Selective tetrahydropyranylation under non-acidic conditions

Article abstract of DOI:10.1055/s-2005-918916

We report that the tetrahydropyranylation of hydroxyl groups, exhibiting especially very low nucleophilicities, can be achieved by means of Mitsunobu reaction with 2-hydroxytetrahydropyran. This reaction led to the protection of phenols and pyridinols without the use of an acidic catalyst. For instance hydroxypyridines could not be protected by dihydropyran under acidic conditions, whereas they underwent a smooth tetrahydropyranylation under Mitsunobu conditions. The method is selective for a phenol over an alcohol. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-918916

2
808
LETTER
Selective Tetrahydropyranylation under Non-Acidic Conditions
a
a
b
a
S
R
elective Tetrahy
a
dropyranyl
b
ation under
N
a
on-Acidic
h
Conditions Azzouz, Laurent Bischoff,* Marc-Henri Fouquet, Francis Marsais
c
Laboratoire de Chimie Organique Fine et Hétérocyclique, IRCOF–INSA Rouen, B.P. 08, 76131 Mont-Saint-Aignan, France
d
I.U.T. Rouen, Rue Lavoisier, 76821 Mont-Saint-Aignan, France
Fax +33(2)35522962; E-mail: laurent.bischoff@insa-rouen.fr
Received 30 June 2005
same way avoid the use of an acid or Lewis acid catalyst.
When we examined the different methods described in the
literature, it appeared that the field of glycosylation under
neutral conditions is much more documented than that of
Abstract: We report that the tetrahydropyranylation of hydroxyl
groups, exhibiting especially very low nucleophilicities, can be
achieved by means of Mitsunobu reaction with 2-hydroxytetra-
hydropyran. This reaction led to the protection of phenols and
pyridinols without the use of an acidic catalyst. For instance simple tetrahydropyranylation. Amongst the methods of
hydroxypyridines could not be protected by dihydropyran under glycosylation, which do not require acid catalysis, we
acidic conditions, whereas they underwent a smooth tetrahydro-
were interested in either the substitution of an anomeric
pyranylation under Mitsunobu conditions. The method is selective
halogen by silver phenolates or the Mitsunobu reaction,
for a phenol over an alcohol.
which was described with 2-hydroxy pyranoses. In the
Key words: protecting groups, glycosylations, acetals, phenols,
pyridines
case of tetrahydropyran, the a-chloro derivative exists but
4
is rather unstable. Moreover, direct substitution by silver
phenolates requires the previous formation of the silver
salt before the protection step. We finally turned our atten-
tion towards the Mitsunobu reaction. This reaction is well
Protection of alcohols and phenols is a widely used tool in
organic synthesis. Indeed, the tetrahydropyranylation of
these moieties has been known for decades, although still
5
described in the case of sugar chemistry but no example
1
has been published for unsubstituted tetrahydropyran. The
only similar example of activation of 2-hydroxytetrahy-
dropyran given in the literature consisted of reacting the
of interest, especially to find out more efficient or solvent-
free catalysis. Generally, this protection is achieved by
means of acidic catalysis-mediated formation of the acetal
through reaction of dihydropyran (DHP) with an alcohol
or phenol. As many different conditions have been de-
scribed, most of them imply that the substrate should not
be sensitive to acids or Lewis acids. Moreover, the hy-
droxyl group to be protected must be nucleophilic enough
to permit the attack onto the cation formed by protonation
of DHP.
latter with trifluoroacetic anhydride for the acetalization
of alcohols.6
PPh3, DEAD
OH
OTHP
X
X
X = N, CH
HO
O
Scheme 1 Tetrahydropyranylation of pyridinols and phenols with
-hydroxytetrahydropyran under Mitsunobu conditions
In our case, we were first interested in obtaining protected
pyridinols such as 2-, 3- and 4-(O-THP)-pyridines. Sur-
prisingly, to our knowledge, no conditions for the prepa-
2
ration of these compounds have been described in the As depicted in Scheme 1, we first carried out the activa-
7
literature. Few examples of O-THP pyridines exist, how- tion of 2-hydroxytetrahydropyran under the conditions of
ever, when the pyridine ring bears a substituent, which a standard Mitsunobu reaction, in the presence of the
renders the nitrogen less nucleophilic. When we attempt- different isomers of hydroxypyridine. For this purpose, 2-
ed to protect these two substrates under various acidic hydroxytetrahydropyran was prepared by hydration of
conditions in the presence of DHP, no trace of the expect- dihydropyran in 0.2 N aqueous HCl. This compound is
ed acetals was observed. This can be due to the basicity of stable for a few days if stored at 4 °C.
the nitrogen atom, which not only deactivates the catalyst
but also lowers the reactivity of the hydroxyl group, espe-
cially in the case of 2- or 4-pyridinone. No reaction was
noticed even in the presence of a molar excess of the acid,
Under classical experimental conditions required for a
Mitsunobu reaction, i.e. a slight excess of PPh and di-
3
ethylazodicarboxylate (DEAD) in THF, 2-hydroxy-
tetrahydropyran reacted smoothly with hydroxy pyridines
at room temperature. The results of the protection of the
p-toluenesulfonic acid or H SO .
2
4
As pyridinols and pyridinones display an acidity higher three different isomers of hydroxypyridine are listed in
2
than phenol, we sought reaction conditions which would Table 1.
be capable of taking advantage of this property and by the
The O-THP pyridines were obtained with concomitant
formation of THP-bearing by-products, presumably re-
sulting from partial dimerization of 2-hydroxy-THP.
Protected 2- and 4-pyridinols were very sensitive to acidic
conditions and could not be purified by means of flash
SYNLETT 2005, No. 18, pp 2808–2810
0
3
.1
1
.2
0
0
5
Advanced online publication: 10.10.2005
DOI: 10.1055/s-2005-918916; Art ID: D17805ST
©
Georg Thieme Verlag Stuttgart · New York

LETTER
Selective Tetrahydropyranylation under Non-Acidic Conditions
2809
Table 1 Tetrahydropyranylation of Pyridinols
The selectivity of this reaction was also examined, by
protecting the phenol moiety in the presence of an amine
or free alcohol. We were pleased to notice that basic com-
pounds, such as 4-aminophenol, could be selectively pro-
tected on the phenol moiety in the presence of the free
amine (entry 5), a reaction which does not seem possible
with DHP under acidic catalysis. Moreover, as described
in Scheme 2, in the case of a molecule bearing at the same
time an alcohol and a phenol, the protection occurs exclu-
sively on the phenol moiety, leaving the alcohol unpro-
tected. This can be easily explained by the fact that the
Mitsunobu reaction involves rather acidic compounds,
thus accounting for the unique phenol deprotonation.
Entry
1
Substrate
Product
Isolated yield (%)
61
OH
OTHP
N
O
N
2
3
OTHP
60
52
N
H
N
N
N
H
O
OTHP
OH
OH
THP–OH
n-Bu
n-Bu
PPh3, DEAD
chromatography on silica gel, even in the presence of tri-
ethylamine. The purification of these compounds proved
HO
THPO
85%
to be difficult and could only be achieved by chromato- Scheme 2 Selective tetrahydropyranylation of a phenol in the
graphy through basic alumina, or bulb-to-bulb distillation presence of a free alcohol
under high vacuum. These reasons account for the fairly
low yields of isolated pure O-THP pyridines, although the
conversions measured by NMR spectra of crude reaction
products were almost quantitative in each case. Moreover,
we observed that the tetrahydropyranylation of 2- and 4-
pyridinones only occurred at the oxygen atom, thus giving
access to their pyridine forms, although the major
tautomer is generally the pyridinone in the case of un-
protected substrates. This was in contrast with alkylation
reactions, which mostly occur on the nitrogen atom and
require phase-transfer conditions for O-protection.3
Furthermore, although the major drawback of the
Mitsunobu reaction lies in the stoichiometric amounts of
by-products arising from the reaction of PPh3 with
DEAD, we could remove most of those by taking up the
crude reaction products in cyclohexane, which precipitat-
ed most of the triphenylphosphine oxide and diethyl hy-
drazinodicarboxylate. The remaining impurities were
subsequently removed by means of column chromato-
graphy through silica gel, except for sensitive compounds,
which were purified through basic alumina.
Having this method of protection to hand, we wished to
determine whether it could be versatile enough to be
generalized to other more classical phenol substrates. As
depicted in Table 2, acceptable yields were obtained, with
phenols bearing various substituents, either electron-do-
nating or electron-withdrawing groups, which generally
account for more difficult protections with dihydropyran
under acidic conditions. For example, cyano- and nitro
phenols (entries 1–3) were easily protected under our
conditions, and their purification made much easier than
in the case of pyridines.
All these examples show that this method is a new useful
tool for the protection of phenols and pyridinols, which
are either very poor nucleophiles or sensitive to acidic
conditions, although it is still applicable to phenols bear-
ing electron-donating substituents. Thus, tetrahydropyra-
nylation under these conditions is complementary to the
numerous methods reported which use dihydropyrane in
the presence of acids or Lewis acid catalysts.
Typical Procedure for the Tetrahydropyranylation
Preparation of 2-hydroxytetrahydropyran was accomplished ac-
cording to ref. 7, by hydrating dihydropyrane with 0.2 M aq HCl 2
h at 0 °C, extracting with CH Cl and drying over MgSO .
Table 2 Tetrahydropyranylation of Phenols
2
2
4
To a solution of the phenol or pyridinol (10 mmol), 2-hydroxytet-
rahydropyran (1.26 g, 11 mmol) and triphenylphosphine (2.88 g, 11
mmol) in anhyd THF (20 mL) was added diethylazodicarboxylate
Entry
Ar–OH
Isolated yield (%)
1
2
3
4
5
6
7
4-Cyanophenol
2-Cyanophenol
4-Nitrophenol
p-Cresol
75
78
81
80
75
67
86
(1.92 g, 11 mmol) dropwise at 0 °C. After stirring 2 h at r.t., THF
was evaporated and the residue taken up in cyclohexane (50 mL)
and left overnight at r.t. Most of the triphenylphosphine oxide and
diethyl hydrazinodicarboxylate crystallized and was filtered off. In
the case of compounds, which are sparingly soluble in cyclohexane,
this precipitation was accomplished in Et O from which only tri-
2
4-Aminophenol
2-Naphthol
phenylphosphine oxide crystallized. After evaporation of the
filtrate, the crude material was purified by means of column
chromatography on basic alumina (pyridinols and 4-aminophenol
derivatives) or silica, using the appropriate cyclohexane–EtOAc
4-Methyl-3-nitrophenol
eluent containing 1% Et N.
3
Synlett 2005, No. 18, 2808–2810 © Thieme Stuttgart · New York

2
810
R. Azzouz et al.
LETTER
Data for Protected Compounds
J = 8.4 Hz). 13C NMR: d = 19.2, 20.9, 25.6, 30.8, 62.4, 96.9, 116.8,
Unless otherwise indicated, R given for TLC analysis were mea-
130.2, 131.3, 155.2. Anal. Calcd for C H O : C, 74.97; H, 8.39.
f
12 16
2
sured on silica gel Merck Kieselgel 60F254 plates. NMR spectra
Found: C, 74.89; H, 8.38.
were recorded on a Bruker Avance 300 MHz, using CDCl as sol-
3
vent, chemical shifts are given in ppm.
O-Tetrahydropyranyl-4-aminophenol
Pale yellow oil; R = 0.6 (basic alumina, EtOAc–cyclohexane–
f
1
3
-Tetrahydropyranyloxypyridine
Et N = 1:1:0.01). H NMR: d = 1.55–1.75 (6 H, m), 3.30 (2 H, br s),
3
Pale yellow oil; R = 0.62 (EtOAc–cyclohexane–Et N = 3:1:0.01).
3.50–3.88 (2 H, m), 5.18 (1 H, t, J = 3.3 Hz), 6.56 (2 H, d, J = 8.7
f
3
1
13
H NMR: d = 1.50–1.80 (6 H, m), 3.78 (2 H, m), 5.38 (1 H, t, J = 3.0
Hz), 7.14 (1 H, dd, J = 6.8, 4.5 Hz), 8.17 (1 H, dd, J = 4.5, 1.2 Hz),
Hz), 6.82 (2 H, d, J = 8.7 Hz). C NMR: d = 19.4, 25.6, 30.9, 62.5,
97.9, 116.6, 118.4, 141.3, 150.4.
1
3
8
1
.35 (1 H, d, J = 2.7 Hz). C NMR: d = 19.8, 25.3, 30.4, 62.4, 97.0,
24.2, 132.5, 140.2, 143.2, 153.7.
O-Tetrahydropyranyl-2-naphtol
Pale yellow oil; R = 0.67 (EtOAc–cyclohexane–Et N = 1:4:0.01).
f
3
1
2
-Tetrahydropyranyloxypyridine
H NMR: d = 1.55–1.64 (6 H, m), 3.57–3.87 (2 H, m), 5.50 (1 H,
13
Pale yellow oil; R = 0.62 (basic alumina, EtOAc–cyclohexane–
t, J = 3.1 Hz), 7.14–7.38 (4 H, m), 7.70–7.80 (3 H, m). C NMR:
d = 19.1, 25.6, 30.8, 62.4, 96.8, 110.8, 119.5, 124.2, 126.6, 127.5,
128, 129.6, 129.8, 134.9, 155.2. Anal. Calcd for C H O : C, 78.92;
f
1
Et N = 3:1:0.01). H NMR: d = 1.50–2.10 (6 H, m), 3.60–3.90 (2 H,
3
m), 6.13 (1 H, t, J = 3.2 Hz), 6.74 (1 H, d, J = 8.3 Hz), 6.83 (1 H,
ddd, J = 7.1, 4.9, 0.7 Hz), 7.53 (1 H, ddd, J = 8.3, 7.1, 1.5 Hz), 7.85
1
5
16
2
H, 7.06. Found: C, 78.85; H, 7.04.
1
3
(1 H, dd, J = 4.9, 1.5 Hz). C NMR: d = 19.3, 25.6, 30.2, 63.1, 93.8,
1
11.7, 117.9, 139.4, 147.6, 162.9.
O-Tetrahydropyranyl-4-methyl-3-nitrophenol
Bright yellow solid; mp 65 °C; R = 0.9 (EtOAc–cyclohexane–
f
1
4
-Tetrahydropyranyloxypyridine
Et N = 1:1:0.01). H NMR: d = 1.70–1.95 (6 H, m), 2.45 (3 H, s),
3
1
White solid; mp 130 °C, bp 90 °C (0.3 mmHg). H NMR: d = 1.40–
1
3.55–3.75 (2 H, m), 5.37 (1 H, t, J = 2.9 Hz), 7.61 (1 H, d, J = 2.2
Hz), 7.15 (1 H, d, J = 8.6 Hz), 7.12 (1 H, dd, J = 8.6, 2.2 Hz).
.90 (6 H, m), 3.57–3.75 (2 H, m), 5.47 (1 H, J = 3.0 Hz), 6.88
1
3
13
(
2 H, dd, J = 4.9, 1.3 Hz), 8.36 (2 H, dd, J = 4.9, 1.3 Hz). C NMR:
C NMR: d = 18.9, 20.1, 25.4, 30.4, 62.4, 97, 112.8, 121.9, 126.6,
d = 18.7, 25.3, 30.2, 62.4, 96.1, 112.1, 151.4, 164.1.
133.6, 149.8, 155.8.
O-Tetrahydropyranyl-4-cyanophenol
1-(4-Tetrahydropyranyloxyphenyl)pentanol
White solid; mp 64 °C; R = 0.65 (EtOAc–cyclohexane–Et N =
Colorless oil; R = 0.42 (basic alumina, EtOAc–cyclohexane = 1:3).
f
3
f
1
1
1
5
:1:0.01). H NMR: d = 1.60–1.85 (6 H, m), 3.60–3.80 (2 H, m),
H NMR: d = 0.89 (3 H, t, J = 7.0 Hz), 1.20–1.90 (12 H, m), 3.50–
.49 (1 H, t, J = 2.9 Hz), 7.10 (2 H, d, J = 8.9 Hz), 7.57 (2 H, d,
4.00 (4 H, m), 4.61 (1 H, t, J = 6.6 Hz), 5.42 (1 H, t, J = 3.2 Hz),
13
13
J = 8.9 Hz). C NMR: d = 18.7, 25.3, 30.4, 62.4, 96.6, 105, 117.3,
7.03 (2 H, d, J = 8.5 Hz), 7.26 (2 H, d, J = 8.5 Hz). C NMR: d =
1
19.7, 134.3, 160.8.
14.4, 19.2, 23.0, 27.3, 28.4, 30.8, 39.1, 62.4, 74.7, 96.7, 116.7,
1
27.4, 138.4, 156.8.
O-Tetrahydropyranyl-2-cyanophenol
Colorless oil; R = 0.62 (EtOAc–cyclohexane–Et N = 1:2:0.01). H
NMR: d = 1.60–1.75 (6 H, m), 3.56–3.80 (2 H, m), 5.50 (1 H, t,
J = 2.6 Hz), 6.96 (1 H, td, J = 7.7, 0.8 Hz), 7.16 (1 H, d, J = 8.7 Hz),
1
f
3
References
(
1) (a) Greene, T. Protective Groups in Organic Synthesis, 3rd
ed.; Wiley: New York, 1999. (b) For a recent review listing
new methods for the protection of hydroxyl groups under
heterogeneous conditions, see: Sartori, G.; Ballini, R.; Bigi,
F.; Bosica, G.; Maggi, R.; Righi, P. Chem. Rev. 2004, 104,
7
.30 (1 H, ddd, J = 8.7, 7.7, 1.7 Hz), 7.49 (1 H, dd, J = 7.7, 1.7 Hz).
C NMR: d = 18.3, 25.4, 30.3, 62.2, 96.9, 103.1, 115.6, 116.9,
21.9, 133.9, 134.6, 159.2. Anal. Calcd for C H NO : C, 70.92; H,
1
3
1
6
1
2
13
2
.45; N, 6.89. Found: C, 70.56; H, 6.53; N, 7.02.
1
99.
O-Tetrahydropyranyl-4-nitrophenol
Pale orange oil; R = 0.72 (EtOAc–cyclohexane–Et N = 1:2:0.01).
(
2) Bordwell, F. G.; Singer, D. L.; Satish, A. V. J. Am. Chem.
Soc. 1993, 115, 3543.
3) Michelot, D.; Meyer, M. Nat. Prod. Res. 2003, 17, 41.
4) Meltzer, P. C.; Wang, P.; Blundell, P.; Madras, B. K. J. Med.
Chem. 2003, 46, 1538.
f
3
1
H NMR: d = 1.50 (6 H, m), 3.60–3.80 (2 H, m), 5.47 (1 H, t, J = 2.8
(
(
1
3
Hz), 7.05 (2 H, d, J = 9.2 Hz), 8.12 (2 H, d, J = 9.2 Hz). C NMR:
d = 18.6, 25.3, 30.3, 62.4, 96.8, 116.6, 126.1, 142.3, 162.5. Anal.
Calcd for C H NO : C, 59.19; H, 5.87; N, 6.27. Found: C, 59.88;
1
1
13
4
(
(
(
5) Aakerfeldt, K.; Garegg, P. J.; Iversen, T. Acta Chem. Scand.,
H, 6.35; N, 6.23.
Ser. B 1979, 33, 467.
6) Bowles, S. A.; Davidson, A. H.; Miller, A.; Thompson, T.
M.; Whittaker, M. Synlett 1993, 111.
7) Murphy, P. J.; Williams, H. L.; Hibbs, D. E.; Hursthouse, M.
B.; Abdul Malik, K. M. Tetrahedron 1996, 52, 8315.
O-Tetrahydropyranyl-p-cresol
Pale yellow oil; R = 0.67 (EtOAc–cyclohexane–Et N = 1:4:0.01).
f
3
1
H NMR: d = 1.50–1.75 (6 H, m), 2.21 (3 H, s), 3.52–3.85 (2 H, m),
.30 (1 H, t, J = 3.4 Hz), 6.88 (2 H, d, J = 8.4 Hz), 7.00 (2 H, d,
5
Synlett 2005, No. 18, 2808–2810 © Thieme Stuttgart · New York