A simple and efficient radical reduction using water-soluble radical initiator and hypophosphorous acid in aqueous alcohol

Article abstract of DOI:10.1016/j.tetlet.2004.09.130

A simple, mild and high-yielding procedure for the reduction of various halogenated compounds using a combination of the water-soluble radical initiater (VA-061), hypophosphorous acid and triethylamine in aqueous alcohol is reported. A simple, mild, and high-yielding procedure for the reduction of various halogenated compounds using a combination of the water-soluble radical initiator, 2,2′-azobis[2-(2-imidazolin-2-yl)propane] (VA-061), a water-soluble chain carrier, hypophosphorous acid, and the base, triethylamine, in aqueous alcohol is described. The reagents used in this method are all water soluble, and therefore, an almost pure desired product can be readily obtained using only an extraction procedure.

Full text of DOI:10.1016/j.tetlet.2004.09.130

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 8927–8929
A simple and efficient radical reduction using water-soluble
radical initiator and hypophosphorous acid in aqueous alcohol
Hisanori Nambu, Anahita Hessamian Alinejad, Kayoko Hata, Hiromichi Fujioka and
Yasuyuki Kita*
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6, Yamada-oka, Suita, Osaka 565-0871, Japan
Received 23 August 2004; revised 14 September 2004; accepted 21 September 2004
Available online 18 October 2004
Abstract—A simple, mild, and high-yielding procedure for the reduction of various halogenated compounds using a combination of
the water-soluble radical initiator, 2,20-azobis[2-(2-imidazolin-2-yl)propane] (VA-061), a water-soluble chain carrier, hypophospho-
rous acid, and the base, triethylamine, in aqueous alcohol is described. The reagents used in this method are all water soluble, and
therefore, an almost pure desired product can be readily obtained using only an extraction procedure.
Ó 2004 Elsevier Ltd. All rights reserved.
Radical reduction is one of the useful synthetic method-
ologies.1 The reductive reagents (e.g., tributyltin hydride
[n-Bu3SnH],1 tris(trimethylsilyl)silane [(TMS)3SiH],1,2
etc.) have often been used in many radical reactions.
However, organotin compounds are toxic and expen-
sive, and are difficult to be completely removed from
the desired reaction products. Silanes are also very
expensive and sometimes difficult to remove. On the
other hand, hypophosphorous acid as a water-soluble
chain carrier is cheap, much less toxic, and easily remov-
able.3,4 Recently, Barton and other groups have re-
ported a radical reaction using hypophosphorous
acid,3 and we have recently reported the radical cycliza-
tion of hydrophobic substrates using the combination of
the water-soluble radical initiator 2,20-azobis[2-(2-imi-
dazolin-2-yl)propane] (VA-061),4 the water-soluble
chain carrier, 1-ethylpiperidinehypophosphite (EPHP),
and the surfactant, the cetyltrimethylammonium bro-
mide (CTAB), in water.5 We now report a radical reduc-
tion in aqueous isopropyl alcohol using the combination
of VA-061, hypophosphorous acid, and triethylamine.
Since these reagents are all water soluble, they can be
easily removed.
We examined the radical reduction of the iodide sub-
strate 1a using VA-061, aqueous H3PO2, and Et3N in
aqueous isopropyl alcohol at 80°C (Scheme 1).6 The
reduction smoothly occurred (30min) to give the reduc-
tive product 27 in a quantitative yield and the almost
pure desired product could be obtained only by extrac-
tion with ethyl acetate. The purity of this product was
1
found to be >98% based on the H NMR analysis.
We then investigated the generality of this reduction
with various halogenated substrates under similar condi-
tions. These compounds used in the reduction are shown
O
O
VA–061 (0.5 equiv.)
I
aq. H3PO2 (10 equiv.)
O
O
Et3N (10 equiv.)
MeO
a: VA–061
MeO
i-PrOH, 80 ˚C, 30 min.
1a
2
Me
N N
Me
Me
Me
quantitative yield
>98% purity analyzed by 1H-NMR
N
N
N
N
H
H
Scheme 1. Radical reduction of 1a using water-soluble reagents.
Keywords: Radical reduction; Hypophosphorous acid; The water-soluble radical initiator; Aqueous alcohol.
*
Corresponding author. Tel.: +81 668798225; fax: +81 668798229; e-mail: kita@phs.osaka-u.ac.jp
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.09.130

8928
H. Nambu et al. / Tetrahedron Letters 45 (2004) 8927–8929
R
O
O
R2
O
N
O
R
R1O
BzO
3: R1 = Ac, R2 = I
4: R1 = Ac, R2 = H
1a: R1 = Me, R2 = I
1b: R1 = Me, R2 = Br
1c: R1 = Me, R2 = Cl
2: R1 = Me, R2 = H
5a: R = I
5b: R = Br
5c: R = Cl
6: R = H
7: R = I
8: R = H
R
Ph
O
Ph
O
O
O
O
O
O
O
O
R2
O
O
O
O
OR1
R
O
R2
R
15: R1 = TMS, R2 = I
15': R1 = H, R2 = I
11: R = I
12: R = H
9: R = I
10: R = H
13: R = I
14: R = H
16: R1 = TMS, R2 = H
17: R1 = Me, R2 = I
18: R1 = Me, R2 = H
Scheme 2. Various substrates of radical reduction.
in Scheme 2. The results are summarized in Table 1.
These iodide substrates 1a, 3, 5, 7, 9, 11, 13, 15, and
17 afforded the reductive product 2, 4, 6, 8, 10, 12, 14,
16, and 188 in excellent yields (entries 1, 2, 4–11), respec-
tively. This reductive method was also used for a large-
scale reaction (10mmol scale; 1a: 3.06g, entry 2), and
the reproducibility of the reaction was confirmed. All
these products purified by an extraction procedure were
1
>98% purity based on the H NMR analysis. The sub-
strates bearing various functional groups (e.g., ester
1a, 3, 7, imide 5, ketone 9, acetal 11, 13, 15, 17, silyl
ether 15, and cyclic ether 11, 13, 15, 17) could be used
in our method.
Table 1. Radical reduction using VA-061, aq H3PO2, and Et3N in
i-PrOH at 80°C
Entry Substrate VA-061 Time (h) Product Yield
(equiv)
(purity)a
We found that this condition was most effective for the
unstable substrate 15 compared with other known con-
ditions (Table 2).3 Under the condition using AIBN, aq
H3PO2 and Et3N in benzene, the corresponding reduced
product 16 was obtained in 34% yield and the desilylated
product was contaminated (entry 3). When the reduc-
tion was carried out in water, the reductive product
was not obtained at all, and the starting material 15
was recovered accompanied with the desilylated sub-
strate 150. Furthermore, our condition was more effec-
tive than the standard reductive condition, AIBN and
n-Bu3SnH in benzene (entry 5). Next, we tried to apply
the bromides 1b, 5b, and chlorides 1c, 5c to our method.
When we used the a-bromocarbonyl substrate 1b, the
reductive product 2 was produced in quantitative yield
(Table 1, entry 3). However, the reductions of the bro-
1
1a
1a
1b
3
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
1
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0
2
2
Quant. (>98%)
Quant. (>98%)
Quant. (>98%)
Quant. (>98%)
Quant. (>98%)
Quant. (>98%)
Quant. (>98%)
Quant. (>98%)
Quant. (>98%)
Quant. (>98%)
95% (>99%)d
2b
3
2
4
4
5
5
6
6
7
8
7
9
10
12
14
.5168
.5188
8
11
13
15
17
9
10c
11c
1
0
a The yields are after purification by extraction procedure. The purity
was analyzed by 1H NMR.
b Large-scale reaction (10mmol, 3.06g).
c Hypophosphorous acid (20equiv) and triethylamine (30equiv) were
used.
d The yield is after purification on PLC plate.
Table 2. Radical reduction of 15 under the various reaction conditions
Entry
Reductive reagent (equiv)
Initiator (equiv)
Base (equiv)
Solvent
Temp (°C)
Time (h)
Yield (%)a
b
1
2
3
4
5
6
H3PO2 (20)
H3PO2 (20)
H3PO2 (20)
H3PO2 (20)
H3PO2 (20)
n-Bu4SnH (5)
VA-061 (0.5)
AIBN (0.5)
AIBN (0.5)
AIBN (0.5)
Et3B (0.5)
Et3N (30)
Et3N (30)
Et3N (30)
NaHCO3 (30)
NaHCO3 (30)
—
i-P.5rOH
i-P.5rOH
Benzene
H2O
8Q0u0ant. (>98%)
88030
Reflux
c
3
34c
d
90
Rt
3
0
H2O
Benzene
12
3
0d
73c
AIBN (0.1)
Reflux
a Yield of isolated 16.
b This yield is after purification by extraction procedure. The purity was analyzed by 1H NMR.
c The yields are after purification by column chromatography.
d Starting material and the desilylated substrate were recovered.

H. Nambu et al. / Tetrahedron Letters 45 (2004) 8927–8929
8929
D. O.; Cho, D. H.; Barton, D. H. R. Synlett 1998, 39–40;
Yorimitsu, H.; Shinokubo, H.; Oshima, K. Chem. Lett.
2000, 104–105; Jang, D. O.; Cho, D. H. Synlett 2002, 631–
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D. O.; Cho, D. H. Tetrahedron Lett. 2002, 43, 5921–5924;
Sugiura, M.; Hagio, H.; Kobayashi, S. Chem. Lett. 2003,
898–899; Khan, T. A.; Tripoli, R.; Crawford, J. J.; Martin,
C. G.; Murphy, J. A. Org. Lett. 2003, 5, 2971–2974.
4. Kita, Y.; Matsugi, M. In Radicals in Organic Synthesis;
Renaud, P., Sibi, M. P., Eds.; Wiley-VCH: Weinheim, 2001;
Vol. 1, pp 1–10. The water-soluble azo-type radical initiator
(VA-061) used in this study is available from Wako Pure
Chemical Industries, Ltd, Osaka, Japan.
mide 5b and chloride 1c were not completed and
afforded the corresponding products 2, 6 in low yields
accompanied by the corresponding alcohol compounds
as a side product. With other chloride 5c, the reduction
did not proceed at all.
In summary, we have discovered that the combination
of a water-soluble azo-type radical initiator (VA-061),
a water-soluble chain carrier (hypophosphorous acid)
and a base (triethylamine) is a simple and efficient reac-
tion system to accomplish radical reductions in aqueous
alcohol. This method makes it easy to purify the desired
product and various substituted substrates can be used
for this method; therefore, we believe that this procedure
may find widespread use in organic synthesis.
5. Kita, Y.; Nambu, H.; Ramesh, N. G.; Anilkumar, G.;
Matsugi, M. Org. Lett. 2001, 3, 1157–1160; Nambu, H.;
Anilkumar, G.; Matsugi, M.; Kita, Y. Tetrahedron 2003,
59, 77–85.
6. General procedure for the preparation of reductive com-
pounds (2): VA-061 (50.1mg, 0.20mmol) was added to a
solution of the iodide substrate (1a) (122mg, 0.40mmol),
hypophosphorous acid in water (0.44mL, 4.0mmol, 50%
solution in water), and Et3N (0.56mL, 4.0mmol) in i-PrOH
(4mL) at room temperature. The reaction mixture was then
stirred and heated to 80°C for 0.5h. The organic solvent in
the reaction mixture was evaporated and then water was
added. The crude mixture was extracted with EtOAc, and
the organic layer was washed with saturated NH4Cl, water
and brine, dried with Na2SO4, and concentrated to afford
the pure reductive compound 27 (72mg, 0.40mmol, quan-
Acknowledgements
This work was supported by Grants-in-Aid for Scientific
Research (S) (No. 7690) from the Ministry of Educa-
tion, Culture, Sports, Science and Technology, Japan.
We thank Wako Pure Chemical Industries, Ltd, for
the generous supply of several water-soluble azo-type
initiators. H.N. and A.H.A. thank the Japan Society
for the Promotion of Science (JSPS) for their postdoc-
toral fellowships.
1
titative yield, purity >98% by H NMR) as a yellowish oil,
which was used without further purification.
IR: ~m 3000cmꢀ1, 2960, 2912, 2837, 1732 (C@O), 1614, 1585,
1444, 1359, 1242, 1176, 1032, 963, 821. 1H NMR (300MHz/
CDCl3/TMS): d 2.06 (s, 3H, CH3C@O), 3.80(s, 3H,
CH3O), 5.03 (s, 2H, CH2O), 6.87 (d, 2H, Ar-H, J = 8.7Hz),
7.28 (d, 2H, Ar-H, J = 8.7Hz). 13C NMR (75MHz/CDCl3/
TMS): d 170.84 (C@O), 159.55 (C), 130.02 (CH), 127.98
(C), 113.85C (CH), 66.01 (CH2O), 55.16 (CH3O), 20.94
(CH3).
References and notes
1. Renaud, P.; Sibi, M. P. Radicals in Organic Synthesis;
Wiley-VCH: Weinheim, 2001, and references cited therein.
2. Chatgilialoglu, C.; Schiesser, C. H. In The Chemistry of
Organic Silicon Compounds; Rappoport, Z., Apeloig, Y.,
Eds.; Wiley: London, 2001; Vol. 3, pp 341–390.
3. Barton, D. H. R.; Jang, D. O.; Jaszberenyi, J. C. Tetrahe-
dron Lett. 1992, 33, 5709–5712; Barton, D. H. R.; Jang, D.
O.; Jaszberenyi, J. C. J. Org. Chem. 1993, 58, 6838–6842;
Jang, D. O. Tetrahedron Lett. 1996, 37, 5367–5368; Jang,
7. Hilborn, J. W.; MacKnight, E.; Pincock, J. A.; Wedge, P. J.
J. Am. Chem. Soc. 1994, 116, 3337–3346.
8. Details of these compounds will be published in the near
future.