Solid-phase tandem radical addition-cyclisation reaction of oxime ethers

Article abstract of DOI:10.1039/b101074n

The solid-phase tandem C-C bond-forming reactions of oxime ethers connected with α,β-unsaturated carbonyl groups proceeded effectively under iodine atom-transfer reaction conditions to give the azacycles or chiral oxacycles after cleavage of the resin.

Full text of DOI:10.1039/b101074n

Solid-phase tandem radical addition–cyclisation reaction of oxime
ethers
Hideto Miyabe, Kayoko Fujii, Hirotaka Tanaka and Takeaki Naito*
Kobe Pharmaceutical University, Motoyamakita, Higashinada, Kobe 658-8558, Japan.
E-mail: taknaito@kobepharma-u.ac.jp
Received (in Cambridge, UK) 31st January 2001, Accepted 20th March 2001
First published as an Advance Article on the web 10th April 2001
The solid-phase tandem C–C bond-forming reactions of
oxime ethers connected with a,b-unsaturated carbonyl
groups proceeded effectively under iodine atom-transfer
reaction conditions to give the azacycles or chiral oxacycles
after cleavage of the resin.
Solid-phase radical reactions have been developed for an
important carbon–carbon bond-forming method on solid sup-
port under mild reaction conditions.1 We have recently
demonstrated that triethylborane as a radical initiator has the
potential to induce intermolecular and intramolecular radical
reactions on solid support.2 Moreover, the employment of
triethylborane and its related radical initiator such as diethylzinc
at low reaction temperature would facilitate the control of
stereochemistry in solid-phase reactions.3 Within our program
directed towards solid-phase radical reactions, the development
of solid-phase multi carbon–carbon bond-forming reactions and
their stereocontrol is the new focus of our efforts. We now
report the tandem radical addition–cyclisation reaction of oxime
ethers anchored to a polymer support.
In our studies on the radical reaction of various oxime ethers
in solution,4 we have recently succeeded in the solution-phase
tandem radical addition–cyclisation reaction of substrates
having two different radical acceptors such as acrylate and
aldoxime ether moieties.5 On the basis of the results in the
solution-phase reactions, we first examined the simple solid-
phase tandem radical addition–cyclisation reaction of aldoxime
ether 3 connected with the a,b-unsaturated carbonyl group.
Preparation of 3 anchored to a polymer support is shown in
Scheme 1. Treatment of a-chloroacetaldoxime ether 1 with
2-aminoethanol followed by acylation with acryloyl chloride
gave oxime ether 2. To enhance the reactivity of resin-bound
substrate, we introduced a temporary spacer by the reaction of
2 with glutaric anhydride. The oxime ether having the spacer
moiety was attached to Wang resin by treatment with DCC in
the presence of DMAP to give 3. The loading level of Wang
resin-bound oxime ether 3 was determined to be 0.81 mmol g21
through quantification of nitrogen by elemental analysis.
To a flask containing aldoxime ether 3 and PriI (30 equiv.) in
toluene a commercially available 1.0 M solution of triethylbor-
ane in hexane was added three times (3 equiv. 3 3) as a radical
initiator at 100 °C (Scheme 1). The reaction mixture was stirred
at 100 °C for 2 h, then the resin was filtered and successively
washed with CH2Cl2, AcOEt, and MeOH. The cleavage of the
resin by treatment with NaOMe gave the desired azacyclic
product 5a in 69% isolated yield. However, the radical
cyclisation of oxime ether 3 at 25 °C did not proceed.2b Good
chemical yields were also observed in the radical reaction using
different radical precursors such as cyclohexyl, cyclopentyl,
and sec-butyl iodides under the iodine atom-transfer reaction
conditions. Moreover, it is noteworthy that this iodine atom-
transfer radical reaction has a practical advantage over the
reaction using toxic tin reagent. A remarkable feature of these
reactions is the construction of two carbon–carbon bonds on
solid support under mild reaction conditions without strictly
anhydrous solvents and reagents. In this reaction, triethylborane
would act as a reagent for trapping the intermediate aminyl
Scheme 1 Reagents and conditions: i, 2-Aminoethanol, 20 °C, 88%; ii,
CH2NCHCOCl, Na2CO3, acetone, H2O, 0 °C, 87%; iii, Glutaric anhydride,
Py, 80 °C, 93%; iv, Wang resin, DCC, DMAP, CH2Cl2, 20 °C; v, RI, Et3B
in hexane, toluene, 100 °C; vi, NaOMe, MeOH, THF, H2O, 20 °C.
radicals to regenerate an ethyl radical; therefore, more than a
stoichiometric amount of triethylborane would be required
(Scheme 2).
Stereocontrol in solid-phase radical reactions has been of
great importance in SPOS (solid-phase organic synthesis).
Based on the above results, we next examined the control of
stereochemistry in the solid-phase tandem radical addition–
cyclisation reaction. Preparation of 10 anchored to a polymer
support is shown in Scheme 3. Monoacetylation of p-xylene
glycol, mesylation of monool with mesyl chloride in the
Scheme 2
DOI: 10.1039/b101074n
Chem. Commun., 2001, 831–832
This journal is © The Royal Society of Chemistry 2001
831

with glutaric anhydride to give carboxylic acid 9 (Scheme 3).
The carboxylic acid 9 was attached to Wang resin by treatment
with DCC in the presence of DMAP in CH2Cl2 at 20 °C for 12 h
to give the resin-bound oxime ether 10.
The reaction of 10 with an ethyl radical proceeded effectively
by treatment with triethylborane to give the chiral oxacycles 11c
in 92% yield after cleavage of the resin, which was carried out
under acidic reaction conditions due to the base-sensitivity of
11c (Scheme 3). However, the reactivity of chiral oxime ether
10 towards other alkyl radicals was quite different from that of
oxime ether 3. The treatment of 10 with PriI (24 equiv. 3 3) and
triethylborane (6 equiv. 3 3) in toluene at 100 °C gave a large
amount of the ethylated product 11c and a small amount of the
isopropylated product 11a after cleavage of the resin. This result
suggests that, in this reaction, the addition of ethyl radical,
generated from triethylborane, competes with the iodine atom-
transfer process because triethylborane, having Lewis acidic
character, probably coordinates the substrate on the polymer-
support and is concentrated on the surface of the resin. A similar
trend has been observed in our previous studies.3 Selective
formation of the desired isopropylated product 11a was
observed in the reaction of 10 (50 mg) using triethylborane (5.9
equiv. 3 3) in PriI–toluene (4+1, v/v, 5 mL) at 100 °C. Based on
1H-NMR analysis, a 8+1 diastereomeric mixture of the
isopropylated oxacyclic product 11a was obtained in 54%
isolated yield. Additionally, in the solid-phase reactions, the
often tedious workup to remove excess reagents from the
reaction mixture was eliminated simply by washing the resin
with solvents. The addition of a bulky cyclohexyl radical
proceeded in slightly low chemical efficiency under the same
reaction conditions to give the alkylated product 11b but with a
similar diastereoselectivity.
In conclusion, we have demonstrated that tandem radical
reactions are an excellent method for the stereoselective
construction of multi carbon–carbon bonds on solid support.
This work was supported by research grants from the
Ministry of Education, Science, Sports and Culture of Japan and
the Science Research Promotion Fund of the Japan Private
School Promotion Foundation. H. M. gratefully acknowledges
financial support from the Takeda Science Foundation and the
Fujisawa Foundation, Japan. This investigation was supported
in part by the Memorial Foundation for Medical and Pharma-
ceutical Research.
Notes and references
Scheme 3 Reagents and conditions: i, BunLi, AcCl, THF, 0 °C, 65%; ii,
MsCl, Et3N, CH2Cl2, 0 °C and then N-hydroxyphthalimide, Et3N, CH2Cl2,
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reflux, 71%; iii, N2H4·H2O, MeOH, 20 °C, 99%; iv, 2,3-isopropylidene-D-
glyceraldehyde, Py, 25 °C, 73%; v, PPTS, MeOH, 65 °C, 74%; vi,
TBDPSCl, imidazole, DMF, 20 °C, 75%; vii, K2CO3, aq. MeOH, 20 °C,
99%; viii, TBDMSCl, imidazole, DMF, 20 °C, 75%; ix, CH2NCHCOCl,
Et3N, CH2Cl2, 0 °C, 65%; x, PPTS, MeOH, 65 °C, 80%; xi, glutaric
anhydride, Py, 80 °C, 99%; xii, Wang resin, DCC, DMAP, CH2Cl2, 20 °C;
xiii, Et3B in hexane, RI+toluene = 4+1, 100 °C; xiv, TFA, CH2Cl2,
20 °C.
presence of triethylamine, and then treatment of the resulting
mesylate with N-hydroxyphthalimide in one-pot afforded the
imide 6 in 71% yield (Scheme 3). Treatment of 6 with hydrazine
monohydrate and subsequent condensation of the resulting
2 (a) H. Miyabe, Y. Fujishima and T. Naito, J. Org. Chem., 1999, 64, 2174;
(b) H. Miyabe, H. Tanaka and T. Naito, Tetrahedron Lett., 1999, 40,
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3 H. Miyabe, C. Konishi and T. Naito, Org. Lett., 2000, 2, 1443.
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(c) H. Miyabe, S. Kanehira, K. Kume, H. Kandori and T. Naito,
Tetrahedron, 1998, 54, 5883.
alkoxyamine with 2,3-isopropylidene- -glyceraldehyde gave
D
the chiral oxime ether 7, which was easily converted to the
secondary alcohol 8. The reaction of 8 with acryloyl chloride
followed by treatment with pyridinium toluene-p-sulfonate in
MeOH gave deprotected benzyl alcohol, which was then treated
5 H. Miyabe, K. Fujii, T. Goto and T. Naito, Org. Lett., 2000, 2, 4071.
832
Chem. Commun., 2001, 831–832