Catalytic and metal-free intramolecular hydroalkoxylation of alkynes

Article abstract of DOI:10.1016/j.tetlet.2019.01.020

Benzyltrimethylammonium hydroxide act as an efficient metal-free catalyst for the intramolecular hydroalkoxylation of alkynes. Notably, the use of microwave irradiation allowed reaction to operate in only two minutes. Under optimized reaction conditions, linear alkynes bearing aryl and heteroaryl substituents were successfully cyclized with good level of stereoselectivity.

Full text of DOI:10.1016/j.tetlet.2019.01.020

Tetrahedron Letters 60 (2019) 534–537
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Catalytic and metal-free intramolecular hydroalkoxylation of alkynes
Alexandre Jean a,b, Jacques Rouden a, Jacques Maddaluno b, Michaël De Paolis b,
,
⇑
Jérôme Blanchet a,
⇑
a Normandie Université, ENSICAEN, UNICAEN, CNRS, Laboratoire LCMT (UMR 6507 & FR 3038), 14000 Caen, France
b Normandie Université, UNIROUEN, INSA de Rouen, CNRS, Laboratoire COBRA (UMR 6014 & FR 3038), 76000 Rouen, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Benzyltrimethylammonium hydroxide act as an efficient metal-free catalyst for the intramolecular
hydroalkoxylation of alkynes. Notably, the use of microwave irradiation allowed reaction to operate in
only two minutes. Under optimized reaction conditions, linear alkynes bearing aryl and heteroaryl sub-
stituents were successfully cyclized with good level of stereoselectivity.
Received 30 November 2018
Revised 7 January 2019
Accepted 9 January 2019
Available online 11 January 2019
Ó 2019 Elsevier Ltd. All rights reserved.
Keywords:
Hydroalkoxylation
Cyclization
Alkynes
Enol ether
Microwave-assisted synthesis
Introduction
of Triton B (benzyltrimethylammonium hydroxide) and micro-
wave irradiations. The overall process conveniently yielded the
Exocyclic enol ethers are a class of heterocycle present in a
range of natural or pharmacology active molecules [1]. (Fig. 1).
Moreover, they are useful intermediates for the synthesis of impor-
tant biomolecules subunits such as C-glycosides [2a,b] or
spirodiketal [2c].
corresponding 5-membered exocyclic enol ethers in a catalytic
and metal-free manner.
Results and discussion
Early strategies for their synthesis relied on the olefination of
parent lactones or isomerisation of endocyclic enol ethers [3].
Intramolecular hydroalkoxylations of alkynes represent a straight
and atom-economical alternative to construct such oxygenated
heterocycles, that could be promoted by numerous metals. Due
to their toxicity, mercury salts [4] have been replaced with transi-
tion metals such as palladium [5a–d], platinum [5e], indium [5f],
copper [5g,h], silver [5i], gold [6] or even lanthanide and actinide
complexes [7]. In sharp contrast, base mediated cyclisation are
much more difficult in absence of any electrophilic activation of
the alkyne moiety and consequently less investigated. With excep-
tion of one reaction reported by Knochel [8a], only conformation-
ally favourable cyclizations leading to benzofurans and involving
excess of inorganic bases are documented (Fig. 2) [8b–e].
Our investigations started with the attempted cyclization of
inactivated alcohol 1a under moderate microwave irradiations.
Using catalytic amount of cesium or potassium hydroxide as base
in highly polar solvents such as N-methylpyrrolidone (NMP) or
dimethylsulfoxyde (DMSO), no conversion to the desired cyclic
enol ethers 2a was observed (Table 1, Entry 1 and 2). Switching
to tetrabutylammonium fluoride in dimethylformamide (DMF)
did not promote the reaction. Surprisingly, when using the strong
organic bases tetrabutyl ammonium hydroxide (TBAH), a clean 5-
exo-dig cyclisation of alcohol 1a was observed in very short reac-
tion time and expected selectivity favouring isomer (Z)-2a. [8b]
Moreover, Triton B gave a slightly improved selectivity with a
(Z)-2a:(E)-2a ratio of 88:12 (Table 1, Entry 6). Thus, non-
activated alkyne 1a was efficiently cyclized upon a catalytic and
metal-free process.
In the context of our recent study regarding selective pyrro-
lidine and pyrrole synthesis [9] we recently discovered that linear
alkynes substituted with an appropriate alcohol moiety could be
rapidly cyclized through a specific combination of a small amount
The amount of Triton B could be decreased to 5 mol% (Table 1,
Entry 7). When 1 mol% Triton B was used, no conversion was
observed after 2 min. Increased concentration gave a complex mix-
ture of unidentified products while decreasing the temperature at
40 °C led to reproducibility problems.
⇑
Corresponding authors.
E-mail addresses: michael.depaolis@univ-rouen.fr (M. De Paolis), jerome.
The nature of the solvent has a decisive influence on the result
blanchet@ensicaen.fr (J. Blanchet).
of the reaction: dioxane, toluene or THF gave no conversion, in line
https://doi.org/10.1016/j.tetlet.2019.01.020
0040-4039/Ó 2019 Elsevier Ltd. All rights reserved.

A. Jean et al. / Tetrahedron Letters 60 (2019) 534–537
535
To assess the critical effect of microwave irradiations, control
experiments with one equivalent of Triton B at room temperature
or at 100 °C using a conventional oil bath heating were performed.
After a prolonged period (3–12 h), no conversion was observed.
However, increasing the temperature to 120 °C during 10 h finally
gave a lower 84% conversion and no selectivity (Z/E 55:45).
With optimized conditions in hand, the scope of the catalytic
reaction was explored with various alcohols (Table 2).
Thus electron-rich arenes connected to alkynyl alcohols were
successfully reacted and converted into cycloethers 2b-2d with
moderate (Z)-selectivity. Those heterocycles displayed poor stabil-
ity and required an additional reduction step (Pd/C, AcOEt, H2) to
be isolated, providing 2-substituted tetrahydrofurans in 81–40%
yield over 2 steps.
Having a lower LUMO, electron-poor alkynes gave better results
leading to stable cyclic ethers 2e and 2f in excellent yields (>98%).
Furthermore, pyridine, pyrazine, quinoline and pyrimidine substi-
tuted alkynes were similarly cyclized in 2 h-j with excellent yields
(86–90%). In some instances, moderate stereoselectivities were
enhanced by isomerisation upon work-up with trifluoroacetic acid
in dichloromethane (2h-i). This was rationalized in terms of
increased stabilization of (Z)-2g-i through intramolecular hydro-
gen bonding between the oxygen atom and the protonated hetero-
cycle. The substitution of the alkyne with electron depleted
heterocycles facilitated considerably the cyclization process.
Hence, a control experiment showed that 1g (Ar = 2-pyridyl)
cyclized into 2g in 93% yield (Z/E 66:34) at room temperature,
but at a much slower pace over 5 h. Replacing the ammonium
hydroxide with catalytic 1,8-diazabicyclo-[5.4.0]undec-7-ene or
1,1,3,3-tetramethylguanidine failed to promote the cyclization of
1g at room temperature.
Fig. 1. Naturally occurring and biologically active exocyclic enol ethers.
The possibility to obtain cyclic enol ethers substituted with
Lewis basic nitrogen heterocycles further illustrate the versatility
of this metal-free process. However, some limitations were noted:
no cyclization occurred with 4-pentyn-1-ol and trimethylsilyl-sub-
stituted alkyne led only to clean desilylation. With more robust tri-
isopropylsilyl group, only degradation compounds were observed.
Intramolecular hydroalkoxylation of alkyne leading to a 6-
membered heterocycle is considerably less documented than 5-
membered counterpart. Therefore cyclization of homologous
phenylhexynol 3 was attempted. Upon treatment with Triton B, a
Fig. 2. Context of base mediated hydroalkoxylation of alkynes.
with known ineffective microwave heating in solvents with low
dielectric constant [10]. More polar solvent such as acetonitrile
gave complete conversion with a lower (Z)-2a selectivity and
dimethyl sulfoxide (DMSO) provided similar selectivity as DMF,
although inseparable side products (<10%) were detected in the
crude reaction mixture (Table 1, Entries 11 and 12).
Table 1
Optimization of 1a 5-exo-dig cyclization.
Entry
Conditions
Yield (%)
(Z):(E)-2aa
1
CsOH (20 mol%), DMF
0
2
3
KOH (20 mol%), DMSO/H20 15:1
KOH (20 mol%), DMSO
0
0
4
TBAF (10 mol%), DMF
0
5
TBAH (10 mol%), DMF
>95 (85:15)
6
7
Triton B (10 mol%), DMF
Triton B (5 mol%), DMF
>95 (88:12)
>95 (88:12)
8
9
10
11
11
12
Triton B (1 mol%), DMF
0
0
0
0
Triton B (10 mol%), 1,4-dioxaneb
Triton B (10 mol%), tolueneb
Triton B (10 mol%), THFb
Triton B (10 mol%), CH3CNb
Triton B (10 mol%), DMSOb
>95 (65/35)
>85 (88/12)
a
Isolated as a (Z/E) mixture, yield and ratio determined by 1H NMR.
60 °C, 3,5 min.
b

536
A. Jean et al. / Tetrahedron Letters 60 (2019) 534–537
Table 2
Scope of Triton B-mediated cyclization of arylalkynyl alcohols.
Entry
1
Yield (%)a
81
(Z):(E)a
2b
2c
88:12
2
40
87:13
3
4
2d
2e
44
75:25
93:7
> 98
5
2f
> 98
87:13
6
7
8
2g
2h
2i
88
86
87
60:40, 98:2b
63:37, 98:2b
88:12, 98:2b
9
2j
90
96:4
Isolated yields; Z/E ratio determined by 1H NMR of crude mixture.
a
Over 2 steps after hydrogenation using Pd/C, see SI for details.
After treatment with CF3CO2H, see SI for details.
b
favour of the (Z)-enol ethers were obtained. The base used in this
reaction, Triton B, is readily available, easy to handle and was used
in catalytic amount. Further studies to clarify the reaction mecha-
nism, in particular the contribution of the counter cation are cur-
rently in progress in our laboratory.
Acknowledgments
The authors thank the CNRS, Normandie université, Labex
Synorg (ANR-11-LABX-0029) and the CRUNCh network for a
fellowship to A.J. The Conseil Régional de Normandie and the
European FEDER fundings are also acknowledged for financial
support.
Scheme 1. 6-exo-dig cycloisomerization of phenylhexynol 3.
6-exo-dig cyclization took place followed by an isomerization, pro-
viding dihydropyran 4 with >90% NMR purity (Scheme 1) [11].
Poor stability of compound 4 prevented further purification by
flash chromatography and subsequent hydrogenation afforded
tetrahydropyran 5 in 65% yield over 2 steps.
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