Radical deoxygenation of alcohols and vicinal diols with N-ethylpiperidine hypophosphite in water

Article abstract of DOI:10.1016/S0040-4039(02)01247-9

Radical deoxygenation of alcohols and vicinal diols with N-ethylpiperidine hypophosphite both in alcohols and in water is described. S-Methyl dithiocarbonate and bis-S-methyl dithiocarbonate of carbohydrates and nucleosides were deoxygenated efficiently under reaction conditions.

Full text of DOI:10.1016/S0040-4039(02)01247-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 5921–5924
Radical deoxygenation of alcohols and vicinal diols with
N-ethylpiperidine hypophosphite in water
Doo Ok Jang* and Dae Hyan Cho
Department of Chemistry, Yonsei University, Wonju 220-710, Republic of Korea
Received 1 June 2002; accepted 28 June 2002
Abstract—Radical deoxygenation of alcohols and vicinal diols with N-ethylpiperidine hypophosphite both in alcohols and in
water is described. S-Methyl dithiocarbonate and bis-S-methyl dithiocarbonate of carbohydrates and nucleosides were deoxy-
genated efficiently under reaction conditions. © 2002 Elsevier Science Ltd. All rights reserved.
8
Radical deoxygenation of alcohols is a very important
reaction for preparing polyfunctionalized compounds
such as biologically important carbohydrates and
reported in the literature recently, works on radical
6,9
reactions in water are relatively rare.
1
nucleoside derivatives. Although various methodolo-
There have been research efforts in which alcohols were
used to reduce the toxicity of the solvent employed in
the radical deoxygenation of alcohols with hypophos-
phorous acid. However, there is no report on water
being used as a sole solvent in radical deoxygenation of
alcohols. As part of our ongoing effort to expand the
gies for deoxygenation of alcohols have been reported,
the Barton–McCombie reaction is the most suitable for
2
7
this purpose. It affords mild reaction conditions in
which sensitive polyfunctionalized molecules can
remain intact.
6
a,c
synthetic utility of hypophosphorous acid in water,
Organotin hydrides, especially tributyltin hydride, have
played a major role as hydrogen sources and radical
we are reporting the results of deoxygenation of alco-
hols and vicinal diols that has been accomplished
efficiently with N-ethylpiperidine hypophosphite
3
chain carriers in radical reactions. It is well known,
however, that organotin compounds are toxic, expen-
sive, and difficult to remove from the desired end
products. Therefore, the use of organotin hydrides is
not suitable for synthesizing drugs and medicines. Sev-
eral attempts have been made to find ideal alternatives
(
EPHP) in water.
We chose S-methyl dithiocarbonate of cyclododecanol
for a model compound and investigated optimal reac-
tion conditions for the deoxygenation of alcohols
Table 1). Treatment of S-methyl dithiocarbonate of
cyclododecanol with EPHP and Et B in MeOH at
room temperature produced cyclododecane in 89%
yield. No new thiocarbonate by-product was detected
from competing hydrolysis of thiocarbonates (entry
). When the reaction was carried out in aqueous
methanol (MeOH:H O, 1:1) at room temperature, half
of the starting material remained even after being
stirred for 10 h (entry 2). The observation implies that
solubility of the substrates is the main factor in obtain-
ing high yields of the desired products in this reaction.
It is presumed that a phase–transfer agent is necessary
to improve the solubility of the substrate in water. The
reaction of S-methyl dithiocarbonate of cyclododecanol
with EPHP in water in the presence of a phase-transfer
agent, cetyltrimehtylammonium bromide (CTAB), and
4
to organotin hydrides. Among them, hypophospho-
(
rous acid has proven to be the most promising substi-
tute for organotin hydrides in various radical reactions
from the viewpoints of cost-effectiveness, toxicity, and
3
5–7
work-up process.
10
1
Water is a very attractive solvent in organic reactions as
it is economic, safe, and shows unique solvent effects.
Although various organic reactions in water have been
2
Keywords: radical reactions; deoxygenation; alcohol; N-ethylpipe-
ridine hypophosphite.
*
Corresponding author. Tel.: +82-33-760-2261; fax: +82-33-760-2182;
e-mail: dojang@dragon.yonsei.ac.kr
0
040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01247-9

5
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D. O. Jang, D. H. Cho / Tetrahedron Letters 43 (2002) 5921–5924
Table 1. Deoxygenation of O-cyclododecyl S-methyl dithiocarbonate with EPHP (10 equiv.)
Entry
Solvent
MeOH
Initiator (equiv.)
CTAB (equiv.)
Temp (°C)
Time (h)
Yield (%)
89
1
2
3
4
5
Et B (10)
0
0
2
2
0
rt
rt
rt
80
80
2.4
10
10
8
3
a
MeOH/H O, 1:1
Et B (10)
48 (49)
2
3
H O
Et B (10)
42 (37)a (19)b
2
3
H O
ABCVA (0.75)
AlBN (1.0)
73
0
2
H O
2
8
a
Yields in parentheses are for the recovered starting material.
The corresponding alcohol was obtained.
b
an initiator, Et B, provided a moderate yield of the
deoxy product along with 19% of the corresponding
derivatives for preparation of 2%,3%-dihydro-2%,3%-
12
3
dideoxynucleosides that are potent anti-HIV agents.
3
alcohol (entry 3). It is assumed that Et B played a
The bis-S-methyl dithiocarbonate of an N -methyl-
uridine derivative was subjected to the radical reac-
tion in water at 80°C, which produced the corre-
sponding olefin in 95% yield (entry 6). A similar
result was obtained with an adenosine derivative
(entries 7–8).
3
role as a Lewis acid hydrolyzing the substrate.
Enhancement of solubility of the substrate was also
limited at room temperature giving 37% of the recov-
ered starting material. We finally optimized the reac-
tion conditions for deoxygenation of alcohols in
water, using CTAB for a surfactant and 4,4%-azobis(4-
cyanovaleric acid) (ABCVA), a water-soluble initiator,
at 80°C affording high yield of the deoxy product
Table 2. Deoxygenation of various alcohols via their S-
methyl dithiocarbonate derivatives with EPHP (5 equiv.)
(
entry 4). In the absence of the phase-transfer
reagent, the reaction in water at 80°C gave cyclodo-
decanol, the hydrolyzed product, without giving the
deoxy product (entry 5).
in the presence of CTAB (2 equiv.) in H O at 80°C
2
S
EPHP, CTAB
R O C SMe
R H
The reaction was applied to the deoxygenation of a
series of substrates (Table 2). A high yield of the
deoxy product was obtained from S-methyl dithiocar-
bonate of a secondary alcohol (entry 1). The carbohy-
drate derivative was also a good substrate for the
reaction (entry 2), while the hydrophobic steroid
derivative gave a low yield of deoxy product accom-
panied with the recovered starting material (entry 3),
although the reaction in EtOH proceeded efficiently
o
ABCVA, H2O, 80 C
Entry
Substrate
ABCVA Time Yield
(
equiv) (h)
(%)
88
S
C
SMe
O
1
2
0
.75
9
9
CH3CH(CH2)8CH3
S
(
entry 4). S-Methyl dithiocarbonate of tertiary alco-
O
C
SMe
hol was readily hydrolyzed under the conditions to
generate the corresponding alcohol (entry 5).
O
O
O
0.75
81
O
O
We next applied our method to transform vicinal
diols into corresponding olefins with EPHP, which
has been possible only by adding an excessive amount
of terminal olefins to prevent phosphorus radical
28(70)a
3
4
1
.0
12
1
5b,11
from being added to the product olefin (Table 3).
O
The conversion of the bis-S-methyl dithiocarbonate of
cyclododecan-1,2-diol into cyclododecene in water was
accomplished efficiently in the absence of extra termi-
nal olefins (entry 1). The reaction was also performed
in EtOH at room temperature with efficiency (entry
-b
S
SMe
91
S
14(75)c
5
O C SMe 0.5
5
2
). The bis-S-methyl dithiocarbonate of
D
-mannitol
aYields in parentheses are for the recovered
and a- -glucose derivatives were converted smoothly
D
b
starting material. Reaction was carried out in EtOH
into the corresponding olefins in high yields under
reaction conditions (entries 3–5). The reaction was
also applicable to dideoxygenation of nucleoside
c
with Et3B (5 equiv) at room temperature. The
corresponding alcohol, hydrolyzed product.

D. O. Jang, D. H. Cho / Tetrahedron Letters 43 (2002) 5921–5924
5923
Table 3. Synthesis of olefins from bis-S-methyl dithiocar-
bonates of vicinal diols with EPHP (10 equiv.) in H O in
the presence of CTAB (2 equiv.) at 80°C
Acknowledgements
2
12
This work was supported by grant (R05-2002-000-
00036-0) from the basic research program of the Korea
Science and Engineering Foundation.
S
C
S
EPHP, CTAB
ABCVA, H2O,
R'
MeS
O
R
O C SMe
R
o
R'
80 C
Entry
Substrate
ABCVA Time Yield
(
equiv) (h)
(%)
References
S
C
1
. (a) Hartwig, W. Tetrahedron 1983, 39, 2609; (b) Mother-
well, W. B.; Crich, D. Free Radical Chain Reactions in
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Perkin Trans. 1 1975, 1574.
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Dickhaut, J.; Thoma, G.; Kulicke, K. J.; Trach, F. Org.
React. 1996, 48, 301.
1
2
0.75
8
92
O
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C
S
-a
1.5
71
2
3
S
3
4
0.75
-a
9
3
85
79
O
O
C SMe
O
O
O
MeS
C O
S
4. For recent reviews: (a) Baguley, P. A.; Walton, J. C.
Angew. Chem., Int. Ed. Engl. 1998, 37, 3072; (b) Studer,
A.; Amrein, S. Synthesis 2002, 835.
S
O C SMe
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Tetrahedron Lett. 1992, 33, 5709; (b) Barton, D. H. R.;
Jang, D. O.; Jaszberenyi, J. C. J. Org. Chem. 1993, 58,
O
5
0.75
8
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Ph
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OMe
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MeS
6
838; (c) McCague, R.; Pritchard, R. G.; Stoodley, R. J.;
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Kaburagi, Y.; Fukuyama, T. J. Am. Chem. Soc. 1999,
21, 3791; (e) Graham, S. R.; Murphy, J. A.; Coates, D.
S
O
2
N
N
1
N
O
TBDMSO
MeS
6
O
0.75
9
95
Tetrahedron Lett. 1999, 40, 2415; (f) Graham, S. R.;
Murphy, J. A.; Kennedy, A. R. J. Chem. Soc., Perkin
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hedron Lett. 2000, 41, 247; (h) Concepcion, G. M.; Mur-
phy, J. A.; Christopher, R. S. Tetrahedron Lett. 2000, 41,
C
S
O
O
C
SMe
S
NH2
N
1833; (i) Takamatsu, S.; Katayama, S.; Hirose, N.; Naito,
7
8
N
1.25
15
58
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M.; Izawa, K. Tetrahedron Lett. 2001, 42, 7605; (j) Jang,
D. O.; Cho, D. Y.; Chung, C.-M. Synlett 2001, 1923.
N
TBDMSO
MeS
N
O
-a
6. (a) Jang, D. O. Tetrahedron Lett. 1996, 37, 5367; (b) Kita,
Y.; Nambu, H.; Ramesh, N. G.; Anikumar, G.; Matsugi,
M. Org. Lett. 2001, 3, 1157; (c) Jang, D. O.; Cho, D. Y.
Synlett 2002, 631.
2
C
S
O
O
C
S
SMe
aReaction was carried out in EtOH with Et3B (5 equiv)
at room temperature.
7
. (a) Graham, A. E.; Thomas, A. V.; Yang, R. J. Org.
Chem. 2000, 65, 2583; (b) Yorimitsu, H.; Shinokubo, H.;
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8
. (a) Li, C.-J.; Chan, T.-H. Organic Reactions in Aqueous
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Grieco, P. A. Organic Synthesis in Water; Blackie Aca-
demic and Professional: London, 1998; (c) Lubineau, A.;
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Knochel, P., Ed.; Springer-Verlag: Berlin, 1999.
In conclusion, we have developed a useful radical pro-
cess for deoxygenation and dideoxygenation of various
alcohols in water or in non-toxic alcohol. It is worth
noting that dideoxygenation of bis-S-methyl dithiocar-
bonate of vicinal diols with EPHP can be accomplished
without adding terminal olefins. The reagents and sol-
vents used in this reaction are non-toxic and inexpen-
sive. The reaction can also be carried out under mild
reaction conditions, and it offers an easy work-up
process. Therefore, the process can be used economi-
cally for deoxygenation of various alcohols on a large
scale.
9
. (a) Minisci, F. Synthesis 1973, 1; (b) Breslow, R.; Light,
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5
924
D. O. Jang, D. H. Cho / Tetrahedron Letters 43 (2002) 5921–5924
n
1
1
0. The reaction in refluxing PrOH gave a solvolysis product
tion of 1,2:5,6-di-O-isopropylidene-3,4-bis-O-[(S-methyl-
thio)thiocarbonyl]- -mannitol (110 mg, 0.25 mmol),
of starting thionocarbonate (Ref. 7a).
1. (a) Typical reaction procedure for dideoxygenation of
vicinal diols in water: A solution of 1,2:5,6-di-O-iso-
D
EPHP (446 mg, 2.49 mmol) and Et B (1.25 mL, 1.25
3
mmol, 1 M solution in THF) in degassed EtOH (5 mL)
was added air (10 mL/h) at room temperature with
syringe pump until the reaction was completed by TLC.
The reaction mixture was diluted EtOAc, then washed
propylidene-3,4-bis-O-[(S-methylthio)thiocarbonyl]-D-
mannitol (98 mg, 0.22 mmol), EPHP (397 mg, 2.22
mmol) and CTAB (162 mg, 0.44 mmol) in degassed water
(5 mL) under argon was treated with ABCVA (20 mg,
with water, dried over anhydrous MgSO , and evapo-
4
0
.06 mmol) three times (3 h interval) at 80°C. After the
rated the solvent in vacuo. The residue was purified by
flash column chromatography over silica gel (hexane/
EtOAc, 9:1) to give 1,2:5,6-di-O-isopropylidene-hex-3-
reaction was completed, the reaction mixture was diluted
EtOAc, then washed with water, dried over anhydrous
MgSO , and evaporated the solvent in vacuo. The residue
(E)-ene-D-threo-1,2:5,6-tetraol (45 mg, 79%).
4
was purified by flash column chromatography over silica
gel (hexane/EtOAc, 9:1) to furnish 1,2:5,6-di-O-isopropy-
12. (a) Chu, C. K.; Bhadti, V. S.; Doboszewski, B.; Gu, Z.
P.; Kosugi, Y.; Pullaiah, K. C.; Van Roey, P. J. Org.
Chem. 1989, 54, 2217; (b) Palmer, S.; Russell, J. D.;
Pallansch, L. A.; Driscoll, J. S.; Buckheit, R. W., Jr.
Antiviral Res. 1999, 41, LB4.
lidene-hex-3-(E)-ene-
b) Typical reaction procedure for dideoxygenation of
vicinal diols in alcohol at room temperature: To a solu-
D-threo-1,2:5,6-tetraol (44 mg, 85%).
(