which was further purifed via column chro-
matography on silica gel (the mixture of petroleum ether and
EtOAc was used as elute) to give 2-(phenylethynyl)benzal-
dehyde (1.83 g) in 89% yield.
Yield: 97%; Light yellow solid; M.p.:103–105 °C (Reported
100–102 °C, Li et al. 2014); 1HNMR (600 MHz, CDCl3):
δ 7.78 (d, J=7.4 Hz, 2H), 7.60 (d, J=6.4 Hz, 1H), 7.37 (t,
J=8.7 Hz, 5H), 7.18 (t, J=7.4 Hz, 1H), 5.98 (s, 1H), 5.54
(s, 2H) ppm.
(Z)‑1‑(4‑methoxybenzylidene)‑1, 3‑dihydroisobenzofuran
(2b)
Yield: 95%; White solid; M.p.:118–120 °C (Reported
118–129 °C, Li et al. 2014); 1HNMR (600 MHz, CDCl3): δ
7.61 (d, J=8.8 Hz, 2H), 7.47 (d, J=7.2 Hz, 1H), 7.24–7.29
(m, 3H), 6.82 (d, J=8.8 Hz, 2H), 5.83 (s, 1H), 5.43 (s, 2H),
3.75 (s, 3H) ppm.
2-(phenylethynyl)benzaldehyde was dissolved in metha-
nol (30 mL), and the resulting mixture was cooled to 0 °C.
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(Z)‑1‑(4‑methylbenzylidene)‑1, 3‑dihydroisobenzofuran
(2c)
J = 6.0 Hz, 2.6 Hz, 2H), 7.36 (d, J= 4.8 Hz, 1H), 7.29 (t,
J=7.9 Hz, 1H), 7.13 (s, 1H), 5.52 (s, 2H) ppm.
Yield: 96%; Light yellow solid; M.p.: 95–97 °C (Reported
95–97 °C, Li et al. 2014); 1HNMR (600 MHz, DMSO-d6):
δ 7.72–7.74 (m, 1H), 7.59 (d, J = 7.8 Hz, 2H), 7.47–7.49
(m, 1H), 7.40–7.42 (m, 2H), 7.14 (d, J = 7.8 Hz, 2H), 6.09
(s, 1H), 5.55 (s, 2H), 2.28 (s, 3H) ppm.
(Z)‑(2‑(isobenzofuran‑1(3H)‑ylidenemethyl)phenyl)
methanol(2i)
Yield: 83%; Light yellow solid; M.p.:128–130 °C (Reported
1
120–122 °C, Mandali et al. 2017); HNMR (600 MHz,
DMSO-d6): δ 8.09 (d, J=7.8 Hz, 1H), 7.78 (d, J=4.5 Hz,
1H), 7.47–7.51(m, 1H), 7.43 (dd, J=5.1 Hz, 3.5 Hz, 2H),
7.38 (d, J = 7.5 Hz, 1H), 7.23 (t, J = 7.2 Hz, 1H), 7.12 (t,
J=7.1 Hz, 1H), 6.21 (s, 1H), 5.54 (s, 2H), 5.16 (t, J=5.6 Hz,
1H), 4.64 (d, J=5.5 Hz, 2H) ppm.
(Z)‑1‑(4‑chlorobenzylidene)‑1, 3‑dihydroisobenzofuran (2d)
Yield: 87%; Light yellow solid; M.p.:105–107 °C
(Reported 102–104 °C, Li et al. 2014); 1HNMR (400 MHz,
CDCl3): δ 7.68 (d, J = 8.6 Hz, 2H), 7.55–7.57 (m, 1H),
7.38 (dd, J = 9.2, 3.3 Hz, 3H), 7.28 (dd, J = 10.5, 3.9 Hz,
2H), 5.90 (s, 1H), 5.52 (s, 2H) ppm.
(Z)‑1‑benzylidene‑5,6‑dimethoxy‑1,3‑dihydroisobenzofur
an(2j)
Yield: 80%; Light yellow solid; M.p.:115–117 °C (Reported
115–117 °C, Li et al. 2014); 1HNMR (600 MHz, CDCl3):
δ 7.71 (d, J=7.3 Hz, 2H), 7.32 (t, J=7.7 Hz, 2H), 7.12 (t,
J=7.4 Hz, 1H), 7.01 (s, 1H), 6.81 (s, 1H), 5.77 (s, 1H), 5.45
(s, 2H), 3.96 (s, 3H), 3.92 (s, 3H) ppm.
(Z)‑methyl4‑(isobenzofuran‑1(3H)‑ylidenemethyl)benzoate
(2e)
Yield: 79%; Light yellow solid; M.p.:111–114 °C
(Reported 113–115 °C, Li et al. 2014); 1HNMR (600 MHz,
CDCl3): δ 8.00 (d, J = 8.4 Hz, 2H), 7.78 (d, J = 8.4 Hz,
2H), 7.61 (s, 1H), 7.38 (m, 3H), 5.98(s, 1H), 5.56 (s, 2H),
3.91 (s, 3H) ppm.
(Z)‑1‑benzylidene‑6‑methoxy‑1, 3‑dihydroisobenzofuran
(2 k)
1
Yield: 73%; White solid; M.p.:118–120 °C; HNMR
(600 MHz, DMSO-d6): δ 7.65 (t, J= 7.5 Hz, 3H), 7.30 (t,
J=7.8 Hz, 2H), 7.08 (t, J=7.8 Hz, 2H), 7.00 (dd, J=8.5 Hz,
2.2 Hz, 1H), 5.96 (s, 1H), 5.51 (s, 2H), 3.81 (s, 3H) ppm;
13CNMR (150 MHz, DMSO-d6): δ 161.0, 156.8, 141.8,
137.0, 128.8, 127.6, 126.9, 125.1, 121.8, 115.8, 106.4, 94.5,
74.7, 56.1 ppm.
(Z)‑1‑(4‑nitrobenzylidene)‑1, 3‑dihydroisobenzofuran (2f)
Yield: 65%; Orange solid; M.p.:156–158 °C (Reported
156–158 °C, Tomás-Mendivil et al. 2015); 1HNMR
(600 MHz, CDCl3): δ 8.21 (d, J = 8.7 Hz, 2H), 7.55 (d,
J = 8.4 Hz, 2H), 7.35–7.39(m, 3H), 7.21 (t, J = 7.5 Hz,
1H), 6.21 (s, 1H), 5.38 (s, 2H) ppm.
HRMS: C16H15O2 for [M + H]+, calculated 239.1073,
found 239.1070.
(Z)‑1‑benzylidene‑5‑methyl‑1, 3‑dihydroisobenzofuran (2 l)
(Z)‑1‑(3‑methylbenzylidene)‑1, 3‑dihydroisobenzofuran
(2 g)
Yield: 84%; White solid; M.p.:106–108 °C (Reported
104–106 °C, Li et al. 2014); 1HNMR (600 MHz, DMSO-d6):
δ 7.68 (d, J=7.3 Hz, 2H), 7.57 (s, 1H), 7.37 (d, J=7.7 Hz,
1H), 7.32 (t, J=7.8 Hz, 2H), 7.24 (d, J=7.7 Hz, 1H), 7.12
(t, J=7.3 Hz, 1H), 6.09 (s, 1H), 5.51 (s, 2H), 2.39 (s, 3H)
ppm.
1
Yield: 87%; Yellow oil; HNMR (600 MHz, CDCl3): δ
7.55 (m, 3H), 7.34 (m, 3H), 7.23 (t, J = 7.6 Hz, 1H), 6.98
(d, J = 7.5 Hz, 1H), 5.93 (s, 1H), 5.53 (s, 2H), 2.38 (s,
3H) ppm.
(Z)‑1‑benzylidene‑5‑chloro‑1, 3‑dihydroisobenzofuran
(2 m)
(Z)‑2‑(isobenzofuran‑1(3H)‑ylidenemethyl)benzaldehyde
(2 h)
Yield: 90%; Light yellow solid; M.p.:117–119 °C; 1HNMR
(600 MHz, DMSO-d6): δ 7.04 (d, J = 1.7 Hz, 1H), 6.82
(d, J = 7.3 Hz, 2H), 6.65 (d, J = 8.1 Hz, 1H), 6.60 (dd,
J = 8.1 Hz, 1.8 Hz, 1H), 6.49 (t, J = 7.8 Hz, 2H), 6.30 (t,
J = 7.4 Hz, 1H), 5.40 (s, 1H), 4.69 (s, 2H) ppm; 13CNMR
Yield: 84%; Light yellow oil; 1HNMR (600 MHz, CDCl3):
δ 10.26 (s, 1H), 8.27 (d, J=7.8 Hz, 1H), 7.79 (d, J=6.6 Hz,
1H), 7.71–7.73 (m, 1H), 7.55 (t, J=8.3 Hz, 1H), 7.41 (dd,
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(151 MHz, DMSO-d6): δ 155.2, 138.6, 136.8, 136.4,
133.6, 129.3, 128.8, 128.1, 125.9, 124.1, 120.4, 97.4,
75.2 ppm;
Results and discussion
Our investigation began with o-alkynylbenzynol 1a as
the model substrate, and the key results are briefy sum-
marized in Table 1. A range of bases were screened frst
with N, N-dimethylformamide (DMF) as solvent at 60 °C.
Gratifyingly, when 1a was treated with 50 mol% cesium
carbonate, the desired cyclization product dihydroisoben-
zofuran 2a was isolated in 70% yield, whose structure was
frstly characterized by NMR spectrum and then confrmed
by X-ray difraction analysis of its analogous 2d. Inferior
results were displayed when other organic bases or inorganic
bases were employed in this reaction, which indicated the
degree of alkalinity or the homogeneity of the reaction mix-
ture is not the key factor. (Table 1, Entry 1–9). The nature
HRMS: C15H12ClO for [M + H]+, calculated 243.0576,
found 243.0571.
(Z)‑1‑benzylidene‑3‑methyl‑1, 3‑dihydroisobenzofuran (2n)
Yield: 94%; Yellow oil; 1HNMR (600 MHz, DMSO-d6): δ
7.73 (dd, J= 6.0 Hz, 2.7 Hz, 1H), 7.70 (d, J= 7.3 Hz, 2H),
7.47 (dd, J = 5.2 Hz, 3.4 Hz, 1H), 7.42 (dd, J = 5.6 Hz,
3.1 Hz, 2H), 7.33 (t, J = 7.8 Hz, 2H), 7.12 (t, J = 6.8 Hz,
1H), 6.10 (s, 1H), 5.83 (q, J = 6.5 Hz, 1H), 1.57 (t,
J = 7.2 Hz, 3H) ppm.
Table 1 Optimization of reaction conditions for intramolecular hydroalkoxylation
Entry
Base
Solvent
Temp (°C)
Time (h)
Yield of 2a (%)a
1
2
3
4
5
6
7
8
K2CO3
Cs2CO3
NEt3
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
60
60
60
60
60
60
60
60
60
60
60
Refux
60
60
60
60
80
24
15
24
15
24
24
15
24
15
24
24
24
15
24
24
15
10
6
NR
70
NR
28
NR
NR
45
26
35
30
40
25
36
NR
Complex
67
93
65
97
62
DBU
DABCO
Pyridine
t-BuOK
KOH
9
CsF
DMF
10
11
12
13
14
15
16
17
18
19b
20c
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Toluene
CH3CN
DCM
1,4-dioxane
THF
MeOH
DMSO
DMF
DMF
DMF
DMF
100
80
80
12
24
Unless noted, the reaction was conducted in a fask equipped with alkynol 1a (1 mmol), base (0.5 equiv.) and solvent (4 mL) under atmospheric
condition;
aIsolated yields after silica gel column chromatography;
b20 mol% Cs2CO3 was used;
c10 mol% Cs2CO3 was used
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Scheme 2 Substrate scope of intramolecular hydroalkoxylationa
of the solvent has an important infuence on the result of
the reaction: DMF proved to be more favorable than oth-
ers (Table 1, Entry 10–15). By comparison, DMF gave a
more clear solution which suggested the good solubility of
Cs2CO3 in DMF might contribute to the efciency of cycli-
zation (Cella and Bacon 1984). To test this assumption, the
cyclization reaction was operated in DMSO (Table 1, Entry
16). As expected, a parallel result was indeed observed. In
light of the above results, the advantage of cesium carbon-
ate might be derived from suitable basicity, good solubility
and weak Lewis acidity of Cs+ (Flessner and Doye 1999)
(more details, please see the proposed mechanism). Slightly
increasing reaction temperature was found to be benefcial.
Up to 93% yield of product was obtained within a shortened
time (93% yield at 80 °C vs 70% yield at 60 °C vs 75% yield
at 100 °C) (Table 1, Entry 16–18). The loading of the base
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to the anion intermediate. At this stage, the coordination
of weak Lewis acidic Cs+ with the triple bond enhanced
its electrophilicity which facilitated nucleophilic attack of
oxygen anion. The intramolecular cyclization proceeds in
a totally stereoselective fashion to give the confguration-
ally stable E-vinylcesium. Protolysis delivered the desired
dihydroisobenzofuran with Z-confguration and regenerated
the base catalyst. Although we are not clear with the origin
of regioselectivity, several theoretical studies indicated that
might be substrate-dependant. In the case of electronically
unbiased acetylenes, exo-dig cyclizations are favored, facili-
tating the approach path of O–H to the triple bond is at an
obtuse angle of 120–127 degrees (Dykstra et al. 1978; Elli-
ott and Richards 1982; Ersenstein et al. 1978; Mellor et al.
1978; Perkins et al. 1981; Strozier et al. 1979).
Scheme 3 The possible reaction pathway
was also investigated. 20 mol% Cs2CO3 proved to be suitable
for this transformation, afording the desired dihydroisoben-
zofuran in nearly quantitative yield (Table 1, Entry 19). But
further decreasing the amount of catalyst resulted in a slow
conversion (Table 1, Entry 20). Notably, all the transfor-
mations were carried out under air atmosphere condition
without the exclusion of moisture and oxygen.
Conclusions
We have developed a straightforward and convenient
method for the synthesis of dihydroisobenzofuran deriva-
tives through intramolecular hydroalkoxylation of aromatic
alkynols under transition-metal-free conditions. The desired
cycloadducts could be obtained with high efciency and uni-
formly excellent stereo- and regio-selectivities. No special
handling for reagents or reaction conditions was necessary
for these transformations. Moreover, the generating double
bonds in the dihydroisobenzofuran skeletons provide a wide
scope for further structural transformations.
After establishing the optimal reaction conditions,
we examined the generality of the highly regioselective
hydroalkoxylation with various substituted alkynols, and
the results were summarized in Scheme 2. It was found that
this catalytic strategy was applicable to various aromatic
alkynols bearing diferent types of substituents, afording the
corresponding dihydroisobenzofuran derivatives in good to
satisfactory yields with uniformly excellent regio- and stere-
oselectivity. This catalytic system was compatible with vari-
ous substituents. Hydroxyl, ester, formyl, nitro, and halide
groups were amenable in this catalytic system. Substitution
electron patterns afected the yields of the products to some
extent. In generally, alkynols with electron-donating sub-
stituents could aford the expected products in better yields
compared to those with withdrawing substituents (2a–2c vs
2d–2f). As indicated by the results of the steric hindrance
investigation, the reaction of alkynols with a substituent at
the para- position proceeded better than the meta- and ortho-
ones (2c vs 2g–2h). The broad generality of the versatile
synthetic method was demonstrated by the variation of R1
(Scheme 2). To our delight, this highly diastereoselective
intramolecular cyclization could be compatible for steric
benzyl alcohol, the resulting highly functionalized dihy-
droisobenzofuran 2n could be isolated in 94% yield. It was
worth mentioning that only one diastereoisomer generated
via exo-dig regioselectivity and anti-addition stereoselec-
tivity was observed in all these substrates. Unfortunately,
when we attempted to adopt this catalytic system to other
alkyl- or terminal alkyne, no corresponding product could
be collected.
Acknowledgements The authors are grateful for the support from
the National Natural Science Foundation of China (21602207), the
Foundation of Henan Educational Committee (17A150022), and the
Doctoral Research Fund of Zhengzhou University of Light Industry
(2014BSJJ009).
Compliance with ethical standards
Conflict of interest On behalf of all authors, the corresponding author
states that there is no confict of interest.
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