Heterogeneous acidic catalysts for the tetrahydropyranylation of alcohols and phenols in green ethereal solvents

Article abstract of DOI:10.3762/bjoc.14.141

The application of heterogeneous catalysis and green solvents to the set up of widely employed reactions is a challenge in contemporary organic chemistry. We applied such an approach to the synthesis and further conversion of tetrahydropyranyl ethers, an important class of compounds widely employed in multistep syntheses. Several alcohols and phenols were almost quantitatively converted into the corresponding tetrahydropyranyl ethers in cyclopentyl methyl ether or 2-methyltetrahydrofuran employing NH₄HSO₄ supported on SiO₂ as a recyclable acidic catalyst. Easy work up of the reaction mixtures and the versatility of the solvents allowed further conversion of the reaction products under one-pot reaction conditions.

Full text of DOI:10.3762/bjoc.14.141

Heterogeneous acidic catalysts for the
tetrahydropyranylation of alcohols and phenols
in green ethereal solvents
Ugo Azzena*, Massimo Carraro, Gloria Modugno, Luisa Pisano and Luigi Urtis
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2018, 14, 1655–1659.
Dipartimento di Chimica e Farmacia, Università degli Studi di Sassari,
via Vienna 2, 07100 – Sassari, Italy
doi:10.3762/bjoc.14.141
Received: 30 April 2018
Accepted: 19 June 2018
Published: 03 July 2018
Email:
Ugo Azzena* - ugo@uniss.it
*
Corresponding author
Associate Editor: L. Vaccaro
Keywords:
© 2018 Azzena et al.; licensee Beilstein-Institut.
License and terms: see end of document.
green chemistry; green solvents; heterogeneous catalysts; multistep
reactions; tetrahydropyranylation
Abstract
The application of heterogeneous catalysis and green solvents to the set up of widely employed reactions is a challenge in contem-
porary organic chemistry. We applied such an approach to the synthesis and further conversion of tetrahydropyranyl ethers, an im-
portant class of compounds widely employed in multistep syntheses. Several alcohols and phenols were almost quantitatively con-
verted into the corresponding tetrahydropyranyl ethers in cyclopentyl methyl ether or 2-methyltetrahydrofuran employing
NH4HSO4 supported on SiO2 as a recyclable acidic catalyst. Easy work up of the reaction mixtures and the versatility of the sol-
vents allowed further conversion of the reaction products under one-pot reaction conditions.
Introduction
Due to their general stability to a wide range of reagents and attention was dedicated to their employment in low impact sol-
ease of removal, tetrahydropyranyl (THP) ethers are widely em- vents.
ployed in multistep organic synthesis for the protection of
hydroxy derivatives [1,2]. In addition, they can be converted From this point of view, it is worth noting that although ethers
into a wealth of useful functional groups [2,3], and found are the solvents of choice for reactions involving highly polar
employment as fragrances or pro-fragrances in everyday life nucleophilic reagents such as organolithium and organomagne-
[
4-7]. Although a lot of work has been devoted to the search of sium compounds or aluminium hydrides, tetrahydropyranyla-
low impact, heterogeneous and recyclable catalysts to promote tion reactions are usually run in hydrocarbons, chloroalkanes or
THP ethers synthesis [2,8-14], to the best of our knowledge no dipolar aprotic solvents [1,2,8-15], thus affording a paradig-
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matic example of the ironic Murphy’s Law of Solvents, recently reacting 4 M solutions of this alcohol with a slight excess
stated by Jessop et al. [16]: “The best solvent for any process (1.1 equiv) of 3,4-dihydro-2H-pyran (2, DHP) in the presence
step is bad for the next step”.
of several acidic heterogeneous catalysts (Scheme 1 and
Table 1). The recovered reaction mixtures were very simply
Starting from these premises and following our interest in the elaborated by filtering the catalyst followed by evaporation of
development of reaction procedures in low impact solvents the solvent in vacuo.
[
17,18], we report here on the tetrahydropyranylation of alco-
hols and phenols in cyclopentyl methyl ether (CPME) and
-methyltetrahydrofuran (2-MeTHF) in the presence of hetero-
geneous acidic catalysts. Indeed, both CPME [19-22] and
-MeTHF [21-25] are characterized by relatively high boiling
2
2
points, a narrow explosion range, hydrophobicity, easy drying
and recovery possibilities. Additionally, CPME is produced via
a 100% atom economical reaction [19,20], whilst 2-MeTHF is
Scheme 1: Synthesis of THP ether 3a.
accessible from renewable resources [21,23]. Finally, it is worth No reaction occurred in both solvents in the absence of an
noting that besides being moderately irritant, both solvents are acidic catalyst as well as in the presence of several ammonium
characterized by low toxicities and are considered negative for salts, i.e., NH4Cl, NH4Br and NH4H2PO4 (Table 1, entries
genotoxicity and mutagenicity [26-28]. Due to these environ- 1–4). On the other hand, inorganic salts with a relatively higher
mentally friendly characteristics, CPME and 2-MeTHF appear acidity, i.e., NH4HSO4, NaHSO4 and KHSO4 [31], as well as
as versatile green alternatives to ethereal solvents such as tetra- Amberlyst 15 and Montmorillonite K10, efficiently promoted
hydrofuran, dioxane, diethyl ether or methyl tert-butyl ether.
practically quantitative conversion of the starting material into
the corresponding tetrahydropyranyl ether 3a within a few
Aiming to the development of a particularly practical and envi- hours in both solvents (Table 1, entries 5–9).
ronmentally friendly procedure to the generation of THP ethers,
we devoted our efforts to the employment of heterogeneous Good results were also obtained with a 25 wt % dispersion of
acidic catalysts [29,30] in order to set up conditions allowing NH4HSO4 over SiO2 (NH4HSO4@SiO2, Table 1, entries 10
easy processing of the reaction mixtures and, possibly, the and 11). Additionally, the supported catalyst, which can be
recovery and recycling of the catalyst.
stored in a desiccator for several months with no detrimental
effects, is particularly easy to recover and was recycled up to
4 times with no evident loss of activity (Table 1, entry 10). Its
Results and Discussion
Taking 2-phenylethanol (1a) as a model compound, we investi- robustness was further assessed by the good qualitative
gated its conversion into the corresponding THP ether 3a by matching between the IR spectra of the fresh and recycled cata-
Table 1: Synthesis of 2-(2-phenylethoxy)tetrahydro-2H-pyran (3a).
entry
solvent
catalyst (%)
3a/1a (%)b
1
2
3
4
5
6
7
8
9
CPME or 2-MeTHF
CPME or 2-MeTHF
CPME or 2-MeTHF
CPME or 2-MeTHF
CPME or 2-MeTHF
CPME
none
<5:>95
<5:>95
<5:>95
<5:>95
94:6
NH4Cl
NH4Br
NH4H2PO4
NH4HSO4
NaHSO4
93:7
CPME
KHSO4
93:7
2-MeTHF
Amberlyst 15
Montmorillonite K10c
NH4HSO4@SiO2d,e
NH4HSO4@SiO2
NH4HSO4@SiO2f
>95:<5
>95:<5
>95:<5
>95:<5
93:7
CPME or 2-MeTHF
CPME
10
11
12
2-MeTHF
CPME
aAll reactions were run at rt during 4 h in the presence of the catalyst (3 mol % of 1a, unless otherwise indicated). bAs determined by 1H NMR
analyses of crude reaction mixtures; no other product was detected besides 1a. c1a/catalyst = 3 wt %. dComparable results were obtained after
4
times recycling of the catalyst. eNo reaction was observed in the presence of a comparable amount of carefully dried SiO2. f3 mol ‰ of 1a.
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Beilstein J. Org. Chem. 2018, 14, 1655–1659.
lysts (see Supporting Information File 1, Figure S1). Addition- to the synthesis of a series of THP ethers of functionalized and
ally, it is worth noting that a comparable result was obtained by non-functionalized alcohols and phenols, including some
reducing the amount of catalyst to one tenth (3 mol ‰ of 1a, known fragrances (3g–j and 3l) [4-7], as illustrated in
Table 1, entry 12).
Scheme 2.
Finally, both CPME and 2-MeTHF proved stable towards such Conversions exceeding 95% were achieved under the mild
an acidic supported catalyst, as established by the absence of conditions illustrated in Scheme 2 with primary aliphatic and
any decomposition product within the reaction mixtures, as de- benzylic alcohols 1b–h. A notable exception is the low conver-
termined by 1H, 13C NMR and gas-liquid chromatography sion of 4-bromobenzyl alcohol 1e in CMPE, most probably due
analyses [32].
to the low solubility of the starting material in this solvent. This
disadvantage was easily overcome by performing the reaction in
Due to the ease of the preparation from particularly cheap 2-MeTHF.
starting materials, the ease of handling and its high activity, we
further investigated the ability of NH4HSO4@SiO2 to catalyze More demanding conditions (2.0 equiv of 2) were required to
the synthesis of different THP ethers in low impact ethereal sol- obtain good conversions of a secondary alcohol, i.e, (1R,2S,5R)-
vents. Accordingly, the reactions were performed in the pres- 2-isopropyl-5-methylcyclohexanol ((−)-menthol, 1i). The reac-
ence of 3 mol ‰ of the catalyst and were successfully applied tion afforded an almost 1:1 mixture of only two diastereoiso-
Scheme 2: Synthesis of THP ethers 3b–l in the presence of NH4HSO4@SiO2. All reactions were run at rt, in the presence of 1.1 equiv of 2 and
3
mol ‰ of catalyst during 4 h, unless otherwise indicated; percentages represent conversion of the starting materials as determined by 1H NMR;
isolated yields are reported in brackets; no other product, besides starting materials, was detected. aNo reaction in the presence of comparable
amounts of NH4Br or SiO2. b1e is almost insoluble in CPME. c1:1 mixture of diastereoisomers.
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Beilstein J. Org. Chem. 2018, 14, 1655–1659.
mers as determined by 1H and 13C NMR analysis of the crude Ar was filtered and dropwise added to a vigorously stirred
reaction mixture, thus suggesting that it occurs with no epimeri- freshly prepared solution of EtMgBr in the same solvent at rt.
zation at C1.
Aqueous work-up and flash chromatography afforded the
desired tertiary alcohol 4fa in 78% yield (Scheme 4).
This result was confirmed by submitting compound 3i to acid-
catalyzed deprotection with H2SO4@SiO2 (25 wt % [33] as Under similar conditions, protection of 1f in CPME, followed
depicted in Scheme 3). Alcohol 1i, was recovered as a single by filtration and dropwise addition of the resulting solution to a
stereoisomer, identical to the commercially available starting suspension of LiAlH4 in the same solvent, afforded the mono-
material, as determined by 1H and 13C NMR analysis of the protected diol 4fb in almost quantitative yield (Scheme 5).
crude reaction mixture (see Supporting Information File 1).
Conclusion
The above reported results show that several heterogeneous
acidic catalysts efficiently promote the tetrahydropyranylation
of an alcoholic model compound in low impact ethereal sol-
vents under mild conditions. Further investigations show that
NH4HSO4@SiO2, easily prepared from inexpensive starting
materials, successfully catalyzes the protection of a variety of
functionalized and non-functionalized alcohols and phenols, in-
cluding an optically pure alcohol with no detrimental effects on
Scheme 3: Deprotection of THP ether 3i.
its stereochemistry. Due to a particularly simple work-up proce-
dure, NH4HSO4@SiO2 can be easily recovered and recycled
Finally, the tetrahydropyranylation of a tertiary alcohol 1j as several times. The easy removal of the acidic catalyst from the
well as of phenols 1k and 1l required, besides the employment reaction mixtures and the versatility of the employed solvents
of 2.0 equiv of DHP, relatively longer reaction times and higher allowed the successful further conversion of the reaction prod-
temperatures. It is worth noting that under our mild reaction ucts with strong nucleophiles under one-pot conditions.
conditions we did not observe any isomerisation of the acid-
sensitive allylic alcohol 1j [34].
Supporting Information
To stress the usefulness of a tetrahydropyranylation reaction
Supporting Information File 1
performed in a green ethereal solvent and in the presence of a
heterogeneous acidic catalyst, we realized two one-pot proce-
dures employing either 2-MeTHF or CPME as a solvent.
Full experimental details, copies of IR spectra of fresh and
recycled NH4HSO4@SiO2 and copies of 1H and 13C NMR
spectra.
[https://www.beilstein-journals.org/bjoc/content/
Accordingly, the mixture obtained by reacting 1f with 1.1 equiv
of 2 and 3 mol ‰ of NH4HSO4@SiO2 in 2-MeTHF under dry
supplementary/1860-5397-14-141-S1.pdf]
Scheme 4: One-pot synthesis of 3-[4-(tetrahydro-2H-pyran-2-yl)oxymethylphenyl]-3-pentanol (4fa).
Scheme 5: One-pot synthesis of 4-(tetrahydro-2H-pyran-2-yloxymethyl)benzyl alcohol (4fb).
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Beilstein J. Org. Chem. 2018, 14, 1655–1659.
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