Oxidation of monotetrahydropyranylated short-chain symmetrical diols

Article abstract of DOI:10.1081/SCC-120023448

The free hydroxyl functions of monotetrahydropyranylated three-to five-carbon symmetrical primary diols are oxidized to aldehydes, without cleavage of the protective group, by using pyridinium dichromate in CH ₂Cl₂ and anhydrous MgSO₄ as a water scavenger. The oxidation procedure is improved for these specific compounds since over oxidation to carboxylic acids and formation of dimeric esters are suppressed.

Full text of DOI:10.1081/SCC-120023448

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Õ
SYNTHETIC COMMUNICATIONS
Vol. 33, No. 18, pp. 3243–3250, 2003
Oxidation of Monotetrahydropyranylated
Short-Chain Symmetrical Diols
Richard J. Petroski*
#
USDA, REE, Agricultural Research Service,
National Center for Agricultural Utilization Research,
Crop Bioprotection Research Unit, Peoria, Illinois, USA
ABSTRACT
The free hydroxyl functions of monotetrahydropyranylated three- to
five-carbon symmetrical primary diols are oxidized to aldehydes,
without cleavage of the protective group, by using pyridinium
dichromate in CH Cl and anhydrous MgSO as a waterscavenger.
2
2
4
The oxidation procedure is improved for these specific compounds
since over oxidation to carboxylic acids and formation of dimeric
esters are suppressed.
*
Correspondence: Richard J. Petroski, Research Chemist, USDA, REE,
Agricultural Research Service, National Center for Agricultural Utilization
Research, Crop Bioprotection Research Unit, 1815 N. University Street,
Peoria, IL 61604, USA; Fax: (309) 681-6693; E-mail: petrosrj@ncaur.usda.gov.
#
Names are necessary to report factually on available data; however, the USDA
neither guarantees nor warrants the standard of the product, and the use of the
name by USDA implies no approval of the product to the exclusion of others that
may also be suitable.
3
243
DOI: 10.1081/SCC-120023448
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
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3
244
Petroski
Key Words: 3-(Tetrahydro-pyran-2-yloxy)-propionaldehyde; 4-(Tetra-
hydro-pyran-2-yloxy)-butyraldehyde; 5-(Tetrahydro-pyran-2-yloxy)-
pentanal; Pyridinium dichromate.
Short-chain bifunctional aldehydes, containing a protected primary
alcohol, were needed as homologating agents for use in the preparation
of certain insect pheromones. The requisite bifunctional aldehydes can be
derived from three- to five-carbon symmetrical diols, monoprotected as
[1]
THP ethers, by partial oxidation of the free hydroxyl function. The
THP protective group was chosen because it is stable to the basic
[
2]
conditions employed in Grignard reactions.
The oxidation of primary alcohols to aldehydes can be accomplished
[
with pyridinium dichromate (PDC) in CH Cl , however, the reaction
3]
2
2
rate decreases and additional PDC reagent (above the 1.5 molar equiva-
[
lents recommended) is often required. Although general improvements
4]
[
5]
[4,6,7]
have been made such as the addition of celite, molecularsieves,
[8]
dry
these additions are not suitable for
[6,7]
acetic acid,
oracetic anhyd ri de,
the partial oxidation of three- to five-carbon symmetrical diols, mono-
protected as THP ethers, because of cleavage of THP ethers (presence of
acid) and overoxidation to carboxylic acids.
[
5]
The use of celite requires five equivalents of PDC. The use of either
freshly-activated molecular sieves or celite resulted in a significant
amount (ca. 10%) of carboxylic acid formation (results observed in this
laboratory). The use of dry acetic acid requires rigorously anhydrous
conditions and the method has only been applied to the oxidation of
[
6,7]
secondary alcohols to ketones.
result in overoxidation to carboxylic acids and subsequent formation of
The use of acetic anhydride can
[8]
dimeric esters. The presence of acid is especially not recommended in
the oxidation of 3-(tetrahydro-pyran-2-yloxy)-propan-1-ol because this
alcohol can isomerize to unwanted 4-[1,3]dioxan-2-yl-butan-1-ol.
[
9,10]
In this article, improved methods for the partial oxidation of mono-
tetrahydropyranylated three- to five-carbon symmetrical diols to alde-
hydes are reported that minimize the formation of unwanted byproducts
and easily remove unreacted PDC from the reaction mixture (Fig. 1).
RESULTS AND DISCUSSION
The preparation of the target compounds is straightforward if certain
precautions are considered. Acidic conditions in the workup of all com-
pounds must be avoided because of the ease at which THP ethers are

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Oxidation of Monotetrahydropyranylated Diols
3245
Figure 1. Oxidation of monotetrahydropyranylated short-chain primary diols
to aldehydes. a: monoprotected diol (20 mmol), PDC (30 mmol), anhydrous
MgSO (50 mmol), CH Cl ( 100 mL to prepare 1 or 2, 300 mL to prepare 3).
4
2
2
For conditions and workup, see EXPERIMENTAL. The structure of 3-(tetra-
hydro-pyran-2-yloxy)-propionic acid 3-(tetrahydro-pyran-2-yloxy)-propyl ester
(
4), the by-product formed in the preparation of 3, is also shown.
[11]
cleaved.
Even workup procedures that employ chromatographic
purification on ordinary silica gel should be avoided because of the slightly
acidic conditions encountered. The solvent was sufficiently dried by adding
anhydrous MgSO to a freshly opened bottle of CH Cl because it was
4
2
2
found that drying the solvent by distillation from CaH and storage over
2
CaH was not necessary for this reaction. Anhydrous MgSO also served
2
4
to remove water, formed as a byproduct of the reaction. The use of freshly-
activated molecular sieves was not necessary to remove the water.
The conversion of 4-(tetrahydro-pyran-2-yloxy)-butan-1-ol to
4-(tetrahydro-pyran-2-yloxy)-butyraldehyde (1) and 5-(tetrahydro-
pyran-2-yloxy)-pentan-1-ol to 5-(tetrahydro-pyran-2-yloxy)-pentanal (2)
resulted in only minor amounts of polar side products, which were
observed as earlier-eluting broad peaks by GC analysis. These bypro-
ducts and small amounts of unreacted starting material were conveniently
removed by washing with a slightly-alkaline buffer solution (pH 8.6).
Isolated yields are generally moderate (ca. 50–60%) due to some loss
of product in the workup.

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3
246
Petroski
Isolation of the desired products resulted in 1 and 2 with purities of 97
and 94%, respectively. The major impurity was 2% of the di-THP ether of
the diol, originally contained in the momoprotected diol starting material.
The synthetic product can be used directly in chain-elongation or similar
reactions, without further purification, because di-THP ethers of diols are
chemically inert to subsequent reactions involving the free aldehyde func-
tion. The diprotected diol impurity can be removed at the deprotection
stage of the synthetic pathway because 1,4-butanediol and 1,5-pentanediol
will be washed away if an aqueous extractive workup is used.
Similar polar byproducts were not observed in the conversion of 3-
tetrahydro-pyran-2-yloxy)-propan-1-ol to 3-(tetrahydro-pyran-2-yloxy)-
(
propionaldehyde (3). The aqueous bufferwash was omitted in the
workup of 3 because it was not required and the compound has
enough water solubility to be partially lost in such a workup. The yield
of the reaction improved to 71%.
The formation of a different side product was observed in the
preparation of 3 (Fig. 1). This side product was tentatively identified as
3-(tetrahydro-pyran-2-yloxy)-propionic acid 3-(tetrahydro-pyran-2-
yloxy)-propyl ester (4) on the basis of late GC/MS elution time relative
to 3 (22.28 min vs. 9.87 min) and mass spectral evidence: MS m/z (% base)
þ
315 (M -1, 0.2), 231 (12), 215 (4), 131 (21), 113 (50), 101 (10), 85 (100).
The formation of dimeric esters in the oxidation of alcohols by PDC has
[
8,12]
been observed previously.
Preparation of 3 by the original method of
[3]
Corey and Schmidt resulted in the formation of as much as 30% of the
unwanted side product 4. The amount of the side product was reduced to
about 2% by using a dilute solution of PDC in CH Cl . and anhydrous
2
2
MgSO as a waterscavanger.
4
Isolation of the desired product resulted in 3 with a yield of 71% and
purity of 91%. The major impurity was about 5% of the di-THP ether of
the diol, originally contained in the momoprotected diol starting mate-
rial. The diprotected diol impurity can be removed at the deprotection
stage of the synthetic pathway because 1,3-propanediol will be washed
away if an aqueous extractive workup is used. The other impurity was
about 2% of the dimeric ester 4. Since compound 3 is known to be labile
[
10]
and was previously used in a Grignard reaction without purification,
the synthetic 3 prepared by this method should be sufficient for use in
similar reactions without further purification.
In summary, reliable methods for the oxidation of the free hydroxyl
functions of monotetrahydropyranylated three- to five-carbon symmet-
rical primary diols have been developed, without cleavage of the protec-
tive group. The compounds are very useful three- to five-carbon
homologating agents foruse in chain-elongation orsimilar re actions.

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Oxidation of Monotetrahydropyranylated Diols
EXPERIMENTAL
3247
General Details
Organic chemicals were purchased from Aldrich (Milwaukee, WI)
unless otherwise stated. Aqueous bicarbonate pH 8.6 buffer was prepared
by adding 8.4 g NaHCO (100 mmol) and 1.38 g K CO (10 mmol) to
3
2
3
200 mL of water.
Preparation of 4-(tetrahydro-pyran-2-yloxy)-butyraldehyde (1). To a
L Erlenmeyer flask were added CH Cl (100 mL), 4-(tetrahydro-
1
pyran-2-yloxy)-butan-1-ol (3.48 g, 20 mmol), anhydrous MgSO (6.0 g,
2
2
4
50 mmol), and 11.6 g (30 mmol) of pyridinium dichromate (PDC). The
flask was purged with argon, stoppered and the reaction mixture was
ꢀ
magmetically stirred at 25 C forca. 48 h until GC/MS analysis indicated
that the reaction was complete. The reaction was terminated by the addi-
tion of hexane (300 mL), which caused the precipitation of unreacted
PDC. The mixture was filtered and the filter cake was washed with
25% diethyl etherin hexane (100 mL). The light o ar nge-tan solution
was concentrated in vacuo to about 150 mL. A dark precipitate formed
during the solvent concentration process. The mixture was filtered and
the filtercake was washed with hexane (50 mL). The solution was
decanted to a 500 mL separatory funnel and washed with aqueous bicar-
bonate pH 8.6 buffer(2 Â 25 mL) to remove polar impurities, that had an
earlier GC retention time than the product. The aqueous washings were
back-extracted with hexane (2 Â 25 mL). The hexane back-extractions
were combined, washed once with the pH 8.6 buffer (5 mL) and combined
with the previous hexane extracts. The solution was dried over anhydrous
Na SO . After removal of the drying agent by filtration, the solvent was
2
4
evaporated, in vacuo, and then residual pyridine was removed by increas-
ꢀ
ing the bath temperature to 35 C to give 1 as a give a pale yellow oil
(
(
1.77 g, 50% yield). The purity of 1 was checked by gas chromatography
GC) and found to be >94%. The majorimpu ri ty was about 2% of the
diprotected (THP) butanediol originally present in the starting material.
þ
Compound 1 spectral data: MS m/z (% base) 171 (M -1, 0.07), 101 (15),
0 0 0
1
5 (77), 71 (100). H NMR ꢀ 1.50–1.93 (8H, m, H-3, 3 , 4 , 5 ), 2.52 (2H,
8
dt, J2-3 ¼ 7.1 and J ¼ 1.7, H-2), 3.40 (1H, dt, J
¼ 9.8 and J ¼ 6.1,
3–4
1–2
4a–4b
3–4
0
H-4), 3.50 (1H, m, H-6 eq), 3.76 (1H, dt, J
¼ 9.8 and J ¼ 6.1, H-4),
4
a–4b
0
0
3
.82 (1H, m, H-6 ax), 4.56 (1H, m, H-2 ), 9.78 (1H, t, J ¼ 1.7, H-1).
1
–2
0
1
3
0
0
C NMR ꢀ 19.3 (C-4 ), 22.5 (C-3), 25.0 (C-5 ), 30.6 (C-3 ), 41.0 (C-2),
0
0
62.1 (C-6 ), 66.2 (C-4), 98.8 (C-2 ), 202.3 (C-1).
Preparation of 5-(tetrahydro-pyran-2-yloxy)-pentanal (2). A similarp re -
paration from 5-(tetrahydro-pyran-2-yloxy)-pentan-1-ol (3.48 g, 20 mmol)

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3
248
Petroski
gave 2 as a pale yellow oil (2.08 g, 56% yield). Purity was checked by gas
chromatography (GC) and found to be >94% 2. The majorimpu ri ty was
about 2% of the diprotected (THP) pentanediol originally present in the
þ
starting material. Compound 2 spectral data: MS m/z (% base) 186 (M ,
0
1
.1), 101 (27), 85 (100), 67 (31), 57 (32). H NMR ꢀ 1.50–1.93 (10H,
0
0
0
m, H-3, 4, 3 , 4 , 5 ), 2.46 (2H, dt, J ¼ 7.1 and J ¼ 1.7, H-2), 3.38
2
–3
1–2
(
1H, dt, J5a–5b ¼ 9.8 and J ¼ 6.2, H-5), 3.49 (1H, ddd, J
4–5
0 0
6 ax–6 ’eq
¼ 11.2,
¼ 9.8
0
J5
0
0
¼ 6.8 and J
0
0
¼ 3.9, H-6 eq), 3.74 (1H, dt, J
ax–6 eq
5 eq–6 eq
5a–5b
and J4–5 ¼ 6.3, H-5), 3.83 (1H, ddd, J
0
0
¼ 11.2, J
0 0
5 ax–6 ax
¼ 7.0 and
6 ax–6 eq
0
0
J
0
0
¼ 3.7, H-6 ax), 4.56 (1H, m, H-2 ), 9.78 (1H, t, J ¼ 1.7, H-1).
1–2
5
eq–6 ax
1
3
0
0
0
C NMR ꢀ 18.8 (C-3), 19.5 (C-4 ), 25.3 (C-5 ), 29.4 (C-4), 30.5 (C-3 ),
0
0
4
3.5 (C-2), 62.2 (C-6 ), 66.8 (C-5), 98.7 (C-2 ), 202.5 (C-1).
Preparation of 3-(tetrahydro-pyran-2-yloxy)-propionaldehyde (3). To a
L Erlenmeyer flask was added CH Cl (300 mL), 3-(tetrahydro-pyran-2-
yloxy)-propan-1-ol (3.48 g, 20 mmol), anhydrous MgSO (6.0 g, 50 mmol),
1
2
2
4
and PDC (11.6 g, 30 mmol). The flask was purged with argon, stoppered
ꢀ
and the reaction mixture was magnetically stirred at 25 C forca . 48 h until
GC/MS analysis indicated that the reaction was complete. The reaction
was terminated by the addition of hexane (900 mL), which caused the
precipitation of unreacted PDC. The mixture was filtered and the filter
cake was washed with 25% diethyl etherin hexane (100 mL). The light
orange-tan solution was concentrated in vacuo to about 150 mL. A dark
precipitate formed during the solvent concentration process. The mixture
was filtered and the filter cake was washed with hexane (50 mL). The
nearly colorless hexane solution, containing the desired product, was
dried over anhydrous Na SO . After removal of the drying agent by filtra-
2
4
tion, the solvent and pyridine were evaporated in vacuo (bath temp. raised
ꢀ
to 35 C to remove residual pyridine) to give 3 as a pale yellow oil (2.52 g,
71% yield). Purity was checked by gas chromatography (GC) and found
to be >91% 3. The product contained two impurities. The first impurity
was about 5% of the diprotected (THP) propanediol, originally present in
the batch of starting material used in this preparation. The second impu-
rity was about 2% of a dimeric ester 4, tentatively identified on the basis of
mass spectral data (see below). Compound 3 spectral data: MS m/z (%
þ
þ
0
1
base) 158 (M , 0.3), 157 (M -1, 3), 101 (61), 85 (100), 57 (62). H NMR ꢀ
0
0
1
3
(
.47–1.67 (6H, m, H-3 , 4 , 5 ), 2.67 (2H, dt, J ¼ 6.0 and J ¼ 1.8, H-2),
2
-3
1–2
0
.49 (1H, m, H-6 eq), 3.73 (1H, dt, J
¼ 10.3 and J ¼ 6.0, H-3), 3.82
2–3
3
a–3b
2–3
0
1H, m, H-6 ax), 4.07 (1H, dt, J
0
¼ 10.3 and J ¼ 5.9, H-3), 4.56 (1H,
3
a–3b
13
0
0
m, H-2 ), 9.78 (1H, t, J ¼ 1.8, H-1). C NMR ꢀ 19.2 (C-4 ), 25.2 (C-5 ),
1
–2
0
0
0
30.3 (C-3 ), 43.7 (C-2), 61.0 (C-3), 62.1 (C-6 ), 98.8 (C-2 ), 201.2 (C-1).
Dimeric ester 4 mass spectral data: MS m/z (% base) 315 (M -1, 0.2),
þ
231 (12), 215 (4), 131 (21), 113 (50), 101 (10), 85 (100).

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Oxidation of Monotetrahydropyranylated Diols
Analysis of Reaction Products
3249
All reactions were monitored by GC using a Hewlett-Packard (HP)
890 Series II instrument equipped with a split/splitless inlet, flame ioni-
zation detectorand inte fr aced to a HP ChemStation data system. The
5
ꢀ
ꢀ
oven temperature was programmed from 50 to 250 C at 10 C/min; the
ꢀ
programmable cool on-column inlet temperature was always 3 C hotter
ꢀ
than the oven temperature and the detector temperature was 250 C. A
DB-5 capillary column (30 m  0.25 mm ID, 0.25 mm film thickness, J&W
Scientific, Folsom, CA) was used with 1 mL sample injections.
Electron impact mass spectra (70 eV) were obtained with an HP 5973
MSD instrument, equipped with a splitless injector. The oven tempera-
ꢀ
ꢀ
ture was programmed from 50 to 250 C at 10 C/min; the injector
ꢀ
ꢀ
temperature was 250 C and the detector temperature was 250 C. An
EC-1 capillary GC column (30 m  0.25 mm, 0.25 mm film thickness,
Alltech, Deerfield, IL) was used with 0.3 mL sample injections.
H NMR, C NMR, and 2D NMR spectra (CDCl ) were obtained on
a Bruker (Bellerica, MA) Advance 400 spectrometer at 400-MHz.
Chemical shifts are referenced to tetramethylsilane; coupling constants
1
J ) are in hertz. Assignments were made with the help of H- and
1
13
3
(
1
3
[13]
C-predictive software.
ACKNOWLEDGMENTS
I thank Bruce W. Zilkowski and Robert J. Bartelt for acquiring
mass spectral data, David Weisleder for acquiring NMR spectra, and
Robert J. Bartelt for helpful discussions.
REFERENCES
1
. Petroski, R.J. Preparation of monotetrahydropyranylated short-
chain symmetrical diols. Synth. Commun. 2003, 33 (18), 3251–3259.
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2
3
1979, 399–402.
4. Herscovici, J.; Antonakis, K. Molecular sieve-assisted oxidations:
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©
2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
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Received in the USA March 18, 2003

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