Efficient preparation of 4-methoxy-5,6-dihydro-2H-pyran

Article abstract of DOI:10.1016/j.tetlet.2008.01.039

We report the efficient synthesis of 4-methoxy-5,6-dihydro-2H-pyran (MDHP) via the TiCl₄ driven elimination of MeOH from 4,4-dimethoxytetrahydropyran. The previous difficulty of preparing MDHP restricted the wider use of 4-methoxytetrahydropyran-4-yl (MTHP) acyclic acetals, which have desirable protecting group properties when compared to more commonly used MOM- and THP-acetals. The behaviour of the elimination on related acetals is also examined.

Full text of DOI:10.1016/j.tetlet.2008.01.039

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Tetrahedron Letters 49 (2008) 1836–1838
Efficient preparation of 4-methoxy-5,6-dihydro-2H-pyran
a
b
a
a,
*
Nitesh Panchal , Arantxa Fernandez-Yarza , Paul Free , Piers R. J. Gaffney
a
Department of Chemistry, Imperial College London, South Kensington Campus, London SW7 2AZ, UK
b
Universidad de Valencia, C/ Dr. Moliner 50, 46100 Burjassot, Valencia, Spain
Received 8 May 2007; revised 21 December 2007; accepted 10 January 2008
Available online 15 January 2008
Abstract
We report the efficient synthesis of 4-methoxy-5,6-dihydro-2H-pyran (MDHP) via the TiCl
,4-dimethoxytetrahydropyran. The previous difficulty of preparing MDHP restricted the wider use of 4-methoxytetrahydropyran-4-yl
MTHP) acyclic acetals, which have desirable protecting group properties when compared to more commonly used MOM- and THP-
4
driven elimination of MeOH from
4
(
acetals. The behaviour of the elimination on related acetals is also examined.
Ó 2008 Elsevier Ltd. All rights reserved.
The protection of hydroxyl groups during the synthesis
of poly-oxygenated natural products is a ubiquitous syn-
thetic process. Acetals are one of the most common classes
4-Methoxytetrahydropyran-4-yl (MTHP) acetals have
the synthetic advantages of both THP and MOM deriva-
tives, in so far as they have a similar range of stability to
THP acetals but, like MOM acetals, generate no new stereo-
1
of –OH protective groups, especially for poly-ols where
pairs of adjacent hydroxyls can be masked simultaneously
as a cyclic acetal, for example, acetonide or benzylidene
derivatives. However, there is a limited choice of reagents
for the protection of isolated hydroxyls as acetals. This is
because the corresponding acyclic acetals of simple car-
bonyl compounds, such as acetone and benzaldehyde, lack
the entropic stabilisation of a ring.
1
genic centres. MTHP-acetals are easily formed by the
acid catalysed addition of an alcohol to 4-methoxy-5,6-
dihydro-2H-pyran (MDHP, 1a, Scheme 1). MDHP has
itself been synthesised by the Brønsted acid catalysed extru-
sion of methanol from 4,4-dimethoxytetrahydropyran (2a),
a compound that we have found is easily prepared on
2
>100 g scale. However, MTHP protection has not been
The most prominent acyclic acetal protective groups are
tetrahydropyran-2-yl (THP) and methoxymethyl (MOM)
derivatives. The former, prepared by treating an alcohol
with readily available 2,3-dihydro-4H-pyran in the pres-
ence of catalytic acid, have a convenient range of stability
for many synthetic purposes, but contain a new stereogenic
centre leading to the formation of diastereomers when pro-
tecting chiral substrates. The latter, prepared by the reac-
tion of an alcohol with MOM–Cl under basic conditions,
require relatively strongly acidic conditions to deprotect
widely used outside nucleotide chemistry, probably because
the requisite MDHP is very expensive (Aldrich Chemical
Co., £61.00 for 1 g, 95% purity). This may reflect the poor
(
due to the lack of alkyl groups to stabilise the intermediate
cation), and MOM–Cl has a limited shelf-life.
*
Corresponding author. Tel.: +44 (020) 7594 5881; fax: +44 (020) 7594
5804.
E-mail address: p.gaffney@imperial.ac.uk (P. R. J. Gaffney).
Scheme 1. Protection of hydroxyl groups as MTHP-acetals.
0
040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.01.039

N. Panchal et al. / Tetrahedron Letters 49 (2008) 1836–1838
1837
yield in the elimination of methanol from 4,4-dimethyl
acetal 2a and difficult purification of MDHP (1a) for which
no improvement in the procedure has been reported for 32
years. We have repeated this procedure many times: typi-
cally in our hands, after quenching the acid catalyst, enol
ether 1a is distilled from the reaction mixture in a yield
of around 55–60%. However, the MDHP is contaminated
by acetal 2a and tetrahydropyran-4-one (3), which are very
difficult to separate due to the similarity of the boiling
points of all three compounds (1a 60–62 °C/15 mmHg; 2a
elimination from 2a, but that this led to concomitant
byproduct formation, we then explored whether 4-halo-4-
methoxytetrahydropyrans could be eliminated under basic
conditions. Despite possible stabilisation of such com-
pounds by the electron withdrawing oxygen of the pyran
ring, none have been reported. However, it was noted that
the related 4-cyano-4-methoxytetrahydropyran (6) could
be prepared in moderate yield by trapping the oxycarbeni-
um cation 5 generated at low temperature from the reac-
tion of dimethyl acetal 2a and stoichiometric titanium
5
6
1–63 °C/11 mmHg; 3 58 °C/12 mmHg). Furthermore,
tetrachloride with tert-butyl isocyanide (Scheme 2).
only about 75% of the starting acetal 2a is returned from
the extrusion as a distillable fraction, the remainder being
a thick, presumably oligomeric, involatile residue.
We reasoned that the addition of a weak base to the ini-
tial mixture of 4,4-dimethoxytetrahydropyran (2a) and
TiCl4 should favour an E1 mechanism to provide the
desired MDHP (1a) in a yield at least similar to 6. Indeed,
Masking the axial 2-O of myo-inositol as its MTHP-ace-
3
tal 4 has been reported to provide a useful building block
after the treatment of 2a with TiCl at À78 °C, the addi-
4
for phosphoinositide synthesis. We sought to repeat this
protection of the axial 2-hydroxyl as part of our continued
efforts in this field. However, the reaction did not proceed
very far, except when using MDHP fractions having mini-
mal contamination by acetal 2a and ketone 5. For this rea-
son, we required a new method for preparing MDHP free
of contamination.
tion of DIPEA or pyridine, followed by aqueous work-
up, gave mainly the desired enol ether 1a. However, this
was contaminated by ketone 5, the product of hydro-
lysis, which we suspected had been generated during the
aqueous work-up as a result of incomplete quenching of
acid.
Using a fivefold excess of pyridine to initiate the elimina-
Apart from Brønsted acids, various Lewis acids have
also been reported to mediate extrusion of methanol from
dimethyl acetals to give the corresponding methyl enol
tion various anhydrous quenches for the TiCl were tested:
4
the addition of tert-BuOH, solid sodium hydrogen carbon-
ate, or solid sodium carbonate to the reaction still led to the
formation of tetrahydropyranone 3 after aqueous work-up.
However, excess pyridine followed by solid potassium
hydroxide gave exclusively the desired MDHP enol ether
1a. Notably, if the pyridine was omitted and only solid
4
a–d
ethers.
a (1 g scale) where the reactions were followed by TLC
These conditions were tested on dimethyl acetal
2
1
and the crude product mixture was analysed by H NMR.
Boron trifluoride–diethyl ether complex has been used
to eliminate cleanly the related dimethyl acetals of N-aryl
piperidin-4-ones. Under these conditions [0 °C with a
slight excess of N,N-diisopropylethylamine (DIPEA) in
CH Cl ] there was no reaction of 2a with stoichiometric
KOH was added after the TiCl then rapid degradation
4
4
a
occurred with no identifiable products. On a 50 g scale
using this quenching procedure an 86% yield of MDHP
(1a) was achieved after distillation having almost no detect-
2
2
6
Lewis acid. However, on doubling the reagent equivalents,
able contamination by either acetal 2a or ketone 3. When
although enol ether 1a started to form, significant ketone 5
the MDHP enol ether 1a from this procedure was used to
prepare 2-O-MTHP myo-inositol 4 from the corresponding
alcohol, the reaction was faster (overnight vs 2 days) and
required less reagent (5 vs 10 equiv) to reach completion
(
as well as starting acetal 2a) was observed by TLC, and
with time the reaction darkened—the latter is assumed to
be related to decomposition. As our aim was to find a
high-yielding route to MDHP (1a), darkening and the
appearance of ketone 5 were taken as the signature of
failure.
3
compared to the published procedure.
To explore the scope of the reaction of tetrahydropyran-
4-yl acetals with TiCl , the elimination conditions were
4
Although
trimethylsilyl
trifluoromethanesulfonate
(
TMSOTf) has been reported to be a general reagent for
4
b
eliminating dimethyl and cyclic acetals, a similar result
to that with Et OÁBF was obtained with this reagent.
2
3
There was no reaction, even at reflux, between dimethyl
acetal 2a and stoichiometric TMSOTf, in CH Cl or
2
2
MeCN, with a slight excess of DIPEA. However, doubling
the amount of reagents led to rapid darkening and produc-
tion of ketone 5. Rapid decomposition was also observed
using 2 equiv of aluminium trichloride and excess triethyl-
amine in diethyl ether at 0 °C, conditions which have been
reported to cleanly eliminate dimethyl acetals of N-sulfonyl
4
c
piperidinones.
Having found with the above Lewis acids that >1 equiv
of reagent was required to initiate significant methanol
4
Scheme 2. TiCl mediated elimination of acetals.

1838
N. Panchal et al. / Tetrahedron Letters 49 (2008) 1836–1838
tested on some other 4,4-dialkyloxy acetals (2b–e). 4-n-
Butyloxy- and 4-allyloxy-4-methoxytetrahydropyrans (2b
and 2c, respectively) were prepared by reaction of MDHP
Supplementary data
1
Experimental procedures and H NMR data for com-
pounds 1b, 1c and 2b–e. Supplementary data associated
with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2008.01.039.
(
1a) with an excess of each of the corresponding alcohols in
the presence of catalytic triphenylphosphonium hydro-
7
bromide. We found that diallyl acetal 2d was cleanly
prepared from triallyl orthoformate generated in situ and
ketone 5 in the presence of catalytic para-toluenesulfonic
acid. However, the reported conversion of ketones to dial-
References and notes
8
1
. Kocienski, P. J. In Protecting Groups, 3rd ed.; Georg Thieme:
Stuttgart, 2005; pp 286–295 and 315–320.
lyl acetals with trimethylsilyl allyl ether and catalytic
TMSOTf failed. Dibutyl acetal 2e was separated chromato-
graphically from the preparation of 2b.
2
. (a) Reese, C. B.; Saffhill, R.; Sulston, J. E. Tetrahedron 1970, 26, 1023–
1
030; (b) Arentzen, R.; Kui, Y.; Reese, C. B. Synthesis 1975, 509–
510.
3. Gaffney, P. R. J.; Reese, C. B. J. Chem. Soc., Perkin Trans. 1 2001,
92–205.
Treatment of diallyl acetal 2d with TiCl at both À78
4
and À60 °C, followed by pyridine, failed to give any reac-
tion. When the reaction was allowed to warm to À40 °C
before the pyridine was added decomposition occurred
with no identifiable products being isolated. In contrast,
1
4
. (a) Faja, M. F.; Reese, C. B.; Song, Q.; Zhang, P.-Z. J. Chem. Soc.,
Perkin Trans. 1 1997, 191–194; (b) Gassman, P. G.; Burns, S. J.; Pfister,
K. B. J. Org. Chem. 1993, 58, 1449–1457; (c) Engler, T. A.; Wanner, J.
J. Org. Chem. 2000, 65, 2444–2457; (d) Cabrera, G.; Fiaschi, R.;
Napolitano, E. Tetrahedron Lett. 2001, 42, 5867–5869.
when dibutyl acetal 2d was treated similarly with TiCl at
4
1
À40 °C, H NMR of the crude showed the desired butyl
5
. Geoffrey, T.; Bird, C.; Olivier, A. Bioorg. Med. Chem. Lett. 1996, 6,
enol ether 1b in the presence of the starting acetal 2d in a
ratio of ca. 4:1. The need for a significant rise in tempera-
ture before elimination occurred, led us to consider the
possibility that steric hindrance might permit selective
elimination of mixed acetals to occur. However, when the
5
15–520.
6
. Preparation of 4-methoxy-5,6-dihydro-2H-pyran (1a): To a stirred
solution of 4,4-dimethoxytetrahydropyran (2a, 50.2 g, 0.34 mol) in
CH
2
Cl
2
(500 mL) at À78 °C was added TiCl
4
(41.4 mL, 0.38 mol) over
2 min. After 1 h, pyridine (137.5 mL, 1.7 mol) was added followed by
ground KOH (108 g, dried at 100 °C). After 20 min the reaction was
brought to room temperature and stirred for further 1 h; if TLC
mixed 4-methyl-4-butyl acetal 2b was treated with TiCl
4
1
at À60 °C, H NMR of the crude product showed no sig-
analysis (hexane–EtOAc 1:1 v/v, R
3) = 0.29) still shows the presence of tetrahydropyranone (3), then
further KOH should be added and stirring continued until a single
product spot is observed. The reaction mixture was poured into Et
f f f
(1a) = 0.76, R (2a) = 0.47, R
nificant selectivity. Notably, applying the same procedure
to allylmethoxy acetal 2c, again with elimination at
À40 °C, did give some allyl enol ether 1c selectively
(
2
O
Ò
(
1 L), then filtered through Celite and the filter bed washed with
(
1c:1a was ca. 9:1).
further Et
2
O (0.25 L). The combined filtrates were washed with water
). This
solution was concentrated under reduced pressure (water bath
30 °C, P1 cm/Hg). To the residue was added triethylamine (5 mL)
In summary, we have developed a clean and efficient
(
0.25 L), then saturated brine (0.25 L) and dried (MgSO
4
synthesis of the reagent MDHP (1a), which had previously
been difficult to prepare and prohibitively expensive to use
on a large scale. This allows ready protection of isolated
hydroxyl groups as their MTHP-acetals which have a
similar stability to, but do not introduce the undesirable
stereogenic centre of, popular THP-ethers.
<
and this was distilled under reduced pressure, with ice cooling of the
receiver flask, using a helix packed fractionation column to give
MDHP (1a, 33.6 g, 86%), bp 60–62 °C/15 mmHg. A Vigreux column
may be used to obtain equally pure MDHP, but the yield will be
reduced by pyridine contaminated fractions. Alternatively, particularly
for smaller scales, after the pyridine has distilled over, the orange/
yellow residue may be flushed through a pad of silica (slurried from
Et
Et
2
O–Et
3 2
N 99:1 v/v) in a large glass sinter, washed with further Et O–
Acknowledgements
3
N until no MDHP remains in the eluent; on an identical scale to the
above, 35.3 g MDHP (91%) was obtained using this procedure.
. Bolitt, V.; Mioskowski, C.; Shin, D.-S.; Falck, J. R. Tetrahedron Lett.
1988, 29, 4583–4586.
We are grateful to the MRC (PG & PF, Grant No. G
20/709) and BBSRC (NP, Grant No. 28/B17388) for
7
1
financial support.
8. Molander, G. A.; Harris, C. R. J. Org. Chem. 1997, 62, 2944–2956.