Radical addition of ethers to alkenes under dioxygen catalyzed by N-hydroxyphthalimide (NHPI)/Co(OAc)2

Article abstract of DOI:10.1016/S0040-4039(02)00613-5

The reaction of various ethers with alkenes bearing an electron-withdrawing substituent in the presence of N-hydroxyphthalimide combined with Co(OAc)₂ under dioxygen produced the corresponding adducts in which oxygen is incorporated to alkenes

Full text of DOI:10.1016/S0040-4039(02)00613-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 3617–3620
Radical addition of ethers to alkenes under dioxygen catalyzed
by N-hydroxyphthalimide (NHPI)/Co(OAc)2
Kazutaka Hirano, Satoshi Sakaguchi and Yasutaka Ishii*
Department of Applied Chemistry, Faculty of Engineering & High Technology Research Center, Kansai University, Suita,
Osaka 564-8680, Japan
Accepted 2 April 2002
Abstract—The reaction of various ethers with alkenes bearing an electron-withdrawing substituent in the presence of N-hydroxy-
phthalimide combined with Co(OAc)2 under dioxygen produced the corresponding adducts in which oxygen is incorporated to
alkenes in good yields. Oxcetane, furan and pyrane smoothly added to ethyl fumarate even at room temperature to give coupling
products in high yields. An acyclic ether like dibutyl ether also added to fumarate under mild conditions to give a hydroxylated
adduct in satisfactory selectivity. © 2002 Published by Elsevier Science Ltd.
The formation of new CꢀC bonds by the addition of
carbon radicals to CꢁC bonds is a powerful strategy in
organic synthesis. A wide variety of methods have
appeared for the generation of carbon radicals.1 How-
ever, the generation of a-etheral carbon radicals from
ethers is limited to peroxide and light induced methods,
which are usually difficult to carry out selectively
under mild conditions. To the best of our knowl-
edge, the radical initiated addition of cyclic ethers to
alkenes was first reported by Wallace and Gritter in
1961.2 Treatment of tetrahydrofuran (THF) with a
radical initiator like t-butyl peroxide at 150°C in the
presence of 1-octene affords 4-dodecanone (40.6%),
which suggests the rearrangement of the initially
formed a-etheral radical to an acyl radical.2 A similar
treatment of THF with 1-octene is reported to form
4-dodecanone as a dominant product and 2-octyltetra-
hydrofuran.3 Furthermore, the reaction of THF with
maleic anhydride under the influence of benzoyl perox-
ide at refluxing temperature produced the correspond-
ing 2-furyl adduct (70%).4 On the other hand,
authors.5 In previous papers, we reported that carbon
radicals can be generated through a catalytic process
from alcohols and acetals by using N-hydroxyphthal-
imide (NHPI) under dioxygen. The reactions of alco-
hols and acetals in the presence of alkenes like methyl
acrylate produced a-hydroxy-g-butyrolactones6 and b-
hydroxy acetals,7 respectively, in good yields. In this
paper, we wish to report the introduction of a-etheral
radicals and molecular oxygen to electron-deficient
alkenes catalyzed by NHPI in the presence of a small
amount of Co(OAc)2 under mild conditions.
A typical reaction was carried out as follows: To a
solution of THF (1) (15 mmol) and diethyl fumarate (2)
(3 mmol) in PhCN (3 mL) was added NHPI (0.3 mmol)
and Co(OAc)2 (0.1×10−3 mmol), and the mixture was
allowed to react under atmospheric dioxygen (1 atm) at
room temperature for 18 h giving adducts diethyl 3-(2%-
furyl)-2-hydroxysuccinate (3a) (62%) and diethyl 3-(2%-
furyl)-2-oxasuccinate (3b) (30%) (Eq. (1)).
(1)
theadditionofetherstohaloalkenesinitiatedbyperoxides
and UV irradiation has also been examined by several
Among the reactions examined in several solvents, we
found that benzonitrile (PhCN) led to adducts 3a and
3b in higher selectivity, as discussed later. Thus, 1 was
reacted with 2 in PhCN under various conditions
(Table 1). The reaction of 1 with 2 in the presence of
Keywords: oxyalkylation; ethers; N-hydroxyphthalimide; catalysis.
* Corresponding author. Tel.: +81-6-6368-0793; fax: +81-6-6339-4026;
e-mail: ishii@ipcku.kansai-u.ac.jp
0040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(02)00613-5

3618
K. Hirano et al. / Tetrahedron Letters 43 (2002) 3617–3620
Table 1. Reaction of tetrahydrofuran (1) to diethyl fumarate (2) by NHPI-catalyst under various conditionsa
Run
NHPI (mol%)
Co(OAc)2 (mol%)
O2/N2 (1 atm)
Conv. (%)b
Yield (%)c
3a
3b
1
2
3
4
5
6
10
5
10
0
10
10
10
10
10
0.1
0.1
0.05
0.1
0
0.1
0.1
0.1
0.1
1.0
1.0
1.0
1.0
97
46
95
62
28
59
30
18
30
No reaction
No reaction
41
32
1.0
0.8/0.2
0.5/0.5
1.0
24
20
44
15
12
29
7
8d
9e
90
1.0
No reaction
a 2 (3 mmol) was allowed to react with 1 (15 mmol) under dioxygen in the presence of NHPI (10 mol%) and Co(OAc)2 (0.1 mol%) at rt for 18
h.
b Conversion of 2.
c Yield based on 2 used.
d 1 (3 mL) was used without solvent.
e Co(acac)3 was used instead of Co(OAc)2.
drawing substituent in the presence of NHPI and
Co(OAc)2 under selected reaction conditions (Table 2).
NHPI (10 mol%) and Co(OAc)2 (0.1 mol%) with
respect to 2 took place even at room temperature to
produce adduct 3a and further oxidized product 3b in
92% total yield (Table 1, run 1). When the amount of
NHPI was halved from 10 to 5 mol%, the conversion of
1 to 3a and 3b markedly decreased (run 2). However,
almost the same results were obtained by the reduction
of Co(OAc)2 by half (run 3). It is important to note
that no reaction was induced by removing either NHPI
or Co(OAc)2 from the reaction system (runs 4 and 5).
In a previous paper, we showed that a cobalt–dioxygen
complex generated in situ from a Co(II) species and
dioxygen abstracts the hydrogen atom from NHPI to
form a phthalimide-N-oxyl (PINO) radical which reacts
with alkanes to initiate the chain reaction.7 It is difficult
to abstract the hydrogen from the NHPI by dioxygen at
room temperature. Therefore, no reaction was observed
in the absence of either NHPI or Co(OAc)2 in the
reaction system. The yield of the adducts, 3a and 3b,
was greatly influenced by the partial pressure of O2 in a
mixed gas of O2 and N2 (runs 6 and 7). The reaction of
1 with 2 without any solvent was approximately com-
pleted in 6 h even at room temperature to form 3a
(44%) and 3b (29%) in 90% conversion (run 8). Fig. 1
shows the effect of various solvents on the reaction of 1
with 2 at 40°C for 6 h. The reaction in acetic acid, ethyl
acetate and acetonitrile resulted in higher conversion of
2, but the selectivity to 3a and 3b was relatively low. In
contrast, the reaction in lipophilic solvents like PhCF3,
PhCl and PhCH3 resulted in adducts, 3a and 3b, in
higher selectivities. It is interesting to note that the
present reaction in PhCN leads to adducts 3a and 3b in
very high selectivities, although the conversion was
moderate. This may be due to the fact that the resulting
adduct radical is easily trapped by dioxygen dissolved
in the solvent rather than the chain transfer to the
alkene owing to the cage effect of the viscous PhCN
solvent.
The reaction of 1 with ethyl malonate without a solvent
at 50°C for 6 h afforded 3a (39%) and 3b (25%) (run 1).
In general, the radical addition to ethyl malonate is
found to proceed more slowly than that to the corre-
sponding fumarate.1 Similarly, 1 added to ethyl acrylate
at 40°C to give ethyl 3-(2%-furyl)-2-hydroxypropionate
(4a) (42%) and ethyl 3-(2%-furyl)-2- oxapropionate (4b)
(22%) (run 2). It is noteworthy that 1 reacted with
methacrolein (5) to afford 2-furyl acetone (6) (68%) as
the sole adduct (run 3).
An outline of the formation of the adduct 6 from 1 and
5 is explained by the following reaction path (Scheme
1). A 2-furyl radical A generated from 1 and PINO
adds to 5 to form an adduct radical B which is trapped
by dioxygen giving a hydroperoxide C. Previously, we
showed that this type of hydroperoxide C is easily
subjected to redox decomposition by Co ions to form
Figure 1. Solvent effect on the reaction of 1 with 2 to 3a and
3b (under O2 (1 atm) in the presence of NHPI (10 mol%) and
Co(OAc)2 (0.1 mol%) at 40°C for 6 h in various solvents.)
Conv. of 2 (ꢀ), yield of 3a+3b (ꢁ).
On the basis of these results, several cyclic ethers were
allowed to react with alkenes bearing an electron-with-

K. Hirano et al. / Tetrahedron Letters 43 (2002) 3617–3620
Table 2. Reaction of various ethers with alkenesa
3619
an alkoxy radical D which readily liberates an alde-
hyde.6 In the present reaction, it is likely that ketone 6
is formed through a similar reaction pathway as above.
On the other hand, several cyclic ethers were reacted
with ethyl fumarate 2 under selected reaction condi-
tions. Trimethylene oxide added relatively slowly to 2
to give the corresponding adducts 7a and 7b in 76%
total yield (run 4). The reaction of 2-methylfurane with
2 took place regioselectively to form adducts 8a and 8b
in which the tertiary radical of the 2-methylfurane
added to 2 (run 5). Tetrahydropyran reacted with 2 to
form 9a and 9b in fair yields (51%) (run 6). In these
reactions, ethers were converted into the corresponding
lactones in 4–6% yields based on the ethers used.
Scheme 1.
Needless to say, the present reaction was extended to
the addition of acyclic ethers to alkenes. For instance,
the reaction of dibutyl ether with 2 under similar condi-
tions as Table 1 (run 1) afforded adducts 10a and 10b
in 56% yield in 67% conversion (Eq. (2)).
In conclusion, we have succeeded in the NHPI-cata-
lyzed radical addition of ethers to alkenes bearing
electron-withdrawing substituents under mild condi-
tions. Unfortunately, these reactions gave diastereoiso-
meric mixtures of the products, but the present method
(2)

3620
K. Hirano et al. / Tetrahedron Letters 43 (2002) 3617–3620
provides a useful synthetic tool for the preparation of
various ether derivatives.
MHz): l=173.4, 171.3, 74.5, 68.9, 65.6, 61.8, 60.9, 53.6,
32.7, 30.4, 13.9; IR (NaCl) 3502, 2939, 1739, 1069, 1030
1
cm−1. 9b: H NMR (CDCl3, 400 MHz): l=4.23 (m,
1
Spectral data. 3a: H NMR (CDCl3, 400 MHz): l=
1H), 4.08 (m, 4H), 3.74 (dd, J=13.0, 27.8 Hz, 2H), 3.43
(s, 1H), 1.59 (m, 6H), 1.17 (m, 6H); 13C NMR (CDCl3,
400 MHz): l=190.0, 172.9, 171.3, 68.7, 68.5, 61.8, 61.0,
53.4, 32.4, 29.7, 20.6, 14.0, 13.9; IR (NaCl) 2939, 1732,
4.66 (d, J=2.6 Hz, 1H), 4.34 (m, 1H), 4.16 (m, 4H),
3.94 (m, 2H), 2.91 (dd, J=2.6, 10.0 Hz, 1H), 2.24 (m,
1H), 1.94 (m, 2H), 1.64 (m, 1H), 1.28 (m, 6H); 13C
NMR (CDCl3, 400 MHz): l=173.4, 170.3, 75.8, 69.9,
67.9, 61.7, 60.9, 53.8, 31.0, 25.6, 14.1, 14.0; IR (NaCl)
1
1199 cm−1. 10a: H NMR (CDCl3, 400 MHz): l=4.62
(dd, J=2.4, 7.3 Hz, 1H), 4.24 (m, 2H), 4.15 (m, 2H),
3.85 (m, 1H), 3.56 (m, 2H), 2.98 (dd, J=2.4, 8.3 Hz,
1H), 1.54 (m, 4H), 1.39 (m, 4H), 1.28 (m, 6H), 0.92 (m,
6H); 13C NMR (CDCl3, 400 MHz): l=173.3, 170.9,
70.8, 69.1, 69.0, 61.5, 60.9, 52.9, 35.3, 32.2, 19.4, 18.1,
14.2, 14.1, 14.0, 13.9; IR (NaCl) 3499, 2959, 2873, 1737,
1460, 1372, 1251, 1180, 1093 cm−1. 10b: 1H NMR
(CDCl3, 400 MHz): l=4.26 (m, 4H), 3.70 (m, 1H), 3.52
(d, J=4.8 Hz, 1H), 2.72 (m, 2H), 1.58 (m, 4H), 1.41 (m,
4H), 1.32 (m, 6H), 0.97 (m, 6H); 13C NMR (CDCl3, 400
MHz): l=191.4, 173.1, 172.9, 64.8, 64.7, 62.9, 62.8,
49.7, 36.3, 27.9, 19.5, 16.0, 14.1, 13.9, 13.8, 13.7; IR
(NaCl) 2965, 1731, 1300, 1103 cm−1.
1
3430, 2982, 1736, 1376, 1276, 1120, 1031 cm−1. 3b: H
NMR (CDCl3, 400 MHz): l=4.39 (m, 1H), 4.22 (m,
4H), 3.69 (m, 2H), 2.98 (d, J=3.9 Hz, 1H), 1.91 (m,
2H), 1.72 (m, 2H), 1.28 (m, 6H); 13C NMR (CDCl3, 400
MHz): l=193.4, 172.8, 170.7, 75.5, 68.2, 61.9, 60.9,
52.6, 29.1, 25.5, 14.1, 14.0; IR (NaCl) 2982, 1732, 1372,
1189, 1067 cm−1. 4a: 1H NMR (CDCl3, 400 MHz):
l=4.24 (m, 2H), 4.07 (m, 1H), 3.81 (m, 2H), 3.55 (dd,
J=2.5, 9.3 Hz, 1H), 1.90 (m, 2H), 1.87 (m, 4H), 1.29
(m, 3H); 13C NMR (CDCl3, 400 MHz): l=174.5, 76.1,
69.4, 67.8, 61.4, 39.3, 31.6, 25.4, 14.1; IR (NaCl) 3419,
2932, 1732, 1203, 1129, 1067 cm−1. 4b: 1H NMR
(CDCl3, 400 MHz): l=4.31 (m, 2H), 4.16 (m, 1H), 3.87
(m, 2H), 3.74 (m, 2H), 2.01 (m, 4H), 1.37 (t, J=7.3 Hz,
3H); 13C NMR (CDCl3, 400 MHz): l=192.7, 160.9,
74.3, 67.9, 62.4, 45.1, 31.4, 25.4, 13.9; IR (NaCl) 2919,
Acknowledgements
1
1736, 1210, 1131, 1010 cm−1. 6: H NMR (CDCl3, 400
This work was partially supported by a Grant-in-Aid
for Scientific Research (S) from the Japan Society for
the Promotion of Science (JSPS).
MHz): l=3.87 (m, 1H), 3.75 (t, J=6.6 Hz, 2H), 2.76
(dd, J=7.3, 15.6 Hz, 2H), 2.20 (s, 3H), 1.89 (m, 4H);
13C NMR (CDCl3, 400 MHz): l=207.2, 74.9, 67.4,
49.5, 29.5, 25.5, 23.8; IR (NaCl) 2957, 2352, 1715, 1356,
1179, 1069 cm−1. 7a: 1H NMR (CDCl3, 400 MHz):
l=5.32 (m, 1H), 4.61 (dd, J=2.9, 10.3 Hz, 1H), 4.53
(m, 2H), 4.21 (m, 4H), 3.67 (t, J=5.4 Hz, 1H), 2.53 (m,
2H), 1.28 (m, 6H); 13C NMR (CDCl3, 400 MHz):
l=173.3, 173.1, 68.8, 68.6, 67.3, 61.9, 60.9, 54.9, 27.4,
14.1, 14.0; IR (NaCl) 3468, 2983, 1715, 1370, 1277,
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1
1137 cm−1. 7b: H NMR (CDCl3, 400 MHz): l=5.31
(m, 1H), 4.33 (m, 2H), 4.21 (m, 2H), 4.10 (m, 2H), 3.93
(s, 1H), 2.57 (m, 2H), 1.26 (m, 6H); 13C NMR (CDCl3,
400 MHz): l=190.3, 170.0, 163.7, 73.9, 68.9, 62.9, 62.8,
57.9, 24.9, 14.1, 13.9; IR (NaCl) 2982, 1737, 1185, 1013
1
cm−1. 8a: H NMR (CDCl3, 400 MHz): l=4.62 (dd,
J=2.7, 10.5 Hz, 1H), 4.26 (m, 2H), 4.15 (m, 2H), 3.88
(m, 2H), 3.09 (d, J=2.7 Hz, 1H), 1.96 (m, 4H), 1.42 (s,
3H), 1.30 (m, 6H); 13C NMR (CDCl3, 400 MHz):
l=173.8, 170.5, 69.6, 69.0, 67.9, 61.8, 61.7, 56.9, 37.7,
23.6, 21.6, 14.1, 14.0; IR (NaCl) 3486, 2980, 1738, 1371,
1240, 1107, 1040 cm−1. 8b: 1H NMR (CDCl3, 400
MHz): l=4.15 (m, 4H), 3.88 (m, 2H), 3.16 (s, 1H), 1.96
(m, 4H), 1.42 (s, 3H), 1.30 (m, 6H); 13C NMR (CDCl3,
400 MHz): l=195.5, 173.8, 170.2, 69.4, 67.0, 60.6, 60.6,
56.7, 34.1, 23.6, 21.6, 14.0, 13.9; IR (NaCl) 2981, 1738,
1372, 1107, 1041 cm−1. 9a: 1H NMR (CDCl3, 400
MHz): l=4.68 (d, J=2.9 Hz, 1H), 4.40 (m, 1H), 4.13
(m, 4H), 3.46 (m, 2H), 2.90 (dd, J=2.9, 9.3 Hz, 1H),
1.67 (m, 6H), 1.28 (m, 6H); 13C NMR (CDCl3, 400
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