1-Ethylpiperidinium Hypophosphite: A Practical Mediator for Radical Carbon-Carbon Bond Formation

Article abstract of DOI:10.1055/s-2001-18781

1-Ethylpiperidinium hypophosphite could be used efficiently as radical chain carrier in the intermolecular carbon-carbon bond formation without using excess of alkenes under mild reaction conditions.

Full text of DOI:10.1055/s-2001-18781

LETTER
1923
1-Ethylpiperidium Hypophosphite: A Practical Mediator for Radical Carbon-
Carbon Bond Formation
1
-Ethylpiperidium
o
H
ypophosph
o
ite:
P
ractica
l
Medi
O
ator for Carbon-Ca
k
rbon Bond Forma
J
tion ang,* Dae Hyan Cho, Chan-Moon Chung
Department of Chemistry, Yonsei University, Wonju 220-710, Korea
Fax +82(33)7602182; E-mail: dojang@dragon.yonsei.ac.kr
Received 21 September 2001
Table Ethylpiperidium Hyphophosphite Mediated Radical Addi-
tion Reactions of Alkyl Halides to Alkenes.
Abstract: 1-Ethylpiperidium hypophosphite could be used effi-
ciently as radical chain carrier in the intermolecular carbon-carbon
bond formation without using excess of alkenes under mild reaction
conditions.
Key words: radical reactions, addition reactions, alkenes, alkyl ha-
lides
Substrate
Alkene
O2
(equiv)
Time
(h)
Yield
(%)
During last two decades, the number of application of rad-
ical reactions in organic synthesis has increased enor-
mously. One of the important application of radical
reactions is the formation of carbon-carbon bonds, either
0.015
0
1
3
98
90
n
inter- or intramolecularly.1 Especially Bu3SnH, organo-
tin hydrides have been widely used as radical chain carri-
ers for the carbon-carbon bond formation. However, they
have several drawbacks including toxicity, high cost, in-
stability to moisture, and difficulty to remove by-product
from desired products. Therefore, they are not suitable for
large-scale work and unacceptable for the pharmaceutical
industry. There have been several research efforts to solve
the problems. One approach is usage of modified tin re-
agents such as water-soluble,2 polymer-supported,3 or flu-
orous tin hydrides.4 Another is to find alternatives other
than organotin reagents such as silanes,5 phosphine-bo-
ranes,6 hypophosphorous acid and amine salts of hypo-
phosphorous acid.7 1-Ethylpiperidium hypophosphite
(EPHP) is the most promising substitute among them for
organotin hydrides in the radical reduction reactions such
as dehalogenation and deoxygenation based on the criteria
of cost-effectiveness, non-toxicity and easy work-up pro-
cess. It has been applied for the construction of carbon-
carbon bonds intramolecuarly.8 However, there is no re-
port that EPHP is used as a radical chain carrier in the in-
termolecular radical carbon-carbon bond formation that is
more difficult than intramolecular carbon-carbon bond
forming reactions.9 In this paper, we wish to report the
scopes and limitations of EPHP as a radical chain carrier
in the intermolecular carbon-carbon bond formations.
0.015
1
94
0.18
12a
12b
1
84
29
97
80
64
86
0.18
0.015
0.015
0.03
1
2
C12H23I
0.045
3
0.015
1
0 (89)c
a At –20 °C, in toluene.
b At –40 °C, in toluene.
c Recovered substrate.
was obtained in 98% isolated yield. The reaction also pro-
ceeded without injection of oxygen, but longer reaction
time was required. It was notable that 1-ethylpiperidium
hypophosphite mediated radical addition reaction could
be accomplished without using large excess of alkenes.
Large excess of alkenes should be used to avoid the reduc-
tion of radical precursors in the organotin hydrides medi-
ated carbon-carbon bond forming reactions. Another
advantage of this process is that by-product are readily re-
moved from desired products by aqueous work-up pro-
cess.
When a mixture of cyclohexyl iodide (1 equiv), phenyl vi-
nyl sulfone (1 equiv), 1-ethylpiperidium hypophosphite (3
equiv) and Et3B (0.25 equiv) in dioxane under argon was
treated with a catalytic amount of oxygen at room temper-
ature followed by aqueous work-up, the addition product
Synlett 2001, No. 12, 30 11 2001. Article Identifier:
1437-2096,E;2001,0,12,1923,1924,ftx,en;Y19701ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

1924
D. O. Jang et al.
LETTER
We chose 1-adamantyl iodide as a model compound to ex-
amine the reactivity of various alkenes under the condi-
tions. The results are summarised in the Table. Vinyl
sulfone produced the addition product in 94% yield. The
reaction could be carried out even at –20 °C to produce the
addition product in 84% yield. At –40 °C, the reaction
could not proceed efficiently. Various electron-deficient
alkenes could be utilised as good radical acceptors under
the conditions. However, alkenes such as 1-octene and
, -unsaturated cyclohexenone afforded 25% and 30% of
addition products, respectively along with reduced prod-
ucts. The reaction could be accomplished with primary
alkyl iodide as a radical precursor to give the correspond-
ing addition product in 86% yield. When alkyl bromide
was used as a radical precursor, the starting bromide was
recovered without obtaining the addition product. Howev-
er, the moderate yield of the addition product could be ob-
tained when the reaction was carried out in boiling
dioxane with excess of alkene (Scheme).
Acknowledgement
This work was supported by Korea Research Foundation Grant
(KRF-2000-DP0268).
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Scheme
In summary, we demonstrated that 1-ethylpiperidium hy-
pophosphite could be used as radical chain carrier in the
carbon-carbon bond formation without using excess of
alkenes. The reaction could be carried out efficiently at
room temperature and offered an easy work-up process.
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Typical procedure was as follows unless noted otherwise:
To a solution of alkyl halide (1.0 equiv), alkene (1.0 equiv), 1-eth-
ylpiperidium hypophosphite (3.0 equiv) and Et3B (0.25 equiv, 1 M
solution in hexanes) in dioxane was added air (1 mL/h, 0.015 equiv
of O2/h) at room temperature with a syringe pump until the reaction
was completed by TLC. The reaction mixture was washed with wa-
ter and then the product was purified by flash chromatography on
silica gel.
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Synlett 2001, No. 12, 1923–1924 ISSN 0936-5214 © Thieme Stuttgart · New York