Radical deoxygenation of alcohols and intermolecular carbon-carbon bond formation with surfactant-type radical chain carriers in water

Article abstract of DOI:10.1016/j.tetlet.2005.01.107

An efficient and mild method is developed for radical deoxygenation of alcohols and formation of carbon-carbon bonds in water without adding additives such as surfactants. The reaction was applied to synthesis of 2′,3′-didehydro-2′,3′-dideoxynucleosides that are potent anti-HIV agents. The reaction afforded environmentally benign reaction conditions.

Full text of DOI:10.1016/j.tetlet.2005.01.107

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 1799–1802
Radical deoxygenation of alcohols and intermolecular
carbon–carbon bond formation with surfactant-type radical
chain carriers in water
a
Dae Hyan Cho and Doo Ok Jang
a,b,
*
a
Department of Chemistry, Yonsei University, Wonju 220-710, Republic of Korea
Center for Bioactive Molecular Hybrids, Yonsei University, Seoul 120-749, Republic of Korea
b
Received 6 January 2005; revised 20 January 2005; accepted 24January 2005
Abstract—An efficient and mild method is developed for radical deoxygenation of alcohols and formation of carbon–carbon bonds
0
0
0
0
in water without adding additives such as surfactants. The reaction was applied to synthesis of 2 ,3 -didehydro-2 ,3 -dideoxynucleo-
sides that are potent anti-HIV agents. The reaction afforded environmentally benign reaction conditions.
Ó 2005 Elsevier Ltd. All rights reserved.
5
Applications of radical reactions in organic synthesis
have attracted much attention in the area of new car-
bon–carbon bond formation and modification of poly-
functionalized compounds in recent years because they
afford neutral reaction conditions in which sensitive
developed, it is quite difficult to accomplish radical
reactions in water without using organic co-solvents.
Reactions reported in the literature in fully water re-
6
quired a surfactant, which may form a micellar system
to obtain high yields of the desired products. Herein, we
report on radical deoxygenation of alcohols and inter-
molecular carbon–carbon bond formation with a surfac-
tant-type radical chain carrier in water.
1
polyfunctionalized molecules can remain intact.
n
Organotin hydrides, especially Bu SnH, have been
3
widely employed in radical reactions. It is notorious,
however, that organotin hydrides are toxic, expensive,
and difficult to remove, and that they often contaminate
products. These reasons have limited the use of organo-
tin hydrides in industrial applications. Research effort
on finding ideal alternatives to organotin hydrides has
Tetraalkylammonium hypophosphites (TAHPs) were
readily prepared by mixing the corresponding tetraalkyl-
ammonium hydroxide with aqueous H PO (Table 1).
3
2
We then examined the reactivity of the prepared TAHPs
as radical chain carriers as well as surfactants. O-
Cyclododecyl-S-methyl dithiocarbonate (1a) has been
chosen as the model compound. The reaction of the xan-
thate 1a with TAHP-1 in the presence of water-soluble
2
been made. And it has been found that phosphorus hy-
drides are efficient substitutes for organotin hydrides in
radical reactions from the viewpoints of cost-effective-
3
0
ness, toxicity, and work-up process.
radical initiator, ABCVA (4,4 -azobis(4-cyanovaleric
acid)), in water yielded 94% of the deoxy product 1b
Recently, water has drawn considerable attention as a
4
reaction solvent in organic synthesis. Compared with
organic solvents generally used for organic reactions,
water is cheap, safe, and environmentally benign show-
ing unique solvent effects. Although radical reactions,
which were performed in aqueous media have been
Table 1. Synthesis of tetraalkylammonium hypophosphites
O
P
H
O
P
H
1
0 min
M
OH + HO
H
M
O
H
rt
+
M
Product
þ
ðCH3Þ N ðCH2Þ15CH3
TAHP-1
TAHP-2
TAHP-3
TAHP-4
3
+
Keywords: Radical water; Phosphorus hydride; Deoxygenation; Sur-
factant; C–C bond formation.
4
Bu N
þ
Bu3N CH3
*
Corresponding author. Tel.: +81 337602261; fax: +81 337602208;
e-mail: dojang@dragon.yonsei.ac.kr
+
(
3 4
CH ) N
0
040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.01.107

1800
D. H. Cho, D. O. Jang / Tetrahedron Letters 46 (2005) 1799–1802
Table 2. Deoxygenation of O-cyclododecyl S-methyl dithiocarbonate
O
Table 4. Deoxygenation of various alcohols via S-methyl dithiocar-
bonate derivatives with TAHP-1 in H
O at 100 °C
with tetraalkylammonium hypophosphites in H
2
2
S
C
Entry Substrate TAHP-1 ABCVA Time Product Yield
a
O
SMe
ABCVA
(equiv)
(equiv)
(h)
(%)
+
TAHP
H O, 100 oC
2
1
2
3
4
5
6
2a
3a
4a
5a
6a
7a
3
3
3
3
3
3
0.5
0.5
0.75
0.5
0.5
0.5
5
7
2b
3b
4b
5b
6b
7b
90
88
7
1
a
1b
12
7
a
80
82
76
Entry TAPH (equiv) ABCVA (equiv) Time (h) Yield (%)
6
1
2
3
4
5
TAHP-1 (3)
TAHP-1 (2)
TAHP-2 (3)
0.5
0.5
5
8
7
94
84
90
6
a
Isolated yields.
0.75
b
b
TAHP-3 (3)
0.75
8
62 (29)
45 (52)
TAHP-4(3)
0.75
8
tive 5a was converted into the corresponding dideoxy
product 5b in 80% yield (entry 4). Then, the reaction
a
Isolated yields.
Recovered starting material.
b
0
0
0
0
was applied to synthesis of 2 ,3 -didehydro-2 ,3 -dide-
oxynucleosides that are potent anti-HIV agents. The
bis-xanthate of N -methyluridine derivative 6a was sub-
3
after 5 h (Table 2, entry 1). With TAHP-2, 90% of the
deoxy product 1b was obtained (entry 3). It is notewor-
thy that radical deoxygenation of alcohols is possible to
perform in water without adding external additives such
as surfactants. We performed the reaction with TAHPs
having short alkyl chains such as TAHP-3 and TAHP-4
giving moderate yields of the deoxy product with the
recovered starting material (entries 4and 5). The longer
the alkyl chains are, the more efficient TAHPs are as
radical chain carriers in water. As expected, the long
alkyl chain promoted the solubility of the substrates
and the formation of a micellar system to accelerate
the reaction.
jected to the radical reaction conditions in water, which
gave the corresponding olefin 6b in 82% yield (entry 5).
A similar result was obtained with an adenosine deriva-
tive 7a (entry 6).
O
O
R
R
O
CH CH(CH ) CH
3
2 9
3
O
O
2a : R = O(C=S)SMe
b : R = H
2
3a : R = O(C=S)SMe
b : R = H
3
R
O
O
To find out the most suitable initiator, we screened a
series of water-soluble radical initiators. ABCVA
were found to be the most effective initiator among the
initiators we employed (Table 3).
Ph
OMe
R
O
R
4
a : R = O(C=S)SMe
b : R = H
5
a : R = O(C=S)SMe
4
We then investigated the generality of the deoxygen-
ation of alcohols using TAHP-1 and ABCVA, which
was the most efficient conditions. Under these condi-
tions, xanthate derivatives of secondary alcohols, 2a
and 3a were readily transformed into the deoxy products
O
O
N
O
Ph
TBDMSO
N
O
OMe
O
O
8
in high yields (Table 4, entries 1 and 2). Hydrophobic
5b
O
N
substrate such as cholestanyl derivative 4a gave poor
yield (entry 3). Next, we performed the dideoxygenation
of bis-xanthates. The bis-xanthate of a-D-glucose deriva-
R
R
CH3
N
6
a : R = O(C=S)SMe
TBDMSO
O
NH2
O
N
N
TBDMSO
N
Table 3. Deoxygenation of O-cyclododecyl S-methyl dithiocarbonate
with TAHP-1 in boiling H O in the presence of various radical
initiators
N
6
b
O
2
R
R
b
a
Entry
Initiator
Time (h)
Yield (%)
NH2
7a : R = O(C=S)SMe
1
2
3
ABCVA
VA-057
V-50
5
94
20
15
N
N
N
8
TBDMSO
8
N
O
4
5
VA-061
8
21
24NR
c
V-70
a
7b
Isolated yields.
0
b
0
ABCVA = 4,4 -azobis(4-cyanovaleric acid), VA-057 = 2,2 -azobis[N-
0
(2-carboxyethyl)-2-methylpropionamidine], V-50 = 2,2 -azobis(2-ami-
dinopropane) dihydrochloride, VA-061 = 2,2 -azobis(2-imidazolin-
0
To expand the utility of our methodology, we subse-
quently investigated radical carbon–carbon bond form-
ing reactions, which generally required a large excess
0
ylpropane), V-70 = 2,2 -azobis(2,4-dimethyl-4-methoxy valeronitrile).
At room temperature.
c

D. H. Cho, D. O. Jang / Tetrahedron Letters 46 (2005) 1799–1802
1801
Table 5. Radical addition reactions of alkyl iodides to phenyl vinyl
sulfone (3 equiv) with TAHP-1 (3 equiv) in the presence of ABCVA
surfactants to promote the reaction. The reagents used
for the reaction are non-toxic and inexpensive, and
the method offers mild and neutral reaction conditions
and an easy work-up process. Therefore, the reaction
may find an application in an environmentally benign
procedure in a large scale.
2
(0.25 equiv) in H O
TAHP-1. ABCVA
R
R
I
+
SO Ph
2
SO Ph
2
H O, 100 oC, 1 h
2
(
1 equiv) (3 equiv)
8
8
8
a: R = c-hexyl
i
b: R = Pr
c: R = (CH ) CO H
2
2
2
a
Acknowledgments
Entry
R
Product
Yield (%)
89
1
2
3
c-Hexyl
c-Hexyl
8a
8a
8b
8c
b
This work was supported by Korea Research Founda-
tion Grant (KRF-2003-002-C00155).
57
i
c
Pr
76
4
5
(CH
2
)
2
CO
2
H
1-Adamantyl
70
0 (70)
d
a
b
c
Isolated yields.
Using 1 equiv of phenyl vinyl sulfone.
References and notes
At 80 °C.
1. (a) Giese, B. Radicals in Organic Synthesis: Formation of
Carbon–Carbon Bonds; Pergamon: Oxford, 1986; (b) Cur-
ran, D. P. In Comprehensive Organic Synthesis; Trost, B.
M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 4, p
d
1-Adamantanol.
7
15; (c) Giese, B.; Kopping, B.; G o¨ bel, T.; Dickhaut, J.;
n
of alkenes to trap radicals when Bu SnH was em-
ployed. The reaction of 1 equiv of cyclohexyl iodide
with 3 equiv of vinylsulfone in the presence of TAHP-
Thoma, G.; Kulicke, K. J.; Trach, F. Org. React. 1996, 48,
301; (d) Motherwell, W.; Crich, D. Free Radical Chain
Reactions in Organic Synthesis; Academic: London, 1992.
. For recent reviews: (a) Baguley, P. A.; Walton, J. C. Angew.
Chem., Int. Ed. 1998, 37, 3072; (b) Studer, A.; Amrein, S.
Synthesis 2002, 835.
. (a) Barton, D. H. R.; Jang, D. O.; Jaszberenyi, J. C.
Tetrahedron Lett. 1992, 33, 5709; (b) Barton, D. H. R.;
Jang, D. O.; Jaszberenyi, J. C. J. Org. Chem. 1993, 58, 6838;
(c) McCague, R.; Pritchard, R. G.; Stoodley, R. J.;
Williamson, D. S. Chem. Commun. 1998, 2691; (d) Tokuy-
ama, H.; Yamashita, T.; Reding, M. T.; Kaburagi, Y.;
Fukuyama, T. J. Am. Chem. Soc. 1999, 121, 3791; (e)
Graham, S. R.; Murphy, J. A.; Coates, D. Tetrahedron
Lett. 1999, 40, 2415; (f) Graham, S. R.; Murphy, J. A.;
Kennedy, A. R. J. Chem. Soc., Perkin Trans. 1 1999, 3071;
3
7
2
3
1
8
and ABCVA in water produced the addition adduct
a in 89% yield (Table 5, entry 1). With 1 equiv of phe-
9
nyl vinyl sulfone, the yield was decreased to 57% (entry
). Similar results were obtained with isopropyl iodide
2
and 3-iodopropionic acid (entries 3 and 4). Tertiary
iodide was readily hydrolyzed to give alcohol under
these conditions (entry 5).
Next, we examined a series of alkenes to uncover the
reactivity as radical acceptors (Table 6). a,b-Unsatu-
rated ester, ketone, and nitrile were found to be good
radical acceptors affording high yields of addition
adducts. As expected, b-substituted alkene did not
proceed under these conditions.
(g) Jang, D. O.; Song, S. H. Tetrahedron Lett. 2000, 41, 247;
(h) Concepcion, G. M.; Murphy, J. A.; Christopher, R. S.
Tetrahedron Lett. 2000, 41, 1833; (i) Takamatsu, S.;
Katayama, S.; Hirose, N.; Naito, M.; Izawa, K. Tetrahe-
dron Lett. 2001, 42, 7605; (j) Jang, D. O.; Cho, D. Y.;
Chung, C.-M. Synlett 2001, 1923.
In conclusion, we have discovered that the combination
of surfactant-type radical chain carrier, TAHP, and
water-soluble radical initiator, ABCVA, is an ideal reac-
tion system to accomplish deoxygenation of alcohols
and carbon–carbon bond formation in water. This
method has no need to add external additives such as
4. (a) Li, C.-J.; Chan, T.-H. Organic Reactions in Aqueous
Media; Wiley: New York, 1997; (b) Grieco, P. A. Organic
Synthesis in Water; Blackie Academic & Professional:
London, 1998; (c) Lubineau, A.; Auge, J. In Modern
Solvents in Organic Synthesis; Knochel, P., Ed.; Springer:
Berlin, 1999; (d) Lubineau, A.; Aug e´ , J.; Queneau, Y.
Synthesis 1994, 741.
5
. (a) Minisci, F. Synthesis 1973, 1; (b) Breslow, R.; Light, J.
Tetrahedron Lett. 1990, 31, 2957; (c) Yamazaki, O.; Togo,
H.; Nogami, G.; Yokoyama, M. Bull. Chem. Soc. Jpn.
1997, 70, 2519; (d) Maitra, U.; Sarma, K. D. Tetrahedron
Lett. 1994, 35, 7861; (e) Jang, D. O. Tetrahedron Lett. 1996,
Table 6. Radical addition reactions of cyclohexyl iodide (1 equiv) to
various alkenes (3 equiv) with TAHP-1 (3 equiv) in the presence of
ABCVA (0.25 equiv) in H
2
O
TAHP-1
c-hexyl
3
7, 5367; (f) Yorimitsu, H.; Shinokubo, H.; Oshima, K.
c-hexyl
I
+
alkene
Y
ABCVA, H O, 1 h
Chem. Lett. 2000, 105; (g) Yorimitsu, H.; Shinokubo, H.;
Oshima, K. Bull. Chem. Soc. Jpn. 2001, 74, 225; For a
recent review: (h) Yorimitsu, H.; Shinokubo, H.; Oshima,
K. Synlett 2002, 674; (i) Ueda, M.; Miyabe, H.; Nishimura,
A.; Miyata, O.; Takemoto, Y.; Naito, T. Org. Lett. 2003, 5,
3835; (j) Nambu, H.; Alinejad, A. H.; Hata, K.; Fujioka,
H.; Kita, Y. Tetrahedron Lett. 2004, 45, 8927.
. (a) Jang, D. O.; Cho, D. Y. Synlett 2002, 631; (b) Jang, D.
O.; Cho, D. Y. Tetrahedron Lett. 2002, 43, 5921; (c) Jang,
D. O.; Cho, D. Y. Synlett 2002, 1523; (d) Kita, Y.; Nambu,
H.; Ramesh, N. G.; Anikumar, G.; Matsugi, M. Org. Lett.
2
9
9
9
a: R = C(O)OCH
3
b: R = C(O)CH
3
c: R = CN
a
Entry
Alkene
Temp (°C)
Product
Yield (%)
1
2
3
4
C(O)OCH3
C(O)CH3
CN
80
80
70
80
9a
9b
9c
77
84
83
0
6
CN
a
Isolated yields.

1802
D. H. Cho, D. O. Jang / Tetrahedron Letters 46 (2005) 1799–1802
2
001, 3, 1157; (e) Nambu, H.; Hata, K.; Matsugi, M.; Kita,
chromatography over silica gel (n-hexane/EtOAc, 8:2) to
furnish 3-deoxy-1,2:5,6-di-O-isopropylidene-a-D-glucofura-
nose (3b) (61 mg, 88%).
Y. Chem. Commun. 2002, 1082; (f) Nambu, H.; Anikumar,
G.; Matsugi, M.; Kita, Y. Tetrahedron 2003, 59, 77.
7
. (a) Giese, B.; Rupaner, R. Synthesis 1988, 219; (b) Giese,
B.; Rupaner, R. Justus Liebigs Ann. Chem. 1987, 231.
. Typical procedure for deoxygenation of alcohols with
TAHP-1: A solution of 1,2:5,6-di-O-isopropylidene-3-O-
9. Typical procedure for carbon–carbon bond formation with
TAHP-1:
0.38 mmol), phenyl vinyl sulfone (191 mg, 1.14mmol) and
A
solution of cyclohexyl iodide (50 lL,
8
TAHP-1 (1.67 mL, 1.14mmol, 0.68 M solution in H O) in
2
(
0
methylthio)thiocarbonyl-a-D-glucofuranose (3a) (100 mg,
.29 mmol) and TAHP-1 (1.26 mL, 0.86 mmol, 0.68 M
solution in H O) in degassed water (20 mL) under argon
degassed water (20 mL) under argon was treated with
ABCVA (35 mg, 0.095 mmol) at 100 °C for 1 h. After the
reaction was completed, the reaction mixture was diluted
2
was treated with ABCVA (27 mg, 0.072 mmol) twice (2.5 h
interval) at 100 °C for 7 h. After the reaction was com-
pleted, the reaction mixture was diluted with EtOAc, then
washed with water, dried over MgSO , and evaporated the
4
solvent in vacuo. The residue was purified by flash column
4
with EtOAc, then washed with water, dried over MgSO ,
and evaporated the solvent in vacuo. The residue was
purified by flash column chromatography over silica gel (n-
hexane/EtOAc, 10:1) to furnish (2-cyclohexyl) ethyl phenyl
sulfone (8a) (85 mg, 89%).