Solvent-free tetrahydropyranylation (THP) of alcohols and phenols and their regeneration by catalytic aluminum chloride hexahydrate

Article abstract of DOI:10.1016/S0040-4039(01)02372-3

A catalytic amount of aluminum chloride hexahydrate enables solvent-free tetrahydropyranylation (THP) of alcohols and phenols at moderate temperatures. A simple addition of methanol helps to regenerate the corresponding alcohols and phenols, thus rendering these protection and deprotection sequences as very efficient transformations at high substrate to catalyst ratios.

Full text of DOI:10.1016/S0040-4039(01)02372-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1143–1146
Solvent-free tetrahydropyranylation (THP) of alcohols and
phenols and their regeneration by catalytic aluminum
chloride hexahydrate
Vasudevan V. Namboodiri and Rajender S. Varma*
Clean Processes Branch, National Risk Management Research Laboratory, US Environmental Protection Agency, MS 443,
26 W. Martin Luther King Drive, Cincinnati, OH 45268, USA
Received 27 November 2001; revised 12 December 2001; accepted 14 December 2001
Abstract—A catalytic amount of aluminum chloride hexahydrate enables solvent-free tetrahydropyranylation (THP) of alcohols
and phenols at moderate temperatures. A simple addition of methanol helps to regenerate the corresponding alcohols and phenols,
thus rendering these protection and deprotection sequences as very efficient transformations at high substrate to catalyst ratios.
Published by Elsevier Science Ltd.
The protection and deprotection of alcohols is a com-
mon event in multi-step organic syntheses and tetra-
hydropyranylation (THP) is one of the most frequently
employed methods.1 The THP ethers are attractive
because they are less expensive, easy to deprotect and
are stable enough to strong basic media, oxidative
conditions, reduction with hydrides, and reactions
involving Grignard reagents, lithium alkyls and alkylat-
ing and acylating reagents. There are several reagents
available for tetrahydropyranylation of alcohols, which
include the use of Brønstead and Lewis acids,2 iodine-
microwave irradiation,3 ion-exchange resins (Amberlyst
H154 and Nafion-H5), zeolites,6 montmorillonite K-107a
or sulfuric acid on silica gel,7b zinc chloride8a or
as THP ether. As a part of an ongoing research pro-
gram to develop solventless chemical transformations,15
herein, we report an efficient aluminum chloride hexa-
hydrate-catalyzed solvent-free tetrahydropyranylation
of alcohols and phenols.
In the present method, alcohol or phenol, 3,4-dihydro-
2H-pyran (DHP) and aluminum chloride catalyst are
mixed together to yield the corresponding THP ether.
After the reaction, the product is purified by simple
filtration through a silica gel pad and evaporation of
the eluent, petroleum ether. A wide variety of hydroxyl-
ated compounds are converted to the corresponding
THP ethers via this procedure and the results are
shown in Table 1. The reactions are reasonably fast,
even with a bulky molecule like benzhydrol (entry 7). It
is important to note that an acid sensitive alcohol like
tert-butanol (entry 8) undergoes protection as tetra-
hydropyranyl ether without the formation of a dehy-
dration product. The study conducted with benzyl
alcohol as the substrate for pyranylation shows that the
rate of reaction decreases with the increase in substrate
to catalyst ratio (Table 2). Increase in temperature with
longer reaction time results in complete pyranylation
even at higher substrate concentration. Higher tempera-
tures are required in the case of substituted benzyl
alcohols (high substrate to catalyst ratio) and with solid
alcohols. An important feature of this method is the
efficient monotetrahydropyranylation of 1,n-diols
(entries 12 and 13), a transformation that is difficult to
accomplish via conventional methods.
AlPO4 on alumina, Envirocat EPZG,9 tributylammo-
8b
nium bromide,10 heteropoly acids,11 p-toluenesulphonic
acid, pyridinium p-sulphonate(PPTS) and triphenyl-
phosphene hydrobromide in ionic liquids as catalysts,12
cyclodextrin,13 and lithium perchlorate–diethylether.14
Although these methods are suitable for many synthetic
conditions, they require a high catalyst to substrate
ratio, have a long reaction time and involve the use of
volatile organic solvents or large amounts of solid
supports which eventually results in the generation of a
large amount of toxic waste. Thus, there is a need for a
solventless and catalytically efficient alternative for the
protection and deprotection of hydroxyl functionality
Keywords: tetrahydropyranylation; aluminum chloride; solvent-free.
* Corresponding author. Fax: (513)-569-7677; e-mail: varma.
rajender@epa.gov
0040-4039/02/$ - see front matter Published by Elsevier Science Ltd.
PII: S0040-4039(01)02372-3

1144
V. V. Namboodiri, R. S. Varma / Tetrahedron Letters 43 (2002) 1143–1146
Table 1. Tetrahydropyranylation of alcoholsa,b
O
AlCl3. 6H2O
O
ROH
RO
+
AlCl3. 6H2O
CH3OH
O
CH3O
Entry
Alcohol
Time (min)
Temperature (°C)
Yield (%) GC (isolated)
1
2
3
4
5
6
7
8
1-Hexanol
3-Hexanol
Cyclohexanol
Phenol
4-Chlorophenol
2-Naphthol
Benzhydrol
tert-Butanol
Geraniol
Allyl alcohol
3-Methyl-2-butene-1-ol
1,2-Ethanediol
1,4-Butanediol
4-Chlorobenzyl alcohol
30
30
30
30
30
30
30
30
180
30
30
30
30
30
30
30
30
60
60
80
80
40
50
30
30
30
30
60
100 (95)1
100 (96)17
93 (88)5
96 (89)13
92 (85)13
96 (88)6c
85 (82)16
100 (95)2c
82 (81)3b,4
100 (98)3b
100 (98)18
76 (74)2a,b
78 (75)2a,b
94 (90)13,16
9
10
11
12
13
14
a AlCl3·6H2O (1 mmol) and 3,4-dihydropyran (110 mmol) and alcohol (100 mmol).
b For complete cleavage of tetrahydropyranyl ethers at room temperature: THP ether (100 mmol), aluminum chloride (1 mmol) and methanol (800
mmol), 30 min at 30°C.
Table 2. Catalytic effect of AlCl3 on tetrahydropyranylation of benzyl alcohola
Benzyl alcohol (mmol)
3,4-Dihydropyran (mmol)
Time (min)
Temperature (°C)
Yield (%) GC
1
100
500
1000
1000
2500
5000
1.1
110
550
1100
1100
2750
5500
5
30
60
60
30
60
90
30
30
30
30
55
80
80
100
100
79
64
100
100
100b
a AlCl3·6H2O (1 mmol).
b For complete cleavage of tetrahydropyranyl ether at high substrate to catalyst ratio: THP ether (5000 mmol), aluminum chloride (1 mmol) and
methanol (20,000 mmol), 1 h at 80°C.
These reactions catalyzed by aluminum chloride do not
require any solvent or solid support and consequently
assist in minimizing the generation of toxic wastes to
the environment. While most of the existing protocols
require distilled and/or dry reagents, the present
method tolerates the presence of moisture although the
reaction rate decreases with increase in water concen-
tration as shown in Fig. 1. It is significant that the
present method is suitable for the preparation of THP–
ether even at higher water content (Fig. 1).
GC–MS when a complete disappearance of the THP
ether occurs with the regeneration of the alcohol and
the formation of tetrahydro-2-(methoxy)-2H-pyran. At
a relatively higher temperature of 80°C, this catalyst is
able to deprotect THP ethers using excess methanol at
high substrate to catalyst ratio (5000 mmol:1 mmol) in
1 h.
Preparative procedure for THP ethers: Aluminum chlo-
ride hexahydrate (1 mmol), DHP (110 mmol) and ben-
zyl alcohol (100 mmol) were mixed in a 50 ml round
bottomed flask and stirred at 30°C and the progress of
the reaction was monitored by TLC and GC–MS
(Table 1). The complete protection was ascertained by
the disappearance of the alcohol signal in the GC. For
solid substrates (entries 6, 7, and 14), moderate heating
was required. The product was purified by filtering the
reaction mixture through a short column of silica gel (2
The capability of aluminum chloride to cleave the THP
protective group is also investigated to establish the
regenerative potential of catalyst. To this end, the THP
ether (100 mmol), aluminum chloride (1 mmol) and
excess methanol (800 mmol) are mixed together at
room temperature affording a complete conversion in
30 min. The deprotection is conveniently followed via

V. V. Namboodiri, R. S. Varma / Tetrahedron Letters 43 (2002) 1143–1146
1145
Figure 1. Yield versus water content. Effect of water content on the reaction of benzyl alcohol (100 mmol) with DHP (110 mmol)
in the presence of AlCl3·6H2O catalyst (1 mmol).
cm length, 0.5 cm diameter) with petroleum ether (ꢀ4
between the US Department of Energy and the US
Environmental Protection Agency.
ml) to obtain pure THP ether (99%).4
All the THP ethers are known compounds and were
characterized by spectral analyses, comparison with
authentic samples (GC and NMR), and also by regen-
eration of the corresponding alcohols or phenols. The
regeneration experiments also reaffirmed that there
were no other side reactions occurring during THP
ether formation.
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Acknowledgements
V.V.N. is a postgraduate research participant at the
National Risk Management Research Laboratory
administered by the Oak Ridge Institute for Science
and Education through an interagency agreement
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