Solvent-free NaHSO4-SiO2-catalyzed efficient tetrahydropyranylation of alcohols and phenols

Article abstract of DOI:10.1080/00397911.2011.629068

A simple and efficient tetrahydropyranylation of alcohols and phenols has been developed using NaHSO₄-SiO₂ (0.5 mol%) as a catalyst under solvent-free conditions to yield corresponding tetrahydropyranyl ethers in excellent yields.

Full text of DOI:10.1080/00397911.2011.629068

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Solvent-Free NaHSO4-SiO2-Catalyzed
Efficient Tetrahydropyranylation of
Alcohols and Phenols
Henok H. Kinfe a , Fanuel M. Mebrahtu a & Paseka T. Moshapo a
a Research Center in Synthesis and Catalysis, Department of
Chemistry, University of Johannesburg, Johannesburg, South Africa
Published online: 21 Feb 2013.
To cite this article: Henok H. Kinfe , Fanuel M. Mebrahtu & Paseka T. Moshapo (2013) Solvent-
Free NaHSO4-SiO2-Catalyzed Efficient Tetrahydropyranylation of Alcohols and Phenols, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
43:9, 1237-1242, DOI: 10.1080/00397911.2011.629068
To link to this article: http://dx.doi.org/10.1080/00397911.2011.629068
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Synthetic Communications1, 43: 1237–1242, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.629068
SOLVENT-FREE NaHSO4-SiO2-CATALYZED EFFICIENT
TETRAHYDROPYRANYLATION OF ALCOHOLS AND
PHENOLS
Henok H. Kinfe, Fanuel M. Mebrahtu, and Paseka T. Moshapo
Research Center in Synthesis and Catalysis, Department of Chemistry,
University of Johannesburg, Johannesburg, South Africa
GRAPHICAL ABSTRACT
Abstract A simple and efficient tetrahydropyranylation of alcohols and phenols has been
developed using NaHSO4-SiO2 (0.5 mol%) as a catalyst under solvent-free conditions to
yield corresponding tetrahydropyranyl ethers in excellent yields.
Keywords Silica-supported sodium hydrogen sulfate; tetrahydropyranylation; THP
ether
INTRODUCTION
Tetrahydropyranyl (THP) is one of the most extensively employed protecting
groups of alcohols in organic chemistry.[1] Its ease of installation and cleavage, ready
availability, and stability to a range of nonacidic reaction conditions such as
hydrides, alkylating agents, Grignard reagents, and organometallic reagents makes
THP ethers a good choice of protecting group. The THP group can be introduced
by reacting an alcohol with dihydropyran (DHP) in the presence of a catalytic
amount of an acid. Several acids including TsOH,[2] pyridinium p-toluenesulfonate
(PPTS),[3] H2SO4-SiO2,[4] and Al(OTf)3
have been reported to affect tetrahydro-
[5,6]
pyranylation of alcohols. However, most of the acid-catalyzed protocols reported so
far suffer from long reaction times, high reaction temperatures, use of organic
solvents, high catalyst loading, strong acidic conditions, and expensive and toxic acids.
Recently, Kamal et al. reported a solvent-free tetrahydropyranylation of
alcohols using Al(OTf)3 as a catalyst.[6] Though this method is more efficient and
Received September 13, 2011.
Address correspondence to Henok H. Kinfe, Research Center in Synthesis and Catalysis,
Department of Chemistry, University of Johannesburg, P.O. Box 524, Auckland Park, Johannesburg
2006, South Africa. E-mail: hhkinfe@uj.ac.za
1237

1238
H. H. KINFE, F. M. MEBRAHTU, AND P. T. MOSHAPO
Table 1. Tetrahydropyranylation of benzyl alcohol at different temperatures and
mol% catalyst loadings
Entry
Amount (mol%)
Temperature (ꢀC)
Time (min)
Yield (%)a
1
2
3
0.5
1
0
0
60
30
5
77
82
90
0.5
25
aIsolated yields.
environmentally friendly than the existing methodologies, taking aluminium triflate’s
high cost, moisture sensitivity, and need for workup using organic solvents into con-
sideration, we felt there was scope for developing an alternative that is more efficient,
is environmentally benign, and has relatively cheaper reaction conditions.
NaHSO4 supported on silica gel has gained momentum as a viable and alterna-
tive acid catalyst for a number of transformations because of its low cost, ease of prep-
aration, mildness, recoverability, reusability, and insensitivity to moisture. It has been
applied as a catalyst in the opening of epoxides into b-hydroperoxy alcohols,[7]
synthesis of trisubstituted quinolines,[8] b-enaminones,[9] N-acylsulfonamides,[10]
aryl-14-H-dibenzo[a.j]xanthenes,[11] amidoalkyl naphthols,[12] coumarins,[13] selective
monoacetylation of unsymmetrical diols,[14] and Ferrier rearrangement of glycals.[15]
Nishiguchi and coworkers reported monotetrahydropyranylation of symmetrical diols
using NaHSO4-SiO2 and related metallic sulfates, Mm(SO4)n–SiO2, as catalysts in a 1:1
DHP and hexane solvent system.[16] Though NaHSO4-SiO2 has been listed as a cata-
lyst in the study by Nishiguchi and coworkers, a thorough examination of the gener-
ality and scope of the catalyst for tetrahydropyranylation of alcohols and phenols
under environmentally benign conditions has not been established yet.
In continuation of our work to develop new, environmentally benign, and
cost-effective synthetic methodologies and in view of the efficiency of the
NaHSO4-SiO2 as an acid catalyst, herein we report an efficient tetrahydropyranyla-
tion of alcohols and phenols using NaHSO4-SiO2 catalyst under solvent-free
conditions in excellent yields.
RESULTS AND DISCUSSION
Tetrahydropyranylation of benzyl alcohol was used as a model reaction to
investigate the optimal reaction conditions such as catalyst loading and temperature.
The results are summarized in Table 1. In our first attempt, a solvent-free solution of
benzyl alcohol and DHP was treated with 0.5 mol% of NaHSO4-SiO2 to afford the
corresponding THP ether 2 in 77% yield in 1 h at 0 ꢀC (Scheme 1). The rate of the
Scheme 1. Tetrahydropyranylation of benzyl alcohol.

TETRAHYDROPYRANYLATION OF ALCOHOLS AND PHENOLS
1239
Table 2. NaHSO4-SiO2-catalyzed tetrahydropyranylation of alcohols and phenols
Entry
Alcohol
Product
Time (min)
Yield (%)a
1
5
90
95
2
5
3
4
5
6
10
10
5
84 (1:1)
94 (1:1)
65b
5
85
80c (mixture of
diastereomers)
7
5
8
9
5
5
5
5
5
93 (1:1)
96
10
11
12
94
96
91
(Continued )

1240
H. H. KINFE, F. M. MEBRAHTU, AND P. T. MOSHAPO
Table 2. Continued
Entry
13
Alcohol
Product
Time (min)
30
Yield (%)a
92c
14
5
95
aIsolated yields.
bslightly low yields are as a result of the high volatility of the product.
cTo dissolve the solid alcohols, 2.5 equivalence of DHP was used.
reaction was accelerated to 30 min by using 1 mol% of the catalyst without significant
improvement in yield (82%) at 0 ꢀC. However, when the reaction was carried out at
room temperature using 0.5 mol% catalyst, it was completed in 5 min and provided
90% yield. Reducing the catalyst loading to 0.2 mol% resulted in a sluggish reaction
and poor yields.
Variation in the total amount of DHP revealed that 1.5 equivalents were suf-
ficient to fully convert the alcohol into the desired THP ether. Treatment of various
primary and secondary alcohols in this way provided efficient access to the desired
THP ethers. While tertiary alcohols were difficult to protect, the reactions proceeded
remarkably well with the other alcohols as long as these were soluble in DHP. A
slight excess, 2.5 equivalents, of DHP was required in the cases of furanose alcohol
13 (Table 2, entry 7) and the sterically hindered 2-iodophenol 25 (Table 2, entry 13).
In all cases complete conversion of the starting alcohol was achieved in a short reac-
tion time and products were identified by 1H and 13C NMR spectroscopy after chro-
matographic purification. No aqueous workup was required as reaction mixtures
were directly loaded onto silica gel for chromatographic purification.
The protocol compares very favorably with reported methods in terms of yield,
catalyst loading, and reaction times. The reaction conditions are also tolerant of a
range of acid-sensitive groups such allyl (Table 2, entry 5), propargyl (Table 2, entry
6), p-methoxy benzyl (Table 2, entry 2), trityl ethers (Table 2, entry 8), and acetals
(Table 2, entry 7 and 8).
To evaluate the generality of the method, various phenols were treated under
the optimized conditions to afford aromatic THP ethers. Interestingly, the reaction
returned excellent yields of the THP ethers in short reaction times (Table 2, entries
9–14). Both activated and deactivated phenols reacted with DHP without significant
discrepancy when compared with their corresponding aryl and aliphatic alcohols,
showing the superiority of the method. In agreement with a recent report in which
Al(OTf)3 in dichloromethane[7] was employed as a catalyst, the current method also
resulted in tetrahydropyranylation of 2-naphthol in 95% yield, which otherwise has
been found to be difficult to protect as a THP ether.
In conclusion, we have demonstrated that NaHSO4 supported on silica gel
under solvent-free conditions is an efficient catalyst for the tetrahydropyranylation

TETRAHYDROPYRANYLATION OF ALCOHOLS AND PHENOLS
1241
of alcohols and phenols. The shorter reaction time, low catalyst loading, low cost
and high stability of the catalyst, compatibility with a wide range of acid-sensitive
groups, and absence of organic solvents (as solvents in both the reaction and
workup) make the method attractive in organic synthesis, being greener and superior
to the previously reported methods.
EXPERIMENTAL
Preparation of the NaHSO4-SiO2 Catalyst[17]
˚
Fourteen g of SiO2 (column chromatographic grade, 60 A, 200–400 mesh) was
added to a solution of 5 g (0.04 mol) of NaHSO4 in 25 mL of water in a 100-mL
round-bottom flask. After stirring the mixture for 15 min at room temperature,
the solvent was removed in vacuo at 40 ꢀC until a free-flowing white solid was
obtained. The catalyst was further dried in an oven maintained at 120 ꢀC for 48 h
prior to use.
General Procedure for the Tetrahydropyranylation
of Alcohols and Phenols
To a mixture of alcohol (1.67 mmol) and dihydro-4H-pyran (2.5 mmol),
NaHSO4-SiO2 (3 mg, 3 mmol NaHSO4=g)[17] was added. The reaction mixture was
stirred at room temperature until thin-layer chromatographic (TLC) analysis showed
complete disappearance of the starting material. After completion of the reaction,
the mixture was directly loaded onto silica gel for chromatographic purification
using 1:9 ethyl acetate–hexane eluent to afford corresponding THP ethers. The struc-
tures of the products were determined from their NMR spectra and by comparison
with those reported in the literature (2,[6] 4,[6] 6,[6] 8,[6] 10,[18] 12,[6] 18,[18,19] 20,[6]
22,[18] 24,[20] 26,[21] and 28.[6]
(3a R,5 R,6 R,6a R)-2,2-Dimethyl-6-(tetrahydro-2H-pyran-2-yloxy)-5-
((tetrahydro-2H-pyran-2-yloxy)methyl)tetrahydrofuro[2,3-d][1,3]
dioxole (14)
Complex diastereoisomeric mixture was obtained; colorless oil; 1H NMR
(CDCl3, 300 MHz): (5.99–5.82 (m, 1H), 4.79–4.10 (m, 5H), 4.01–3.33 (m, 6H),
1.86–0.81 (m, 18H); 13C NMR (CDCl3, 75 MHz): d111.5, 105.1, 105.0, 104.9,
101.2, 101.1, 99.3, 99.2, 98.7, 98.4, 95.8, 95.6, 84.1, 84.0, 82.2, 81.5, 81.1, 79.7,
77.4, 77.0, 76.9, 76.6, 65.6, 65.1, 64.4, 64.3, 63.4, 63.3, 62.3, 62.2, 61.9, 61.6, 30.6,
30.5, 30.4, 26.8, 26.7, 26.2, 25.4, 25.3, 25.2, 19.8, 19.19.5, 19.3, 19.1, 19.0; HRMS
(ESI) m=z (M þ Na): calcd. 381.1889; found 381.1890.
(3a R, 5 R, 6 R, 6a R)-2,2-Dimethyl-6-(tetrahydro-2H-pyran-2-yloxy)-5-
(trityloxymethyl)tetrahydrofuro[2,3-d][1,3]dioxole (16)
Diastereomeric mixture (1:1) was obtained; colorless oil; 16a:1H NMR
(CDCl3, 300 MHz): d7.50–7.10 (m, 15H), 5.90 (d, J ¼ 3.9 Hz, 1H), 4.80–4.71 (m,
1H), 4.58–4.24 (m, 3H), 3.87–3.76 (m, 1H), 3.60–3.20 (m, 3H), 1.67–0.88 (m, 12H);

1242
H. H. KINFE, F. M. MEBRAHTU, AND P. T. MOSHAPO
16b: 1H NMR (CDCl3, 300 MHz): d5.85 (d, J ¼ 3.6 Hz, 1H), 4.67 (d, J ¼ 3.6 Hz, 1H),
3.14 (t, J ¼ 8.7 Hz, 1H); 13C NMR (CDCl3, 75 MHz): d143.8, 143.6, 128.7, 128.5,
127.8, 127.7, 127.0, 126.9, 111.6, 111.5, 104.9, 104.8, 100.6, 99.3, 94.5, 86.8, 86.7,
84.1, 82.0, 80.0, 79.5, 78.9, 76.4, 63.3, 61.8, 61.1, 60.1, 30.2, 30.0, 26.8, 26.2, 26.1,
25.15, 25.1, 19.7, 18.0; HRMS (ESI) m=z (M þ Na): calcd. 539.2410; found 539.2405.
ACKNOWLEDGMENTS
Research funds of the University of Johannesburg and the Research Center for
Synthesis and Catalysis are gratefully acknowledged. We also thank Dr. Gareth
Arnott for proofreading our manuscript.
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