Oxidation of alkylcatecholboranes with functionalized nitroxides for chemical modification of cyclohexene, perallylated polyglycerol and of poly(butadiene)

Article abstract of DOI:10.1002/ejoc.201001043

The present communication reports on the synthesis of alkoxyamines by hydroboration of olefins with catecholborane and subsequent oxidation by using nitroxides. Oxidation occurs via a radical process and the intermediately formed C-radicals are trapped by the nitroxides to form the corresponding alkoxyamines. If functionalized nitroxides are used, the method allows incorporation of interesting functional moieties via this approach. The novel method is applied for chemical modification of cyclohexene as a test substrate. More importantly, it is also shown that the reaction sequence can be used for chemical modification of macromolecules containing multiple double bonds. This is documented by successful functionalization of poly(butadiene) and of perallylated polyglycerol. Functionalized poly(butadiene)s can be prepared by a reaction sequence comprising olefin hydroboration and nitroxide induced oxidation to give poly(alkoxyamines). If the nitroxide is charged with aninteresting functional moiety such as a sugar derivative or a polyethylene glycol tail, the trapping process delivers the corresponding functionalized chemically modified poly(olefins) in a one-pot process.

Full text of DOI:10.1002/ejoc.201001043

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201001043
Oxidation of Alkylcatecholboranes with Functionalized Nitroxides for
Chemical Modification of Cyclohexene, Perallylated Polyglycerol and of
Poly(butadiene)
Christine B. Wagner[a] and Armido Studer*[a]
Keywords: Polymers / Hydroboration / Polymer modification / Boron / Radicals / Nitroxides
The present communication reports on the synthesis of alk-
oxyamines by hydroboration of olefins with catecholborane
and subsequent oxidation by using nitroxides. Oxidation oc-
curs via a radical process and the intermediately formed C-
ties via this approach. The novel method is applied for chem-
ical modification of cyclohexene as a test substrate. More im-
portantly, it is also shown that the reaction sequence can be
used for chemical modification of macromolecules containing
radicals are trapped by the nitroxides to form the correspond- multiple double bonds. This is documented by successful
ing alkoxyamines. If functionalized nitroxides are used, the
method allows incorporation of interesting functional moie-
functionalization of poly(butadiene) and of perallylated poly-
glycerol.
to form alkoxyamine 3 (Scheme 1). In the present com-
munication we report on the application of this reaction for
the introduction of various functional moieties into cyclo-
hexene as a test olefin as well as into macromolecules con-
taining multiple double bonds. The sequence comprises cat-
echolborane(CatBH)-mediated hydroboration followed by
nitroxide oxidation to give the corresponding alkoxyamines.
The mild process should allow the use of olefins with
nitroxides containing various interesting functional groups.
Introduction
There are two reasons for introducing boryl substituents
into polymers: a) boron atoms alter the physical properties
of a polymer,[1] and b) boron substituents can be used as
reactive functional groups that are readily replaced/substi-
tuted for further chemical modification of the polymers by
oxidation, C–C coupling or other reactions. B-containing
polymers have successfully been prepared by polymeriza-
tion of boron-containing monomers.[1–4] In addition, bo-
rylated polymers are accessible by introducing the boryl
substituents into an existing polymer via chemical modifi-
cation of the polymer backbone or its side chains. Along
this line, direct transition-metal-catalyzed C–H borylation
has been achieved.[5] Moreover, lithiated polymers react
with B-electrophiles to give borylated polymers,[1,6] and
silylated polystyrene has been reported to react with BBr3
in an electrophilic aromatic substitution to yield B-substi-
tuted polystyrene.[7] Most obviously, hydroboration can be
used for the transformation of polymers containing alkene
moieties into the corresponding B-containing polymers.[8]
Alkylcatecholboranes have been applied as precursors for
generation of C-radicals upon reaction with TEMPO
(2,2,6,6-tetramethylpiperidine-N-oxyl radical).[9,10,11] In
these reactions, one equivalent of the nitroxide reacts with
a B-alkylcatecholborane 1 in a formal homolytic substitu-
tion at boron to the boric ester 2 and the corresponding C-
centered radical, which is subsequently trapped by TEMPO
Scheme 1. Transformation of olefins into TEMPO-derived alk-
oxyamines.
Results and Discussion
We first tested the reaction of cyclohexylcatecholborane,
readily prepared by treating cyclohexene in CH2Cl2 with
catecholborane (CatBH) in the presence of catalytic
amounts of N,N-dimethylacetamide,[12] with different
TEMPO derivatives to afford the corresponding alk-
oxyamines. This reaction was reported by Renaud to occur
in a good yield with the parent TEMPO as an oxidant/C-
radical trapping reagent.[13] We used 12 different nitroxides
[a] Organisch-Chemisches Institut, Westfälische Wilhelms-
Universität,
Corrensstraße 40, 48149 Münster, Germany
Fax: +49-251-8336523
E-mail: studer@uni-muenster.de
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001043.
View this journal online at
wileyonlinelibrary.com
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Chemical Modification of Poly(olefins)
in these studies. Experimental details on the synthesis of
TEMPO derivatives that are not commercially available can
be found in the Supporting Information. Oxidation was
best conducted by adding the nitroxide (2.2 equiv.) to the
in situ generated boron compound 1 (R = C6H11) in the
presence of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimid-
inone (DMPU) to provide alkoxyamines 4a–k in moderate
to good yields (Scheme 2). By using the 4-oxo-TEMPO de-
rivative as an oxidant, the targeted alkoxyamine 4a was ob-
tained in 59% isolated yield. 4-hydroxy-TEMPO and its
protected derivatives afforded the corresponding trapping
products 4b–d in up to 76% yield. Importantly, more valu-
able groups such as a small PEG-tail (see 4h) or a propargyl
group, ready for subsequent click chemistry (see 4g), can be
introduced by this approach.
Along the ether tether, we could also show that the
amino group can be used for conjugation of interesting
functionalities to the nitroxide component. Thus, acetyl and
Boc-protected 4-amino-TEMPO worked well in this oxi-
dation/trapping sequence (see 4e,f). Moreover, with Boc-
phenylalanine-conjugated amino-TEMPO the desired alk-
oxyamine 4i (77%) was obtained and a similar result was
achieved with a dipeptide conjugated TEMPO derivative to
give alkoxyamine 4j in 75% yield. Protected sugar deriva-
tives can be conjugated to give olefins via this route as
documented by the successful preparation of the mannose
derivative 4k.
We then decided to apply the hydroboration/oxidation
sequence to macromolecules containing multiple double
bonds as a novel method for conjugation of interesting moi-
eties to polymers for preparation of functionalized macro-
molecules. Chemical modification of polymers by using
click-type chemistry has recently gained increased atten-
tion.[14] Towards this end, we chose poly(butadiene) 5 (Mn
= 1800 g/mol, PDI = 1.34, according to 1H NMR: ratio 1,2-
Scheme 2. Oxidation of cyclohexylcatecholborane with various
vs. 1,4-addition, 1.8:1) and perallylated polyglycerol 7, that nitroxides.
Scheme 3. Chemical functionalization of poly(butadiene) 5.
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C. B. Wagner, A. Studer
SHORT COMMUNICATION
is readily prepared from commercially available polyglycerol formed were eventually purified by dialysis (see SI for
(Mn = 6000 g/mol, PDI Ͻ 1.5),[15] as substrates. We found details). We found that only a small amount of 6 was lost
1
that the catecholborane-mediated hydroboration of these during purification. By H NMR analysis we determined
systems was best conducted by using RhCl(PPh3)3 as cata- the ratio of unreacted olefinic protons to characteristic
1
1
lyst. By applying H NMR spectroscopy we found that the protons of the conjugated alkoxyamine in 6 (for H NMR
initial hydroboration of poly(butadiene) occurred highly spectra, see the SI). We were pleased to find that our two
preferentially at the vinylic olefins, the internal olefins were step sequence worked also on a more complex substrate
converted to a smaller extent. Since hydroboration under such as 5. By using TEMPO as oxidant/trapping reagent,
the applied conditions on small molecular weight olefins we isolated 6a with a ratio of 1:1.12 of remaining olefins to
occurs with perfect regiocontrol, we assume that the ter- alkoxyamines. A slightly lower degree of functionalization
minal olefins were transformed with high regiochemistry. was achieved with the propargylated OH-TEMPO as a
However, hydroboration of the internal olefins likely oc- trapping reagent (see 6b). The PEG-tail did not change
curred without any regiocontrol as indicated in Scheme 3. reaction outcome to a large extent since a similar result as
The intermediately formed hydroboration product was then compared with the TEMPO-trapping experiment was ob-
converted into the poly(alkoxyamine) without any prior pu- tained (see 6c). We could also show that a protected sugar
rification in a one pot process by treatment with a nitroxide derivative was conjugated to poly(butadiene) by this
in the presence of DMPU.[13] The poly(alkoxyamines)- method (see 6d).
Scheme 4. Chemical functionalization of perallylated polyglycerol 7.
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Chemical Modification of Poly(olefins)
Flash column chromatography (FC) was carried out on Merck sil-
ica gel 60 (40–63 µm) with an argon pressure of about 0.6–1.0 bar.
Dialysis was performed in chloroform using a benzoylated cellulose
membrane (MWCO 2000, Sigma).
Since all hydroborations were performed under identical
conditions the varying degree of functionalization needs
some comments. To destroy excess catecholborane that was
used for the initial hydroboration we always added a small
amount of EtOH. It was recently shown that MeOH com-
plexed to a borane might become a quite good radical re-
ducing reagent.[16] Therefore, we currently believe that the
EtOH present in combination with a CatB-Lewis acid
might act as a reducing reagent and thereby might reduce
the degree of alkoxyamine functionalization in our reac-
tions.[17] It was not possible to identify the reduction prod-
uct due to peak overlap.
Characterization: 1H and 13C NMR spectra were recorded on a
Bruker DPX 300 (1H: 300 MHz; 13C: 75 MHz), a Bruker AV 400
(1H: 400 MHz; 13C: 100 MHz) or a Varian 500 INOVA (1H:
500 MHz) spectrometer at room temperature. ESI-MS (m/z) and
HRMS (m/z) were performed on a Bruker MicroTof. Melting
points were determined on a Stuart SMP10 and are uncorrected.
Infrared spectra were recorded on a Digilab Varian 3100 FT-IR
Excalibur Series.
Representative Example for the Alkoxyamination of Cyclohexene:
According to a procedure described by Renaud et al.,[9] catechol-
borane (95 µL, 0.90 mmol, 2.0 equiv.) was added at 0 °C to a solu-
tion of cyclohexene (46 µL, 0.45 mmol) and N,N-dimethylacet-
amide (4 µL, 0.05 mmol, 10 mol-%) in CH2Cl2 (0.8 mL) and the
mixture was heated in a sealed tube to 60 °C for 3 h. EtOH (26 µL,
0.45 mmol, 1.0 equiv.) was added slowly at 0 °C and the solution
was stirred for 15 min at room temperature. After the addition of
DMPU (54 µL, 0.45 mmol, 1.0 equiv.) and 4-oxo-TEMPO
(169 mg, 0.990 mmol, 2.2 equiv.) the reaction was stirred overnight
at room temperature. The reaction mixture was filtered through a
plug of silica gel (MTBE as eluent). The filtrate was concentrated
under reduced pressure and the residue was purified by FC.
Finally, we applied the hydroboration/oxidation/nitroxide
trapping cascade to the modification of perallylated poly-
glycerol 7.[15] Experiments were conducted in analogy to
those performed on 5 and results are summarized in
1
Scheme 4. Degree of functionalization was estimated by H
NMR analysis as described above for poly(butadiene). Five
different nitroxides were used in these studies. The oxi-
dation/trapping sequence provided dendritic type architec-
tures decorated with various interesting functionalities.
Hence, a propargyl substituent was successfully introduced
via this approach onto 7 (see 8b) and also pegylation of
perallylated polyglycerol was possible (see 8c). More im-
portantly, decoration of 7 with biologically interesting
groups such as protected sugars (see 8d) and protected phe-
nylalanine (see 8e) could be achieved clearly documenting
the potential of our approach. It is important to note that
experiments are easy to conduct without the need for any
special equipment.
Representative Example for the Alkoxyamination of Poly(butadiene):
According to a procedure described by Renaud et al.,[9] catechol-
borane (53 µL, 0.50 mmol, 2.0 equiv.) was added at 0 °C to a solu-
tion of poly(butadiene) 5 (24 mg, approximately 0.25 mmol of
double bonds) and RhCl(PPh3)3 (5 mg, 5 µmol, 2 mol-%) in
CH2Cl2 (0.8 mL) and the mixture was stirred for 3 h at room tem-
perature. EtOH (15 µL, 0.25 mmol, 1.0 equiv.) was added slowly at
0 °C and the solution was stirred for 15 min at room temperature.
After the addition of DMPU (30 µL, 0.25 mmol, 1.0 equiv.) and
TEMPO (86 mg, 0.55 mmol, 2.2 equiv.) the reaction was stirred
overnight at room temperature. The reaction mixture was filtered
Conclusions
In summary, we showed that hydroboration with cate- through a plug of celite (CH2Cl2 as eluent). The filtrate was concen-
trated under reduced pressure and the residue was purified by di-
alysis.
cholborane followed by oxidation by using a functionalized
nitroxide leads to the corresponding C-radical which is im-
mediately trapped by the nitroxide to provide a function-
alized alkoxyamine. The reaction sequence tolerates various
interesting functionalities that are propargyl ethers, free hy-
droxy groups, PEG tails and protected amines. Along this
line it was shown that protected sugars and also amino ac-
ids can be conjugated to olefins via this novel approach.
Importantly, this method can be applied for the chemical
modification of poly(butadiene) and of perallylated polygly-
cerol to give the corresponding functionalized macromole-
cules.
Supporting Information (see also the footnote on the first page of
this article): Experimental details, compound characterization data,
copies of the NMR spectra.
Acknowledgments
The Deutsche Forschungsgemeinschaft (DFG) is acknowledged for
funding our research (Stu 9/1).
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SHORT COMMUNICATION
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Received: July 22, 2010
Published Online: September 17, 2010
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